Mitochondrial thermal proteome profiling for the study of oncometabolite interactome
Collaborators: Mikhail Savitski & Sinem Saka (EMBL) with Monther Abu-Remaileh (Stanford)
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.
Our project aims to generate a new method to study mitochondrial-specific effects of oncometabolites by combining thermal proteome profiling (TPP, Savitski lab at EMBL) with rapid mitochondrial immunopurification (mito-IP, Abu-Remaileh lab at Stanford). Mitochondrial thermal proteome profiling (mito-TPP) will track direct targets of molecules and perturbations on the mitochondrial proteome. Therefore, mito-TPP will be a novel and powerful method to explore the effects of oncometabolites on mitochondria, providing new insights into their pro-oncogenic mechanisms and novel therapeutic targets to treat tumors harboring mutations in TCA cycle enzymes.
This project is supported by a Bridging Excellence Fellowship, awarded to Pablo Rivera Mejías.
Pablo Rivera Mejias
Bridging Excellence Fellow