PRMT6 Drives Hearing Loss by Promoting Asymmetric Arginine Dimethylation-Mediated FOXG1 Degradation and Suppressing Mitophagy.

OBJECTIVE:Age-related hearing loss (ARHL) is a progressive and irreversible sensorineural impairment with incompletely understood mechanisms. This study investigates the role of protein arginine methyltransferase 6 (PRMT6) and its regulatory mechanisms in ARHL. METHODS:In vivo, D-galactose (D-gal)-induced aging mouse models were established. Auditory brainstem response (ABR), cochlear β-galactosidase activity, and PRMT6 expression were measured, and the therapeutic effects of the PRMT6 inhibitor EPZ020411 were evaluated. In vitro, D-gal-treated HEI-OC1 cells were employed. PRMT6 was silenced using siRNA. Cellular senescence and apoptosis were assessed by SA-β-gal staining and TUNEL assay. Mitochondrial function was evaluated by JC-1 staining, ROS levels, ATP content, and transmission electron microscopy. Mitophagy was determined by LC3-TOM20 co-localization and the GFP-LC3-RFP-LC3ΔG reporter system. Asymmetric arginine dimethylation of FOXG1 was measured by immunoprecipitation with the D6A8 antibody, and FOXG1 protein stability was assessed by a cycloheximide chase assay. RESULTS:Aging mice exhibited elevated ABR thresholds, increased β-gal activity, and upregulated PRMT6, all reversed by EPZ020411. PRMT6 silencing attenuated cellular senescence and apoptosis, improved mitochondrial membrane potential, elevated ATP content, reduced ROS accumulation, and ameliorated mitochondrial damage. PRMT6 silencing also enhanced autophagic flux. Notably, PRMT6 silencing did not alter FOXG1 mRNA but upregulated FOXG1 protein and decreased its asymmetric arginine dimethylation, prolonging FOXG1 half-life. FOXG1 knockdown partially reversed the enhanced mitophagy, impaired mitochondrial function, and abrogated the anti-apoptotic protection conferred by PRMT6 silencing. CONCLUSION:PRMT6 exacerbates D-gal-induced cochlear aging by promoting asymmetric arginine dimethylation of FOXG1, accelerating FOXG1 degradation, and inhibiting mitophagy. The PRMT6-FOXG1-mitophagy axis represents a potential therapeutic target for D-gal-induced cochlear aging.