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Nat Chem Biol DOI:10.1038/s41589-019-0291-9

Mitochondrial metabolism promotes adaptation to proteotoxic stress.

Publication TypeJournal Article
Year of Publication2019
AuthorsTsvetkov, P, Detappe, A, Cai, K, Keys, HR, Brune, Z, Ying, W, Thiru, P, Reidy, M, Kugener, G, Rossen, J, Kocak, M, Kory, N, Tsherniak, A, Santagata, S, Whitesell, L, Ghobrial, IM, Markley, JL, Lindquist, S, Golub, TR
JournalNat Chem Biol
Volume15
Issue7
Pages681-689
Date Published2019 07
ISSN1552-4469
KeywordsAnimals, Cell Survival, Cells, Cultured, Humans, Mice, Mitochondria, Oxidative Stress, Proteasome Inhibitors, Small Molecule Libraries
Abstract

The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but are key to understanding how tumor cells, particularly in vivo, are largely resistant to proteasome inhibitors. Analysis of cancer cell lines, mouse xenografts and patient-derived tumor samples all showed an association between mitochondrial metabolism and proteasome inhibitor sensitivity. When cells were forced to use oxidative phosphorylation rather than glycolysis, they became proteasome-inhibitor resistant. This mitochondrial state, however, creates a unique vulnerability: sensitivity to the small molecule compound elesclomol. Genome-wide CRISPR-Cas9 screening showed that a single gene, encoding the mitochondrial reductase FDX1, could rescue elesclomol-induced cell death. Enzymatic function and nuclear-magnetic-resonance-based analyses further showed that FDX1 is the direct target of elesclomol, which promotes a unique form of copper-dependent cell death. These studies explain a fundamental mechanism by which cells adapt to proteotoxic stress and suggest strategies to mitigate proteasome inhibitor resistance.

DOI10.1038/s41589-019-0291-9
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31133756?dopt=Abstract

Alternate JournalNat. Chem. Biol.
PubMed ID31133756