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

Abstract

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.

Metabolomic profiling of blood plasma in patients with primary brain tumours: Basal plasma metabolites correlated with tumour grade and plasma biomarker analysis predicts feasibility of the successful statistical discrimination from healthy subjects – a preliminary study

“…It is generally accepted that cancer cells show increased consumption of and dependence on glutamine as glutamine metabolism fuels TCA cycle, nucleotide and fatty acid biosynthesis, and redox balance in cancer cells . In addition to serve as a major biosynthetic substrate for cancer cells, glutamine metabolism can maintain the TCA cycle by replenishing TCA cycle through α‐ketoglutarate and thus also cell survival during impaired mitochondrial pyruvate transport . Production of high‐energy phosphates by glutaminolysis represents important hallmark of GBM metabolism .…”

“…In addition to serve as a major biosynthetic substrate for cancer cells, glutamine metabolism can maintain the TCA cycle by replenishing TCA cycle through α‐ketoglutarate and thus also cell survival during impaired mitochondrial pyruvate transport . Production of high‐energy phosphates by glutaminolysis represents important hallmark of GBM metabolism . Besides this, glutamine is also important substrate for proline biosynthetic pathway.…”

Consideration of Ketogenic Metabolic Therapy as a Complementary or Alternative Approach for Managing Breast Cancer

“…Glucose and glutamine are the major fermentable fuels used by cancer cells with impaired OxPhos (39,46). Glucose is fermented to lactic acid through glycolysis in the cell cytoplasm, while glutamine is fermented to succinic acid through glutaminolysis in the tricarboxylic acid (TCA) cycle.…”

“…In addition to aerobic fermentation in the cytoplasm, glutaminolysis can also support high-energy phosphate synthesis in the mitochondria through the sequential conversion of glutamine-glutamate-alpha-ketoglutarate-succinyl CoA-succinate (Figure 2) (46). ATP synthesis through the succinate-CoA ligase reaction in the TCA cycle can compensate for reduced ATP synthesis through either glycolysis or OxPhos.…”

“…ATP synthesis through the succinate-CoA ligase reaction in the TCA cycle can compensate for reduced ATP synthesis through either glycolysis or OxPhos. We recently proposed that most of the ATP synthesized in tumor cells would come from mitochondrial substrate level phosphorylation (mSLP) at the succinate ligase reaction (46). Evidence showing that mSLP can compensate for OxPhos deficiency in cancer is emerging (57)(58)(59)(60).…”