Mitochondrial VHL rewires cell metabolism in hypoxia

Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated form of hypoxia-inducible factors for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits MCCC2, an essential subunit of leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and PRMT5-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of pathological hypoxia and functionally associated with VHL mutation subtypes in cancer.