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Authordc.contributor.authorCárdenas, César 
Authordc.contributor.authorLovy, Alenka 
Authordc.contributor.authorSilva Pavéz, Eduardo 
Authordc.contributor.authorUrra Faúndez, Félix 
Authordc.contributor.authorMizzoni, Craig 
Authordc.contributor.authorAhumada Castro, Ulises 
Authordc.contributor.authorBustos, Galdo 
Authordc.contributor.authorJaña, Fabián 
Authordc.contributor.authorCruz, Pablo 
Authordc.contributor.authorFarías, Paula 
Authordc.contributor.authorMendoza, Elizabeth 
Authordc.contributor.authorHuerta, Hernán 
Authordc.contributor.authorMurgas, Paola 
Authordc.contributor.authorHunter, Martín 
Authordc.contributor.authorRíos, Melany 
Authordc.contributor.authorCerda Arancibia, Oscar 
Authordc.contributor.authorGeorgakoudi, Irene 
Authordc.contributor.authorZakarian, Armen 
Authordc.contributor.authorMolgó, Jordi 
Authordc.contributor.authorFoskett, James Kevin 
Cita de ítemdc.identifier.citationSci. Signal. 13, eaay1212 (2020)es_ES
Abstractdc.description.abstractSpontaneous Ca2+ signaling from the InsP(3)R 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 InsP(3)R activity or mitochondrial Ca2+ uptake increased alpha-ketoglutarate (alpha KG) abundance and the NAD(+)/NADH ratio, indicating that constitutive endoplasmic reticulum (ER)-to-mitochondria Ca2+ transfer promoted optimal alpha KG dehydrogenase (alpha KGDH) activity. Reducing mitochondrial Ca2+ inhibited alpha KGDH 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 alpha KGDH 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 alpha KGDH 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.es_ES
Patrocinadordc.description.sponsorshipComisión Nacional de Investigador Científica y Tecnológica (CONICYT) CONICYT FONDECYT 1160332 11170291 3140458 3170813 United States Department of Health & Human Services National Institutes of Health (NIH) - USA R37GM56328 S10OD021624 P30NS047243 Emerson Collective Cancer Research Fund ANID/FONDAP 15150012es_ES
Publisherdc.publisherAAAS. American Association for the Advancement of Sciencees_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.uri*
Sourcedc.sourceScience Signalinges_ES
Keywordsdc.subjectAlpha-ketoglutarate dehydrogenasees_ES
Keywordsdc.subjectElectron-transport chaines_ES
Keywordsdc.subjectReductive carboxylationes_ES
Títulodc.titleCancer cells with defective oxidative phosphorylation require endoplasmic reticulum–to–mitochondria Ca2+ transfer for survivales_ES
Document typedc.typeArtículo de revistaes_ES
dcterms.accessRightsdcterms.accessRightsAcceso Abierto
Indexationuchile.indexArtículo de publicación ISI
Indexationuchile.indexArtículo de publicación SCOPUS

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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile