Abstract
Musculoskeletal diseases are the leading cause of disability-adjusted life years. Mitochondria, often referred to as the "powerhouses" of cells, are believed to play a role in regulating cellular metabolism and differentiation, potentially influencing the occurrence and progression of musculoskeletal diseases. However, the exact causal relationships remain to be defined. This study aimed to investigate the causal relationships between mitochondrial biological functions and musculoskeletal diseases (including osteoarthritis (OA), osteoporosis, rheumatoid arthritis (RA), and ankylosing spondylitis through Mendelian randomization (MR) analysis). We systematically summarized data related to mitochondrial functional proteins and musculoskeletal diseases from the IEU OpenGWAS and UK Biobank databases. We used single nucleotide polymorphisms significantly associated with musculoskeletal diseases as instrumental variables. The inverse variance weighting method performed the main MR analysis. We used Mendelian randomized residual sum of pleiotropy and outliers, MR-Egger regression, Cochran Q statistic, Rucker Q statistic, Radial-MR, weighted median, simple mode, weighted mode, and leave-one-out analysis methods as supplementary analyses. First, 14 positive mitochondrial functional proteins were screened out. After Bonferroni correction, COA3 and COX4I2 were found to be causally related to OA and act as protective factors. We identified a causal relationship between SLC25A18 and RA as a risk factor. This study provides genetic support and offers new evidence regarding the roles of COA3, COX4I2, and SLC25A18 in the pathophysiology of OA and RA. This study paves the way for a deeper understanding of the pathological mechanisms of musculoskeletal diseases and provides information for their prevention strategies and treatments.