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. 


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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!


Pablo Rivera Mejias
Bridging Excellence Fellow