An epigenetic mechanism might be the reason why aerobic glycolysis encourages effector T cell differentiation ??

In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis [process by which glucose is converted to pyruvate plus a proton (H+); the free energy released is used to form the high-energy molecules ATP (adenosine triphosphate) and NADH (reduced nicotinamide adenine dinucleotide) is the Reason for Life on this planet],followed by lactic acid fermentation in cytosol –– rather than by the comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria that most normal cells carry out. The latter (mitochondrial) process is aerobic (i.e. uses oxygen). Malignant tumor cells typically grow rapidly, and exhibit glycolytic rates up to 200X higher than that of normal cells of origin; this occurs even if oxygen is plentiful.

Otto Warburg postulated this change in metabolism is the fundamental cause of cancer (the Warburg hypothesis). Today, most researchers believe that mutations in oncogenes and tumor-suppressor genes are more likely to be responsible for malignant transformation. The Warburg effect is thus considered to be a result of these mutations –– rather than the cause of cancer.

Aerobic glycolysis is a metabolic hallmark of activated T cells, and has been implicated in augmenting effector T cell responses –– including expression of the proinflammatory cytokine interferon-g (IFNg), via 3 untranslated region (3UTR)mediated mechanisms. In the report attached, authors show that lactate dehydrogenase-A (LDHA) is induced in activated T cells to support aerobic glycolysis, but promotes IFNg expression, independently of its 3UTR. Instead, LDHA maintains high concentrations of acetylcoenzyme-A to enhance histone acetylation and transcription of the mouse Ifng gene. Ablation of LDHA in T cells protects mice from immunopathology triggered by excessive IFNg expression or deficiency of regulatory T cells. These exciting findings are consistent with an epigenetic mechanism being the reason why aerobic glycolysis encourages effector T cell differentiation. Thus, these data suggest that LDHA might be a drug target in autoinflammatory diseases.

Science   28 Oct 2o16; 354: 481-484

This entry was posted in Center for Environmental Genetics, Evolution and genetics, Gene environment interactions. Bookmark the permalink.