Hongbo Chang
Pingge He
Weidi Liu2
Zhentao Wang- 1Second School of Clinical Medicine, Henan University of Chinese Medicine, Zhengzhou, China
- 2Department of Cardiovascular Medicine, Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
Mitochondria play a central role in energy production and signal transduction in cardiomyocytes. Their dysfunction is a key contributor to the development and progression of heart failure (HF). Beyond energy metabolism, mitochondria regulate calcium homeostasis, autophagy, protein synthesis, lipid metabolism, and gene expression through close interactions with other organelles. Disruption of these interactions has been linked to HF pathophysiology.This review focuses on the dynamic communication between mitochondria and five major organelles—the endoplasmic reticulum, lysosomes, ribosomes, lipid droplets, and the nucleus. We outline how these interactions maintain cardiac homeostasis and describe how their dysfunction contributes to HF. We also highlight emerging therapeutic strategies targeting these organelle networks.
1 Introduction
Heart failure (HF) is one of the leading causes of hospitalization and mortality worldwide, with the prevalence continuing to rise in line with global population aging (1). Despite advances in therapeutic strategies, HF remains a significant public health issue. Imposing a substantial burden on global health and healthcare expenditures, HF urgently needs to be addressed with novel and effective treatment approaches (1).
The pathophysiological mechanisms of HF are complex and multifactorial and include metabolic dysregulation, oxidative stress, inflammatory responses, and myocardial remodeling, all of which contribute to the progressive deterioration of cardiac function (2). Mitochondria play a pivotal role in maintaining cardiomyocyte function, being responsible for generating adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) while regulating calcium homeostasis and redox balance. Mitochondria play a crucial role in the development and functional maturation of the embryonic heart through non-energetic metabolic processes (3). Given the heart's extremely high energy demands, mitochondrial integrity is essential for sustaining normal cardiac function, and mitochondrial dysfunction is recognized as a key pathological mechanism in the development and progression of HF. Mitochondrial dysfunction manifests as impaired oxidative metabolism, excessive production of reactive oxygen species (ROS), mitochondrial DNA damage, and activation of cell death signals (4), maladaptive changes that further accelerate the progression of HF. In addition to their autonomous functions, mitochondria establish dynamic and coordinated interactions with other organelles, enabling integrated regulation of metabolism, signaling, and cellular quality control (5–7).
Recent studies have shown that inter-organelle communication, especially the interactions between mitochondria and the endoplasmic reticulum, lysosomes, ribosomes, lipid droplets (LDs), and the nucleus, is crucial for maintaining cellular homeostasis. Disruption of these interactions is often closely associated with the onset and progression of HF. However, the spatial-temporal dynamics and specific molecular mechanisms governing these interactions under both normal and pathological conditions remain poorly understood. In this review, we aim to provide a comprehensive overview of the functional crosstalk between mitochondria and these five key organelles, focusing on their roles in maintaining cardiac homeostasis, the pathological alterations observed in HF, and potential therapeutic strategies. Furthermore, we aim to provide new insights into the mitochondria-organelle interactome and offer theoretical support for HF pathogenesis research and the development of targeted interventions by integrating the latest research advancements in this field.
2 Mitochondria-ER interactions: calcium signaling and energy homeostasis
2.1 Main forms of mitochondria-ER interactions
Mitochondria and the ER interact through a specialized physical contact site known as the mitochondria-associated ER membranes (MAMs), a structure first described in the 1950s and successfully isolated from liver tissue in the 1990s (8). MAMs are located at the interface between outer mitochondrial membranes (OMMs) and the ER, which are referred to as mitochondria-ER contact sites (MERCs). At MERCs, the physical connection between the two organelles is maintained by protein complexes, ensuring an appropriate intermembrane distance that facilitates inter-organelle communication (9). The structural dynamics of MAMs are highly adjustable and regulated by cellular metabolic and stress conditions. For example, the number of MAMs can be significantly increased by hypoxia or ER stress, and the efficiency of material exchange, such as lipid transport, is directly influenced by the width of the gap between MAMs, with tight contacts (<10 nm) being more conducive to lipid transfer (10–12). In different cell types, the proportion of the mitochondrial surface covered by MAMs typically ranges from 4% to 20% and can adapt to changes in the metabolic state. For example, in the liver after feeding, the MERC coverage can increase from 4% to 11% (13). Mass spectrometry analysis has identified approximately 1,000 proteins localized to MAMs in the brain and liver, underscoring their pivotal role in maintaining cellular homeostasis (14).
A primary role of MAMs is regulating calcium signaling to support mitochondrial energy metabolism. The IP3R–GRP75–VDAC complex facilitates the transfer of Ca2+ from the ER to the mitochondrial matrix via the mitochondrial calcium uniporter (MCU). IP3R1 and IP3R2 are highly enriched at MAMs and, by controlling mitochondrial calcium influx, they activate tricarboxylic acid (TCA) cycle dehydrogenases, thereby enhancing ATP synthesis (15–17).This process is further regulated by several key proteins. FUN14 domain-containing protein 1 (FUNDC1), located at MAMs, promotes calcium exchange by interacting with IP3R2 on the ER membrane, thereby maintaining MAM integrity and contributing to calcium-dependent mitochondrial bioenergetics (18–21). Sigma-1 receptor (Sig-1R), a stress-responsive chaperone, dissociates from BiP and stabilizes IP3R to enhance calcium transfer under both basal and stress conditions (22). On the ER side, sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) helps re-sequester calcium into the ER lumen, forming a feedback loop to maintain cytosolic and mitochondrial calcium homeostasis (23). In addition, mitochondrial calcium uptake is tightly controlled by regulatory proteins such as MICU1 and MCUb, which prevent excessive calcium influx under resting conditions. Together, these proteins ensure precise calcium signaling between the ER and mitochondria (24, 25).
MAMs are also essential metabolic hubs, coordinating lipid trafficking and synthesis. They mediate the transport of phosphatidylserine (PS) from the ER to mitochondria, where it is converted into phosphatidylethanolamine (PE), a major mitochondrial phospholipid (26, 27). MAMs also regulate cholesterol transport, cardiolipin biosynthesis, and sterol regulatory element-binding protein 1 (SREBP1)-mediated lipid synthesis, thereby contributing to mitochondrial membrane composition and function under stress conditions (28, 29).
Additionally, MAMs modulate mitochondrial dynamics to adapt to energy demands. Mitochondrial fission is initiated at MAMs via recruitment of dynamin-related protein 1 (Drp1) to mitochondrial fission 1 protein (FIS1), while fusion is regulated by mitofusin 1/2 (MFN1/2) and optic atrophy protein 1 (OPA1), which coordinate outer and inner membrane fusion, respectively (30–32). A proper balance between fission and fusion is essential for maintaining mitochondrial integrity, and its disruption is linked to mitochondrial dysfunction and cardiomyocyte damage.
Moreover, MAMs integrate endoplasmic reticulum stress (ERS) and apoptotic signaling. They are enriched with ERS sensors including BiP (binding immunoglobulin protein), IRE1α, and PERK, as well as apoptotic regulators such as Bcl-2 and Bax (32–35). Under mild stress, these pathways help restore cellular homeostasis, but prolonged activation can trigger mitochondrial Ca2+ overload, cytochrome c release, and apoptosis. Therefore, MAMs serve as an essential interface for the coordination of survival and death signaling in cardiomyocytes (Supplementary Figure S1).
2.2 Mitochondria-ER crosstalk dysregulation in HF
In heart failure (HF), the structure and function of MAMs are disrupted, leading to dysregulated calcium signaling, mitochondrial dysfunction, and cardiomyocyte injury (36). Key MAM-associated proteins show altered expression in HF. FUNDC1, which normally supports mitochondrial dynamics and calcium signaling, is often downregulated under pathological stress. Its loss disrupts interactions with IP3R2, leading to MAM dissociation, reduced mitochondrial and cytosolic Ca2+ levels, and impaired ATP production (18, 19). Similarly, sigma-1 receptor (Sig-1R) deficiency impairs mitochondrial calcium uptake and exacerbates cardiac remodeling (22).SERCA2a, responsible for pumping Ca2+ back into the ER, is frequently reduced in HF, resulting in sustained cytosolic calcium elevation and impaired ER-mitochondrial calcium cycling (23). The downregulation of OPA1, MFN1, and MFN2 further impairs mitochondrial morphology and tethering with the ER (37, 38). In parallel, deletion of Drp1 alters mitochondrial fission dynamics, leading to abnormal elongation, enhanced mitophagy, calcium overload, and ROS accumulation, which in turn trigger mPTP opening and apoptosis (39, 40). Loss of MFN2 exacerbates these effects by compromising both fusion and ER tethering (41, 42). Under conditions of prolonged ER stress, the initially protective PERK–eIF2α pathway becomes maladaptive, promoting apoptosis through CHOP activation and further exacerbated by IRE1α-mediated IP3R sensitization (43–46). Meanwhile, disruption of the balance between Bcl-2 and Bax—both enriched at MAMs—contributes to mitochondrial permeability transition and cytochrome c release, leading to cardiomyocyte death (47–50).
3 Mitochondria-lysosome interactions: autophagy and cardiomyocyte homeostasis
3.1 Main forms of mitochondria-lysosome interactions
As mitochondria and lysosomes are functionally interconnected, lysosomal dysfunction is often accompanied by mitochondrial damage. For example, defective lysosomal acidification can lead to alterations in mitochondrial dynamics and impairment of mitochondrial respiration (51, 52). Research into Pompe disease has revealed that mutations in the acid alpha-glucosidase (GAA) gene cause lysosomal glycogen accumulation, resulting in mitochondrial structural abnormalities and energy metabolism disorders, ultimately leading to hypertrophic cardiomyopathy and HF (53). This research highlights the crucial role of lysosomal integrity in maintaining mitochondrial homeostasis. Lysosome-associated proteins such as Ras-related proteins Rab5 and Rab7A, along with their respective guanine nucleotide exchange factors (GEFs), play regulatory roles in mitochondrial function (54). Conversely, the loss of mitochondrial proteins, including apoptosis-inducing factor (AIF), OPA1, PTEN-induced putative kinase 1 (PINK1), and mitochondrial transcription factor A (TFAM), compromises lysosomal activity (55).
Lysosomes primarily eliminate damaged mitochondria using two key mechanisms. One is by PINK1/Parkin-mediated mitophagy, in which damaged mitochondria are selectively recognized and degraded via autophagy receptors such as optineurin (OPTN) and nuclear dot protein 52 (NDP52) (56, 57). The other is by delivery of specific mitochondrial components by mitochondria-derived vesicles (MDVs) to lysosomes for degradation, thereby providing an alternative quality control mechanism (58).
Super-resolution electron microscopy has revealed novel forms of interaction known as mitochondria-lysosome contacts (MLCs). Approximately 15% of lysosomes form physical contact with mitochondria for durations ranging from 60 s to 13 min (59, 60). MLCs are bidirectionally regulated by components from both mitochondria and lysosomes. MLC formation is promoted by active GTP-bound Rab7, whereas the Rab7 GTPase-activating protein TBC1 domain family member 15 (TBC1D15) is recruited by FIS1 to mitochondria, facilitating Rab7 GTP hydrolysis and thereby promoting MLC dissociation (Supplementary Figure S1).
The physiological functions of MLCs include the following: (1) Regulating mitochondrial fission: MLCs mark and facilitate mitochondrial fragmentation to maintain mitochondrial dynamics and homeostasis (59). (2) Modulating lysosomal function: MLCs affect lysosomal transport and degradation capacity through Rab7 signaling (59). (3) Mediating calcium signaling: The lysosomal calcium channel transient receptor potential mucolipin 1 (TRPML1) interacts with the mitochondrial calcium channel's VDAC and mitochondrial calcium uniporter (MCU) to enhance mitochondrial oxidative phosphorylation (61).
Mitochondria-lysosome interactions form dynamic contact sites that enable the bidirectional exchange of metabolites and signaling molecules, playing a crucial role in maintaining intracellular homeostasis.
3.2 Mitochondria-lysosome crosstalk dysregulation in HF
Rab7 is a member of the small GTPase family that plays a crucial role in lysosome maturation, autophagosome-lysosome fusion, and endocytic pathways, including late endosome trafficking and lysosomal degradation of internalized materials. The UM-X7.1 hamster model, which simulates human dilated cardiomyopathy (DCM), experienced extensive autophagic vacuolar degeneration of cardiomyocytes along with upregulation of Rab7, ubiquitin, and cathepsin D. The disruption of the plasma membrane was compromised in these cardiomyocytes, suggesting that Rab7 may play a role in autophagy-related cell death (62). Rab7 participates in the BAG3-mediated chaperone-assisted selective autophagy (CASA), a pathway that removes damaged actin filaments and mitochondria. This process is activated by Bcl-2-associated athanogene 3 (BAG3) through stress-induced dephosphorylation, and BAG3 directly interacts with Rab7A and binds to microtubule-associated protein 1A/1B-light chain 3B (LC3B) to mediate autophagosome-lysosome fusion (63). This mechanism is particularly relevant in HF, as mutations in BAG3 lead to CASA dysregulation, resulting in protein homeostasis disruption, myocardial energy metabolism defects, and cardiomyocyte death (63).
In models of DCM and left ventricular non-compaction (LVNC) caused by gene mutations, mutations in Pleckstrin homology domain containing M2 (PLEKHM2) lead to abnormal accumulation of Rab5, Rab7, and Rab9-positive endosomes, affecting lysosomal positioning and ultimately disrupting autophagic flux (64). Rab7 dysfunction can cause the accumulation of cellular waste in cardiomyocytes, adversely affecting myocardial metabolism and contractile function and contributing to the progression of HF. Rab7 directly interacts with the mitochondrial fusion protein MFN2 to regulate the fusion of autophagosomes and lysosomes (65). Therefore, the loss of MFN2 impairs Rab7-mediated autophagic flux, leading to autophagosome accumulation, mitochondrial dysfunction, and cardiomyocyte injury (65). These findings suggest that Rab7 regulates autophagic flux and also plays a key role in maintaining mitochondrial quality control. Thus, Rab7 exerts a dual role in the pathogenesis of HF: On the one hand, it promotes lysosomal maturation and autophagic flux, helping to maintain cardiomyocyte homeostasis; on the other hand, under pathological conditions, excessive Rab7 activation may lead to autophagic cell death. The existence of this dual role suggests that modulation of Rab7 activity may represent a novel therapeutic strategy for the treatment of HF (Supplementary Table S1).
In HF, lysosomes play a crucial role in eliminating damaged mitochondria through autophagic pathways, promoting cardiac function recovery. The restoration of mitochondrial homeostasis, in turn, enhances lysosomal activity, collectively regulating the process of myocardial remodeling (66). TBC1D15 is a key regulatory factor in mitochondria-lysosome interactions. In acute myocardial infarction and ischemia-reperfusion (I/R) injury, TBC1D15 facilitates the clearance of damaged mitochondria, alleviates cardiomyocyte damage, and improves mitochondrial function (67). Moreover, TBC1D15 can directly bind to the mitochondrial fission protein Drp1, promoting the selective fission of damaged mitochondria and rendering them more susceptible to lysosomal degradation (68). This process reduces oxidative stress, inhibits cardiomyocyte apoptosis, and enhances cardiac function (68). TBC1D15-mediated mitochondria-lysosome interactions may offer therapeutic potential in cardiac protection by maintaining myocardial energy metabolism, reducing mitochondrial damage, and delaying ventricular remodeling.
In myocardial ischemia-reperfusion injury (I/R), the lysosomal Ca2+ channel TRPML1 becomes dysfunctional, resulting in impaired autophagic flux and hindering the effective degradation of damaged mitochondria, thereby exacerbating cardiomyocyte injury (69). Restoration of TRPML1 activity enhances lysosomal activity, promotes autophagic degradation, and facilitates mitochondrial clearance, ultimately improving cardiomyocyte survival (69). Interestingly, TRPML1 inhibition has also been shown to preserve mitochondrial function by reducing lysosomal Ca2+ release and decreasing oxidative stress, indicating that TRPML1 may exert bidirectional regulatory effects under different pathological conditions (70). Because patients with HF often exhibit autophagic dysfunction and mitochondrial defects, TRPML1 may play a critical role in myocardial energy metabolism, cell survival, and ventricular remodeling by modulating mitochondria-lysosome interactions.
4 Mitochondria-ribosome interactions: protein synthesis and myocardial injury
4.1 Major forms of mitochondria-ribosome interactions
Ribosomes are the exclusive sites for protein synthesis, distributed in both the cytoplasm and mitochondria. Mammalian mitochondrial ribosomes (mitoribosomes) are primarily responsible for synthesizing essential subunits required for the OXPHOS system and are therefore essential for maintaining ATP production (71). Mitochondrial proteins originate from both the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). Among the proteins, mitochondrial ribosomal proteins (MRPs), which are encoded by nDNA, must be synthesized in cytoplasmic ribosomes before being imported into mitochondria to support the mitochondrial translation machinery (72, 73). MRPs are indispensable for mitochondrial function and cellular homeostasis, and their dysregulation has been closely associated with various cardiovascular diseases. For example, decreased expression of the following proteins has been linked to the development of heart disease: mitochondrial ribosomal protein S3 (MRPS3), mitochondrial ribosomal protein S22 (MRPS22), mitochondrial ribosomal protein 10 (MRP10), and mitochondrial ribosomal protein S44 (MRPS44) (74, 75). Furthermore, protein synthesis in cardiomyocytes is directly regulated by the heart-specific ribosomal gene ribosomal protein L3-like (RPL3l), and mutations in RPL3l may impair ribosomal function, ultimately leading to cardiac remodeling and myocardial injury (76, 77) (Supplementary Figure S1).
4.2 Mitochondria-ribosome crosstalk dysregulation in HF
Mitochondrial ribosomal protein S5 (MRPS5) is a critical component of the mitochondrial small subunit, playing a crucial role in regulating mitochondrial protein translation and maintaining myocardial homeostasis. The MRPS5 V336Y mutation leads to mitochondrial translation errors, reducing the fidelity of synthesized proteins (78). MRPS5 deficiency disrupts mitochondrial ultrastructure, impairs ATP production, and suppresses the expression of Krüppel-like factor 15 (KLF15) via the c-Myc-mediated signaling pathway, leading to metabolic dysregulation, myocardial hypertrophy, and HF (79) (Supplementary Table S1).
Ribosomal protein L3-like (RPL3l) is a muscle-specific ribosomal protein that plays a vital role in cardiac development and function. Genetic studies have shown that RPL3l variants are strongly associated with pediatric and neonatal DCM, primarily through an autosomal recessive inheritance pattern (homozygous or compound heterozygous mutations), and can lead to acute HF (80–82). Notably, RPL3l-related HF is the only known human disease linked to a tissue-specific ribosome (83). Additionally, predicted loss-of-function (pLOF) variants in RPL3l are associated with an increased risk of atrial fibrillation and cardiomyopathy, highlighting its potential role in cardiac rhythm regulation and myocardial remodeling (77).
Further research has revealed that RPL3l is regulated by myosin light chain 4 (MYL4) and succinate dehydrogenase complex flavoprotein subunit A (SDHA) and is significantly associated with immune cell infiltration, indicating that it may influence DCM progression through inflammatory mechanisms (84). RPL3l deficiency can induce compensatory upregulation of ribosomal protein L3 (RPL3), enhancing mitochondria-ribosome interactions, thereby modulating cardiac mitochondrial function and promoting ATP production (85). RPL3l also plays a crucial role in translation elongation. Its deficiency leads to increased ribosome collisions, inhibiting the synthesis of myocardial contraction-related proteins and ultimately impairing cardiac contractile function (86). These findings suggest that the pathological processes of cardiomyopathy are influenced by RPL3l through multiple mechanisms, including inflammatory regulation, mitochondria-ribosome interactions, and translational control, providing new insights into the pathogenesis of DCM and potential therapeutic strategies.
5 Mitochondria-LD interactions: cardiac lipid metabolism regulation
5.1 Major forms of mitochondria-LD interactions
Meeting the high energy demand of the heart depends on fatty acid oxidation (FAO), the primary source of ATP production. As intracellular energy storage organelles, LDs are responsible for storing and regulating neutral lipid metabolism. In recent years, the mitochondria-LD interaction has been recognized as a crucial regulator of cardiac lipid metabolism. This interaction mainly manifests in two forms: peridroplet mitochondria and LD-anchored mitochondria (87, 88). Peridroplet mitochondria are mitochondria that are somewhat separated from the LD but still maintain a close relationship, as observed in brown adipocytes, aiding in the efficient use of fatty acids (FAs). LD-anchored mitochondria are mitochondria that are highly attached to LDs and directly participate in lipid metabolism and energy supply regulation.
This interaction process is mediated by several proteins, including Plin5, mitochondria-associated GTPase 2 (MIGA2), MFN2, and tumor susceptibility gene 101 (TSG101) (89) (Supplementary Figure S1). For example, Plin5 facilitates LD expansion and FA transfer to the surface of LDs. Plin5 also localizes to mitochondria, and its overexpression enhances the association between LDs and mitochondria (90, 91). MIGA2 serves as a molecular bridge between mitochondria, the ER, and LD biogenesis (92). Interacting with Perilipin 1 (Plin1), MFN2 enhances the contact between mitochondria and LDs, promoting FA transfer and β-oxidation (93). TSG101, together with vacuolar protein sorting 13D (VPS13D), participates in the endosomal sorting complex required for transport (ESCRT) mechanism, facilitating FA transport from LDs to mitochondria and enhancing β-oxidation efficiency (94).
Additionally, AMP-activated protein kinase (AMPK), acting as an energy sensor in cells, regulates mitochondria-LD interactions under fasting conditions, promoting lipid breakdown and oxidative metabolism (95). These coordinated mechanisms ensure dynamic organelle interactions between mitochondria and LDs and adaptation to different metabolic demands.
5.2 Mitochondria-LD crosstalk dysregulation in HF
In HF, abnormal mitochondria-LD interactions may lead to myocardial lipotoxicity, oxidative stress imbalance, and energy metabolism disorders. Plin5 acts as a surface protein on LDs, bridging the interaction between LDs and mitochondria. Plin5 inhibits lipolysis, reducing the release of free FAs (FFAs) and preventing excessive oxidative phosphorylation of FAs in mitochondria, which otherwise contributes to ROS accumulation, thus maintaining myocardial energy homeostasis (96). Plin5 overexpression can enhance physical contact between LDs and mitochondria, reduce mitochondrial fission, and lower the rate of FA oxidation, which alleviates lipotoxic damage and decreases HF progression (97). In contrast, Plin5 deficiency accelerates lipolysis, exposing mitochondria to excessive FA load; induces oxidative stress; and promotes myocardial hypertrophy, ultimately exacerbating HF (98). Additionally, Plin5 regulates the Pirin (PIR)/nuclear factor kappa B (NF-κB) axis to inhibit lipotoxicity and ferroptosis, providing further evidence of its protective role in diabetic cardiomyopathy and HF (99). Under stress conditions, PKA-mediated Plin5 phosphorylation promotes lipolysis, suggesting that Plin5 may play a bidirectional role in energy metabolism (100) (Supplementary Table S1).
However, under physiological conditions, AMPK, a central regulator of myocardial energy metabolism, activates peroxisome proliferator-activated receptor-alpha (PPAR-α) and its downstream FA oxidation-related genes, promoting FA mobilization and enhancing mitochondrial FAO capacity, thereby maintaining myocardial ATP production (101). However, during HF, reduced AMPK activity leads to decreased expression of PPAR-α and its downstream genes, limiting the heart's ability to use FA, further exacerbating energy supply deficiencies, ultimately leading to abnormal LD accumulation and lipotoxic damage, accelerating HF progression (102).
6 Mitochondria-nucleus interactions: metabolic and gene expression regulation
6.1 Major forms of mitochondria-nucleus interactions
Mitochondria-nucleus interactions play a pivotal role in regulating cellular functions, primarily through anterograde regulation and retrograde signaling, two coordinated processes that together ensure the maintenance of energy metabolism, stress responses, and mitochondrial biogenesis. Anterograde regulation refers to nuclear control over mitochondrial function and biogenesis via transcription factor activation. In response to stimuli such as cold exposure or exercise, the nucleus activates key transcription factors, including nuclear respiratory factor 1 (NRF1), nuclear factor erythroid 2-related factor 2 (NRF2), and peroxisome proliferator-activated receptors (PPARs), to regulate mitochondrial gene expression and metabolic pathways (Supplementary Figure S1). Among the actions performed by these factors, NRF1 activates mitochondrial transcription factor A (TFAM), promoting mitochondrial biogenesis (103); NRF2 regulates antioxidant defense pathways, protecting cells from oxidative stress (104); and PPARs enhance the expression of enzymes involved in mitochondrial FA oxidation, supporting ATP production and maintaining cardiac energy homeostasis (105). Additionally, the estrogen-related receptor (ERR) family (ERR-α, ERR-β, and ERR-γ) works in concert with peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) to regulate a broad set of mitochondrial genes, enhancing mitochondrial adaptability and function (106) (Supplementary Figure S1). As a transcriptional coactivator, PGC-1α is activated by AMPK under increased energy demand (e.g., during exercise) to promote mitochondrial biogenesis and energy metabolism (107).
Retrograde signaling refers to the transmission of signals originating from mitochondria back to the nucleus, which regulates metabolic reprogramming and stress response mechanisms to prevent mitochondrial dysfunction (108). Studies have shown that mitochondria can accumulate around the nucleus to support high nuclear energy demands and accelerate retrograde signal transmission, thereby modulating mitochondrial biogenesis and autophagy (109). Under hypoxic or mitochondrial stress conditions, mitochondria cluster in perinuclear regions, enhancing ROS signaling, which affects hypoxia adaptation and cell survival (110). The translocator protein (TSPO) may act as a key scaffold protein mediating mitochondria-nuclear envelope interactions, thereby regulating cholesterol transport and nuclear transcriptional activity (111, 112).
6.2 Mitochondria-nucleus crosstalk dysregulation in HF
NRF1 is a key regulator of mitochondrial biogenesis, playing a crucial role in maintaining protein homeostasis and redox balance. It is particularly involved in neonatal heart regeneration and adult cardioprotection (113). Studies have shown that hypermethylation of NRF1-binding sites during HF suppresses the expression of downstream genes involved in oxidative metabolism, leading to metabolic reprogramming and acceleration of cardiac dysfunction (114). Lin28a has been found to activate the NRF1-TFAM axis, thereby improving mitochondrial function and reducing cardiomyocyte apoptosis, further underscoring the critical role of NRF1 in HF progression (115) Recent evidence also shows that NRF1 directly activates CFLAR transcription to inhibit death receptor-mediated apoptosis in cardiomyocytes under hypoxic conditions, adding to its cardioprotective repertoire (116) (Supplementary Table S1).
The Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway is a key regulatory axis in cellular defense against oxidative and electrophilic stress. Under normal conditions, Keap1 mediates the ubiquitination and degradation of Nrf2, maintaining its low basal levels (117). However, under oxidative stress or electrophilic accumulation, Keap1 undergoes conformational changes, preventing Nrf2 degradation and allowing its nuclear translocation to activate the expression of antioxidant genes (117). In both patients with HF and animal models, Nrf2 expression is generally downregulated, leading to impaired antioxidant defenses, maladaptive cardiac remodeling, and worsened cardiac function. Conversely, Nrf2 overexpression or pathway activation enhances the antioxidant capacity of cardiomyocytes, alleviates cardiac remodeling, and improves HF outcomes (118).
In HF, Nrf2 expression is regulated by multiple mechanisms, including transcriptional repression mediated by microRNAs (e.g., miR-27a, miR-28a, and miR-34a) (119, 120), direct inhibition by glycogen synthase kinase-3 (GSK-3) (118), and modulation of the Keap1-Nrf2 signaling axis by phosphoglycerate mutase family member 5 (PGAM5) (121). Additionally, cardiogenic extracellular vesicles (EVs) are enriched with Nrf2-targeting miRNAs that may act on central autonomic regulatory regions, such as the rostral ventrolateral medulla (RVLM), to enhance sympathetic nerve activity, increase cardiac workload, and further exacerbate HF progression (122).
PPARs comprise three subtypes, PPARα, PPARβ/δ, and PPARγ, which all play crucial roles in cardiac metabolic regulation. In HF, the downregulation of PPARα, which primarily regulates FAO and energy metabolism (123), impairs myocardial lipid metabolism and reduces ATP production (124). However, excessive PPARα activation may exacerbate cardiac lipotoxicity. Glycogen synthase kinase-3 alpha (GSK-3α) enhances the transcriptional activity of PPARα on lipid uptake and storage-related genes through phosphorylation at the Ser280 site, promoting myocardial lipid accumulation and diabetic cardiomyopathy (125). PPARβ/δ exerts cardioprotective effects by promoting mitochondrial biogenesis, enhancing oxidative metabolism, and upregulating antioxidant enzymes such as Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and manganese superoxide dismutase (Mn-SOD), thereby mitigating oxidative stress-induced damage (126–128). PPARβ/δ activation increases mitochondrial DNA copy number, facilitates FA and glucose oxidation, and improves cardiac function under pressure overload, delaying pathological cardiac remodeling (126). In contrast, PPARβ/δ deficiency results in mitochondrial dysfunction, impaired FAO, and maladaptive cardiac metabolic remodeling, ultimately leading to myocardial hypertrophy and cardiac dysfunction (127). PPARγ primarily regulates insulin sensitivity, lipid metabolism, and inflammatory responses, playing a dual role in myocardial remodeling and HF progression (128, 167). PPARγ activation alleviates oxidative stress and myocardial fibrosis by inhibiting the NF-κB axis and transforming growth factor-beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathways, thereby improving cardiac function (129, 130). However, excessive PPARγ activation can lead to myocardial lipid accumulation, increasing cardiac workload and potentially triggering DCM (131).
ERRα and ERRγ are key regulators of cardiomyocyte maturation, acting as transcriptional activators of metabolic and structural genes in the adult heart (106). Cardiac-specific overexpression of ERRγ induces cardiomyocyte hypertrophy, increased cell death, and fibrosis, ultimately leading to HF (132). In patients with chronic congestive HF, ischemic HF, and idiopathic end-stage HF, ERRα and its target genes are significantly downregulated.
A master regulator of mitochondrial biogenesis, PGC-1α is activated through phosphorylation by AMPK and deacetylation by sirtuin 1 (SIRT1), These modifications cooperatively enhance PGC-1α activity, thereby enhancing mitochondrial gene expression mediated by NRF1, NRF2, and ERRα. This PGC-1α–mediated pathway improves cardiac energy metabolism and reduces ROS levels, exerting cardioprotective effects (133). Gene therapy with adeno-associated virus (AAV)-mediated anti-miR-199a upregulates the PGC-1α/ERRα axis, restores mitochondrial function, and alleviates cardiac hypertrophy (134). Additionally, overexpression of C1q/tumor necrosis factor-related protein 5 (CTRP5) activates the AMPKα2 signaling pathway, leading to increased PGC-1α expression, reduced ischemia-reperfusion injury, and improved infarct-induced HF outcomes (135).
7 Therapeutic strategies targeting organelle crosstalk in HF
7.1 Targeting mitochondria-ER crosstalk for therapeutic intervention
Intervention strategies targeting MAMs dysfunction have emerged as a crucial research direction in HF treatment. For example, the Danqi Pill has been shown to regulate the coordination between unc-51-like autophagy activating kinase 1 (ULK1) and PGAM5, thereby enhancing FUNDC1-mediated mitophagy, potentially influencing mitochondria-ER interactions and preserving myocardial energy metabolism (136). Moxibustion therapy upregulates OPA1 expression while reducing DRP1 and FIS1 levels, thereby inhibiting excessive autophagy and suppressing doxorubicin (DOX)-induced FUNDC1 signaling, ultimately mitigating myocardial injury (137). Treatment with the antioxidant α-lipoic acid (α-LA) alleviates pressure overload-induced ventricular remodeling via a FUNDC1-dependent mechanism (138).
Selective serotonin reuptake inhibitors (SSRIs), such as fluvoxamine, exert cardioprotective effects by activating the Sig-1R and its downstream Akt-endothelial nitric oxide synthase (eNOS) signaling pathway, improving cardiac dysfunction induced by transverse aortic constriction and pressure overload (139). Mitochondrial division inhibitor ameliorates HF by preventing excessive mitochondrial fission and mitophagy (140). Fenofibrate protects the myocardium from hypertension-induced remodeling by maintaining the balance of MFN2, DRP1, and Parkin, thereby stabilizing mitochondria-ER contact sites (141).
Moreover, resveratrol has been shown to activate the SIRT1/MFN2 axis, improving DOX-induced mitochondrial dysfunction, reducing cardiomyocyte apoptosis, and stabilizing mitochondria-ER interactions, alleviating mitochondrial stress and energy metabolism disorders (142). Ferulic acid, astragaloside, and tyrosol mitigate cardiomyocyte apoptosis by inhibiting excessive activation of the PERK/eIF2α/activating transcription factor 4 (ATF4)/CHOP pathway, alleviating ERS-induced cardiac damage (143). Additionally, left ventricular assist device (LVAD) therapy reverses the imbalance of the Bcl-2/Bax ratio in patients with HF, supporting the pathological role of MAMs in HF progression (144) (Supplementary Table S1).
7.2 Therapeutic implications of mitochondria-lysosome crosstalk in autophagic regulation
Research has demonstrated that administration of factors targeting Rab7 regulation can ameliorate the pathological progression of HF. Administration of granulocyte colony-stimulating factor (G-CSF) can significantly reduce Rab7-associated autophagic activity, decreasing cardiomyocyte death and improving both cardiac function and survival rates (62). Administration of resveratrol exerts cardioprotective effects by activating the SIRT1/forkhead box O1 (FOXO1)/Rab7 axis, promoting autophagic flux, alleviating oxidative stress-induced damage, and improving cardiac function in diabetic cardiomyopathy models (145). Administration of ferulic acid provides significant cardioprotective effects in hypoxia/reoxygenation (H/R) injury models by inhibiting PTEN-induced kinase 1 (PINK1)/Parkin-dependent mitophagy, thereby reducing mitochondrial-lysosomal interactions, mitigating H/R-induced cardiomyocyte apoptosis, and preserving mitochondrial function (146) (Supplementary Table S1).
7.3 Restoring mitochondria-ribosome coordination to enhance cardiac protein homeostasis
Targeting MRPs and cardiac-specific ribosomal factors, such as RPL3l, may offer novel therapeutic strategies for HF. For example, administration of exogenous Klf15 has been shown to partially reverse MRPS5 deficiency-induced cardiac dysfunction, suggesting that modulation of the MRPS5-Klf15 axis may help correct myocardial metabolic abnormalities and delay HF progression (79). MYL4 and SDHA have been identified as upstream regulators of RPL3l, highlighting the potential of targeting the MYL4-SDHA-RPL3l axis as a new strategy for mitigating cardiac remodeling and treating HF (84) (Supplementary Table S1).
7.4 Modulating mitochondria-LD interactions to restore cardiac lipid metabolism
Therapeutic strategies targeting mitochondrial-LD interactions, with a focus on optimizing LD metabolism, reducing lipotoxicity, and mitigating oxidative stress, have emerged as novel approaches for HF intervention. Acetylcholine (ACh) enhances mitochondrial-LD interactions by upregulating Plin5, thereby promoting LD lipolysis and reducing cardiomyocyte apoptosis (147). Metformin, resveratrol, and exercise regulate Plin5 expression, optimize FA metabolism, decrease cardiac LD accumulation, and improve energy homeostasis (148). In addition, a randomized controlled trial in nondiabetic HFrEF patients demonstrated that metformin significantly increased total antioxidant capacity and attenuated left ventricular remodeling, supporting its potential cardioprotective role beyond glycemic control (149). Maintaining an optimal LD reservoir is a crucial strategy for preventing oxidative stress, as excessive lipolysis can trigger ROS release and exacerbate myocardial injury. N-acetylcysteine (NAC), a precursor of glutathione, reduces oxidative stress and improves cardiac function (96). Moreover, cardiac contractility modulation, a non-pharmacological intervention, can enhance myocardial energy metabolism via the AMPK-PPAR-α axis, reducing abnormal LD and glycogen accumulation while increasing ATP production. This effect is likely associated with AMPK-mediated promotion of mitochondrial-LD contacts and enhancement of FA oxidation capacity (102) (Supplementary Table S1).
7.5 Targeting mitochondria-nucleus communication for metabolic and gene regulation
Various pharmacological agents can ameliorate HF progression by modulating NRF1 and related pathways. For example, the Danqi Pill enhances glucose metabolism and mitochondrial function via the HIF-1α/PGC-1α pathway, improving myocardial energy supply and HF outcomes (150). Perindopril and carvedilol activate the PGC-1α/NRF1/TFAM axis, promoting mitochondrial biogenesis, enhancing antioxidant capacity, and increasing ATP production to improve cardiac function (151, 152).
Recent studies have extended these findings to HFpEF, a major HF subtype with distinct metabolic dysregulation. In mouse models, berberine improved cardiac function by restoring mitochondrial homeostasis and reducing apoptosis through AMPK/PGC-1α signaling, accompanied by NRF1 and TFAM upregulation (153). Similarly, hydrogen sulfide (H₂S) alleviated diastolic dysfunction by activating the PGC-1α/NRF1/TFAM axis and correcting mitochondrial abnormalities, whereas genetic CSE deletion aggravated these defects but could be rescued by NaHS or the PGC-1α activator ZLN005 (154).
Targeting the Keap1-Nrf2 pathway has also emerged as a crucial therapeutic strategy for HF. Tanshinone IIA sulfonate (TIIA) interacts hydrophobically with Keap1, facilitating its dissociation and degradation, thereby upregulating Nrf2 transcription and reducing H₂O₂-induced cardiomyocyte apoptosis (155), a meta-analysis of 14 RCTs confirmed its clinical efficacy as an adjunctive HF therapy (156). Puerarin activates the Nrf2/ROS pathway, downregulates Keap1 expression, and promotes Nrf2 nuclear translocation, ultimately attenuating myocardial fibrosis (157). Additionally, the Yiqi Huoxue Recipe improves mitochondrial membrane potential and reduces cardiomyocyte apoptosis through the Keap1/Nrf2/HIF-1α axis, mitigating myocardial injury in HF models (158).
As a precursor of flavin adenine dinucleotide (FAD), riboflavin activates the SCAD-DJ-1-Keap1-Nrf2 pathway, reduces oxidative stress, and enhances cardiac function (159). LingGui-Zhu-Gan Decoction (LGZGD) has been shown to attenuate oxidative damage and cardiomyocyte apoptosis via the Nrf2/Keap1/HO-1 signaling pathway (160). PPARα agonists, such as fenofibrate, have been shown in the ACCORD Lipid trial to reduce heart failure hospitalization or cardiovascular death in patients with type 2 diabetes (HR = 0.82, P = 0.048). A Korean nationwide cohort study further confirmed a lower risk of HF hospitalization with fenofibrate use (HR = 0.907) (161, 162). Statins such as atorvastatin exert cardioprotective effects by inhibiting the advanced glycation end-products-receptor for advanced glycation end-products-extracellular signal-regulated kinase 1/2 signaling pathway through PPARγ, thereby reducing myocardial fibrosis (130).
A multicenter, randomized, double-blind clinical trial demonstrated that Qili Qiangxin Capsules significantly reduced NT-proBNP levels, improved cardiac function, and slowed adverse cardiac remodeling in patients with chronic HF (163). Laboratory studies further revealed that Qili Qiangxin Capsules upregulate PPARγ, alleviating post-myocardial infarction cardiac remodeling, preserving cardiac function, and reducing apoptosis and fibrosis (164). Xin-shu-bao tablets also exert cardioprotective effects in HFrEF by regulating PPARγ/MFGE8-mediated lipid metabolism and attenuating ventricular remodeling (165).Together, these findings underscore the potential of multi-target traditional therapies to modulate mitochondrial–nuclear crosstalk and lipid homeostasis in subtype-specific HF management (Supplementary Table S1).
8 Concluding remarks
Current research has revealed the key role of organelle interactions, particularly involving mitochondria, in maintaining cellular homeostasis and contributing to the pathogenesis of heart failure (HF). However, several important questions remain unresolved. One major gap is the lack of systematic understanding of how the spatiotemporal characteristics of mitochondrial-organelle crosstalk evolve across different HF subtypes and disease stages. Notably, emerging clinical and experimental evidence suggests that mitochondrial dynamics, calcium signaling, and metabolic coupling via MAMs or other contact sites are not uniformly altered in HF but differ significantly between HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). For example, HFpEF is often associated with enhanced MAMs formation and increased mitochondrial calcium influx, while HFrEF typically exhibits MAMs disruption and mitochondrial calcium depletion—highlighting the need for subtype-specific mechanistic investigation (166).
Moreover, conflicting findings persist regarding the role of specific regulators such as MFN2 or FUNDC1 in different experimental models, reflecting variability in disease modeling strategies and technical approaches. To address these inconsistencies, future studies should prioritize the use of clinically relevant models and human myocardial samples to dynamically profile mitochondrial-organelle interactions throughout disease progression and therapeutic intervention. This will help clarify whether these interactions are causative, compensatory, or maladaptive at different HF stages.
Furthermore, research should aim to develop precision strategies targeting organelle interactions—for instance, enhancing specific tethering proteins or modulating inter-organelle calcium exchange—to restore myocardial metabolic homeostasis and prevent maladaptive remodeling. With the advancement of tools such as single-cell multi-omics, high-content imaging, and mitochondrial proximity labeling, it will become increasingly feasible to decode the organelle interactome with high spatiotemporal resolution.
In conclusion, achieving a deeper and more differentiated understanding of mitochondrial-organelle interactions across HF phenotypes will provide a mechanistic foundation for the development of targeted, personalized therapeutic approaches—offering new hope for improving prognosis and treatment response in this heterogeneous disease.
Author contributions
HC: Project administration, Writing – original draft, Funding acquisition, Conceptualization, Writing – review & editing. PH: Writing – review & editing, Visualization, Writing – original draft. WL: Writing – review & editing. HW: Writing – review & editing. ZW: Funding acquisition, Project administration, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by the National Natural Fund (No. 82205082), the Henan Provincial Science and Technology Research and Development Joint Fund Project (No. 232301420066), and the Key Scientific Research Project for Higher Education Institutions of Henan Province (Grant No. 24A360001).
Acknowledgments
We convey our great appreciation to our colleagues, who contributed their constructive work to this rapidly expanding field.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcvm.2025.1641023/full#supplementary-material
References
1. Savarese G, Becher PM, Lund LH, Seferovic P, Rosano GMC, Coats AJS. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. (2022) 17:3272–87. doi: 10.1093/cvr/cvac013
2. Tanai E, Frantz S. Pathophysiology of heart failure. Compr Physiol. (2015) 1:187–214. doi: 10.1002/cphy.c140055
3. Shi J, Jin Y, Lin S, Li X, Zhang D, Wu J, et al. Mitochondrial non-energetic function and embryonic cardiac development. Front Cell Dev Biol. (2024) 12:1475603. doi: 10.3389/fcell.2024.1475603
4. Zhou B, Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. (2018) 9:3716–26. doi: 10.1172/JCI120849
5. Pinton P. Mitochondria-associated membranes (MAMs) and pathologies. Cell Death Dis. (2018) 4:413. doi: 10.1038/s41419-018-0424-1
6. Islinger M, Godinho LF, Costello J, Schrader M. The different facets of organelle interplay—an overview of organelle interactions. Front Cell Dev Biol. (2015) 3:56. doi: 10.3389/fcell.2015.00056
7. Marín-García J, Pi Y, Goldenthal MJ. Mitochondrial-nuclear cross-talk in the aging and failing heart. Cardiovasc Drugs Ther. (2006) 6:477–91. doi: 10.1007/s10557-006-0584-6
8. Vance JE. Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem. (1990) 13:7248–56.
9. Çoku J, Booth DM, Skoda J, Pedrotty MC, Vogel J, Liu K, et al. Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance. EMBO J. (2022) 8:e108272. doi: 10.15252/embj.2021108272
10. Wu W, Lin C, Wu K, Jiang L, Wang X, Li W, et al. FUNDC1 Regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions. EMBO J. (2016) 13:1368–84. doi: 10.15252/embj.201593102
11. Bravo R, Vicencio JM, Parra V, Troncoso R, Munoz JP, Bui M, et al. Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J Cell Sci. (2011) 13:2143–52. doi: 10.1242/jcs.080762
12. Csordás G, Renken C, Várnai P, Walter L, Weaver D, Buttle KF, et al. Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol. (2006) 7:915–21. doi: 10.1083/jcb.200604016
13. Sood A, Jeyaraju DV, Prudent J, Caron A, Lemieux P, McBride HM, et al. A mitofusin-2-dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver. Proc Natl Acad Sci U S A. (2014) 45:16017–22. doi: 10.1073/pnas.1408061111
14. Poston CN, Krishnan SC, Bazemore-Walker CR. In-depth proteomic analysis of mammalian mitochondria-associated membranes (MAM). J Proteomics. (2013) 79:219–30. doi: 10.1016/j.jprot.2012.12.018
15. de Ridder I, Kerkhofs M, Lemos FO, Loncke J, Bultynck G, Parys JB. The ER-mitochondria interface, where Ca2+ and cell death meet. Cell Calcium. (2023) 112:102743. doi: 10.1016/j.ceca.2023.102743
16. Quest AFG, Gutierrez-Pajares JL, Torres VA. Caveolin-1: an ambiguous partner in cell signalling and cancer. J Cell Mol Med. (2008) 4:1130–50. doi: 10.1111/j.1582-4934.2008.00331.x
17. Gouriou Y, Gonnot F, Wehbi M, Brun C, Gomez L, Bidaux G. High-sensitivity calcium biosensor on the mitochondrial surface reveals that IP3R channels participate in the reticular Ca2+ leak towards mitochondria. PLoS One. (2023) 18:e0285670. doi: 10.1371/journal.pone.0285670
18. Li G, Li J, Shao R, Zhao J, Chen M. FUNDC1: a promising mitophagy regulator at the mitochondria-associated membrane for cardiovascular diseases. Front Cell Dev Biol. (2021) 9:788634. doi: 10.3389/fcell.2021.788634
19. Wu S, Lu Q, Wang Q, Ding Y, Ma Z, Mao X, et al. Binding of FUNDC1 with inositol 1,4,5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum (ER) membranes maintains mitochondrial dynamics and function in hearts in vivo. Circulation. (2017) 23:2248–66. doi: 10.1161/CIRCULATIONAHA.117.030235
20. Guo J, Ma T, Wang B, Xing B, Huang L, Li X, et al. Zn2+ protects H9C2 cardiomyocytes by alleviating MAMs-associated apoptosis and calcium signaling dysregulation. Cell Signal. (2025) 127:111629. doi: 10.1016/j.cellsig.2025.111629
21. Ma Y, Li D, Zhou X, Chen X, Hou C, Li Y, et al. METTL3-mediated M6a modification of FUNDC1/IP3R2 pathway facilitates cardiac hypertrophy in obesity hypertension. Life Sci. (2025) 377:123780. doi: 10.1016/j.lfs.2025.123780
22. Abdullah CS, Alam S, Aishwarya R, Miriyala S, Panchatcharam M, Bhuiyan MAN, et al. Cardiac dysfunction in the sigma 1 receptor knockout mouse associated with impaired mitochondrial dynamics and bioenergetics. J Am Heart Assoc. (2018) 20:e009775. doi: 10.1161/JAHA.118.009775
23. Wang J, Hu X, Jiang H. ER stress-induced apoptosis: a novel therapeutic target in heart failure. Int J Cardiol. (2014) 2:564–5. doi: 10.1016/j.ijcard.2014.08.118
24. Xu H, Yu W, Sun M, Bi Y, Wu NN, Zhou Y, et al. Syntaxin17 contributes to obesity cardiomyopathy through promoting mitochondrial Ca2+ overload in a parkin-MCUb-dependent manner. Metab Clin Exp. (2023) 143:155551. doi: 10.1016/j.metabol.2023.155551
25. Saneto RP, Perez FA. Mitochondria-associated membrane scaffolding with endoplasmic reticulum: a dynamic pathway of developmental disease. Front Mol Biosci. (2022) 9:908721. doi: 10.3389/fmolb.2022.908721
26. Wang Y, Zhang X, Wen Y, Li S, Lu X, Xu R, et al. Endoplasmic reticulum-mitochondria contacts: a potential therapy target for cardiovascular remodeling-associated diseases. Front Cell Dev Biol. (2021) 9:774989. doi: 10.3389/fcell.2021.774989
27. He P, Chang H, Qiu Y, Wang Z. Mitochondria associated membranes in dilated cardiomyopathy: connecting pathogenesis and cellular dysfunction. Front Cardiovasc Med. (2025) 12:1571998. doi: 10.3389/fcvm.2025.1571998
28. Kuwahara K, Nishikimi T, Nakao K. Transcriptional regulation of the fetal cardiac gene program. J Pharmacol Sci. (2012) 119:198–203. doi: 10.1254/jphs.12r04cp
29. Benaroya H. Mitochondria and MICOS—function and modeling. Rev Neurosci. (2024) 35:503–31. doi: 10.1515/revneuro-2024-0004
30. Zhang Z, Liu L, Wu S, Xing D. Drp1, mff, Fis1, and MiD51 are coordinated to mediate mitochondrial fission during UV irradiation-induced apoptosis. FASEB J Off Publ Fed Am Soc Exp Biol. (2016) 1:466–76. doi: 10.1096/fj.15-274258
31. Casellas-Díaz S, Larramona-Arcas R, Riqué-Pujol G, Tena-Morraja P, Müller-Sánchez C, Segarra-Mondejar M, et al. Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development. EMBO Rep. (2021) 9:e51954. doi: 10.15252/embr.202051954
32. Noone J, O’Gorman DJ, Kenny HC. OPA1 Regulation of mitochondrial dynamics in skeletal and cardiac muscle. Trends Endocrinol Metab TEM. (2022) 10:710–21. doi: 10.1016/j.tem.2022.07.003
33. Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere J-P, et al. PERK Is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ. (2012) 11:1880–91. doi: 10.1038/cdd.2012.74
34. Carreras-Sureda A, Jaña F, Urra H, Durand S, Mortenson DE, Sagredo A, et al. Non-canonical function of IRE1α determines mitochondria-associated endoplasmic reticulum composition to control calcium transfer and bioenergetics. Nat Cell Biol. (2019) 6:755–67. doi: 10.1038/s41556-019-0329-y
35. Lalier L, Mignard V, Joalland MP, Lanoé D, Cartron PF, Manon S, et al. TOM20-mediated Transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis. Cell Death Dis. (2021) 2:182. doi: 10.1038/s41419-021-03471-8
36. Hoppins S, Nunnari J. Cell biology. Mitochondrial dynamics and apoptosis–the ER connection. Science. (2012) 6098:1052–4. doi: 10.1126/science.1224709
37. Zhang Y, Yao J, Zhang M, Wang Y, Shi X. Mitochondria-associated endoplasmic reticulum membranes (MAMs): possible therapeutic targets in heart failure. Front Cardiovasc Med. (2023) 10:1083935. doi: 10.3389/fcvm.2023.1083935
38. Chen L, Gong Q, Stice JP, Knowlton AA. Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res. (2009) 1:91–9. doi: 10.1093/cvr/cvp181
39. Goh KY, Qu J, Hong H, Liu T, Dell’Italia LJ, Wu Y, et al. Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes. Cardiovasc Res. (2016) 1:79–89. doi: 10.1093/cvr/cvv230
40. Song M, Mihara K, Chen Y, Scorrano L, Dorn GW. Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab. (2015) 2:273–86. doi: 10.1016/j.cmet.2014.12.011
41. Qin Y, Li A, Liu B, Jiang W, Gao M, Tian X, et al. Mitochondrial fusion mediated by fusion promotion and fission inhibition directs adult mouse heart function toward a different direction. FASEB J Off Publ Fed Am Soc Exp Biol. (2020) 1:663–75. doi: 10.1096/fj.201901671R
42. de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. (2008) 7222:605–10. doi: 10.1038/nature07534
43. Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I, Shea O, et al. Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol. (2011) 6:1309–28. doi: 10.1128/MCB.00911-10
44. Ren J, Bi Y, Sowers JR, Hetz C, Zhang Y. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol. (2021) 7:499–521. Nature Publishing Group. doi: 10.1038/s41569-021-00511-w
45. Son SM, Byun J, Roh S-E, Kim SJ, Mook-Jung I. Reduced IRE1α mediates apoptotic cell death by disrupting calcium homeostasis via the InsP3 receptor. Cell Death Dis. (2014) 4:e1188. doi: 10.1038/cddis.2014.129
46. Parmar VM, Schröder M. Sensing endoplasmic reticulum stress. Adv Exp Med Biol. (2012) 738:153–68. doi: 10.1007/978-1-4614-1680-7_10
47. Chen QM, Tu VC. Apoptosis and heart failure. Am J Cardiovasc Drugs. (2002) 1:43–57. doi: 10.2165/00129784-200202010-00006
48. Williams RS. Apoptosis and heart failure. N Engl J Med. (1999) 10:759–60. doi: 10.1056/NEJM199909023411012
49. Koglin J, Granville DJ, Glysing-Jensen T, Mudgett JS, Carthy CM, McManus BM, et al. Attenuated acute cardiac rejection in NOS2 -/- recipients correlates with reduced apoptosis. Circulation. (1999) 6:836–42. doi: 10.1161/01.cir.99.6.836
50. Condorelli G, Morisco C, Stassi G, Notte A, Farina F, Sgaramella G, et al. Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation. (1999) 23:3071–8. doi: 10.1161/01.cir.99.23.3071
51. Dehay B, Bové J, Rodríguez-Muela N, Perier C, Recasens A, Boya P, et al. Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci Off J Soc Neurosci. (2010) 37:12535–44. doi: 10.1523/JNEUROSCI.1920-10.2010
52. Hughes AL, Gottschling DE. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature. (2012) 7428:261–5. doi: 10.1038/nature11654
53. Zhang M, Niu J, Xu M, Wei E, Liu P, Sheng G. Interplay between mitochondrial dysfunction and lysosomal storage: challenges in genetic metabolic muscle diseases with a focus on infantile onset pompe disease. Front Cardiovasc Med. (2024) 11:1367108. doi: 10.3389/fcvm.2024.1367108
54. Demers-Lamarche J, Guillebaud G, Tlili M, Todkar K, Bélanger N, Grondin M, et al. Loss of mitochondrial function impairs lysosomes. J Biol Chem. (2016) 19:10263–76. doi: 10.1074/jbc.M115.695825
55. Baixauli F, Acín-Pérez R, Villarroya-Beltrí C, Mazzeo C, Nuñez-Andrade N, Gabandé-Rodriguez E, et al. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab. (2015) 3:485–98. doi: 10.1016/j.cmet.2015.07.020
56. Wong YC, Holzbaur ELF. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci U S A. (2014) 42:E4439–4448. doi: 10.1073/pnas.1405752111
57. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. (2015) 7565:309–14. doi: 10.1038/nature14893
58. Sugiura A, McLelland G-L, Fon EA, McBride HM. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. (2014) 19:2142–56. doi: 10.15252/embj.201488104
59. Wong YC, Ysselstein D, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis. Nature. (2018) 7692:382–6. doi: 10.1038/nature25486
60. Aston D, Capel RA, Ford KL, Christian HC, Mirams GR, Rog-Zielinska EA, et al. High resolution structural evidence suggests the sarcoplasmic reticulum forms microdomains with acidic stores (lysosomes) in the heart. Sci Rep. (2017) 7:40620. doi: 10.1038/srep40620
61. Peng W, Wong YC, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1. Proc Natl Acad Sci U S A. (2020) 32:19266–75. doi: 10.1073/pnas.2003236117
62. Miyata S, Takemura G, Kawase Y, Li Y, Okada H, Maruyama R, et al. Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor. Am J Pathol. (2006) 2:386–97. doi: 10.2353/ajpath.2006.050137
63. Ottensmeyer J, Esch A, Baeta H, Sieger S, Gupta Y, Rathmann MF, et al. Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic. Curr Biol CB. (2024) 18:4170–4183.e9. doi: 10.1016/j.cub.2024.07.088
64. Muhammad E, Levitas A, Singh SR, Braiman A, Ofir R, Etzion S, et al. PLEKHM2 Mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction. Hum Mol Genet. (2015) 25:7227–40. doi: 10.1093/hmg/ddv423
65. Zhao T, Huang X, Han L, Wang X, Cheng H, Zhao Y, et al. Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem. (2012) 28:23615–25. doi: 10.1074/jbc.M112.379164
66. Evans S, Ma X, Wang X, Chen Y, Zhao C, Weinheimer CJ, et al. Targeting the autophagy-lysosome pathway in a pathophysiologically relevant murine model of reversible heart failure. JACC Basic Transl Sci. (2022) 12:1214–28. doi: 10.1016/j.jacbts.2022.06.003
67. Yu W, Sun S, Xu H, Li C, Ren J, Zhang Y. TBC1D15/RAB7-regulated mitochondria-lysosome interaction confers cardioprotection against acute myocardial infarction-induced cardiac injury. Theranostics. (2020) 24:11244–63. doi: 10.7150/thno.46883
68. Sun S, Yu W, Xu H, Li C, Zou R, Wu NN, et al. TBC1D15-Drp1 interaction-mediated mitochondrial homeostasis confers cardioprotection against myocardial ischemia/reperfusion injury. Metab Clin Exp. (2022) 134:155239. doi: 10.1016/j.metabol.2022.155239
69. Sui Z, Wang M-M, Xing Y, Qi J, Wang W. Targeting MCOLN1/TRPML1 channels to protect against ischemia-reperfusion injury by restoring the inhibited autophagic flux in cardiomyocytes. Autophagy. (2022) 12:3053–5. doi: 10.1080/15548627.2022.2072657
70. Xing Y, Sui Z, Liu Y, Wang M, Wei X, Lu Q, et al. Blunting TRPML1 channels protects myocardial ischemia/reperfusion injury by restoring impaired cardiomyocyte autophagy. Basic Res Cardiol. (2022) 1:20. doi: 10.1007/s00395-022-00930-x
71. Gustafsson CM, Falkenberg M, Larsson N-G. Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem. (2016) 85:133–60. doi: 10.1146/annurev-biochem-060815-014402
72. Cheong A, Lingutla R, Mager J. Expression analysis of mammalian mitochondrial ribosomal protein genes. Gene Expr Patterns GEP. (2020) 38:119147. doi: 10.1016/j.gep.2020.119147
73. Antolínez-Fernández Á, Esteban-Ramos P, Fernández-Moreno MÁ, Clemente P. Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis. Front Cell Dev Biol. (2024) 12:1410245. doi: 10.3389/fcell.2024.1410245
74. Wang F, Zhang D, Zhang D, Li P, Gao Y. Mitochondrial protein translation: emerging roles and clinical significance in disease. Front Cell Dev Biol. (2021) 9:675465. doi: 10.3389/fcell.2021.675465
75. Lanfear DE, Yang JJ, Mishra S, Sabbah HN. Genome-wide approach to identify novel candidate genes for beta blocker response in heart failure using an experimental model. Discov Med. (2011) 59:359–66.
76. Xue S, Barna M. Specialized ribosomes: a new frontier in gene regulation and organismal biology. Nat Rev Mol Cell Biol. (2012) 6:355–69. doi: 10.1038/nrm3359
77. Vad OB, Monfort LM, Paludan-Müller C, Kahnert K, Diederichsen SZ, Andreasen L, et al. Rare and common genetic variation underlying atrial fibrillation risk. JAMA Cardiol. (2024) 8:732–40. doi: 10.1001/jamacardio.2024.1528
78. Akbergenov R, Duscha S, Fritz A, Juskeviciene R, Oishi N, Schmitt K, et al. Mutant MRPS5 affects mitoribosomal accuracy and confers stress-related behavioral alterations. EMBO Rep. (2018) 11:e46193. doi: 10.15252/embr.201846193
79. Gao F, Liang T, Lu YW, Fu X, Dong X, Pu L, et al. A defect in mitochondrial protein translation influences mitonuclear communication in the heart. Nat Commun. (2023) 14:1595. doi: 10.1038/s41467-023-37291-5
80. Al-Hassnan ZN, Almesned A, Tulbah S, Alakhfash A, Alhadeq F, Alruwaili N, et al. Categorized genetic analysis in childhood-onset cardiomyopathy. Circ Genomic Precis Med. (2020) 5:504–14. doi: 10.1161/CIRCGEN.120.002969
81. Das BB, Gajula V, Arya S, Taylor MB. Compound heterozygous missense variants in RPL3l genes associated with severe forms of dilated cardiomyopathy: a case report and literature review. Child Basel Switz. (2022) 10:1495. doi: 10.3390/children9101495
82. Nannapaneni H, Ghaleb S, Arya S, Gajula V, Taylor MB, Das BB. Further evidence of autosomal recessive inheritance of RPL3l pathogenic variants with rapidly progressive neonatal dilated cardiomyopathy. J Cardiovasc Dev Dis. (2022) 3:65. doi: 10.3390/jcdd9030065
83. Murphy MR, Ganapathi M, Lee TM, Fisher JM, Patel MV, Jayakar P, et al. Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy. bioRxiv [Preprint]. (2025). 2025.01.02.630345. doi: 10.1101/2025.01.02.630345
84. Bajpai AK, Gu Q, Orgil B-O, Alberson NR, Towbin JA, Martinez HR, et al. Exploring the regulation and function of Rpl3l in the development of early-onset dilated cardiomyopathy and congestive heart failure using systems genetics approach. Genes. (2023) 1:53. doi: 10.3390/genes15010053
85. Milenkovic I, Santos Vieira HG, Lucas MC, Ruiz-Orera J, Patone G, Kesteven S, et al. Dynamic interplay between RPL3- and RPL3l-containing ribosomes modulates mitochondrial activity in the mammalian heart. Nucleic Acids Res. (2023) 11:5301–24. doi: 10.1093/nar/gkad121
86. Shiraishi C, Matsumoto A, Ichihara K, Yamamoto T, Yokoyama T, Mizoo T, et al. RPL3l-containing Ribosomes determine translation elongation dynamics required for cardiac function. Nat Commun. (2023) 14:2131. doi: 10.1038/s41467-023-37838-6
87. Benador IY, Veliova M, Mahdaviani K, Petcherski A, Wikstrom JD, Assali E, et al. Mitochondria bound to lipid droplets have unique bioenergetics, composition, and dynamics that support lipid droplet expansion. Cell Metab. (2018) 4:869–885.e6. doi: 10.1016/j.cmet.2018.03.003
88. Cui L, Liu P. Two types of contact between lipid droplets and mitochondria. Front Cell Dev Biol. (2020) 8:618322. doi: 10.3389/fcell.2020.618322
89. Liao P-C, Yang EJ, Borgman T, Boldogh IR, Sing CN, Swayne TC, et al. Touch and go: membrane contact sites between lipid droplets and other organelles. Front Cell Dev Biol. (2022) 10:852021. doi: 10.3389/fcell.2022.852021
90. Wang H, Sreenivasan U, Hu H, Saladino A, Polster BM, Lund LM, et al. Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. J Lipid Res. (2011) 12:2159–68. doi: 10.1194/jlr.M017939
91. Pollak NM, Jaeger D, Kolleritsch S, Zimmermann R, Zechner R, Lass A, et al. The interplay of protein kinase a and perilipin 5 regulates cardiac lipolysis. J Biol Chem. (2015) 3:1295–306. doi: 10.1074/jbc.M114.604744
92. Freyre CAC, Rauher PC, Ejsing CS, Klemm RW. MIGA2 Links mitochondria, the ER, and lipid droplets and promotes de novo lipogenesis in adipocytes. Mol Cell. (2019) 5:811–825.e14. doi: 10.1016/j.molcel.2019.09.011
93. Boutant M, Kulkarni SS, Joffraud M, Ratajczak J, Valera-Alberni M, Combe R, et al. Mfn2 is critical for brown adipose tissue thermogenic function. EMBO J. (2017) 11:1543–58. doi: 10.15252/embj.201694914
94. Wang J, Fang N, Xiong J, Du Y, Cao Y, Ji W-K. An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions. Nat Commun. (2021) 1:1252. doi: 10.1038/s41467-021-21525-5
95. Herms A, Bosch M, Reddy BJN, Schieber NL, Fajardo A, Rupérez C, et al. AMPK Activation promotes lipid droplet dispersion on detyrosinated microtubules to increase mitochondrial fatty acid oxidation. Nat Commun. (2015) 6:7176. doi: 10.1038/ncomms8176
96. Kuramoto K, Okamura T, Yamaguchi T, Nakamura TY, Wakabayashi S, Morinaga H, et al. Perilipin 5, a lipid droplet-binding protein, protects heart from oxidative burden by sequestering fatty acid from excessive oxidation. J Biol Chem. (2012) 28:23852–63. doi: 10.1074/jbc.M111.328708
97. Kolleritsch S, Kien B, Schoiswohl G, Diwoky C, Schreiber R, Heier C, et al. Low cardiac lipolysis reduces mitochondrial fission and prevents lipotoxic heart dysfunction in perilipin 5 mutant mice. Cardiovasc Res. (2020) 2:339–52. doi: 10.1093/cvr/cvz119
98. Wang C, Yuan Y, Wu J, Zhao Y, Gao X, Chen Y, et al. Plin5 deficiency exacerbates pressure overload-induced cardiac hypertrophy and heart failure by enhancing myocardial fatty acid oxidation and oxidative stress. Free Radic Biol Med. (2019) 141:372–82. doi: 10.1016/j.freeradbiomed.2019.07.006
99. Shen X, Zhang J, Zhou Z, Yu R. PLIN5 Suppresses lipotoxicity and ferroptosis in cardiomyocyte via modulating PIR/NF-κB axis. Int Heart J. (2024) 3:537–47. doi: 10.1536/ihj.24-002
100. Zhang X, Xu W, Xu R, Wang Z, Zhang X, Wang P, et al. Plin5 bidirectionally regulates lipid metabolism in oxidative tissues. Oxid Med Cell Longev. (2022) 2022:4594956. doi: 10.1155/2022/4594956
101. Gélinas R, Mailleux F, Dontaine J, Bultot L, Demeulder B, Ginion A, et al. AMPK Activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. Nat Commun. (2018) 1:374. doi: 10.1038/s41467-017-02795-4
102. Zhang F, Liu L, Xie Y, Wang J, Chen X, Zheng S, et al. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway. Open Med. (2022) 1:365–74. doi: 10.1515/med-2022-0415
103. Popov L. Mitochondrial biogenesis: an update. J Cell Mol Med. (2020) 9:4892–9. doi: 10.1111/jcmm.15194
104. da Costa RM, Rodrigues D, Pereira CA, Silva JF, Alves JV, Lobato NS, et al. Nrf2 as a potential mediator of cardiovascular risk in metabolic diseases. Front Pharmacol. (2019) 10:382. doi: 10.3389/fphar.2019.00382
105. Kaimoto S, Hoshino A, Ariyoshi M, Okawa Y, Tateishi S, Ono K, et al. Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure. Am J Physiol Heart Circ Physiol. (2017) 2:H305–13. doi: 10.1152/ajpheart.00553.2016
106. Sakamoto T, Matsuura TR, Wan S, Ryba DM, Kim JU, Won KJ, et al. A critical role for estrogen-related receptor signaling in cardiac maturation. Circ Res. (2020) 12:1685–702. doi: 10.1161/CIRCRESAHA.119.316100
107. Jäger S, Handschin C, St.-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci U S A. (2007) 29:12017–22. doi: 10.1073/pnas.0705070104
108. Walker BR, Moraes CT. Nuclear-mitochondrial interactions. Biomolecules. (2022) 3:427. doi: 10.3390/biom12030427
109. Dzeja PP, Bortolon R, Perez-Terzic C, Holmuhamedov EL, Terzic A. Energetic communication between mitochondria and nucleus directed by catalyzed phosphotransfer. Proc Natl Acad Sci U S A. (2002) 15:10156–61. doi: 10.1073/pnas.152259999
110. Al-Mehdi A-B, Pastukh VM, Swiger BM, Reed DJ, Patel MR, Bardwell GC, et al. Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci Signal. (2012) 231:ra47. doi: 10.1126/scisignal.2002712
111. Desai R, East DA, Hardy L, Faccenda D, Rigon M, Crosby J, et al. Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response. Sci Adv. (2020) 51:eabc9955. doi: 10.1126/sciadv.abc9955
112. Fan J, Papadopoulos V. Mitochondrial TSPO deficiency triggers retrograde signaling in MA-10 mouse tumor leydig cells. Int J Mol Sci. (2020) 1:252. doi: 10.3390/ijms22010252
113. Cui M, Atmanli A, Morales MG, Tan W, Chen K, Xiao X, et al. Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance. Nat Commun. (2021) 1:5270. Nature Publishing Group. doi: 10.1038/s41467-021-25653-w
114. Pepin ME, Drakos S, Ha C-M, Tristani-Firouzi M, Selzman CH, Fang JC, et al. DNA Methylation reprograms cardiac metabolic gene expression in end-stage human heart failure. Am J Physiol Heart Circ Physiol. (2019) 4:H674–84. doi: 10.1152/ajpheart.00016.2019
115. Zhang M, Niu X, Hu J, Yuan Y, Sun S, Wang J, et al. Lin28a protects against hypoxia/reoxygenation induced cardiomyocytes apoptosis by alleviating mitochondrial dysfunction under high glucose/high fat conditions. PLoS One. (2014) 10:e110580. doi: 10.1371/journal.pone.0110580
116. Li H, Ma Y, Li J, Hou S, Song H, Zhu Y, et al. Nuclear respiratory factor-1 promotes CFLAR transcription in H9C2 cardiomyocytes, protecting them against hypoxia-induced apoptosis. Mol Biol Rep. (2025) 52:558. doi: 10.1007/s11033-025-10636-7
117. Baird L, Yamamoto M. The molecular mechanisms regulating the KEAP1-NRF2 pathway. Mol Cell Biol. (2020) 13:e00099–20. doi: 10.1128/MCB.00099-20
118. Konishi M, Baumgarten A, Ishida J, Saitoh M, Anker SD, Springer J. Protein levels in Keap1-Nrf2 system in human failing heart. Int J Cardiol. (2016) 225:62–4. doi: 10.1016/j.ijcard.2016.09.128
119. Ye H, Xu G, Zhang D, Wang R. The protective effects of the miR-129-5p/keap-1/Nrf2 axis on ang II-induced cardiomyocyte hypertrophy. Ann Transl Med. (2021) 2:154. doi: 10.21037/atm-20-8079
120. Vashi R, Patel BM. NRF2 In cardiovascular diseases: a ray of hope!. J Cardiovasc Transl Res. (2021) 3:573–86. doi: 10.1007/s12265-020-10083-8
121. Li S, Wen P, Zhang D, Li D, Gao Q, Liu H, et al. PGAM5 Expression levels in heart failure and protection ROS-induced oxidative stress and ferroptosis by Keap1/Nrf2. Clin Exp Hypertens. (2023) 1:2162537. doi: 10.1080/10641963.2022.2162537
122. Tian C, Gao L, Rudebush TL, Yu L, Zucker IH. Extracellular vesicles regulate sympatho-excitation by Nrf2 in heart failure. Circ Res. (2022) 8:687–700. doi: 10.1161/CIRCRESAHA.122.320916
123. Han L, Shen W-J, Bittner S, Kraemer FB, Azhar S. PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part I: PPAR-α. Future Cardiol. (2017) 3:259–78. doi: 10.2217/fca-2016-0059
124. Schiffrin EL. Peroxisome proliferator-activated receptors and cardiovascular remodeling. Am J Physiol Heart Circ Physiol. (2005) 3:H1037–43. doi: 10.1152/ajpheart.00677.2004
125. Nakamura M, Liu T, Husain S, Zhai P, Warren JS, Hsu C-P, et al. Glycogen synthase kinase-3α promotes fatty acid uptake and lipotoxic cardiomyopathy. Cell Metab. (2019) 5:1119–1134.e12. doi: 10.1016/j.cmet.2019.01.005
126. Liu J, Wang P, Luo J, Huang Y, He L, Yang H, et al. PPARβ/δ activation in adult hearts facilitates mitochondrial function and cardiac performance under pressure-overload condition. Hypertension. (2011) 2:223–30. doi: 10.1161/HYPERTENSIONAHA.110.164590
127. Wang P, Liu J, Li Y, Wu S, Luo J, Yang H, et al. PPARδ is an essential transcriptional regulator for mitochondrial protection and biogenesis in adult heart. Circ Res. (2010) 5:911–9. doi: 10.1161/CIRCRESAHA.109.206185
128. Rostami A, Palomer X, Pizarro-Delgado J, Barroso E, Valenzuela-Alcaraz B, Crispi F, et al. PPARβ/δ prevents inflammation and fibrosis during diabetic cardiomyopathy. Pharmacol Res. (2024) 210:107515. doi: 10.1016/j.phrs.2024.107515
129. He Z, Zhang X, Chen C, Wen Z, Hoopes SL, Zeldin DC, et al. Cardiomyocyte-specific expression of CYP2J2 prevents development of cardiac remodelling induced by angiotensin II. Cardiovasc Res. (2015) 3:304–17. doi: 10.1093/cvr/cvv018
130. Chen M, Li H, Wang G, Shen X, Zhao S, Su W. Atorvastatin prevents advanced glycation end products (AGEs)-induced cardiac fibrosis via activating peroxisome proliferator-activated receptor gamma (PPAR-γ). Metabolism. (2016) 4:441–53. doi: 10.1016/j.metabol.2015.11.007
131. Son N-H, Park T-S, Yamashita H, Yokoyama M, Huggins LA, Okajima K, et al. Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice. J Clin Invest. (2007) 10:2791–801. doi: 10.1172/JCI30335
132. Lasheras J, Pardo R, Velilla M, Poncelas M, Salvatella N, Simó R, et al. Cardiac-specific overexpression of ERRγ in mice induces severe heart dysfunction and early lethality. Int J Mol Sci. (2021) 15:8047. doi: 10.3390/ijms22158047
133. Waldman M, Cohen K, Yadin D, Nudelman V, Gorfil D, Laniado-Schwartzman M, et al. Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving “SIRT1 and PGC-1α.”. Cardiovasc Diabetol. (2018) 1:111. doi: 10.1186/s12933-018-0754-4
134. Yan H, Wang H, Zhu X, Huang J, Li Y, Zhou K, et al. Adeno-associated virus-mediated delivery of anti-miR-199a tough decoys attenuates cardiac hypertrophy by targeting PGC-1alpha. Mol Ther Nucleic Acids. (2020) 23:406–17. doi: 10.1016/j.omtn.2020.11.007
135. Peng M, Liu Y, Zhang X, Xu Y, Zhao Y, Yang H. CTRP5-overexpression Attenuated ischemia-reperfusion associated heart injuries and improved infarction induced heart failure. Front Pharmacol. (2020) 11:603322. doi: 10.3389/fphar.2020.603322
136. Wang X, Jiang Y, Zhang Y, Sun Q, Ling G, Jiang J, et al. The roles of the mitophagy inducer danqi pill in heart failure: a new therapeutic target to preserve energy metabolism. Phytomedicine. (2022) 99:154009. doi: 10.1016/j.phymed.2022.154009
137. Xia R, Wang W, Gao B, Ma Q, Wang J, Dai X, et al. Moxibustion alleviates chronic heart failure by regulating mitochondrial dynamics and inhibiting autophagy. Exp Ther Med. (2022) 5:359. doi: 10.3892/etm.2022.11286
138. Li W, Yin L, Sun X, Wu J, Dong Z, Hu K, et al. Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling. Cell Death Dis. (2020) 7:599. doi: 10.1038/s41419-020-02805-2
139. Bhuiyan MS, Tagashira H, Fukunaga K. Crucial interactions between selective serotonin uptake inhibitors and sigma-1 receptor in heart failure. J Pharmacol Sci. (2013) 3:177–84. doi: 10.1254/jphs.12r13cp
140. Givvimani S, Munjal C, Tyagi N, Sen U, Metreveli N, Tyagi SC. Mitochondrial division/mitophagy inhibitor (mdivi) ameliorates pressure overload induced heart failure. PLoS One. (2012) 3:e32388. doi: 10.1371/journal.pone.0032388
141. Castiglioni L, Gelosa P, Muluhie M, Mercuriali B, Rzemieniec J, Gotti M, et al. Fenofibrate reduces cardiac remodeling by mitochondrial dynamics preservation in a renovascular model of cardiac hypertrophy. Eur J Pharmacol. (2024) 978:176767. doi: 10.1016/j.ejphar.2024.176767
142. Zhang Q, Zhang Y, Xie B, Liu D, Wang Y, Zhou Z, et al. Resveratrol activation of SIRT1/MFN2 can improve mitochondria function, alleviating doxorubicin-induced myocardial injury. Cancer Innov. (2023) 4:253–64. doi: 10.1002/cai2.64
143. Monceaux K, Gressette M, Karoui A, Pires Da Silva J, Piquereau J, Ventura-Clapier R, et al. Ferulic acid, pterostilbene, and tyrosol protect the heart from ER-stress-induced injury by activating SIRT1-dependent deacetylation of eIF2α. Int J Mol Sci. (2022) 12:6628. doi: 10.3390/ijms23126628
144. Bartling B, Milting H, Schumann H, Darmer D, Arusoglu L, Koerner MM, et al. Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure. Circulation. (1999) 19 Suppl:II216–223. doi: 10.1161/01.cir.100.suppl_2.ii-216
145. Wang B, Yang Q, Sun Y, Xing Y, Wang Y, Lu X, et al. Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J Cell Mol Med. (2014) 8:1599–611. doi: 10.1111/jcmm.12312
146. Luo C, Zhang Y, Guo H, Han X, Ren J, Liu J. Ferulic acid attenuates hypoxia/reoxygenation injury by suppressing mitophagy through the PINK1/parkin signaling pathway in H9c2 cells. Front Pharmacol. (2020) 11:103. doi: 10.3389/fphar.2020.00103
147. Wu Q, Zhao M, He X, Xue R, Li D, Yu X, et al. Acetylcholine reduces palmitate-induced cardiomyocyte apoptosis by promoting lipid droplet lipolysis and perilipin 5-mediated lipid droplet-mitochondria interaction. Cell Cycle Georget Tex. (2021) 18:1890–906. doi: 10.1080/15384101.2021.1965734
148. Mehdi F, Keihan GS, Asadollah AS, Effat F. The effects of resveratrol, metformin, cold and strength training on the level of perilipin 5 in the heart, skeletal muscle and brown adipose tissues in mouse. Cell Biochem Biophys. (2018) 4:471–6. doi: 10.1007/s12013-018-0860-7
149. Kamel AM, Ismail B, Abdel Hafiz G, Sabry N, Farid S. Effect of metformin on oxidative stress and left ventricular geometry in nondiabetic heart failure patients: a randomized controlled trial. Metab Syndr Relat Disord. (2024) 22:49–58. doi: 10.1089/met.2023.0164
150. Zhang Q, Guo D, Wang Y, Wang X, Wang Q, Wu Y, et al. Danqi pill protects against heart failure post-acute myocardial infarction via HIF-1α/PGC-1α mediated glucose metabolism pathway. Front Pharmacol. (2020) 11:458. doi: 10.3389/fphar.2020.00458
151. Zhu Z, Li H, Chen W, Cui Y, Huang A, Qi X. Perindopril improves cardiac function by enhancing the expression of SIRT3 and PGC-1α in a rat model of isoproterenol-induced cardiomyopathy. Front Pharmacol. (2020) 11:94. doi: 10.3389/fphar.2020.00094
152. Yao K, Zhang WW, Yao L, Yang S, Nie W, Huang F. Carvedilol promotes mitochondrial biogenesis by regulating the PGC-1/TFAM pathway in human umbilical vein endothelial cells (HUVECs). Biochem Biophys Res Commun. (2016) 4:961–6. doi: 10.1016/j.bbrc.2016.01.089
153. Hu Y, Chen X, Zhao Q, Li G, Zhang H, Ma Z, et al. Berberine improves cardiac insufficiency through AMPK/PGC-1α signaling-mediated mitochondrial homeostasis and apoptosis in HFpEF mice. Int Immunopharmacol. (2025) 155:114613. doi: 10.1016/j.intimp.2025.114613
154. Huang S, Chen X, Pan J, Zhang H, Ke J, Gao L, et al. Hydrogen sulfide alleviates heart failure with preserved ejection fraction in mice by targeting mitochondrial abnormalities via PGC-1α. Nitric Oxide Biol Chem. (2023) 136–137:12–23. doi: 10.1016/j.niox.2023.05.002
155. Yan S-H, Zhao N-W, Geng Z-R, Shen J-Y, Liu F-M, Yan D, et al. Modulations of Keap1-Nrf2 signaling axis by TIIA ameliorated the oxidative stress-induced myocardial apoptosis. Free Radic Biol Med. (2018) 115:191–201. doi: 10.1016/j.freeradbiomed.2017.12.001
156. Shao H, Fang C, Huang Y, Ye Y, Tong R. Sodium tanshinone ⅡA sulfonate injection as adjunctive therapy for the treatment of heart failure: a systematic review and meta-analysis. Phytomedicine Int J Phytother Phytopharm. (2022) 95:153879. doi: 10.1016/j.phymed.2021.153879
157. Cai S-A, Hou N, Zhao G-J, Liu X-W, He Y-Y, Liu H-L, et al. Nrf2 is a key regulator on puerarin preventing cardiac fibrosis and upregulating metabolic enzymes UGT1A1 in rats. Front Pharmacol. (2018) 9:540. doi: 10.3389/fphar.2018.00540
158. Hu L, Xu Y, Wang Q, Liu M, Meng L, Yan D, et al. Yiqi huoxue recipe inhibits cardiomyocyte apoptosis caused by heart failure through Keap1/Nrf2/HIF-1α signaling pathway. Bioengineered. (2021) 1:969–78. doi: 10.1080/21655979.2021.1900634
159. Xu Q, Cao Y, Zhong X, Qin X, Feng J, Peng H, et al. Riboflavin protects against heart failure via SCAD-dependent DJ-1-Keap1-Nrf2 signalling pathway. Br J Pharmacol. (2023) 23:3024–44. doi: 10.1111/bph.16184
160. Wang X, Tang T, Zhai M, Ge R, Wang L, Huang J, et al. Ling-gui-zhu-gan decoction protects H9c2 cells against H2O2-induced oxidative injury via regulation of the Nrf2/Keap1/HO-1 signaling pathway. Evid Based Complement Altern Med Ecam. (2020) 2020:8860603. doi: 10.1155/2020/8860603
161. Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-González I, Briel M. Fibrates for primary prevention of cardiovascular disease events. Cochrane Database Syst Rev. (2016) 11:CD009753. doi: 10.1002/14651858.CD009753.pub2
162. Park J, Song H, Moon S, Kim Y, Cho S, Han K, et al. Cardiometabolic benefits of fenofibrate in heart failure related to obesity and diabetes. Cardiovasc Diabetol. (2024) 23:343. doi: 10.1186/s12933-024-02417-6
163. Li X, Zhang J, Huang J, Ma A, Yang J, Li W, et al. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the effects of qili qiangxin capsules in patients with chronic heart failure. J Am Coll Cardiol. (2013) 12:1065–72. doi: 10.1016/j.jacc.2013.05.035
164. Tao L, Shen S, Fu S, Fang H, Wang X, Das S, et al. Traditional Chinese medication qiliqiangxin attenuates cardiac remodeling after acute myocardial infarction in mice. Sci Rep. (2015) 5:8374. doi: 10.1038/srep08374
165. Zhang F, Li Z, Zhang Y, Yang J, Xiao H, Li X, et al. Xin-shu-bao tablets ameliorates ventricular remodeling against HFrEF via PPARγ/MFGE8 pathway based on MALDI-MSI and lipidomics. J Ethnopharmacol. (2025) 347:119741. doi: 10.1016/j.jep.2025.119741
166. Shou J, Huo Y. Changes of calcium cycling in HFrEF aoid HFpEF. Mechanobiol Med. (2023) 1:100001. doi: 10.1016/j.mbm.2023.100001
Keywords: mitochondria-organelle interaction, heart failure, calcium signaling, proteostasis, metabolic regulation, therapeutic target
Citation: Chang H, He P, Liu W, Wu H and Wang Z (2025) Unraveling mitochondrial crosstalk: a new frontier in heart failure pathogenesis. Front. Cardiovasc. Med. 12:1641023. doi: 10.3389/fcvm.2025.1641023
Received: 4 June 2025; Accepted: 2 July 2025;
Published: 15 July 2025.
Edited by:
Yang Yang, First Affiliated Hospital of Zhengzhou University, ChinaReviewed by:
Dating Sun, First Affiliated Hospital of Wenzhou Medical University, ChinaJianru Wang, First Affiliated Hospital of Henan University of Traditional Chinese Medicine, China
Copyright: © 2025 Chang, He, Liu, Wu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhentao Wang, MTM4MDM4MTc3OTZAMTM5LmNvbQ==
†These authors have contributed equally to this work