iAAA-mitochondrial protease YME1L1 regulates the degradation of short-lived mitochondrial transporter SLC25A38

Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.