Mitochondrial metabolism promotes adaptation to proteotoxic stress

The mechanisms by which cells adapt to proteotoxic stress are largely unknown, but 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 NMR-based analyses further showed that FDX1 is the direct target of elesclomol, which promotes a unique form of copper-dependent cell death. These studies elucidate a fundamental mechanism by which cells adapt to proteotoxic stress and suggests strategies to mitigate proteasome inhibitor-resistance.