Mitochondrial thermal proteome profiling for the study of oncometabolite interactome

Deregulation of mitochondrial metabolism is associated with several pathologies, including tumorigenesis. In particular, mutations in genes encoding tricarboxylic acid (TCA) cycle enzymes are present in a wide variety of human cancers. These mutations lead to the excessive accumulation of mitochondrial-derived metabolites that act as pro-oncogenic signaling molecules, the reason why they have been termed oncometabolites. Several mitochondrial and cytonuclear effects of oncometabolites have been described, including inhibition of mitochondrial respiration and α-ketoglutarate-dependent dioxygenases. However, these defects do not fully explain the pro-tumorigenic properties of oncometabolites, indicating additional mitochondrial or cellular proteome effects. Therefore, an unbiased interactome approach to studying oncometabolite-protein interactions within mitochondria and cancer cells is necessary to provide novel insights into the role of mitochondrial-derived metabolites in cancer.