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

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.

SUBMITTER: Cardenas C

PROVIDER: S-EPMC9387586 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Cardenas Cesar C Lovy Alenka A Silva-Pavez Eduardo E Urra Felix F Mizzoni Craig C Ahumada-Castro Ulises U Bustos Galdo G Jaňa Fabian F Cruz Pablo P Farias Paula P Mendoza Elizabeth E Huerta Hernan H Murgas Paola P Hunter Martin M Rios Melany M Cerda Oscar O Georgakoudi Irene I Zakarian Armen A Molgó Jordi J Foskett J Kevin JK

Science signaling 20200714 640

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 ...[more]

PMID: 32665411

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Project description:SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

Dataset Information

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

Publications

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca<sup>2+</sup> transfer for survival.

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