Editors' ChoiceMetabolism

Metabolic adaption through regulated proteolysis

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Science Signaling  19 Nov 2019:
Vol. 12, Issue 608, eaba2257
DOI: 10.1126/scisignal.aba2257

Induced mitochondrial protein turnover enables cells to metabolically adapt to oxygen and nutrient deprivation.

Solid tumors, such as pancreatic ductal adenocarcinomas (PDACs), must grow in oxygen- and nutrient-poor environments. MacVicar et al. discovered that induced turnover of mitochondrial proteins by the inner mitochondrial membrane protease YME1L enabled cells to metabolically adapt to oxygen and nutrient deprivation. Cells lacking YME1L showed defects in anchorage-independent growth and glutamine-dependent respiration. The growth defect was rescued by expression of wild-type YME1L but not a catalytically inactive mutant. YME1L substrates that decreased in abundance in hypoxic cells included the mitochondrial fusion factor OPA1, protein translocase subunits, mitochondrial lipid transfer proteins, and proteins involved in mitochondrial metabolism. Hypoxia-inducible factor 1α (HIF-1α) depletion resulted in the increased abundance of YME1L substrates. The multiprotein complex mammalian target of rapamycin complex 1 (mTORC1) is inhibited by hypoxia or nutrient deprivation, and YME1L substrate abundance was decreased by pharmacological inhibition or genetic inactivation of mTORC1, as well as glutamine depletion, which suppresses mTORC1 activity. Pharmacological mTORC1 inhibition, amino acid depletion, or hypoxia decreased the import of mitochondrial proteins and the abundance of the lipid phosphatidylethanolamine in mitochondrial membranes. Knockdown of the phosphatidic acid phosphatase LIPIN1, which is an mTORC1 target, attenuated the decrease in YME1L substrate abundance that occurred with mTORC1 inhibition. These results suggested that the inhibition of mTORC1 signaling by hypoxia and/or nutrient depletion leads to LIPIN1-mediated changes in lipid metabolism that culminate in decreases in phosphatidylethanolamine, which increases the proteolysis of YME1L substrates. LIPIN1 knockdown resulted in defective growth of wild-type cells as spheroids (in which cells experience hypoxia), but not that of YME1L-deficient cells. YME1L knockdown decreased the size of spheroids and the growth of xenografted tumors formed from PDAC cell lines, and YME1L substrate abundance was reduced and HIF-1α abundance was increased in human PDAC samples. Thus, cells can metabolically adapt to oxygen and nutrient deprivation by inducing the degradation of specific mitochondrial proteins.

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