Yongzheng Guo

Mitochondrial dysfunction is a hallmark of aging and is closely linked to the progression of cardiovascular disease. Yeast mitochondrial escape 1-like (YME1L) is an adenosine triphosphate (ATP)-dependent i-AAA (intermembrane space AAA, AAA=ATPase associated with diverse cellular activities) protease embedded in the mitochondrial inner membrane that maintains mitochondrial homeostasis by regulating proteostasis, cristae architecture, and metabolic adaptation. Notably, YME1L influences mitochondrial fusion–fission dynamics, respiratory chain supercomplex organization, and oxidative phosphorylation efficiency through the regulated processing of optic atrophy protein 1 (OPA1). Accumulating evidence suggests that age-associated impairment of YME1L function contributes to mitochondrial fragmentation, energetic insufficiency, and reduced stress tolerance, particularly in long-lived, high-energy demand tissues. In the cardiovascular system, experimental models indicate that YME1L deficiency disrupts cristae organization, promotes maladaptive metabolic remodeling, and promotes heart failure-like phenotypes. Conversely, preservation of YME1L activity supports mitochondrial integrity and enhances cardiac resilience under hemodynamic stress. In addition to cardiomyocytes, YME1L also supports endothelial mitochondrial homeostasis, thereby linking mitochondrial proteostasis to vascular aging and diastolic dysfunction. Although YME1L has been extensively studied in cancer biology, its relevance to aging-related cardiovascular vulnerability is increasingly recognized, especially in cardio-oncology, where therapy-induced mitochondrial stress may be exacerbated by age-dependent decline in mitochondrial quality control. This review integrates current evidence supporting YME1L as a context-dependent regulator of mitochondrial stress adaptation, with particular emphasis on the roles of YME1L in cardiovascular aging, heart failure with preserved ejection fraction (HFpEF), and stress tolerance. Rather than positioning YME1L as a universal therapeutic target, we discuss how modulating YME1L-associated pathways may help preserve mitochondrial resilience and mitigate age-related cardiovascular dysfunction.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent end‐manifestation of cardiovascular diseases currently lacking effective treatment. Using a high‐fat diet and L‐NAME‐induced mouse model, untargeted metabolomic profiling is performed and trigonelline is identified as a markedly reduced metabolite in HFpEF hearts. Oral trigonelline supplementation alleviates metabolic syndromes, including obesity, insulin resistance, and hepatic injury, leading to improved cardiac function in HFpEF mice. AMPK inhibition blunts the protective effects of trigonelline despite trigonelline per se not activating AMPK directly. Gut microbiota is required in AMPK activation and consequent beneficial effects on HFpEF mice by trigonelline. Further investigations demonstrate that trigonelline significantly restores HFpEF mouse gut microbiome dysbiosis by decreasing Firmicutes and increasing Bacteroidetes. In conclusion, the studies demonstrate that trigonelline supplementation mitigates HFpEF‐associated metabolic disorders and improves cardiac function via gut microbiome alterations‐mediated AMPK activation. These findings suggest that trigonelline has therapeutic potential for HFpEF.

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.

The incidence of heart failure with preserved ejection fraction (HFpEF) increases with the ageing of populations. This study aimed to explore ageing-associated gene signatures in HFpEF to develop new diagnostic biomarkers and provide new insights into the underlying mechanisms of HFpEF. Mice were subjected to a high-fat diet combined with L-NG-nitroarginine methyl ester (l-NAME) to induce HFpEF, and next-generation sequencing was performed with HFpEF hearts. Additionally, separate datasets were acquired from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were used to identify ageing-related DEGs. Support vector machine, random forest, and least absolute shrinkage and selection operator algorithms were employed to identify potential diagnostic genes from ageing-related DEGs. The diagnostic value was assessed using a nomogram and receiver operating characteristic curve. The gene and related protein expression were verified by reverse transcription PCR and western blotting. The immune cell infiltration in hearts was analysed using the single-sample gene-set enrichment analysis algorithm. The results showed that the merged HFpEF datasets comprised 103 genes, of which 15 ageing-related DEGs were further screened in. The ageing-related DEGs were primarily associated with immune and metabolism regulation. AGTR1a, NR3C1, and PRKAB1 were selected for nomogram construction and machine learning-based diagnostic value, displaying strong diagnostic potential. Additionally, ageing scores were established based on nine key DEGs, revealing noteworthy differences in immune cell infiltration across HFpEF subtypes. In summary, those results highlight the significance of immune dysfunction in HFpEF. Furthermore, ageing-related DEGs might serve as promising prognostic and predictive biomarkers for HFpEF.

Cardiovascular disease remains a leading cause of death and disability worldwide. Heart failure (HF) is the end stage of various cardiovascular diseases. Despite recent advancements in understanding of HF pathogenesis and treatment, the prognosis of patients with HF remains poor. Inflammation is a key player in the development of HF, and its role in the pathogenesis of HF has been extensively studied. Inflammation is associated with elevated HF risk and adverse prognosis. Targeting cardiac inflammation has been suggested as a promising treatment strategy for HF. However, almost all clinical trials on the anti-inflammatory treatment of HF have not indicated improved clinical outcomes, and some have reported deterioration of the condition, possibly because of limited understanding of the specific role of inflammation in HF. The summary of inflammatory mechanisms contributing to the pathogenesis of different HF types, current anti-inflammation therapies for HF, and the results of clinical trials could provide new perspectives for understanding and targeting the role of inflammation in HF through the development of effective clinical therapeutic strategies.

Stimulator of interferon genes (STING) has recently been found to play a crucial role in cardiac sterile inflammation and dysfunction. The role of stimulator of interferon genes (STING) in cardiac sterile inflammation and dysfunction has been recently discovered. This study aims to examine the involvement of STING in pathological cardiac remodeling and the mechanisms that govern the activation of the STING pathway. To investigate this, transverse aortic constriction (TAC) was performed on STING knockout mice to induce pressure overload-induced cardiac remodeling. Subsequently, cardiac function, remodeling, and inflammation levels were evaluated. The STING pathway was found to be activated in the pressure overload-stressed heart and angiotensin II (Ang II)-stimulated cardiac fibroblasts. Loss of STING expression led to a significant reduction in inflammatory responses, mitochondrial fragmentation, and oxidative stress in the heart, resulting in attenuated cardiac remodeling and dysfunction. Furthermore, the exacerbation of pressure overload-induced STING-mediated inflammation and pathological cardiac remodeling was observed when mitophagy was suppressed through the silencing of Parkin, an E3 ubiquitin ligase. Taken together, these findings indicate that STING represents a newly identified and significant molecule implicated in the process of pathological cardiac remodeling and that mitophagy is an upstream mechanism that regulates STING activation. Targeting STING may therefore provide a novel therapeutic strategy for pathological cardiac remodeling and heart failure.