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Nat Chem Biol. 2019 Jul;15(7):681-689. doi: 10.1038/s41589-019-0291-9. Epub 2019 May 27.

Mitochondrial metabolism promotes adaptation to proteotoxic stress.

Author information

1
Broad Institute of Harvard and MIT, Cambridge, MA, USA. ptsvetko@broadinstitute.org.
2
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
3
Biochemistry Department, University of Wisconsin-Madison, Madison, WI, USA.
4
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
5
OnTarget Pharmaceutical Consulting LLC, Lexington, MA, USA.
6
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
7
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
8
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
9
Molecular Genetics Department, University of Toronto, Toronto, ON, Canada.
10
Howard Hughes Medical Institute, Chevy Chase, MD, USA.
11
Broad Institute of Harvard and MIT, Cambridge, MA, USA. golub@broadinstitute.org.
12
Howard Hughes Medical Institute, Chevy Chase, MD, USA. golub@broadinstitute.org.
13
Harvard Medical School, Boston, MA, USA. golub@broadinstitute.org.
14
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. golub@broadinstitute.org.

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.

PMID:
31133756
DOI:
10.1038/s41589-019-0291-9
[Indexed for MEDLINE]

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