On the Origin of ATP Synthesis in Cancer

Abstract

ATP is required for mammalian cells to remain viable and to perform genetically programmed functions. Maintenance of the DG 0 ATP hydrolysis of À56 kJ/mole is the endpoint of both genetic and metabolic processes required for life. Various anomalies in mitochondrial structure and function prevent maximal ATP synthesis through OxPhos in cancer cells. Little ATP synthesis would occur through glycolysis in cancer cells that express the dimeric form of pyruvate kinase M2. Mitochondrial substrate level phosphorylation (mSLP) in the glutamine-driven glutaminolysis pathway, substantiated by the succinate-CoA ligase reaction in the TCA cycle, can partially compensate for reduced ATP synthesis through both Ox-Phos and glycolysis. A protracted insufficiency of OxPhos coupled with elevated glycolysis and an auxiliary, fully operational mSLP, would cause a cell to enter its default state of unbridled proliferation with consequent dedifferentiation and apoptotic resistance, i.e., cancer. The simultaneous restriction of glucose and glutamine offers a therapeutic strategy for managing cancer.

Mitochondrial Fuel Dependence on Glutamine Drives Chemo-Resistance in the Cancer Stem Cells of Hepatocellular Carcinoma

“…Unexpectedly, the ATP level of R-HepG2 remained steady under the DOX treatment, regardless of the DOX input concentration ( Figure 5 A). Since the total ATP was produced from both glycolysis and the mitochondria, we hypothesized that this was a result of metabolic plasticity which allowed dynamic shifting between glycolysis-dependent and mitochondria-dependent ATP production within a low and constant ATP production profile [ 23 ]. To test this, we looked into the major metabolic pathways that fuel the metabolic requirement of cells ( Figure 5 B).…”

“…The oxidation of glutamine-derived αKG in the TCA cycle yields ATP by the catalysis of succinyl-CoA by succinate-CoA ligase (SUCL) in the absence or presence of oxygen through the mSLP. The resulting TCA intermediate succinate continues to be oxidized in the TCA cycle and yields reducing equivalents such as NADH and FADH 2 for the OXPHOS of the ETC [ 23 , 25 ]. The FAO pathway fuels the mitochondria by importing long chain fatty acids through the carnitine palmitoyltransferase-1a (CPT-1a) to the mitochondrial matrix.…”

Approaches to Monitor ATP Levels in Living Cells: Where Do We Stand?

“…Many studies have investigated the role of ATP in the development, progression and maintenance of cancer cells [153]. Although the detailed description of cancer-related metabolic alterations are not in the scope of the present review and have been discussed elsewhere [154,155], it deserves to be mentioned that the tumour microenvironment contains a high concentration of ATP, which is then released into the extracellular environment in an uncontrolled manner by cancer cells. In addition, cancer cells have the ability to absorb extracellular ATP and use it to activate molecular programs for tumour progression [156,157].…”

“…The study of the tumoral release of ATP, its role and its mechanisms of action are a hot topic to ameliorate current anticancer therapies [158]. Among cancer-related metabolic alterations [154,155], the Warburg effect is one of the most studied ones [159]. Recent evidence proposes that this process is an epiphenomenon parallel to tumorigenesis [160].…”

Mitochondria, Oxidative Stress, cAMP Signalling and Apoptosis: A Crossroads in Lymphocytes of Multiple Sclerosis, a Possible Role of Nutraceutics

“…Interestingly, upon activation, T cells also augment glutaminolysis process, that producing α-ketoglutarate, supplies the mitochondrial tricarboxylic acid (TCA) [ 35 , 36 ]. This is important in proliferating cells in which the intermediates of TCA cycle are continually depleted for their use in biosynthetic pathways [ 36 , 37 ]. Thus, mitochondrial metabolism plays a crucial role in T cell activation.…”