The ABHD10-KCMF1 Complex Mitigates Cochlear Aging by Regulating Mitochondrial Lipid Metabolism

Presbycusis is caused by multiple factors, the mechanisms of which are not fully understood. This study investigated mitochondria-related genes in presbycusis, a condition with multifactorial and incompletely understood mechanisms, by combining Mendelian randomization analysis and functional validation. Genetically predicted higher ABHD10 expression was identified as a protective factor against presbycusis and was regulated by methylation sites such as cg15684481, whereas methylation at other sites inhibited ABHD10 expression and alleviated the condition. In contrast, ABHD10 was upregulated in d-galactose-induced HEI-OC1 cells and aged mouse cochlear hair cells, where it promoted senescence. Silencing ABHD10 in senescent cells reduced P21 and P16 protein levels, decreased reactive oxygen species levels, improved mitochondrial membrane potential, and lowered lipid droplet formation along with triglycerides and fatty acids. Co-immunoprecipitation experiments showed that ABHD10 interacts with KCMF1, indicating that the complex may regulate cellular metabolism and stress responses through signaling pathways. This was supported by GO and KEGG analyses linking ABHD10 to aging-related processes such as energy metabolism and oxidative stress. Overall, ABHD10 functions as a context-dependent mitochondrial regulator, with the ABHD10-KCMF1 axis integrating mitochondrial quality control, lipid homeostasis, and redox balance, thereby offering a potential druggable target for presbycusis.