Editorial: Mitochondria in Metabolic Reprogramming and Immune Activation: The Key Gene and Therapeutic Target

Yongzheng Guo^*

• First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Mitochondria are now widely recognized as regulatory hubs that extend far beyond their canonical role in energy production. Acting at the crossroads of metabolic adaptation, redox homeostasis, innate immune signaling, and cell fate determination, mitochondria influence both physiological processes and pathological states1,2. Their dysfunction has been implicated in a broad spectrum of human diseases, including autoimmunity, cardiovascular disorders, chronic inflammation, and cancer3. Understanding how mitochondrial metabolic remodeling intersects with immune activation is therefore essential for uncovering key molecular drivers and therapeutic targets. This Research Topic was designed to highlight such advances and to foster new perspectives at the interface of mitochondrial biology, immunology, and translational medicine. This collection brings together five original and review articles, each offering novel mechanistic insights and translational opportunities. Despite spanning diverse biological contexts, from autoimmune disease and myocardial infarction to periodontitis and cancer, all converge on a unifying theme: mitochondria as orchestrators of immunometabolic crosstalk and potential targets for therapeutic intervention. Mitochondrial DNA and Autoimmune Diseases Mitochondrial DNA (mtDNA) functions not only as a biomarker of mitochondrial health but also as a potent damage-associated molecular pattern (DAMP). Liu et al. employed bidirectional Mendelian randomization and clinical validation to demonstrate a causal association between decreased mtDNA copy number in peripheral blood and heightened susceptibility to autoimmune diseases such as Crohn's disease, type 1 diabetes, and rheumatoid arthritis. These findings indicate that instability of the mitochondrial genome may directly contribute to immune dysregulation, highlighting mtDNA content as a potentially modifiable target for managing autoimmunity. Mitochondria at the Intersection of Aging, Cell Death, and Tumor Immunity Wang et al. provided a comprehensive review of mitochondrial roles in immunosenescence, regulated cell death, and tumor immune evasion. They emphasized how mitochondrial metabolic shifts, reactive oxygen species generation, and mitochondrial outer membrane permeabilization influence apoptotic signaling and immune cell activation. Their synthesis underscores the therapeutic potential of mitochondria-targeted strategies for enhancing anti-tumor immunity and delaying age-associated immune dysfunction. Vitamin A–Induced Metabolic Reprogramming in Periodontitis Cheng et al. investigated the role of vitamin A in modulating mitochondrial metabolism and macrophage polarization during chronic oral inflammation. They demonstrated that retinoids leads to metabolic rewiring of macrophages via the JAK–STAT pathway, and attenuation of periodontitis-associated inflammation. This study highlights nutrient– mitochondria–immune crosstalk as a novel axis of immunometabolic regulation, providing a promising direction for therapeutic modulation of inflammatory diseases. Mitochondrial Regulation of Post-Infarction Inflammation Hou et al. conducted a bioinformatics-driven analysis to identify mitochondria-related genes governing immune cell infiltration and inflammatory responses following myocardial infarction. Their findings revealed key regulatory nodes within mitochondrial metabolic pathways that influence immune recruitment and reparative remodeling of the ischemic myocardium. This integrative analysis bridges mitochondrial gene networks with immunopathology, underscoring the potential of mitochondria-focused strategies in cardiovascular disease. Therapeutic Targeting of Mitochondrial Protease ClpP in Cancer Kong et al. reviewed the structure–function relationship and therapeutic relevance of caseinolytic mitochondrial matrix peptidase proteolytic subunit (ClpP), a pivotal regulator of mitochondrial proteostasis. They summarized recent progress in the development of ClpP agonists that selectively disrupt mitochondrial homeostasis in cancer cells, leading to impaired oxidative phosphorylation and apoptosis. This work reinforces the emerging concept of mitochondria as druggable nodes for selective oncologic interventions4,5. Collectively, these contributions highlight mitochondria's multifaceted roles in shaping disease-specific immune responses and emphasize their potential as biomarkers and therapeutic targets. Future research should focus on delineating cell type–specific mitochondrial signaling networks, using multi-omics approaches to map immunometabolic pathways, and developing combinatorial strategies that balancing mitochondria for therapeutic gain. By bridging fundamental biology with translational insights, these studies collectively point toward a new generation of mitochondria-targeted diagnostics and interventions with broad relevance across immunological, metabolic, and cardiovascular disorders.