LANDSCAPE OF THE MITOCHONDRIAL Hsp90 METABOLOME IN TUMORS

Reprogramming of tumor cell metabolism contributes to disease progression and resistance to therapy, but how this process is regulated on the molecular level is unclear. Here we report that Heat Shock Protein 90 (Hsp90)-directed protein folding in mitochondria controls central metabolic networks in tumor cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis, and cellular redox status. Specifically, mitochondrial Hsp90, but not cytosolic Hsp90, binds and stabilizes the electron transport chain Complex II subunit succinate dehydrogenase-B, maintaining cellular respiration under low-nutrient conditions, and contributing to hypoxia-inducible factor-1α-mediated tumorigenesis in patients carrying succinate dehydrogenase-B mutations. Thus, Hsp90-directed proteostasis in mitochondria regulates tumor cell metabolism, and may provide a tractable target for cancer therapy.