Yme1l substrate quantification under Leucine and Glutamine starvation as well as Torin treatment

Metabolic reprogramming of mitochondria occurs during development, cell differentiation and in cancer and is coupled to changes in mitochondrial mass and shape. Here, we demonstrate that the i-AAA protease YME1L rewires the proteome of pre-existing mitochondria in response to hypoxia or nutrient starvation. Inhibition of mTORC1 induces a lipid signalling cascade via the phosphatidic acid phosphatase LIPIN1, which decreases phosphatidylethanolamine levels in mitochondrial membranes and promotes proteolysis. YME1L degrades mitochondrial protein translocases, lipid transfer proteins and metabolic enzymes to acutely limit mitochondrial biogenesis and support cell growth. YME1L-mediated mitochondrial reshaping ensures spheroid and xenograft growth of pancreatic ductal adenocarcinoma (PDAC) cells. Similar mitochondrial proteome changes occur in tumor tissues of PDAC patients, suggesting that YME1L is relevant to the pathophysiology of specific solid tumors. Our results identify the mTORC1-LIPIN1-YME1L axis as a novel post-translational regulator of mitochondrial proteostasis at the interface