A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering, 2019, To et al

Andy · Nov 16, 2019

Highlights

Genome-wide CRISPR screens were performed with multiple mitochondrial inhibitors

Loss of G6PD, PFKP, or GPX4 is synthetic lethal with mitochondrial dysfunction

“Intra-mitochondrial” interactions are pervasive

Fitness defect from CV inhibition is alleviated by simultaneous loss of CI activity

Summary
Mitochondrial dysfunction is associated with a spectrum of human conditions, ranging from rare, inborn errors of metabolism to the aging process. To identify pathways that modify mitochondrial dysfunction, we performed genome-wide CRISPR screens in the presence of small-molecule mitochondrial inhibitors. We report a compendium of chemical-genetic interactions involving 191 distinct genetic modifiers, including 38 that are synthetic sick/lethal and 63 that are suppressors. Genes involved in glycolysis (PFKP), pentose phosphate pathway (G6PD), and defense against lipid peroxidation (GPX4) scored high as synthetic sick/lethal. A surprisingly large fraction of suppressors are pathway intrinsic and encode mitochondrial proteins. A striking example of such “intra-organelle” buffering is the alleviation of a chemical defect in complex V by simultaneous inhibition of complex I, which benefits cells by rebalancing redox cofactors, increasing reductive carboxylation, and promoting glycolysis. Perhaps paradoxically, certain forms of mitochondrial dysfunction may best be buffered with “second site” inhibitors to the organelle.
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Paywall, https://www.cell.com/cell/fulltext/S0092-8674(19)31182-1
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A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering, 2019, To et al

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A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering, 2019, To et al

Andy Committee Member

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