Background

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. 

Project

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. 

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Interested in finding out more about working at the interface of metabolism and organelle biology? Get in touch, we would love to hear from you!