Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca(2+) transfer for survival.
Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca(2+) transfer for survival.
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DOI：
10.1126/scisignal.aay1212
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发表时间：
2020-07-14
影响因子：
7.3
通讯作者：
Foskett, J. Kevin
中科院分区：
文献类型：
--
作者：
Cardenas, Cesar;Lovy, Alenka;Silva-Pavez, Eduardo;Urra, Felix;Mizzoni, Craig;Ahumada-Castro, Ulises;Bustos, Galdo;Jana, Fabian;Cruz, Pablo;Farias, Paula;Mendoza, Elizabeth;Huerta, Hernan;Murgas, Paola;Hunter, Martin;Rios, Melany;Cerda, Oscar;Georgakoudi, Irene;Zakarian, Armen;Molgo, Jordi;Foskett, J. Kevin
InsP3R胞内钙离子释放通道向线粒体的自发钙信号是氧化磷酸化(OXPHOS)和ATP产生的关键。在OXPHOS缺陷的细胞中，还原羧化取代了氧化代谢，以维持大量的还原当量和代谢前体。为了研究线粒体钙摄取在调节这些细胞中的生物能量学中的作用，我们使用了OXPHOS活性细胞和OXPHOS缺陷细胞。抑制InsP3R活性或线粒体钙摄取增加了α-酮戊二酸(αKG)的丰度和NAD+/NADH的比值，表明结构性内质网(ER)到线粒体的钙离子转移促进了αKG脱氢酶(αKGDH)的最佳活性。线粒体Ca~(2+)的减少抑制了αKGDH的活性，增加了NAD+，从而在氧磷酶活性和缺氧酶缺陷的细胞中诱导了依赖于SIRT1的自噬。尽管OXPHOS功能细胞中的自噬通量促进了细胞的存活，但在OXPHOS缺陷细胞中，由于自噬小体-溶酶体融合受到抑制，自噬通量受到了损害。αKGDH的抑制和OXPHOS缺陷细胞自噬通量的降低导致了显著的细胞死亡，以响应钙从内质网到线粒体的构成通量的中断。这些结果表明，线粒体在维持氧磷酶活性和缺氧酶缺陷细胞的生物能量平衡中起着基础性的作用，其中钙离子对αKGDH活性的调节起着关键作用。无论癌细胞处于何种OXPHOS状态，抑制内质网到线粒体的钙离子转移可能代表了一种针对癌细胞的一般治疗策略。
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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影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
64.5
作者：
Mallilankaraman K;Doonan P;Cárdenas C;Chandramoorthy HC;Müller M;Miller R;Hoffman NE;Gandhirajan RK;Molgó J;Birnbaum MJ;Rothberg BS;Mak DO;Foskett JK;Madesh M
通讯作者：
Madesh M
影响因子：
4
作者：
Cárdenas, C;Liberona, JL;Jaimovich, E
通讯作者：
Jaimovich, E
影响因子：
4.8
作者：
Demers-Lamarche, Julie;Guillebaud, Gerald;Germain, Marc
通讯作者：
Germain, Marc