Thioredoxin protects against diabetic hearing loss by regulating TOMM22 mediated mitochondrial autophagy in hair cells and inhibiting microglial M1 polarization

Abstract

Abstract Hearing loss is a prevalent yet mechanistically unclear complication of diabetes. This research aims to systematically investigate the role of thioredoxin (Trx) in diabetic hearing loss and elucidate its underlying molecular mechanisms through clinical, bioinformatics, and experimental analyses. Clinically, elevated serum Trx levels were associated with decreased otoacoustic emission (OAE) parameters, suggesting its potential as a serum biomarker. Bioinformatics analysis revealed that TOMM22 is critical for mitophagy. In vivo, Trx overexpression effectively mitigated the hyperactivation of apoptosis, mitophagy, and M1 microglial activation in diabetic mouse cochlear tissue. An in vitro advanced glycation end-product (AGE)-induced HEI-OC1 cell model demonstrated that Trx1 overexpression inhibited PINK1/Parkin-mediated mitophagy, increased the mitochondrial membrane potential, and reduced apoptosis by maintaining TOMM22 expression. Conversely, CCCP-mediated inhibition of TOMM22 reversed the protective effects of Trx1. Moreover, Trx1 drove microglial polarization towards the anti-inflammatory M2 phenotype. Furthermore, coculture of microglia conditioned medium with HEI-OC1 cells confirmed that Trx1 indirectly protects auditory cells. Thus, Trx protects hearing via dual mechanisms: cell autonomously by regulating the TOMM22/PINK1 axis to maintain mitochondrial homeostasis and noncell autonomously by inducing microglial M2 polarization to improve the auditory microenvironment. These findings provide novel insights into diabetic hearing loss pathogenesis and identify Trx as a potential therapeutic target.