Research ArticleMetabolism

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum–to–mitochondria Ca2+ transfer for survival

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Science Signaling  14 Jul 2020:
Vol. 13, Issue 640, eaay1212
DOI: 10.1126/scisignal.aay1212

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Staying alive without oxidative phosphorylation

Oxidative phosphorylation is used by many cell types to produce ATP and requires low-level, constitutive Ca2+ flow from the ER to the mitochondria. Cardenas et al. found that this ER-to-mitochondria Ca2+ flow was critical for the survival of cells defective in oxidative phosphorylation, a phenotype that is common in cancer cells. In the absence of oxidative phosphorylation, important metabolites can be generated through reductive carboxylation, a pathway that requires the Ca2+-sensitive enzyme α-ketoglutarate dehydrogenase (αKGDH) and NADH. Manipulations that blocked ER-to-mitochondria Ca2+ flow resulted in suppression of αKGDH activity, increases in the NAD+/NADH ratio, and enhanced autophagy that failed to promote cell survival. These results highlight that mitochondrial Ca2+ influx regulates metabolic pathways in addition to oxidative phosphorylation, which could be targeted in specific cancer subtypes.

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