Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis

Chinopoulos, Christos and Seyfried, Thomas N. (2018) Mitochondrial Substrate-Level Phosphorylation as Energy Source for Glioblastoma: Review and Hypothesis. ASN NEURO, 10. ISSN 1759-0914


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Glioblastoma multiforme (GBM) is the most common and malignant of the primary adult brain cancers. Ultrastructural and biochemical evidence shows that GBM cells exhibit mitochondrial abnormalities incompatible with energy production through oxidative phosphorylation (OxPhos). Under such conditions, the mitochondrial F0-F1 ATP synthase operates in reverse at the expense of ATP hydrolysis to maintain a moderate membrane potential. Moreover, expression of the dimeric M2 isoform of pyruvate kinase in GBM results in diminished ATP output, precluding a significant ATP production from glycolysis. If ATP synthesis through both glycolysis and OxPhos was impeded, then where would GBM cells obtain high-energy phosphates for growth and invasion? Literature is reviewed suggesting that the succinate-CoA ligase reaction in the tricarboxylic acid cycle can substantiate sufficient ATP through mitochondrial substrate-level phosphorylation (mSLP) to maintain GBM growth when OxPhos is impaired. Production of high-energy phosphates would be supported by glutaminolysis-a hallmark of GBM metabolism-through the sequential conversion of glutamine -> glutamate -> alpha-ketoglutarate -> succinyl CoA -> succinate. Equally important, provision of ATP through mSLP would maintain the adenine nucleotide translocase in forward mode, thus preventing the reverse-operating F0-F1 ATP synthase from depleting cytosolic ATP reserves. Because glucose and glutamine are the primary fuels driving the rapid growth of GBM and most tumors for that matter, simultaneous restriction of these two substrates or inhibition of mSLP should diminish cancer viability, growth, and invasion.

Item Type: Article
Additional Information: Funding Agency and Grant Number: Foundation for Metabolic Cancer Therapies; Claudia & Nelson Peltz Foundation; Crossfit Inc.; [FIKP-61822-64888-EATV]; [VEKOP 2.3.3-15-2016-00012]; [NKFIH KH129567]; [2017-2.3.4-TET-RU-2017-00003] Funding text: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors would like to acknowledge support from the Foundation for Metabolic Cancer Therapies, the Claudia & Nelson Peltz Foundation, Crossfit Inc., Joseph Maroon, Joe Mercola, and Ellen Davis to T. N. S. and grants FIKP-61822-64888-EATV, VEKOP 2.3.3-15-2016-00012, NKFIH KH129567, and 2017-2.3.4-TET-RU-2017-00003 to C. C. Összes idézések száma a WoS-ban: 0
Uncontrolled Keywords: IN-VIVO; Dietary restriction; Bioenergetics; OXIDATIVE-PHOSPHORYLATION; THERAPIES; GLIOMAS; nucleoside diphosphate kinase; alpha-ketoglutarate; PYRUVATE-KINASE M2; CITRIC-ACID CYCLE; LACTATE-DEHYDROGENASE; GLUTAMINE-METABOLISM;
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia
R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry / idegkórtan, neurológia, pszichiátria
Depositing User: MTMT SWORD
Date Deposited: 29 Jan 2019 11:43
Last Modified: 29 Jan 2019 11:43

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