Abstract
BACKGROUND: Mitochondria are central to immune regulation, inflammation, and cellular metabolism. Growing evidence suggests that mitochondrial dysfunction contributes to autoimmune disease (AD) pathogenesis by modulating inflammatory pathways and immune cell function. However, the causal relationships between mitochondria-related proteins and ADs remain unclear. METHODS: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine causal associations between 67 mitochondria-related proteins and 10 ADs, using GWAS data from the IEU OpenGWAS and FinnGen databases. Colocalization analysis assessed whether genetic signals for mitochondrial proteins and ADs overlapped. Protein-protein interaction (PPI) networks and functional enrichment analyses were used to explore biological functions. Sensitivity analyses evaluated pleiotropy and heterogeneity to ensure robustness. RESULTS: MR analysis revealed significant causal associations, including SLC9B2 with rheumatoid arthritis (RA), MRM3 with ulcerative colitis (UC) and inflammatory bowel disease (IBD), and PDK1 with UC and IBD. Reverse MR indicated bidirectional effects, with UC influencing SLC9B2 and C1QBP expression. Colocalization analysis confirmed shared genetic variants, linking mitochondrial proteins to inflammatory regulation. CONCLUSION: This study provides genetic evidence for the causal role of mitochondrial proteins in autoimmune inflammation, identifying potential biomarkers and therapeutic targets. Future research integrating multi-omic and functional validation is needed to advance mitochondria-targeted therapies for ADs. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13755-025-00358-2.