Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration

Abstract

The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditiselegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine–GCN2–SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.