Mitochondrial dysfunction and the regulatory cell death crosstalk network in chronic obstructive pulmonary disease: from oxidative stress mechanisms to targeted therapeutic strategies

Abstract

The sustained progression of chronic obstructive pulmonary disease (COPD) may not be independently driven by a single process such as chronic inflammation, oxidative stress, or cell death, but rather originates from a cross-amplification network among “mitochondrial dysfunction-oxidative stress-regulated cell death.” In the context of mitochondrial damage, excessive generation of reactive oxygen species (ROS), damage and release of mitochondrial DNA (mtDNA), and dysregulation of mitochondrial quality control (MQC) collectively promote airway epithelial injury, sustained inflammation, alveolar destruction, and tissue remodeling. Furthermore, regulated cell death modalities such as apoptosis, necroptosis, pyroptosis, and ferroptosis are not isolated from each other but are coupled under a shared context of mitochondrial stress, exhibiting different dominant patterns across various cell types and disease stages. Adopting an integrated perspective encompassing mitochondrial dysfunction, amplified oxidative stress, and the regulated cell death (RCD) cross-network, this article synthesizes current research regarding COPD-related mechanisms, with a focus on mitochondrial damage markers, RCD activity indicators, mechanism-oriented patient stratification, and potential therapeutic strategies targeting mitochondrial homeostasis and cell death pathways. This framework facilitates the transition of COPD understanding from the traditional chronic inflammation model to a more stratified and translationally promising mitochondrial-cell death network model.

1 Introduction

Chronic obstructive pulmonary disease (COPD) is one of the major chronic respiratory diseases globally, leading to morbidity, disability, and mortality, with a high burden of illness and significant clinical heterogeneity (1, 2). Although cigarette smoking is still considered the most important risk factor for COPD, a growing number of studies have shown that a considerable proportion of COPD cases occur in non-smokers, suggesting that its development and progression are not solely driven by smoking but are associated with multiple factors such as air pollution, occupational exposure, and adverse early-life exposures (3–5). These factors can jointly contribute to the occurrence and progression of COPD by influencing lung development trajectories, redox homeostasis, and immune-inflammatory responses, indicating that the traditional framework of explaining the disease based on a single exposure factor is insufficient to fully capture its complex pathological basis (6).

In the classical pathogenesis of COPD, oxidative stress and chronic inflammation have long been considered core mechanisms (7). Cigarette smoke, ozone, fine particulate matter, biomass fuel smoke, and other harmful exposures can trigger the excessive production of reactive oxygen species (ROS), leading to airway epithelial injury, persistent activation of inflammation, destruction of alveolar structures, and progressive worsening of airflow limitation (8–10). However, the continuous progression of COPD cannot be fully explained by a single inflammatory pathway or a single oxidative stress event. A more reasonable understanding is that oxidative stress, chronic inflammation, cell aging, and regulated cell death interact under the common background of organelle stress, forming a continuously amplifying pathological network during disease progression (11, 12). Therefore, identifying common pathological hubs that connect these processes is of great significance for understanding the chronic progression and multi-system involvement of COPD.

Mitochondrial research entered the field of COPD initially mainly from observations of tobacco smoke-induced oxidative damage and energy metabolism abnormalities. Subsequent studies gradually found that in COPD-related airway epithelial cells, alveolar cells, immune cells, and skeletal muscle, changes such as mitochondrial morphological abnormalities, decreased respiratory chain function, loss of membrane potential, elevated mtROS, and mitochondrial DNA damage can occur (13, 14). These findings have expanded the mechanistic understanding of COPD from the traditional “inflammation-oxidative stress” model to an integrated framework of “mitochondrial stress-quality control imbalance-inflammation amplification-cell fate alteration.” Recent studies on mitochondrial dysfunction and integrated cell death patterns have also provided new theoretical support for understanding how mitochondrial damage connects inflammation, oxidative stress, and multiple forms of regulated cell death (15).

In recent years, the role of mitochondrial dysfunction in COPD has received widespread attention (16). Mitochondria are not only the core sites for cellular energy metabolism and redox reactions but also important hubs integrating stress perception, inflammatory signal transduction, and cell fate regulation (17, 18). During mitochondrial dysfunction, excessive ROS generation, mitochondrial DNA (mtDNA) damage and release, decreased membrane potential, and imbalance in mitochondrial quality control (MQC) can jointly drive airway epithelial injury, maintenance of inflammation, cell aging, and tissue remodeling (19, 20). Meanwhile, regulated cell death modes such as apoptosis, necroptosis, pyroptosis, and ferroptosis are increasingly recognized as involved in the pathological process of COPD, forming a mutually reinforcing cross-network with mitochondrial damage and oxidative stress (21). Therefore, mitochondrial dysfunction may be an important pathological hub connecting harmful exposures, oxidative stress, sustained inflammation, tissue destruction, and the cell death network (22).

Building on this understanding, this article reviews the progress of COPD-related mechanistic research from the perspective of the “mitochondrial dysfunction-oxidative stress-regulated cell death” cross-network. This review first outlines mitochondrial structural and functional abnormalities in COPD, including changes in mitochondrial morphology, respiratory chain dysfunction, mtDNA damage, and the characteristics of mitochondrial involvement in different tissues; then discusses the dysregulation of mitochondrial quality control mechanisms, focusing on mitochondrial biogenesis, mitophagy, and the inflammatory network mediated by mitochondrial damage-associated molecular patterns (DAMPs); the third part analyzes the oxidative stress amplification loop, elaborating on ROS sources, mtROS-mediated mitochondrial damage, and Nrf2-related antioxidant defense imbalance; the fourth part discusses the interplay among various regulated cell death modes, further emphasizing the RCD characteristics of different cell types and disease stages; finally, it summarizes potential therapeutic strategies targeting mitochondrial homeostasis and RCD pathways, and discusses key challenges in patient stratification, biomarkers, and clinical translation. Through this structure, this article aims to provide a more integrated mitochondrial-cell death network framework for understanding COPD mechanisms and potential precision interventions.

2 Initial mitochondrial injury: the starting point of the COPD pathological network

The “mitochondrial hub” does not imply that mitochondrial dysfunction is the sole or sufficient initial cause of COPD, but rather emphasizes its role in connecting and amplifying multiple pathological processes. Mitochondria can sense stimuli such as cigarette smoke, PM2.5, inflammatory cytokines, oxidative load, and metabolic stress, and further influence oxidative stress, inflammatory activation, and cell death programs through mtROS generation, decreased membrane potential, mtDNA damage and release, imbalance in mitochondrial quality control, and DAMPs signaling (23, 24). Therefore, mitochondrial injury may have a strong driving effect in certain cell types or disease stages, while in other contexts, it is more suitable as a contributing factor that mutually promotes inflammation, oxidative stress, and tissue damage. Based on this definition, this article regards mitochondrial structural and functional abnormalities as an important integrative platform in the COPD pathological network, providing a common organelle basis for subsequent oxidative stress amplification, inflammatory activation, and initiation of cell death programs.

2.1 Mitochondrial morphological changes

Morphological abnormalities such as mitochondrial fragmentation, swelling, and cristae structural disruption have been reported in airway epithelial cells, alveolar epithelial cells, and cells of the pulmonary vasculature of COPD patients. These changes are important morphological evidence of impaired mitochondrial function (25, 26). Smoking and the oxidative stress it induces are considered key factors driving these changes. Under conditions of sustained mitochondrial stress, the originally relatively stable mitochondrial network can undergo fragmentation and remodeling, manifesting as reduced mitochondrial volume, irregular morphology, damaged cristae structure, and decreased network continuity (27).

At the molecular level, mitochondrial morphological homeostasis depends on the dynamic balance between fusion and fission processes. Fusion-related proteins mainly include Mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1), while the fission process is primarily regulated by dynamin-related protein 1 (DRP1). Existing studies in COPD lung tissue, alveolar epithelial cells, or smoke exposure models have reported a decrease in fusion-related proteins such as MFN2 and OPA1, as well as a trend of enhanced DRP1-related fission signaling (28–30). These changes suggest that mitochondrial dynamics may shift towards enhanced fission and impaired fusion, and are associated with mitochondrial fragmentation, cristae disorganization, and decreased membrane potential.

In addition to pulmonary cells, abnormalities in mitochondrial density, morphology, and dynamics regulation have also been reported in COPD-related skeletal muscle, suggesting that mitochondrial structural changes are not limited to local lung tissue but may contribute to the development of COPD extrapulmonary phenotypes (31, 32). It should be noted that differences exist between studies in terms of sample source, COPD severity, smoking status, detection methods, and statistical reporting methods. Therefore, molecular changes from a single study should not be directly extrapolated to all COPD patients. Overall, mitochondrial fragmentation, swelling, and cristae disruption constitute important morphological features of mitochondrial abnormalities in COPD, providing a structural basis for subsequent respiratory chain dysfunction, enhanced oxidative stress, and dysregulation of cell fate (33, 34). These conclusions still need to be interpreted in conjunction with the sample size, effect size, and statistical results of specific studies.

2.2 Respiratory chain function and energy metabolism disorders

Respiratory chain dysfunction and energy metabolism disorders are important functional manifestations of mitochondrial abnormalities in COPD, characterized by decreased activity of electron transport chain complexes, reduced mitochondrial membrane potential (ΔΨm), insufficient ATP production, and abnormally elevated mitochondrial reactive oxygen species (mtROS) (35). As an important subunit of mitochondrial respiratory chain complex I, NDUFS2 has been reported in COPD lung macrophage-related studies to be associated with impaired mitochondrial respiratory function, oxidative phosphorylation capacity, and phagocytic function (36). These findings suggest that respiratory chain abnormalities not only represent energy metabolism disorders but may also affect the function of pulmonary immune cells.

Furthermore, persistent harmful exposures such as smoking can directly damage mitochondrial DNA and respiratory chain components, promoting increased electron leakage and providing a basis for subsequent mtROS accumulation and oxidative stress amplification (37, 38). A decrease in ΔΨm is an important marker of respiratory chain dysfunction. Once the proton gradient of the inner mitochondrial membrane is compromised, oxidative phosphorylation efficiency decreases, ATP production is reduced, and processes with high energy demands are preferentially affected (39). In COPD-related skeletal muscle, decreased respiratory chain complex activity and reduced oxidative phosphorylation capacity are associated with diminished exercise tolerance and muscle dysfunction, suggesting that mitochondrial energy metabolism abnormalities exist not only in the lungs but also contribute to the extrapulmonary phenotype of the disease (40).

Respiratory chain dysfunction also leads to mtROS accumulation. Excessive mtROS not only promotes lipid peroxidation, protein oxidative modification, and mtDNA damage but can also affect the NAD⁺/NADH balance and multiple metabolic regulatory pathways, driving cells to shift from relatively efficient oxidative phosphorylation to alternative energy acquisition methods, manifesting as glucose and lipid metabolism imbalance and metabolic reprogramming (41, 42). In addition, changes in mitochondrial membrane lipid composition can further affect membrane protein stability and complex assembly efficiency, exacerbating energy metabolism disorders (43). Since different studies employ heterogeneous sample types and detection platforms, indicators such as respiratory chain complex activity, OCR, ATP production, membrane potential, and mtROS should be interpreted in the context of specific experimental designs.

2.3 mtDNA damage and mitochondrial stress markers

mtDNA is highly sensitive to oxidative stress, and its oxidative damage, copy number changes, and extracellular release can reflect the state of mitochondrial stress in COPD. Smoking-induced mitochondrial injury can cause a decrease in mitochondrial membrane potential, dynamic imbalance, and activation of DNA damage response, thereby promoting the transfer of mtDNA from mitochondria to the cytoplasm or its release into the extracellular environment (44). Clinical studies have found elevated levels of cell-free mtDNA (cf-mtDNA) in the plasma of COPD patients and the serum of animals in smoke-induced emphysema models, suggesting that cf-mtDNA can serve as a candidate biomarker reflecting the burden of mitochondrial injury (45). In vitro experiments further indicate that sublethal concentrations of cigarette smoke extract (CSE) can promote the transfer of mtDNA to the cytoplasm and extracellular space, accompanied by upregulation of DNA damage-related molecules and DNA sensors (46). This section primarily emphasizes the significance of mtDNA as a marker of mitochondrial injury and stress burden. Its role as a DAMP mediating innate immune recognition and inflammatory amplification will be further discussed in Section 3.3.

In addition to cf-mtDNA, various mitochondria-related genes also exhibit dysregulated expression in COPD lung tissue. Existing studies have reported that alterations in the expression of genes such as NDUFS2, BAX, and DLST are associated with mitochondrial respiratory chain function, cell viability, and disease-related immune phenotypes (47). Furthermore, the dysregulated expression of non-coding RNAs, including long non-coding RNAs related to mitochondrial function regulation, suggests that post-transcriptional regulation may be involved in the disruption of mitochondrial homeostasis in COPD (48). Overall, mtDNA damage, elevated cf-mtDNA, and abnormalities in mitochondria-related genes together constitute important features of mitochondrial stress in COPD, providing a molecular basis for subsequent inflammatory recognition and cellular fate imbalance.

It should be pointed out that cf-mtDNA is currently more suitable as a candidate stratification marker rather than a mature diagnostic indicator. Existing studies suggest that plasma or serum cf-mtDNA may be associated with COPD severity, risk of acute exacerbation, smoking exposure, and tissue injury burden. However, differences exist between studies in sample processing, detection platforms, copy number normalization methods, and control population selection (49). Therefore, there is currently no unified cutoff directly applicable for clinical diagnosis or classification, nor are there fully validated sensitivity, specificity, and dynamic range. Since cf-mtDNA can also be elevated in acute lung injury, infection, cardiovascular disease, metabolic diseases, and other inflammatory conditions, its disease specificity is limited. In the future, if cf-mtDNA is to be used for COPD stratification, it would be more suitable to combine it with indicators such as 8-OHdG, MDA, GDF15, FGF21, NLRP3/Gasdermin D (GSDMD), or GPX4, rather than using it as a standalone diagnostic marker (50).

2.4 Mitochondrial dysfunction in different tissues and organs

Mitochondrial dysfunction in COPD is not limited to a single cell type but exhibits certain specificity across different structures within the lung and some extrapulmonary tissues. In airway epithelial cells, following continuous exposure to harmful stimuli such as cigarette smoke, mitochondria can show enhanced fission, impaired fusion, and decreased activity, accompanied by increased intracellular oxidative stress and aging-related changes (51). Among these, enhanced DRP1 activation is closely related to excessive mitochondrial fission, and GNPAT can further aggravate mitochondrial functional injury and cell apoptosis by stabilizing DRP1 (52). These changes suggest that airway epithelium is one of the earliest and most persistently affected sites of mitochondrial abnormalities in COPD.

In the alveolar region, particularly in alveolar type II epithelial cells (ATII), decreased expression of MFN2 and OPA1 suggests impaired mitochondrial fusion, thereby promoting mitochondrial injury, cellular senescence, and the formation of a local inflammatory microenvironment (28, 29). Meanwhile, activation of the NEAT1/PINK1-related mitophagy pathway indicates that alveolar cells initiate corresponding quality control responses in response to mitochondrial injury caused by smoke or particulate matter exposure (53). In pulmonary vascular-related cells, mitochondrial injury is more associated with elevated reactive oxygen species, endothelial dysfunction, and pulmonary vascular remodeling, and may participate in the occurrence of complications such as COPD complicated by pulmonary hypertension (54, 55).

Beyond pulmonary structures, skeletal muscle is one of the most representative extrapulmonary tissues affected in COPD. Studies have shown that impaired mitochondrial biogenesis, enhanced fission, and decreased energy metabolism efficiency in the skeletal muscle of COPD patients can together promote muscle atrophy, decreased endurance, and dysfunction (56). Additionally, molecules such as DKK3 are implicated in COPD-related sarcopenia by inducing mitochondrial functional imbalance (57). Therefore, from the intrapulmonary airways and alveoli to extrapulmonary skeletal muscle, mitochondrial abnormalities are not isolated events but may jointly participate in local injury and systemic phenotype formation in COPD. Mitochondrial abnormalities in different tissues do not simply occur in parallel but may correspond to different biomarkers, disease stages, and clinical phenotypes. Overall, mitochondrial abnormalities in COPD are not a single-level structural damage but simultaneously involve morphological disruption, insufficient energy production, mtDNA damage, and functional decline in different tissues. These changes together constitute the mitochondrial basis for subsequent oxidative stress, inflammatory activation, and cellular fate imbalance. Whether mitochondrial injury can be promptly repaired or cleared depends on the integrity of the mitochondrial quality control system (Table 1).

2.5 Areas of controversy and unresolved questions

Although existing evidence supports the presence of mitochondrial structural and functional abnormalities in COPD, changes in mitochondrial dynamics are not consistently observed across all studies. Some studies report a decrease in fusion-related proteins such as MFN2 and OPA1, accompanied by enhanced DRP1-related fission signaling; however, other studies have observed enhanced fusion responses, no significant changes in dynamic indicators, or inconsistent directions of changes in fusion/fission-related proteins in specific cell types, exposure durations, or disease stages (58, 59). This suggests that mitochondrial dynamics abnormalities are not a fixed “enhanced fission—decreased fusion” pattern, but may be influenced by cell type, injury severity, disease stage, and compensatory status.

These differences may primarily arise from three factors. First, different cell types respond distinctly to smoke, inflammation, and oxidative stress: airway and alveolar epithelial cells are more susceptible to exogenous stimuli, mitochondrial changes in macrophages may primarily reflect metabolic reprogramming and immune dysfunction, while mitochondrial abnormalities in appendicular skeletal muscle more closely resemble long-term energy metabolism disorders (60, 61). Second, disease stage may affect the direction of mitochondrial dynamics: in early stress states, mitochondrial fusion or moderate mitophagy may serve a compensatory role, whereas in long-term injury or advanced disease, enhanced fission, cristae structural damage, and energy depletion may be more prominent (62). Third, tissue source, cell sorting methods, smoke exposure dose and duration, detection platforms, morphological quantification methods, and the distinction between total protein levels and activation status also affect study conclusions (63).

As a marker of mitochondrial damage, cf-mtDNA also has translational limitations. Existing studies suggest it may be associated with COPD staging, acute exacerbation risk, and tissue injury burden, but there is currently a lack of standardized detection protocols, unified units, defined clinical cutoffs, and established benchmarks for sensitivity, specificity, and dynamic range (64). Differences in sample types, DNA extraction methods, qPCR targets, and copy number normalization across studies limit comparability of results. Additionally, cf-mtDNA is not specific to COPD and can be elevated in infections, acute lung injury, atherosclerotic cardiovascular disease, metabolic diseases, and other inflammatory conditions (65, 66). Therefore, cf-mtDNA is currently more suitable as a candidate indicator for mechanistic research and risk stratification, rather than as a standalone diagnostic marker for COPD.

Future research should prioritize three issues: first, evaluate mitochondrial fusion, fission, mitophagy, respiratory function, and mtDNA release separately in different cell types and COPD stages, avoiding reliance on a single indicator to infer overall mitochondrial status; second, clarify the relationship between mitochondrial indicators and lung function decline, acute exacerbations, emphysema progression, appendicular skeletal muscle function, and prognosis in longitudinal cohorts; third, establish standardized cf-mtDNA detection and reporting procedures, and assess its incremental value when combined with 8-OHdG, MDA, GDF15, FGF21, inflammasome-related molecules, and ferroptosis-related indicators. Only by addressing these issues can mitochondrial abnormalities be further translated from mechanistic observations into reliable bases for COPD phenotyping and intervention selection (Figure 1).

Figure 1

3 Imbalance of mitochondrial quality control: a key link in the persistence of injury

Under normal conditions, mitochondrial biogenesis, dynamic regulation, and mitophagy collectively maintain the homeostasis of mitochondrial quantity, structure, and function. When damaged mitochondria can be promptly cleared and replenished by newly generated mitochondria, cells may still maintain a compensatory state. However, in the context of persistent exposure and chronic inflammation in COPD, reduced mitochondrial biogenesis, imbalance in fusion/fission, and insufficient or excessive activation of mitophagy transform mitochondrial injury from a transient stress into a chronic cumulative process (19). Among these, the role of mitophagy is highly context-dependent: moderate activation facilitates the clearance of damaged mitochondria, while insufficient clearance or sustained excessive activation may worsen mitochondrial homeostatic imbalance. Thus, MQC imbalance serves as an intermediate link connecting initial mitochondrial injury to subsequent amplification of oxidative stress (67).

3.1 Reduced mitochondrial biogenesis

Mitochondrial biogenesis is a fundamental process for maintaining mitochondrial quantity renewal and functional stability. Its core regulatory axis primarily includes peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM), and their upstream regulatory molecules (68). PGC-1α is considered a key transcriptional coactivator for mitochondrial biogenesis, cooperating with various nuclear transcription factors to promote mtDNA replication, mitochondrial protein expression, and maintenance of oxidative phosphorylation capacity (69). TFAM directly participates in mtDNA transcription and stabilization, processes that are crucial for maintaining mitochondrial genome integrity (70).

Current studies indicate that the expression of mitochondrial biogenesis-related molecules is generally downregulated in the lung tissue and airway epithelial cells of COPD patients. This includes reduced transcriptional levels of PPARGC1B, PPRC1, and PPARD, alterations that are more pronounced in severe cases (71). Furthermore, decreased PGC-1α expression is often accompanied by reduced mitochondrial number, weakened respiratory chain activity, and diminished antioxidant capacity, suggesting that mitochondrial pathology in COPD involves not only “increased injury” but also “insufficient renewal” (72). This decline in regenerative capacity makes it difficult for cells to replenish functionally intact mitochondria in a timely manner, thereby exacerbating bioenergetic metabolic dysfunction and oxidative stress burden (73).

The SIRT1/AMPK–PGC-1α–TFAM axis is an important regulatory pathway connecting energy sensing, mitochondrial biogenesis, and metabolic adaptation. Tobacco smoke and other harmful exposures can inhibit SIRT1 and AMPK activity, thereby weakening PGC-1α-mediated mitochondrial transcriptional programs, leading to reduced mtDNA replication, mitochondrial protein expression, and oxidative phosphorylation capacity (74–76). This change is not confined to lung tissue. In COPD skeletal muscle, PGC-1α downregulation is also associated with reduced mitochondrial density, decreased oxidative phosphorylation efficiency, and impaired exercise tolerance (77). Overall, reduced mitochondrial biogenesis in COPD essentially reflects a decline in mitochondrial renewal and compensatory capacity.

3.2 Autophagy and mitophagy

Within the mitochondrial quality control system, mitophagy is responsible for selectively clearing damaged mitochondria and is a crucial mechanism for maintaining mitochondrial homeostasis (78). In the context of chronic oxidative stress and the inflammatory microenvironment in COPD, the expression of autophagy/mitophagy-related proteins in airway epithelial cells, alveolar cells, and skeletal muscle tissue can be altered, indicating that this quality control program has been dysregulated (79–81).

The most well-studied pathway is the PINK1/Parkin pathway. When mitochondrial membrane potential decreases, PINK1 accumulates on the outer mitochondrial membrane and recruits the E3 ubiquitin ligase Parkin, ubiquitinating damaged mitochondria for subsequent degradation via autophagosomes and lysosomes (82). Moderate mitophagy helps reduce the accumulation of damaged mitochondria, lower mtROS release, and alleviate inflammation and cellular injury (83). Therefore, mitophagy is primarily a protective compensatory response. However, the key issue in COPD is not whether mitophagy is activated, but whether its intensity and duration are appropriate. Insufficient mitophagy leads to the retention of damaged mitochondria, further increasing ROS generation and amplifying membrane potential loss, protein oxidation, and mtDNA damage (84). For example, in COPD-related skeletal muscle dysfunction, CSE can downregulate Parkin expression, block the clearance of damaged mitochondria, promote ROS accumulation and MuRF-1-mediated protein degradation, ultimately driving muscle atrophy (85). Conversely, under persistent mitochondrial injury, sustained excessive activation of mitophagy may also lead to excessive loss of mitochondrial quantity, further reducing ATP production and exacerbating energy crisis (86).

The transition of mitophagy from a protective response to a pathological process may depend on injury intensity and duration, cellular energy status, redox state, and the compensatory capacity of other quality control pathways (87). Transient or moderate injury is typically recognized through PINK1/Parkin, BNIP3/NIX, FUNDC1, or other receptor/adaptor pathways, and can be cleared when autophagosome formation and lysosomal degradation function are relatively intact, thereby reducing mtROS burden, decreasing DAMPs release, and maintaining cellular homeostasis (88, 89). Conversely, if smoke exposure, inflammatory stimulation, or oxidative stress persists, the scope of mitochondrial injury expands, ATP/AMP ratio decreases, and energy-sensing signals such as AMPK, mTOR, and ULK1 become imbalanced, potentially exposing cells to both insufficient clearance of damaged mitochondria and excessive loss of functional mitochondria (90). When mitochondrial biogenesis is insufficient to compensate for mitochondrial clearance, or lysosomal degradation capacity is limited, mitophagy may shift from protective quality control to a pathological process promoting energy depletion, inflammation amplification, and cell death (91).

In airway smooth muscle cells, excessive mitophagy induced by ERK1/2 activation is believed to be associated with cellular structural damage (92). In addition to PINK1/Parkin, pathways such as MAPK15-ULK1, PI3K/Akt/mTOR, and SIRT1 also participate in mitophagy regulation, collectively influencing its intensity, duration, and cell-type-specific responses (93, 94). Therefore, abnormal mitophagy in COPD should be understood as a dynamic regulatory imbalance rather than simple enhancement or suppression. From a therapeutic perspective, the “mitophagy paradox” suggests that simply enhancing or inhibiting mitophagy may be overly simplistic. A more rational strategy should involve modulation based on disease stage and cellular state: in early or reversible injury stages, promoting selective clearance of damaged mitochondria while supporting PGC-1α-related mitochondrial biogenesis; in stages of persistent injury or significant energy depletion, avoiding excessive clearance of functional mitochondria while simultaneously improving lysosomal degradation capacity, redox homeostasis, and energy metabolism (95). In the future, stratification based on indicators such as mtROS, membrane potential, PINK1/Parkin activity, LC3-II/I, p62, PGC-1α, and ATP/AMP ratio may help determine whether mitophagy is in a protective or pathological state (Table 2).

3.3 Mitochondrial DAMP release: a link between MQC dysfunction and inflammatory initiation

Mitochondrial injury not only signifies energy metabolism failure but may also lead to the exposure of endogenous danger signals. Due to the bacterial ancestry of mitochondria, once their components are released from compromised organelles, they can be recognized by the host immune system as DAMPs, thereby providing upstream stimulation for subsequent inflammatory responses (96). In COPD, mitochondrial DAMPs primarily include mtDNA, cardiolipin, ATP, and certain mitochondrial protein components (97, 98). Rather than simply understanding DAMP release as passive leakage following mitochondrial injury, it is more appropriate to view it as a consequence of mitochondrial quality control failure.

MQC abnormalities can promote DAMP exposure through multiple pathways. First, insufficient mitophagy leads to the persistent retention of mitochondria with decreased membrane potential and severe oxidative damage, thereby heightening the risk of mtDNA oxidation, fragmentation, and release into the cytoplasm or extracellular space. Second, imbalances in mitochondrial fusion/fission can disrupt mitochondrial network integrity, making it more difficult to effectively isolate and eliminate damaged mitochondria, further increasing the risk of DAMP leakage. Third, decreased mitochondrial membrane integrity or opening of the permeability transition pore can facilitate the escape of mtDNA, ATP, and other mitochondrial contents; meanwhile, abnormal exposure of cardiolipin from the inner membrane to the outer membrane indicates remodeling of the mitochondrial membrane structure and may serve as an important signal for inflammatory recognition (99–102). Therefore, mitochondrial DAMP release is not a single pathway event but rather the result of the combined effects of mitochondrial membrane injury, mitophagy imbalance, dynamic abnormalities, and oxidative stress.

The impact of MQC imbalance on inflammation depends not only on whether DAMPs are generated but also on whether damaged mitochondria can be promptly cleared and whether new mitochondria can be replenished. Insufficient mitochondrial biogenesis limits the renewal of functional mitochondria; inadequate mitophagy leads to the accumulation of damaged mitochondria, whereas excessive mitophagy may cause loss of functional mitochondria and energy crisis (103, 104). All these changes can increase the likelihood of DAMP release and persistent inflammation. Overall, this section primarily emphasizes how MQC imbalance controls the production and release of mitochondrial DAMPs; how these DAMPs further activate inflammasomes and induce pyroptosis will be discussed in detail in Section 5.2 (Figure 2).

Figure 2

4 Oxidative stress amplification loop: from mitochondrial damage to persistent inflammation

Building upon the aforementioned mitochondrial damage and MQC imbalance, oxidative stress can be understood as a core amplification mechanism driving the continuous expansion of the COPD pathological network. Exogenous ROS, ROS from inflammatory cells, and mtROS converge, sustaining COPD tissues in a state of high oxidative load for a prolonged period. More importantly, mitochondria are both targets of ROS attack and significant sources of sustained ROS generation. Therefore, this chapter focuses on how ROS sources, mtROS-mediated mitochondrial damage, specific positive feedback loops, and antioxidant defense imbalance collectively maintain the oxidative stress state in COPD.

4.1 Sources of ROS in COPD

Oxidative stress is a core pathological link in the occurrence and progression of COPD, and the continuous accumulation of ROS is the primary driver of this process. ROS in COPD mainly originate from exogenous exposure and endogenous generation, which interact to jointly promote airway damage, persistent inflammation, and lung tissue remodeling (105, 106). Exogenous ROS are primarily related to environmental factors such as smoking and air pollution (107). Cigarette smoke is rich in free radicals and oxidizing chemicals, which can directly damage the airway epithelium and activate alveolar macrophages and other inflammatory cells, thereby amplifying local oxidative stress and inflammatory responses (108). In addition to cigarette smoke, fine particulate matter such as PM2.5 can also deposit in the respiratory tract, causing a local increase in ROS and promoting airway inflammation, epithelial barrier damage, and an increased risk of acute exacerbations (109).

Endogenous ROS mainly originate from oxidase systems and mitochondria. The expression and activity of the NADPH oxidase (NOX) family can be elevated in COPD lung tissue, with subtypes such as NOX1, NOX2, NOX4, and NOX5 participating in ROS generation and activating inflammation-related pathways like NF-κB and COX-2, thereby promoting the maintenance of airway inflammation (110). Concurrently, damage to the mitochondrial respiratory chain increases electron leakage, leading to enhanced generation of mtROS. Unlike exogenous ROS, mtROS are not only a result of oxidative damage but also a significant driving factor for the continuous deterioration of mitochondrial function (111). Furthermore, COPD patients often experience depletion of glutathione (GSH) and a decline in other antioxidant reserves, making it difficult to promptly clear excess ROS (112). Elevated activity of certain endogenous enzymes, such as monoamine oxidase B, may also participate in the amplification of ROS in smoking-related lung injury (113). Overall, ROS in COPD are driven by exogenous oxidative exposure, NOX system activation, and mitochondrial respiratory chain abnormalities, forming a mutually amplifying pathological network during the process of continuous damage.

4.2 Damage of mtROS to mitochondria and cellular components

The “vicious cycle of oxidative stress” primarily refers to the reciprocal amplification among mtROS accumulation, aggravated mitochondrial damage, decreased antioxidant defense, and activation of inflammation/RCD. Moderate levels of mtROS can participate in cellular signaling regulation, but under the context of sustained exposure and chronic inflammation in COPD, excessive mtROS can transform from signaling molecules into damaging factors, further disrupting mitochondrial structural integrity and cellular homeostasis (114). First, mtROS can attack mitochondrial membrane lipids, especially those rich in unsaturated fatty acids, leading to lipid peroxidation, altered membrane fluidity, and decreased membrane potential (115). Following structural damage to the membrane, maintaining the proton gradient across the inner mitochondrial membrane becomes compromised; consequently, oxidative phosphorylation efficiency declines, ultimately exacerbating ATP synthesis deficits and precipitating an energy crisis (116, 117).

Second, mtROS can cause oxidative modification of mtDNA, changes in copy number, and transcriptional abnormalities, impairing respiratory chain protein synthesis and further reducing electron transfer efficiency (118, 119). Third, mtROS can oxidize mitochondrial proteins, leading to conformational changes and functional inactivation of respiratory chain complex proteins, membrane transport proteins, and quality control-related proteins, thereby affecting complex assembly, membrane permeability, and mitochondrial turnover (120, 121). Therefore, mtROS amplification in COPD is not a vague “vicious cycle” but is maintained by several specific positive feedback loops. First, mtROS can damage mtDNA, leading to impaired expression and assembly of mitochondrially-encoded respiratory chain complex subunits, and decreased electron transfer efficiency further increases electron leakage, generating more mtROS (122). Second, mtROS can induce peroxidation of cardiolipin and other mitochondrial membrane lipids, reducing membrane potential and disrupting the stability of respiratory chain complexes, and complex assembly defects further exacerbate electron leakage and mtROS generation (123). Third, sustained mtROS load can inhibit PGC-1α-related mitochondrial biogenesis, making it difficult for damaged mitochondria to be promptly replaced by newly functional ones, leading to the accumulation of damaged mitochondria and continuous mtROS release (124). Fourth, mtROS can also affect the Keap1–Nrf2 antioxidant axis; acute or moderate oxidative stress can activate Nrf2 through Keap1 cysteine modification, while long-term high-intensity oxidative stress may lead to Nrf2 response exhaustion or inhibition, decreasing ROS clearance capacity and further strengthening the oxidative load (125). These loops collectively constitute the molecular basis for the persistence of mtROS and self-amplification of mitochondrial damage in COPD.

When mitochondrial protein folding stress persists, the mitochondrial unfolded protein response (UPRmt) may be triggered to enhance the expression of mitochondrial chaperones, proteases, and antioxidant-related genes, thereby helping to restore mitochondrial protein homeostasis (126). UPRmt differs from the classical endoplasmic reticulum stress response (ER stress); the latter primarily senses the accumulation of misfolded proteins in the ER lumen and regulates protein folding and secretion load through pathways like PERK, IRE1, and ATF6. In contrast, UPRmt emphasizes the retrograde stress signal sent from the mitochondria to the nucleus upon impaired mitochondrial protein homeostasis, participating in the regulation of mitochondrial chaperones, protein degradation, metabolic adaptation, and antioxidant responses (127, 128). In the context of COPD, UPRmt can be understood as a compensatory protective mechanism following mitochondrial protein oxidative damage; however, if the mtROS load remains excessively high or the mitochondrial quality control system is imbalanced, this compensation may be insufficient to restore homeostasis, instead indicating that the mitochondria have entered a state of sustained stress (129). Finally, mtROS are also important upstream signals for inflammation and cell death pathways. Continuously elevated mtROS can promote inflammasome activation and drive various cell death modalities such as apoptosis, necroptosis, and ferroptosis (130). This mtROS–mitochondrial damage positive feedback is a crucial foundation for the persistence of oxidative stress in COPD.

4.3 Imbalance of antioxidant defense pathways

Oxidative stress in COPD not only stems from increased ROS generation but is also closely related to a decline in antioxidant defense capacity. Among these, the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is one of the core regulatory systems for maintaining cellular antioxidant homeostasis (27, 131). Nrf2 can induce the expression of various antioxidant and detoxification-related genes, including HO-1, SOD, GCLC, and GSH metabolism-related molecules, thereby helping cells resist oxidative damage (132, 133). In COPD, endogenous antioxidant defense impairment, represented by Nrf2 pathway inhibition and Keap1-Nrf2 regulatory imbalance, is an important basis for the persistence of oxidative stress (134). This pathway also represents a promising therapeutic target for restoring antioxidant defenses in future ferroptosis-related interventions. It should be noted that Nrf2’s response to oxidative stress is not unidirectional or linear. Acute or moderate ROS exposure typically promotes Nrf2 stabilization and nuclear translocation through Keap1 cysteine modification, thereby inducing antioxidant gene expression, constituting an adaptive protective response (135). However, in the setting of long-term, high-intensity oxidative stress in COPD, this protective response may be progressively depleted or remodeled, manifesting as insufficient Nrf2 nuclear translocation, decreased downstream antioxidant enzyme expression, enhanced proteasomal degradation, transcriptional repression, or epigenetic dysregulation (109, 136). In other words, the Nrf2 pathway may undergo a biphasic change of “early activation—chronic exhaustion/inhibition,” rather than simply being continuously enhanced or continuously decreased.

Tobacco smoke and other harmful exposures can continuously induce ROS generation, leading to oxidative damage to mitochondrial DNA, membrane lipids, and proteins; simultaneously, hindered Nrf2 nuclear translocation and decreased expression of its downstream antioxidant enzymes further weaken the cell’s ability to clear the oxidative load (137, 138). This bidirectional imbalance of “ROS increase—defense decrease” keeps COPD airway and alveolar tissues in a state of oxidative stress for a long time. Under normal conditions, Keap1 and Nrf2 jointly maintain the dynamic balance of the antioxidant response; while under the context of sustained COPD-related stress, the Keap1-Nrf2 regulatory relationship becomes imbalanced, which can manifest as insufficient Nrf2 activation, restricted nuclear translocation, and difficulty in effectively initiating the antioxidant transcriptional program (134). This biphasic characteristic also helps explain the limited clinical efficacy of some antioxidant treatments. If the disease is in an early stage or the endogenous Nrf2 response is still recoverable, Nrf2 activators may help enhance antioxidant defense; but in advanced stages or under long-term high oxidative load, if the Nrf2 pathway is already in a state of exhaustion, imbalance, or epigenetic suppression, simply activating Nrf2 may be difficult to reverse systemic oxidative damage, potentially yielding limited or unstable efficacy (139, 140). Therefore, interventions targeting Nrf2 require stratification based on disease stage, oxidative stress load, and endogenous antioxidant response status.

Insufficient antioxidant defense results not only in the accumulation of oxidative damage but also disrupts mitochondrial homeostasis (141). Inhibition of the Nrf2 pathway can exacerbate mitochondrial damage, a decline in membrane potential, and energy metabolism disorders, while worsening mitochondrial function leads to more mtROS generation, further amplifying the oxidative stress load (142). Existing studies also suggest that oxidative stress-related genes such as HSPA1A, GCLC, and IL-1β exhibit abnormal expression in COPD, indicating that antioxidant defense imbalance involves multi-level transcriptional regulatory changes (143, 144). Therefore, Keap1–Nrf2 imbalance in COPD not only weakens antioxidant defense but also further aggravates mitochondrial damage and chronic oxidative stress, providing a basis for the spread of oxidative stress to extrapulmonary tissues.

4.4 Systemic oxidative stress and multi-organ damage

Oxidative stress in COPD is not confined to the local lung environment. As the disease progresses, the persistent oxidative and inflammatory load can spread to extrapulmonary tissues via the circulatory system, contributing to systemic manifestations such as skeletal muscle dysfunction and cardiovascular comorbidities (145). Rather than generalizing this process as “multi-organ damage,” it is more specifically understood as: COPD-related systemic oxidative stress primarily affects tissues highly sensitive to energy metabolism and inflammatory signals.

Skeletal muscle represents one of the most prominently affected extrapulmonary tissues. COPD patients often experience decreased exercise tolerance, muscle weakness, and sarcopenia, which are closely related to impaired skeletal muscle mitochondrial function and elevated oxidative stress (146). Under sustained oxidative load, the efficiency of the skeletal muscle mitochondrial respiratory chain declines, leading to insufficient ATP production and increased mtROS accumulation, which further promotes protein degradation and impairs muscle fiber function (147). Therefore, skeletal muscle abnormalities are not merely secondary to reduced activity but may be a direct consequence of COPD systemic oxidative stress and metabolic imbalance.

The cardiovascular system is another important target organ for COPD comorbidities. Long-term oxidative stress and chronic low-grade inflammation may be involved in endothelial dysfunction, abnormal vascular reactivity, and the progression of atherosclerosis, and are considered potential bridging mechanisms for the increased risk of coronary heart disease, heart failure, and other cardiovascular events in COPD patients (148, 149). Although existing evidence supports an association between oxidative stress and cardiovascular comorbidities, the magnitude of this effect and the underlying causal pathways remain confounded by multiple factors, including smoking, age, metabolic status, and comorbidity burden (150, 151). Therefore, a more cautious statement would be: persistent systemic oxidative stress may participate in the process of pulmonary chronic inflammation extending to vascular lesions and cardiovascular risk, rather than solely determining these damage outcomes.

From a clinical assessment perspective, peripheral oxidative stress markers provide clues for understanding the systemic oxidative state in COPD. Studies have shown that oxidative damage indicators such as 8-hydroxy-2’-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) can be elevated in COPD patients, especially during acute exacerbations, and are associated with disease severity, lung function decline, and prognostic risk (152, 153). Additionally, mitokines such as GDF15 and FGF21 have been proposed to reflect mitochondrial stress and systemic metabolic abnormalities (154). GDF15 is a stress-responsive cytokine induced by mitochondrial stress, inflammatory stimuli, and tissue damage, involved in energy intake, metabolic adaptation, and inflammatory regulation; in COPD, its elevation may indicate systemic mitochondrial stress, increased inflammatory load, and worse clinical outcomes (155). FGF21 is a metabolic regulator related to energy metabolism, lipid oxidation, and insulin sensitivity, which can be induced under conditions of mitochondrial dysfunction and nutritional/oxidative stress (156); in COPD, elevated FGF21 may reflect both mitochondrial damage and represent a compensatory response to maintain metabolic homeostasis (157). Although these mitokines have not yet entered routine clinical classification systems, they are helpful for understanding COPD extrapulmonary phenotypes from the perspective of systemic metabolism and mitochondrial stress. Thus, oxidative stress in COPD not only reflects the burden of local and systemic damage but also establishes a common pathological foundation for the subsequent activation of various regulated cell death modalities via mtROS accumulation, inhibition of antioxidant defenses, and DAMP release (Figure 3).

Figure 3

5 Regulated cell death: the downstream execution phase of the mitochondrial stress network

In COPD, various regulated cell death modalities do not occur in isolation but are activated against a common background of mitochondrial stress and oxidative damage (84). Changes in mitochondrial membrane permeability, elevated mtROS, release of DAMPs, and disruption of iron homeostasis can respectively drive RCD programs such as apoptosis, necroptosis, pyroptosis, and ferroptosis (158). It should be emphasized that the RCD network in COPD is not a static parallel pathway but exhibits distinct cell- and stage-specificity: airway epithelial cells are more susceptible to exogenous exposure and barrier damage, macrophages are more prominent in amplifying inflammation, airway smooth muscle cells are primarily involved in airway remodeling, and skeletal muscle reflects extrapulmonary energy metabolism disorders (159, 160). Therefore, this chapter will discuss different RCD modalities by integrating “mechanism type—cell localization—stage characteristics” to reflect the dynamic and heterogeneous nature of the COPD cell death network.

5.1 Mitochondria-mediated apoptosis and necroptosis

In the cell death network associated with mitochondrial dysfunction, apoptosis and necroptosis are not independent of each other but share upstream stress signals at multiple nodes and can undergo switching or crosstalk under certain conditions (161). Persistent tobacco smoke exposure, oxidative stress, and mitochondrial damage provide a common activation background for these two cell death modalities. In mitochondria-mediated intrinsic apoptosis, mitochondrial outer membrane permeabilization is a key step. After Bcl-2 family protein imbalance, Bax and Bak aggregate on the mitochondrial outer membrane, promoting the release of cytochrome c into the cytoplasm, which in turn facilitates apoptosome formation and activates the caspase-9/caspase-3 cascade (162, 163). The loss of mitochondrial membrane potential serves as both a hallmark of mitochondrial damage and a mechanism that further amplifies apoptotic signals (164). From a cell type perspective, apoptosis is often associated with the loss of airway epithelial cells and alveolar epithelial cells, repair disorders, and alveolar structural degeneration; in skeletal muscle, persistent energy deficits and oxidative stress may also enhance susceptibility to apoptosis, contributing to muscle atrophy and decreased exercise tolerance (165).

Necroptosis is more characterized by membrane rupture, leakage of cellular contents, and secondary enhancement of inflammation. Elevated mtROS can promote the activation of RIPK3 and its substrate MLKL, which oligomerizes and inserts into the cell membrane to form pores, ultimately leading to loss of membrane integrity (166). Under conditions of significant mitochondrial damage, the RIPK3/MLKL signaling may also cross-talk with Bax/Bak, Drp1, and changes in membrane permeability, causing cell death that was originally biased towards apoptosis to shift towards more inflammatory necroptosis (167, 168). This switch is not solely determined by an ill-defined “stress threshold” but may be regulated by several molecular switches. For example, when caspase-8 activity is inhibited or absent, RIPK1/RIPK3 signaling is more likely to shift from apoptotic regulation to necroptosis execution; when RIPK1 is deubiquitinated by enzymes such as CYLD, it can also promote the formation of RIPK1-dependent death complexes (169); additionally, severe ATP depletion can weaken the energy-demanding apoptotic program, making cells more inclined to enter inflammatory necrotic-like death (170). This switch is typically more likely to occur in moderate-to-late stage COPD and acute exacerbation environments with higher injury burden, failure of inflammatory clearance, or obvious cellular energy crisis.

The convergence of these two pathways is evident in three key aspects: first, altered membrane permeability serves as a common foundation; second, mtROS amplifies both apoptotic signals and RIPK3/MLKL-mediated necroptosis; and third, calcium homeostasis imbalance and mPTP opening exacerbate membrane potential loss and energy failure, driving the transition from relatively “quiet” apoptosis to highly inflammatory necroptosis. Therefore, in the context of persistent damage in COPD, apoptosis and necroptosis are better understood as two death programs that share a background of mitochondrial damage and can be coupled with each other.

5.2 Mitochondrial DAMPs and pyroptosis

Among inflammatory cell deaths associated with mitochondrial dysfunction, pyroptosis is one of the important mechanisms for inflammatory amplification and tissue damage in COPD. MQC imbalance can promote the release of mitochondrial DAMPs such as mtDNA, cardiolipin, and ATP, and these danger signals subsequently trigger inflammasome activation and pyroptosis execution programs (67). Overall, pyroptosis in COPD proceeds via the cascade of “mitochondrial damage/DAMPs release—inflammasome sensor activation—caspase-1 activation—GSDMD cleavage,” driving persistent local inflammation and aggravated tissue damage.

During mitochondrial dysfunction, mtDNA leakage serves as a pivotal event linking organelle damage to inflammatory sensing. After an increase in mitochondrial membrane permeability or mPTP opening, mtDNA can enter the cytoplasm and be recognized by DNA sensing systems such as cGAS–STING, thereby inducing type I interferon and inflammation-related signals, forming a cross-amplification loop with inflammasome activation (171–173). Meanwhile, abnormal exposure of cardiolipin and elevated mtROS can provide stimulatory conditions for NLRP3 inflammasome assembly; ATP release can further promote inflammasome activation through ion efflux mediated by the P2X7 receptor (174). Therefore, mitochondrial DAMPs are important upstream signals that convert mitochondrial damage into inflammatory cell death.

After NLRP3 inflammasome activation, it promotes the activation of caspase-1, which in turn mediates the mature release of IL-1β and IL-18 and cleaves GSDMD. The N-terminal fragment of GSDMD inserts into the cell membrane to form pores, leading to cell swelling, disruption of membrane integrity, and pyroptosis (175, 176). In COPD, the significance of pyroptosis lies not only in the cell death itself but also in the release of pro-inflammatory cytokines that can promote the recruitment of inflammatory cells and aggravate airway and alveolar damage.

Regarding cell specificity, pyroptosis is predominantly observed in alveolar macrophages and airway epithelial cells, contributing to inflammatory cell infiltration. Pyroptosis of macrophages can promote the release of IL-1β and IL-18, driving neutrophil recruitment and maintenance of local inflammation; pyroptosis of airway epithelial cells may disrupt the epithelial barrier, making it easier for exogenous stimuli, pathogens, and inflammatory mediators to enter the airway microenvironment. Additionally, GSDMD cleavage fragments can affect mitochondrial membrane stability and interact with cardiolipin, leading to decreased membrane potential and persistently elevated ROS (177, 178). However, this mechanism is still mainly derived from specific experimental studies, and direct validation in COPD models still needs further strengthening. Overall, pyroptosis may be more prominent during the inflammatory amplification phase, acute exacerbation phase, or the chronic inflammatory stage of moderate-to-late disease, serving as an important node connecting mitochondrial DAMPs release, innate immune activation, and persistent inflammation in COPD (179).

5.3 Mitochondrial iron homeostasis and ferroptosis

Ferroptosis has been a subject of intense investigation in COPD research in recent years, but summarizing it merely as “increased lipid peroxidation leading to ferroptosis” is insufficient to reflect its mitochondrial characteristics (160). Mitochondria are not only victims of oxidative damage but also important sites for iron homeostasis regulation and amplification of lipid peroxidation (180). The onset of ferroptosis in COPD is closely linked to imbalances in mitochondrial iron metabolism.

Mitochondrial iron homeostasis depends on fine regulation of iron import, utilization, and storage. The Mitoferrin family of proteins is responsible for importing iron into mitochondria, providing substrates for the synthesis of iron-sulfur clusters and heme, which in turn participate in respiratory chain complex assembly and maintenance of mitochondrial metabolism (181). Once mitoferrin expression or function is abnormal, the mitochondrial iron load can change, affecting electron transport efficiency and promoting ROS generation (182). In the chronic oxidative stress environment of COPD, even a slight imbalance in mitochondrial iron homeostasis can be further amplified.

In addition to iron transport, NCOA4-mediated ferritinophagy is also a key mechanism regulating cellular iron availability (183). After ferritin is selectively degraded by autophagy, free iron is released into the reactive iron pool. If this process is unbalanced, it increases the likelihood of iron participating in Fenton reactions, promoting hydroxyl radical generation and accumulation of lipid peroxidation (184). In the context of COPD, smoke exposure, mitochondrial damage, and antioxidant system exhaustion collectively drive iron-dependent oxidative pressure to exceed the defense threshold. In other words, ferritinophagy and mitochondrial iron import together determine whether a cell enters a ferroptosis-susceptible state (7, 185).

The GSH/GPX4 system is a core defense against ferroptosis. GSH provides a reducing substrate for GPX4, enabling it to clear membrane lipid peroxides and prevent the propagation of lipid peroxidation chain reactions. Once GSH is depleted or GPX4 activity declines, membrane lipids rich in polyunsaturated fatty acids are more prone to irreversible peroxidation, thereby driving ferroptosis (186, 187). Furthermore, mitochondrial glutathione homeostasis and related transport mechanisms are also involved in this process, indicating that mitochondria not only affect ROS production but also participate in determining whether the antioxidant defense can be maintained (188). It is noteworthy that there may be bidirectional crosstalk between mitophagy and ferroptosis. Free iron released by ferritinophagy can enter mitochondria and expand the mitochondrial iron load, while damaged mitochondria themselves may also become an important source of the cellular reactive iron pool (189). If mitophagy is insufficient, damaged mitochondria persist, exacerbating mtROS generation and lipid peroxidation; if mitophagy is excessive or coexists with iron homeostasis imbalance, it may promote iron release and energy failure, further increasing susceptibility to ferroptosis (190).

Additionally, mitochondrial CoQ10 is also an important component of the anti-ferroptosis defense. CoQ10 can act as a lipid radical scavenger, participating in GPX4-independent ferroptosis resistance (191); the FSP1-related CoQ10 reduction system is mainly localized to the plasma membrane, but the mitochondrial CoQ10 pool is equally important for maintaining electron transport, membrane antioxidant capacity, and limiting lipid peroxidation (192). Therefore, the occurrence of ferroptosis in COPD may depend not only on the GSH/GPX4 defense mechanism but is also co-regulated by mitochondrial iron homeostasis, mitophagy status, and the CoQ10 antioxidant network.

From a cellular and tissue localization perspective, ferroptosis may be more significant in cells such as airway epithelial cells, alveolar structural cells, and skeletal muscle that are under long-term oxidative load and metabolic stress. Airway epithelial cells are rich in membrane lipid components susceptible to oxidative damage and are directly exposed to smoke and particulate matter stimulation, making them more prone to lipid peroxidation accumulation (193); iron homeostasis imbalance and weakened GPX4 defense in the alveolar region may promote membrane structural damage and alveolar destruction; long-term energy metabolism disorders, elevated mtROS, and insufficient antioxidant defense in skeletal muscle may also enhance susceptibility to ferroptosis and contribute to extrapulmonary phenotypes (194). Ultimately, mitochondrial iron accumulation, elevated ROS, and heightened susceptibility to oxidation of membrane lipids can form a “high iron—high oxidation—high lipid peroxidation” microenvironment (195). Peroxidation of mitochondrial membranes and related lipids not only weakens mitochondrial metabolic capacity but also promotes the spread of lipid peroxidation on a larger scale, driving cells into the ferroptosis program (196). Therefore, ferroptosis in COPD arises from the convergence of mitochondrial iron homeostasis imbalance, impaired GSH/GPX4 defense, abnormal mitophagy, and a weakened CoQ10 antioxidant network. Compared with pyroptosis and necroptosis, ferroptosis more prominently features membrane damage caused by sustained lipid peroxidation and iron homeostasis imbalance, potentially playing a more persistent role in the progression of emphysema, chronic structural destruction, and extrapulmonary energy metabolism disorders. This also explains the potential value of targeting iron metabolism, lipid peroxidation, and the mitochondrial antioxidant system (Figure 4).

Figure 4

5.4 RCD network spatiotemporal integration: from parallel pathways to dynamic pathological patterns

Based on the above discussion, the RCD network in COPD is not a simple juxtaposition of multiple death pathways but a dynamic system that changes with cell type, injury intensity, and disease stage. Spatiotemporal specificity is not an additional concept independent of RCD mechanisms but a key principle for understanding when, where, and how different RCD modalities participate in COPD progression.

From the perspective of cell types, airway epithelial cells are the earliest and most continuously exposed to smoke and pollutants, making them more prone to decreased mitochondrial membrane potential, elevated mtROS, and barrier damage, thereby initiating RCD such as apoptosis, ferroptosis, and pyroptosis (14). Macrophages primarily mediate inflammatory amplification and immune regulation, and their mitochondrial damage is often associated with metabolic reprogramming, polarization imbalance, and inflammasome activation; thus, pyroptosis and necroptosis are more characteristic (197, 198). Evidence regarding airway smooth muscle cells is relatively limited, but their mitochondrial stress and oxidative damage may contribute to proliferation/apoptosis imbalance and airway remodeling (199). Appendicular skeletal muscle exhibits an extrapulmonary phenotype, where under conditions of chronic energy deficiency and oxidative stress, mitochondrial abnormalities are more likely to be associated with apoptosis, mitophagy imbalance, and increased susceptibility to ferroptosis.

From the perspective of disease stages, early COPD more commonly features a coexistence of stress adaptation and damage repair. At this stage, cells may ensure survival through adjustments in mitochondrial dynamics, moderate mitophagy, and metabolic reprogramming; if damage exceeds the compensatory threshold, increased apoptosis and cellular senescence accumulation gradually occur. As the disease progresses, persistent oxidative stress, DAMPs release, and chronic inflammation favor more inflammatory death modalities, such as increased pyroptosis and necroptosis; simultaneously, iron homeostasis imbalance and lipid peroxidation accumulation also predispose cells to ferroptosis (200, 201). That is, the early stage tends toward “stress-adaptation-partial apoptosis,” while the middle to late stages are more prone to “persistent damage-inflammatory amplification-structural destruction.” These transitions may not be solely determined by accumulated damage but may also involve active molecular switches. From the early to middle stages, decreased cellular ATP, limited caspase activity, or enhanced RIPK1/RIPK3 signaling may shift the death modality from caspase-dependent apoptosis to necroptosis (202). From the middle to late stages, when DAMPs release exceeds clearance capacity, the NLRP3 inflammasome and Caspase-1/GSDMD axis are more easily and persistently activated, driving pyroptosis and inflammatory amplification (203). In the late stage or systemic phenotype, depletion of the GSH/GPX4 defense system, iron homeostasis imbalance, and lipid peroxidation accumulation may establish ferroptosis as a predominant mode of sustained damage (204). The inflammatory microenvironment also influences death modality selection; for example, TNF-α, IL-1β, IL-18, and type I interferon-related signals can alter the relative activities of caspase, RIPK, and inflammasome pathways, thereby shaping different RCD patterns (202).

From the perspective of tissue outcomes, apoptosis and cell aging are more associated with epithelial cell loss, repair impairment, and alveolar structural degeneration (205); pyroptosis and necroptosis more readily trigger inflammatory factor release and local inflammatory amplification, driving immune cell recruitment and tissue destruction (206); ferroptosis prominently features lipid peroxidation, membrane damage, and oxidative stress amplification, and may participate in alveolar destruction and extrapulmonary energy metabolism disorders (207). Mitophagy has a biphasic effect: moderate mitophagy helps clear damaged mitochondria and limit inflammation, but insufficient or excessive mitophagy can lead to damage accumulation or energy depletion, respectively, thereby promoting cell death (208, 209). Additionally, the recently proposed concept of PANoptosis provides a supplementary perspective for understanding the RCD cross-network. PANoptosis is defined as the integrated activation of multiple RCD programs, such as apoptosis, necroptosis, and pyroptosis, through shared molecular platforms. Its core is not a single pathway but a complex regulatory network mediated by the interplay of molecules such as caspases, RIPK1/RIPK3, inflammasomes, and gasdermins (210). Although direct evidence for PANoptosis in COPD remains limited, in an environment with persistent DAMPs release, elevated mtROS, and inflammatory cytokine stimulation, multiple death programs may be activated synchronously or sequentially (211). Therefore, PANoptosis can serve as an important research direction for explaining RCD overlap and pathway switching in COPD in the future. Consequently, the RCD patterns in COPD exhibit distinct cell- and stage-specificity and collectively contribute to disease progression and pathological heterogeneity (Figure 5).

Figure 5

6 From mechanistic pathways to targeted interventions: mitochondria and RCD-directed therapy

Based on the aforementioned mechanisms, mitochondria and RCD-directed therapy can target different pathological nodes: mitochondria-targeted antioxidants primarily address mtROS accumulation, MQC regulation focuses on mitochondrial renewal and damage clearance, and RCD intervention targets downstream inflammatory or oxidative cell death (212). It is important to emphasize that the translational basis of each strategy varies significantly: pulmonary rehabilitation and exercise training have demonstrated clinical benefits; in contrast, MitoQ and other mitochondria-targeted antioxidants have yielded only limited human data in COPD, whereas strategies inhibiting ferroptosis, pyroptosis, and necroptosis remain primarily in the preclinical stage. Therefore, this section will further discuss the level of evidence, delivery barriers, and translational priorities in conjunction with mechanistic rationale.

6.1 Antioxidants and mitochondria-targeted antioxidants

Oxidative stress and mitochondrial dysfunction are critical pathological underpinnings of COPD, making interventions targeting ROS clearance and mitochondrial protection mechanistically rational. Compared with traditional non-targeted antioxidants, mitochondria-targeted antioxidants (MTAs) are designed to act specifically at the key sites of ROS generation, theoretically allowing for more direct attenuation of mtROS accumulation, stabilization of membrane potential, and limitation of inflammatory amplification (213, 214).

Currently, representative agents under extensive study include MitoQ and coenzyme Q10 (CoQ10). MitoQ can accumulate within mitochondria, thereby reducing oxidative damage and improving mitochondrial homeostasis; CoQ10 possesses dual attributes as an electron transport chain cofactor and an antioxidant molecule, contributing to the maintenance of energy metabolism and limitation of lipid peroxidation (215, 216). In vitro and animal experiments have shown that MTAs have the potential to reduce mtROS, improve membrane potential, and alleviate tissue damage (217, 218). However, direct clinical evidence in COPD patients remains limited, with existing studies focusing more on surrogate markers or extrapulmonary effects, and it has not yet been fully demonstrated that they can stably improve lung function, reduce exacerbations, or alter long-term outcomes. Therefore, the key question in this direction has shifted from “whether it is mechanistically rational” to “identifying suitable patient populations, determining optimal timing and delivery methods, and establishing long-term safety profiles.”

Delivery issues are a significant barrier to the translation of MTAs. Systemically administered MitoQ or CoQ10 must undergo multiple steps including absorption, plasma transport, tissue distribution, and mitochondrial uptake, and whether effective concentrations can be achieved in airway epithelial cells, alveolar cells, or alveolar macrophages remains unclear. CoQ10 is highly lipophilic, with individual variations in oral absorption and tissue distribution; although MitoQ has a mitochondrial targeting design, pulmonary tissue exposure, long-term accumulation, and cell-type selectivity still require further evaluation (219). Inhaled delivery may increase local pulmonary concentrations and reduce systemic exposure, but it still faces pharmacokinetic/pharmacodynamic barriers such as formulation stability, particle deposition site, macrophage uptake, airway irritation, and long-term safety (220). Therefore, future MTA studies should simultaneously assess pulmonary tissue drug exposure, mitochondrial functional endpoints, and clinical outcomes, rather than relying solely on peripheral oxidative stress markers.

6.2 Regulating mitochondrial quality control

MQC includes mitochondrial biogenesis, dynamics regulation, and mitophagy, and is a key mechanism for maintaining mitochondrial quantity, structure, and functional stability (221). Given the presence of insufficient mitochondrial renewal, dynamic imbalance, and abnormal clearance of damaged mitochondria in COPD, MQC represents an attractive direction for intervention.

From a translational perspective, the PGC-1α/SIRT1/AMPK axis and the PINK1/Parkin-related mitophagy pathway are two relatively practical entry points. Theoretically, activating the PGC-1α/SIRT1/AMPK axis can enhance mitochondrial biogenesis and metabolic adaptive capacity, particularly suitable for COPD subgroups with insufficient mitochondrial renewal, impaired energy metabolism, or significant skeletal muscle function decline (222); the PINK1/Parkin pathway focuses on the recognition and clearance of damaged mitochondria and may be more suitable for pathological states with high mtROS burden and significant accumulation of damaged mitochondria (223). In contrast, while directly targeting fusion/fission proteins is mechanistically clear, these processes are integral to normal cellular homeostasis; thus, systemic intervention may lead to off-target effects and safety concerns.

It is important to note that enhancing MQC is not invariably beneficial. In the early stages of mitochondrial damage, promoting moderate mitophagy and supporting biogenesis may help limit the spread of damage (224); whereas in chronic late stages or under sustained high-intensity stress, excessive activation of mitophagy may exacerbate ATP depletion and functional failure (225). Therefore, the therapeutic strategy may differ at different stages of COPD: early stages should prioritize maintaining adaptation and repair, while late stages require avoiding uncontrolled clearance and irreversible energy failure. Current MQC regulation research is still mainly derived from cellular and animal models, and future studies should further clarify which patients have reversible MQC abnormalities, which indicators can be used for stratification, and whether different regulatory strategies are needed at different disease stages (226).

6.3 Targeting necroptosis and pyroptosis

Both necroptosis and pyroptosis have significant pro-inflammatory characteristics, so inhibiting these two types of cell death programs is expected to reduce DAMP release, attenuate inflammatory amplification, and alleviate airway and alveolar damage (227, 228). In terms of necroptosis, the RIPK1/RIPK3/MLKL axis is the main target. Experimental studies have shown that smoke exposure can promote the activation of RIPK3 and MLKL, while genetic knockout or pharmacological intervention in related pathways can reduce airway inflammation, alveolar destruction, and emphysema-like changes (229). For pyroptosis, the NLRP3 inflammasome, caspase-1, and GSDMD form a direct therapeutic cascade; inhibiting NLRP3 or downstream pyroptosis pathways can reduce the release of IL-1β and IL-18, and alleviate epithelial damage and inflammatory infiltration (230–232). Since mtROS and mtDNA release can simultaneously participate in the amplification of necroptosis and pyroptosis, combined inhibition of upstream mitochondrial damage and downstream inflammatory cell death signals is theoretically synergistic (233). However, this direction is still primarily a preclinical pathway, with very limited drug validation at the patient level. At the same time, necroptosis and pyroptosis pathways are also involved in host defense, infection response, and inflammatory clearance, and excessive inhibition may weaken anti-infection capabilities (234). Therefore, while this strategy is mechanistically attractive, it still requires more safety and population stratification evidence before forming a clear clinical pathway.

6.4 Targeting ferroptosis

Ferroptosis is characterized by the interplay of iron homeostasis imbalance, lipid peroxidation, and mitochondrial damage, and represents one of the potential therapeutic avenues for COPD. Smoking, chronic oxidative stress, GSH depletion, and weakened GPX4 defenses can collectively increase the susceptibility of COPD tissues to ferroptosis and contribute to alveolar damage, exacerbation of inflammation, and the formation of some extrapulmonary phenotypes (235). Interventions targeting ferroptosis mainly include three types of strategies: (1) reducing reactive iron load, exemplified by the use of iron chelators to attenuate Fenton reaction activity (236); (2) inhibiting the lipid peroxidation chain reaction via agents such as Ferrostatin-1 (237); and (3) enhancing endogenous antioxidant defenses, particularly by restoring the GSH/GPX4 and Nrf2-mediated protective axes (238). These strategies have shown protective potential in experimental models, but therapeutic approaches targeting ferroptosis in COPD are still primarily grounded in mechanistic research and preclinical evidence. Therefore, ferroptosis is currently more suitable to be positioned as a “potential therapeutic target” rather than a mature strategy with a clear clinical pathway. Future efforts need to clarify the true contribution of ferroptosis in different COPD phenotypes and establish stratification indicators that reflect iron homeostasis, lipid peroxidation, and GPX4 functional status.

6.5 Exercise rehabilitation and mitochondrial function remodeling

In addition to pharmacological interventions, exercise training and pulmonary rehabilitation are among the few strategies in COPD with clear clinical benefits that can also improve mitochondrial function. COPD patients often have decreased skeletal muscle mitochondrial density, reduced oxidative phosphorylation efficiency, and impaired exercise tolerance, while regular exercise can promote mitochondrial biogenesis through the AMPK/SIRT1–PGC-1α axis, improve oxidative metabolic capacity, and enhance antioxidant adaptation (40). From a translational perspective, pulmonary rehabilitation not only improves exercise tolerance and quality of life but may also partially reverse the extrapulmonary mitochondrial phenotype in COPD by promoting skeletal muscle mitochondrial renewal, improving metabolic flexibility, and reducing systemic inflammatory burden (239). In contrast to drug targets that remain in the early translational stage, exercise rehabilitation offers distinct advantages, including high clinical accessibility, established efficacy, and a favorable safety profile. Future research could further incorporate PGC-1α, GDF15, FGF21, peripheral blood oxidative stress markers, and muscle function parameters into pulmonary rehabilitation studies to determine which patients are most likely to benefit at the mitochondrial functional level.

6.6 Combination and personalized strategies

If the preceding sections answer “which pathological nodes can be intervened upon,” then combination and personalized strategies must answer “who should receive treatment, how to combine, and what indicators to use to judge efficacy.” The premise of combination therapy is mechanistic phenotyping. Not all COPD patients are dominated by the same pathological axis: some patients have more prominent mitochondrial oxidative stress and epithelial damage, others are characterized by inflammasome activation and enhanced pyroptosis, and still others are closer to phenotypes dominated by iron homeostasis imbalance, emphysema progression, or skeletal muscle mitochondrial function decline (240, 241). Therefore, molecular biomarkers such as cf-mtDNA, 8-OHdG, MDA, GDF15, FGF21, as well as NLRP3, GSDMD, and GPX4, can serve as criteria for patient stratification and efficacy evaluation in exploratory studies (242).

Combination regimens should not be a mere additive combination of drugs but should be tailored to the dominant pathological axis. Several combinations with more mechanistic logic can be considered: First, for patients with “high mitochondrial oxidative stress load,” MitoQ or CoQ10 combined with long-acting bronchodilators/inhaled corticosteroids could be explored to control airway symptoms and inflammation with standard inhaled therapy while reducing mtROS and mitochondrial damage through MTAs (243, 244); Second, for patients with “active inflammasome/pyroptosis,” NLRP3 pathway inhibitors combined with mitochondria-targeted antioxidants could be explored to simultaneously reduce DAMP-driven inflammasome activation and upstream mtROS sources (245); Third, for patients with “ferroptosis susceptibility” or significant emphysema progression, iron homeostasis regulation or lipid peroxidation inhibition strategies combined with Nrf2/GSH/GPX4 supportive therapy could be considered to simultaneously reduce reactive iron load and enhance anti-lipid peroxidation capacity (20). Fourth, for patients with “skeletal muscle dysfunction/extrapulmonary metabolic abnormalities,” standard intrapulmonary treatment should be combined with pulmonary rehabilitation, nutritional support, and PGC-1α-related mitochondrial biogenesis promotion strategies to improve exercise tolerance and systemic mitochondrial phenotype (246, 247). Future research also needs to clarify endpoint selection in advance. Simply observing a decrease in short-term inflammatory markers is insufficient to determine whether these strategies have real clinical value. A more comprehensive endpoint system should simultaneously cover mechanistic and clinical levels: the former includes changes in oxidative stress, biomarkers, mitochondrial function, and RCD pathway activity; the latter includes lung function, exacerbation frequency, exercise tolerance, radiographic progression of emphysema, skeletal muscle function, and quality of life. Only by connecting mechanistic signals with clinical benefits can combination and personalized strategies move from concept to verifiable pathways (Table 3).

7 Translational challenges and future perspectives

Although the “mitochondrial dysfunction-oxidative stress-regulated cell death” framework provides an integrated explanation for the pathogenesis of COPD, its clinical translation still faces multiple challenges. Existing evidence mainly comes from animal models, cell experiments, and cross-sectional clinical observations, which are insufficient to determine the causal weight of each mechanistic node in different COPD subtypes and disease stages. Furthermore, a paucity of robust biomarker panels persists that can simultaneously reflect mitochondrial damage, oxidative stress burden, and RCD activity, and the intervention window remains unclear. Therefore, future research should gradually shift from single-mechanism validation to a continuous translational pathway of “mechanism-based classification—biomarker validation—proof-of-concept trials—clinical endpoint assessment.”

7.1 Limitations of current evidence

Although studies on mitochondrial dysfunction and its relationship with RCD in COPD have increased significantly, the overall evidence base still has limitations. First, most existing studies are cross-sectional observations, in vitro experiments, and animal models, which can yield mechanistic insights but are insufficient to adequately recapitulate the long-term progression, recurrent exacerbations, and multisystem involvement of human COPD (248, 249). Particularly in cigarette smoke exposure models, many results are more suitable for explaining specific stages or local processes rather than being equivalent to the complex and persistent disease state of clinical patients (14). Second, COPD exhibits significant heterogeneity, with differences among patients in exposure background, inflammatory phenotype, emphysema severity, exacerbation tendency, and extrapulmonary complications. Therefore, “mitochondrial dysfunction” should not be regarded as a uniform mechanistic label for all patients (250). Some patients may primarily present with epithelial damage and alveolar destruction, others may show more prominent inflammatory maintenance and immune imbalance, and still others may manifest skeletal muscle dysfunction and systemic metabolic abnormalities (251). If this heterogeneity is ignored, mechanistic research will struggle to translate into actionable treatment strategies. Third, many key mechanisms related to mtROS, NLRP3, pyroptosis, ferroptosis, UPRmt, or mitochondrial membrane permeability were initially elucidated in the context of cardiovascular, renal, neurological, or oncology research (252, 253). While these findings are heuristic, they cannot automatically equate to pathological reality in COPD. Currently, many mechanistic pathways are biologically plausible but lack direct validation in COPD-specific models and patient samples (254). Finally, clinical translational evidence remains weak. Although antioxidants, mitochondrial protectants, metabolic regulators, and experimental interventions have been proposed to potentially improve COPD-related mitochondrial damage, most remain in preclinical or early exploratory stages, with limited high-quality trial data supporting real clinical benefits (114).

7.2 Biomarkers and disease classification

If research on mitochondrial dysfunction and the RCD network is to truly move toward clinical application, the key is not to discover more single molecules but to establish a mechanism-based biomarker system that can **facilitate** patient stratification (255). COPD has long been assessed primarily based on symptoms, lung function, and exacerbation risk, but these indicators are insufficient to reflect the dominant pathological processes underlying the disease in individual patients (256). Therefore, a more meaningful question is: Can we identify patients with “high mitochondrial damage burden,” “active inflammatory RCD,” “ferroptosis susceptibility,” or “the extrapulmonary mitochondrial failure/sarcopenia-related phenotype” (257).

Based on current evidence, four candidate mechanistic subtypes can be preliminarily proposed. The first is the oxidative stress-mitochondrial damage type, which may be characterized by elevated cf-mtDNA, 8-OHdG, and MDA, along with abnormal mitokines such as GDF15 and FGF21, indicating high mitochondrial stress and systemic metabolic burden (258). The second is the inflammasome-pyroptosis active type, likely characterized by enhanced NLRP3-related signaling, elevated IL-1β/IL-18, and prominent GSDMD cleavage features (259). The third is the iron homeostasis imbalance-ferroptosis susceptible type, possibly accompanied by abnormalities in GPX4, SLC7A11, ACSL4, and lipid peroxidation indicators (260, 261). The fourth is the extrapulmonary mitochondrial failure/sarcopenia-related type, often presenting with decreased exercise tolerance, skeletal muscle dysfunction, and systemic metabolic changes, requiring simultaneous assessment of intrapulmonary and extrapulmonary mechanisms (262, 263).

It should be emphasized that the above four subtypes should currently be regarded as hypothesis-generating research frameworks rather than mature clinical classification systems. At this stage, it is not possible to accurately estimate the prevalence of each subtype in the COPD population, nor is it clear whether these subtypes are stable in individual patients or may shift with exacerbations, disease progression, smoking cessation, treatment, or rehabilitation interventions. From a clinical perspective, emphysema-dominant patients may be more likely to exhibit mitochondrial damage and ferroptosis susceptibility features, chronic bronchitis or frequent exacerbation patients may lean toward an inflammasome/pyroptosis active state, and those with significant exercise intolerance, sarcopenia, or metabolic abnormalities may be closer to the extrapulmonary mitochondrial failure phenotype (136). However, these inferences still require validation through prospective cohorts and mechanistic biomarkers and cannot be directly used as clinical diagnostic criteria.

Future validation of this classification framework can follow this pathway: First, integrate clinical phenotypes, CT imaging, lung function, exacerbation history, and multi-omics data in a discovery cohort to identify candidate mechanistic subgroups; second, validate biomarker combinations using peripheral blood, sputum, bronchial brushings, or tissue samples in independent cohorts; third, assess the relationship between each subtype and lung function decline, exacerbations, emphysema progression, skeletal muscle function, and mortality risk; finally, test whether different subtypes exhibit differential treatment responses in mechanism-enriched clinical trials. Only after completing this validation chain can biomarkers transition from “mechanism-proving tools” to a basis for disease classification and treatment selection (264–266).

7.3 Multi-omics and systems biology integration

The value of multi-omics and systems biology lies not only in increasing data dimensions but also in helping address three key issues in COPD mitochondrial and RCD research: identifying subtypes, finding bridging molecules, and predicting treatment responses (267, 268). Single biomarkers are insufficient to capture the complex molecular heterogeneity of COPD patients, whereas combined analyses of transcriptomics, proteomics, metabolomics, lipidomics, and mitochondrial-specific omics are more likely to identify patient subgroups characterized by different pathological axes (269). For example, some patients may exhibit more prominent mitochondrial respiratory chain abnormalities and metabolic reprogramming; others may show inflammasome activation and immune cell remodeling; and still others may be characterized by iron metabolism disorders and lipid peroxidation (270).

Future multi-omics integration should further incorporate information at the cell type and regulatory level. Single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin sequencing can identify specific mitochondrial stress and RCD signals in airway epithelial cells, alveolar epithelial cells, macrophages, endothelial cells, smooth muscle cells, and skeletal muscle cells. Epigenomics, including DNA methylation, histone modification, and chromatin accessibility, may help explain why some patients exhibit persistent mitochondrial dysfunction and inflammatory memory even after smoking cessation. Lipidomics is particularly important for ferroptosis research, as it can capture changes in membrane lipid peroxidation, polyunsaturated fatty acid remodeling, and CoQ10-related antioxidant defenses. Mitochondrial-specific omics, such as mtDNA sequencing, mtDNA copy number/heteroplasmy analysis, and mitochondrial proteomics, can directly assess mitochondrial genome damage, respiratory chain complex abnormalities, and alterations in mitochondrial protein homeostasis. Large COPD cohorts and consortia, such as SPIROMICS, COPDGene, and related multi-omics projects, have already integrated clinical phenotypes, imaging, transcriptomics, proteomics, metabolomics, or genetic information to identify molecular features associated with emphysema, airway disease, exacerbations, inflammatory burden, and systemic phenotypes (271). Although not all of these studies are centered on mitochondria or RCD, their data frameworks suggest that molecular subtypes in COPD may be closely related to energy metabolism, immune inflammation, oxidative stress, and tissue remodeling pathways, providing important resources for subsequent validation of mitochondrial-RCD classification. Future studies can further overlay mtDNA, lipidomics, mitochondrial proteomics, and single-cell data on these cohorts to clarify whether mitochondrial abnormalities are drivers, accompanying markers, or predictors of treatment response for certain clinical phenotypes.

Additionally, multi-omics can help identify “bridging molecules” connecting different pathological layers. Many studies have separately observed mitochondrial damage, inflammatory responses, cell death, and extrapulmonary phenotypes, but the key nodes truly linking these processes remain unclear (272, 273). Systems biology analysis can screen for regulatory nodes from complex networks that simultaneously associate with mitochondrial homeostasis, RCD signaling, and clinical phenotypes, such as pathways involving SIRT1, Nrf2, PINK1/Parkin, NLRP3, and GPX4 (274). These bridging molecules are more likely than simple differentially expressed genes to become targets or classification bases. Future multi-omics integration should also serve treatment response prediction, such as identifying who is more likely to benefit from antioxidant therapy, inflammatory RCD inhibition, or pulmonary rehabilitation/mitochondrial biogenesis promotion strategies (275, 276). Therefore, valuable multi-omics research should align molecular networks with clinical problems to form an interpretable, verifiable, and classifiable mechanistic framework.

7.4 Clinical trials and guideline transition

The greatest challenge in moving from mechanistic research to clinical application is not to prove again that “mitochondria are important,” but to translate mechanistic information into implementable trial designs and evaluable clinical pathways (277). At present, mitochondrial and RCD-targeted therapies in COPD are still in the developmental stage, have not entered routine guideline frameworks, and have not yet formed stable, reproducible clinical strategies.

First, future clinical trials need to address patient selection. If trial subjects lack mechanistic stratification and are enrolled solely based on a broad COPD diagnosis, genuine therapeutic signals may be diluted (278). A more feasible design is enrichment based on candidate biomarkers and mechanistic phenotypes, such as prioritizing patients with high oxidative stress burden, elevated cf-mtDNA, rapid emphysema progression, or significant skeletal muscle dysfunction. Second, endpoint design needs to be more layered. For mechanism-guided interventions, relying solely on short-term lung function changes as a measure of efficacy is often insufficiently sensitive (279). A more reasonable strategy is to set parallel mechanistic and clinical endpoints: the former includes changes in cf-mtDNA, 8-OHdG, MDA, GDF15, inflammasome-related indicators, or ferroptosis-related molecules; the latter includes exacerbations, exercise tolerance, imaging-based emphysema progression, skeletal muscle function, and quality of life improvement (280, 281). Only when mechanistic improvements correspond to clinical outcome improvements can relevant therapies move toward guideline inclusion (282). Third, combination therapy models may be more suitable for the clinical reality of COPD than monotherapy approaches. The current COPD management system is still based on standard pathways including bronchodilators, inhaled corticosteroids, smoking cessation, pulmonary rehabilitation, and exacerbation management (283). Future mitochondrial or RCD-targeted interventions are more likely to serve as supplements to standard therapy rather than replacements. That is, the more realistic question is not “can it cure COPD alone,” but “can it provide additional benefits to patients with specific mechanistic subtypes on top of standard therapy.” Therefore, in the foreseeable future, mitochondrial and RCD-related interventions are better positioned as mechanism-guided exploratory treatment pathways; their entry into guidelines requires high-quality stratified clinical trials, reproducible biomarker validation, and accumulation of evidence demonstrating tangible clinical benefits.

7.5 Future research directions

Based on current evidence foundations and translational bottlenecks, research on mitochondrial dysfunction and the RCD network in COPD urgently needs to shift from “mechanism expansion” to a continuous pathway of “mechanism validation—classification establishment—clinical translation.” First, future research should place greater emphasis on cell-type specificity. COPD pathogenesis is not driven by a single cell population; rather, distinct cell types exhibit heterogeneous responses to mitochondrial damage and RCD activation. Airway epithelial cells and alveolar epithelial cells are more directly exposed to smoke and environmental stimuli, macrophages are more involved in inflammatory amplification and immune regulation, airway smooth muscle cells are related to airway remodeling, and skeletal muscle cells reflect extrapulmonary energy metabolism and systemic damage (284). Key questions include: which type of mitochondrial abnormality dominates in different cell types, which RCD is more decisive, and how these mechanisms transition from early stress adaptation to late persistent damage, senescence accumulation, and structural remodeling with disease progression (285). Second, mechanism-based biomarkers and disease classification systems will be key to precision therapy. Future research should not merely focus on screening differentially expressed genes but should develop biomarker panels that can be derived from clinical samples, validated in independent cohorts, and linked to outcomes (286). Establishing candidate biomarker panels centered on core pathological axes such as oxidative stress, mitochondrial damage, inflammatory RCD, and iron homeostasis imbalance will help integrate disparate mechanistic studies into a more clinically meaningful classification framework (287). In other words, the most critical step from mechanism discovery to precision intervention is establishing a classification system that supports patient stratification and efficacy prediction.

On this basis, mechanism-guided small-scale proof-of-concept trials should become an important focus for the next stage. Rather than directly conducting large-scale trials without stratification, it is better to first carry out enriched exploratory studies on patient subgroups with relatively clear mechanistic signals. Such trials can prioritize patients with high mitochondrial damage burden or active specific RCD pathways and simultaneously set molecular and clinical endpoints to assess whether the intervention truly provides continuous evidence from mechanistic improvement to clinical benefit. Only by systematically validating the linkage between “mechanism-biomarker-efficacy” can relevant treatment strategies move from theoretical potential to verifiable clinical pathways. Therefore, future research should focus on mechanistic classification, biomarker validation, and stratified clinical trials to drive mitochondrial and RCD-related mechanisms from theoretical frameworks to verifiable translational pathways (Figure 6).

Figure 6

8 Conclusion

Mitochondrial dysfunction is a key link in the pathological progression of COPD, with its significance not only lying in impaired energy metabolism but also in its position as a convergence point among oxidative stress, chronic inflammation, cell aging, and regulated cell death. Persistent mitochondrial damage can drive airway epithelial injury, the perpetuation of inflammation, and tissue remodeling through mtROS accumulation, abnormal mtDNA release, quality control imbalance, and metabolic reprogramming. Therefore, integrating COPD-related pathological processes from the common hub of mitochondria helps to more systematically understand the molecular basis of disease progression and extrapulmonary phenotypes. Current evidence indicates that various forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, and ferroptosis, are coupled with mitochondrial damage and together constitute a pro-inflammatory and pro-injury interconnected network in COPD. Although different cell death programs have their own characteristics, they often share upstream basic events such as altered mitochondrial membrane permeability, enhanced oxidative stress, DAMPs release, and iron homeostasis imbalance. However, most current evidence primarily comes from cell experiments and animal models, with relatively limited direct evidence from COPD patient samples and clinical studies. Therefore, the disease specificity and clinical applicability of the related mechanistic pathways still require further validation. In the future, the focus of this field should shift from merely accumulating mechanistic clues to establishing a more mechanistically robust and translatable research framework. Specifically, it is necessary to further advance cell type- and disease stage-specific mechanistic validation, establish a mechanistic biomarker and disease classification system centered on the mitochondrial damage and RCD network, and conduct stratified, proof-of-concept clinical studies on this basis. Only by truly linking mechanistic research, biomarker screening, and intervention pathway evaluation can research on mitochondria and RCD move from pathological explanation to verifiable precision intervention strategies.

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