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.

Abstract

Spontaneous Ca2+ signaling from the InsP3R intracellular Ca2+ release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca2+ uptake in regulating bioenergetics in these cells, we used OXPHOS-competent and OXPHOS-defective cells. Inhibition of InsP3R activity or mitochondrial Ca2+ uptake increased α-ketoglutarate (αKG) abundance and the NAD+/NADH ratio, indicating that constitutive endoplasmic reticulum (ER)–to–mitochondria Ca2+ transfer promoted optimal αKG dehydrogenase (αKGDH) activity. Reducing mitochondrial Ca2+ inhibited αKGDH activity and increased NAD+, which induced SIRT1-dependent autophagy in both OXPHOS-competent and OXPHOS-defective cells. Whereas autophagic flux in OXPHOS-competent cells promoted cell survival, it was impaired in OXPHOS-defective cells because of inhibition of autophagosome-lysosome fusion. Inhibition of αKGDH and impaired autophagic flux in OXPHOS-defective cells resulted in pronounced cell death in response to interruption of constitutive flux of Ca2+ from ER to mitochondria. These results demonstrate that mitochondria play a fundamental role in maintaining bioenergetic homeostasis of both OXPHOS-competent and OXPHOS-defective cells, with Ca2+ regulation of αKGDH activity playing a pivotal role. Inhibition of ER-to-mitochondria Ca2+ transfer may represent a general therapeutic strategy against cancer cells regardless of their OXPHOS status.

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