Autoimmune diseases (AIDs) such as SLE, RA, AS, and pSS arise from dysregulated immune responses, causing self-tissue damage. Beyond genetic and environmental factors, mitochondrial energy metabolism has emerged as a key regulator of immune function. Mitochondria not only produce ATP via oxidative phosphorylation (OXPHOS) but also modulate ROS, calcium signaling, and inflammasome activation. Shifts in mitochondrial metabolism determine immune cell fate and cytokine profiles, while mitochondrial dysfunction—marked by impaired OXPHOS or excess ROS—drives autoantigen release and chronic inflammation. Recent multi-omics studies in the International Journal of Rheumatic Diseases further link mitochondrial dysfunction to autoimmune pathogenesis. Luo et al. integrated genetic (SMR, eQTL, mQTL, pQTL) data across multiple AIDs, whereas Chen et al. (2025) combined bulk and single-cell transcriptomics with machine learning to reveal altered OXPHOS pathways in AS. Together, these findings highlight mitochondrial metabolism as a central hub in immune dysregulation and a promising therapeutic target in AIDs. Luo et al. 1 address a longstanding question: Is mitochondrial dysfunction a cause or consequence of AIDs? Using MR, which leverages genetic variants as instrumental variables to infer causality while minimizing confounding and reverse causation, the authors analyzed data from large-scale genome-wide association studies (GWAS) encompassing 10 AIDs with sample sizes ranging from 303 590 to 456 348 participants. They focused on 1136 mitochondrial-related genes from the MitoCarta database, integrating cis-QTL data: eQTL from 31 684 individuals, mQTL from 1980, and pQTL from 35 559. Key findings reveal four “Grade-II” mitochondrial genes with robust causal associations across AIDs, validated by heterogeneity in dependent instruments (HEIDI) tests and Bayesian colocalization. For MM, ATAD3A expressions were causally linked to increased risk, while UQCRH exerted protective effects. SND1 was associated with OA risk. Notably, TOP1MT showed protective effects against pSS. A striking observation was the dual role of UQCRH in MM, where the variant rs41292543 mediated causal effects via methylation but protection via expression. These results were bolstered by validation steps, including phenome-wide association studies (PheWAS), bidirectional MR with mtDNA copy number, and multi-omics integration. For example, reduced mtDNA copy number causally increased risks for SLE and RA, aligning with prior observations of mtDNA mutations in AIDs like MS and SLE. The study highlights how epigenetic (mQTL) and transcriptional (eQTL) layers amplify genetic predispositions, suggesting that mitochondrial dynamics, including fission and fusion regulated by genes such as ATAD3A, serve as potential therapeutic nodes. ATAD3A, which participates in mitochondrial membrane organization, may promote inflammation by altering reactive oxygen species levels and mitophagy, whereas TOP1MT, a mitochondrial DNA topoisomerase, could influence autoantigen presentation. This multi-omics approach overcomes limitations of traditional GWAS, which often overlook mitochondrial genes, and provides a framework for precision medicine. The identification of causal variants serves to prioritize candidate genes for subsequent functional verification, as opposed to the direct establishment of pharmacological targets. Although genes like UQCRH emerge as potential focal points for experimental research, genetic causality does not equate to clinical efficacy. Consequently, OXPHOS modulators, such as metformin, represent hypothesis-generating leads that require extensive validation through robust preclinical and clinical trials before their therapeutic potential can be established. Focusing on ankylosing spondylitis (AS), a prototypical HLA-B27-associated and IL-17-driven spondyloarthropathy, Chen et al. 2 applied multi-omics and computational analyses to investigate mitochondrial OXPHOS dysregulation. Bulk RNA-seq of PBMCs from 16 AS patients and 16 controls (GSE25101) identified OXPHOS as a top-enriched pathway by GSEA and PCA. Single-cell RNA-seq revealed cell-type-specific elevation of OXPHOS activity, particularly in monocytes and dendritic cells. WGCNA identified two OXPHOS-related gene modules, and integrated machine learning including SVM-RFE, random forest, and LASSO highlighted three hub genes: LAMTOR2, APBB1IP, and DGKQ, which were validated by RT-PCR and scRNA-seq. LAMTOR2 was enriched in monocytes and dendritic cells and associated with Th17 differentiation through mTOR signaling, linking metabolism and inflammation. These findings suggest that OXPHOS reprogramming and LAMTOR2-mediated signaling are key drivers of AS immune pathology and potential therapeutic targets that complement anti-IL-17 therapy. To further illustrate the interplay between mitochondrial function and immune regulation, the following table summarizes select key genes and pathways implicated in AIDs, drawing from the reviewed studies and broader literature (Table 1). These elements highlight how mitochondrial dynamics, metabolism, and signaling modulate immune cell behavior and disease risk. 3 These studies converge on a central theme: Mitochondrial energy metabolism orchestrates immune tolerance and inflammation in AIDs. Luo et al.'s causal framework complements Chen et al.'s mechanistic dissection, revealing shared pathways. For instance, OXPHOS components like UQCRH overlap with AS-enriched modules, suggesting trans-disease relevance. Broader implications extend to other immune-related diseases. In inflammatory bowel disease (IBD) or psoriasis, often comorbid with AS, mitochondrial dysfunction exacerbates barrier defects and cytokine storms. Precision medicine could involve mtDNA-targeted therapies or OXPHOS modulators, guided by genetic profiling. Challenges remain: Tissue-specific effects and sex biases in AIDs warrant further scRNA-seq integration with spatial transcriptomics. The studies by Luo et al. and Chen et al. advance our understanding of mitochondrial energy metabolism as a modifiable regulator in AIDs. By integrating genetic inference with multi-omics analyses, they highlight candidate genes such as TOP1MT, UQCRH, and LAMTOR2 for further mechanistic investigation. These findings provide a conceptual and experimental framework for exploring mitochondrial–immune interactions, rather than immediate therapeutic translation. Before clinical trials of mitochondrial-targeted interventions can be contemplated, additional studies are required to validate these targets in disease-relevant cellular and animal models, clarify tissue- and cell-specific effects, and establish safety and pharmacodynamic profiles. Such a stepwise investigation will be essential to evaluate the feasibility of translating a metabolic–immunologic paradigm into rheumatologic practice. S.-B.Y., P.-H.C., and M.-Y.W. conceived and drafted the manuscript, C.-J.L. provided valuable discussion. C.-J.L. and C.-C.W. reviewed and edited of the manuscript. All authors have read and agreed to the published version of the manuscript. The authors have nothing to report. This research was funded by the Kaohsiung Veterans General Hospital (KSVGH-114-090) and Kaohsiung Municipal Minsheng Hospital (KMSH-11406). The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. The authors do not have permission to share data.
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