Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters

Abstract

Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.

Creatine supplementation reduces the cerebral oxidative and metabolic stress responses to acute in utero hypoxia in the late‐gestation fetal sheep

“…We hypothesise that this relationship results from a decrease in fetal tissue aerobic metabolism due to the increased creatine levels maintaining ATP turnover for longer under hypoxic conditions, thereby reducing the need for oxidative phosphorylation (Scopes, 1973). The relationship between reduced hypoxaemia during UCO and the smaller changes of cerebral pyruvate and lactate (discussed further below) also supports the hypothesis that there is a reduced reliance on mitochondrial bioenergetics during UCO conferred by increased creatine levels (Bouillaud et al, 2021). We have previously reported from the same cohort of fetuses that creatine supplementation had no effect on state I, IV or III mitochondrial respiration in the cerebral grey or white matter 72 h after UCO (Muccini et al, 2022).…”

Inhibition of Succinate Dehydrogenase by Pesticides (SDHIs) and Energy Metabolism

“…A critical issue is, therefore, the efficiency of oxygen to generate ATP, quantified by the ATP/O 2 ratio. A limited increase of it could be obtained by a rearrangement of the oxidative metabolism, such as a shift from fatty acid to glucose oxidation or, notably, if SDH activity is repressed but recruitment of anaerobic ATP formation pathways is required for a significant improvement [ 35 ].…”

“…The best-known example of an anaerobic ATP formation pathway is lactic fermentation, which does not need oxygen at all. Hence, its ATP/O 2 is irrelevant (infinite), and a modest contribution to energy metabolism increases considerably the cellular ATP/O 2 ; this issue might be overlooked when the Warburg effect is considered [ 35 ]. Therefore, as the contribution of lactic fermentation to ATP regeneration increases, ATP/O 2 rises considerably.…”

Glutor, a Glucose Transporter Inhibitor, Exerts Antineoplastic Action on Tumor Cells of Thymic Origin: Implication of Modulated Metabolism, Survival, Oxidative Stress, Mitochondrial Membrane Potential, pH Homeostasis, and Chemosensitivity

“…Neoplastic cells display dependence on glycolysis for their massive bioenergetic and biosynthetic requirements (1)(2)(3). Consequently, cancer cells display upregulated expression of various high-affinity glucose transporters (GLUT) to facilitate glucose uptake for accelerated glycolysis.…”