Impact of genetically predicted characterization of mitochondrial DNA quantity and quality on osteoarthritis

Background: Existing studies have indicated that mitochondrial dysfunction may contribute to osteoarthritis (OA) development. However, the causal association between mitochondrial DNA (mtDNA) characterization and OA has not been extensively explored. Methods: Two-sample Mendelian randomization was performed to calculate the impact of mitochondrial genomic variations on overall OA as well as site-specific OA, with multiple analytical methods inverse variance weighted (IVW), weighted median (WM), MR-Egger and MR-robust adjusted profile score (MR-RAPS). Results: Genetically determined mitochondrial heteroplasmy (MtHz) and mtDNA abundance were not causally associated with overall OA. In site-specific OA analyses, the causal effect of mtDNA abundance on other OA sites, including hip, knee, thumb, hand, and finger, had not been discovered. There was a suggestively protective effect of MtHz on knee OA IVW OR = 0.632, 95% CI: 0.425–0.939, p-value = 0.023. No causal association between MtHz and other different OA phenotypes was found. Conclusion: MtHz shows potential to be a novel therapeutic target and biomarker on knee OA development. However, the variation of mtDNA abundance was measured from leukocyte in blood and the levels of MtHz were from saliva samples rather than cartilage or synovial tissues. Genotyping samples from synovial and cartilage can be a focus to further exploration.