Slc16a5 (MCT6) knockout induces sex-dependent changes in auditory function, hair cell viability and cochlear transcriptomic programs in the mouse

The maintenance of cochlear homeostasis requires precise metabolic regulation, yet the specific roles of monocarboxylate transporters in auditory function remain poorly understood. Monocarboxylate transporter 6 (Mct6), encoded by Slc16a5, is a membrane transporter of the solute carrier 16 family involved in the cellular transport of metabolites related to energy metabolism and signaling. Here, we investigated the impact of Mct6 deficiency on cochlear physiology, hair cell viability and molecular stability in mice. We identified Mct6 as a critical, sex-dependent regulator of cochlear stress resistance. Physiological assessment revealed divergent functional trajectories between the two sexes: Female Mct6-KO mice exhibited early-onset high-frequency hearing loss by 6 weeks of age. Conversely, male Mct6-KO mice displayed a transient protective phenotype, characterized by preserved auditory function compared to age-matched wild-type controls at 12 weeks. Consistent with these functional differences, outer hair cell survival showed a similar pattern, with exacerbated cell loss in females and attenuated loss in males. Transcriptomic profiling by RNA-sequencing revealed that Mct6 deletion altered the expression of estrogen-responsive genes, suggesting a potential mechanism underlying the observed sex-dependent effects. While Mct6 deletion was associated with a shared stress response in both sexes, as evident by upregulation of heat shock proteins, downstream molecular cascades differed between sexes. Together, these findings demonstrate that Mct6 is important for maintaining cochlear homeostasis and auditory resilience through sex-specific molecular mechanisms that differentially govern stress adaptation and degeneration in the inner ear.