Mitochondrial transfer protects against cisplatin-induced hearing loss by fumarate-mediated activation of mitophagy.

Sensorineural hearing loss (SNHL) affects millions of individuals worldwide, with platinum-based chemotherapeutics identified as a significant cause. In this study, we elucidate the mechanism by which mitochondrial transfer from mesenchymal stem/stromal cells (MSCs) protects against cisplatin-induced cochlear injury in a mouse model. Systemically administered MSCs home to the cochlea and transfer mitochondria to damaged spiral ganglion neurons (SGNs) via tunneling nanotubes, leading to elevated intracellular levels of the Krebs cycle intermediate fumarate, which activates mitophagy to eliminate dysfunctional mitochondria. Mechanistically, dimethyl fumarate (DMF)-a clinically available fumarate derivative-covalently modifies the phosphatase PPP1CB at cysteine 126, thereby blocking PPP1CB-mediated dephosphorylation of mitofusin 2 (MFN2), which in turn enhances mitophagy and ultimately preserves auditory function. These findings reveal that MSCs orchestrate mitochondrial replacement in damaged SGNs by delivering healthy mitochondria and facilitating the removal of impaired ones, underscoring the therapeutic potential of this strategy for treating SNHL related to mitochondrial dysfunction.