The mitochondrial H(+)-ATP synthase and the lipogenic switch: new core components of metabolic reprogramming in induced pluripotent stem (iPS) cells.

摘要: Induced pluripotent stem (iPS) cells share some basic properties, such as self-renewal and pluripotency, with cancer cells, they also appear to several metabolic alterations that are commonly observed in human tumors. The cells' glycolytic phenotype, first reported by Otto Warburg, is necessary for the optimal routing of somatic pluripotency. However, how iPS establish a Warburg-like phenotype whether pathways support bioenergetics produced same mechanisms selected during tumorigenic process remain largely unexplored. We recently investigated reprogramming-competent metabotype involves changes activation/expression status H(+)-ATPase, which core component mitochondrial oxidative phosphorylation repressed at both activity protein levels carcinomas, lipogenic switch, refers marked overexpression hyperactivity acetyl-CoA carboxylase (ACACA) fatty acid synthase (FASN) enzymes has been nearly all examined types. A comparison starting population mouse embryonic fibroblasts their cell progeny revealed reprogramming significant increase expression ATPase inhibitor factor 1 (IF1), accompanied extremely low catalytic β-F1-ATPase subunit. pharmacological inhibition ACACA FASN activities markedly decreases efficiency, notably upregulated cells. Importantly, exhibited intracellular accumulation neutral lipid bodies; however, these bodies may be reflection intense lysosomal/autophagocytic rather than bona fide droplet formation were unresponsive modulation PPARgamma activities. AMPK agonist metformin, endows bioenergetic infrastructure protected against reprogramming, was found drastically elongate fibroblast mitochondria, fully reverse high IF1/β-F1-ATPase ratio downregulate ACACA/FASN H(+)-ATP ACACA/FASN-driven switch newly characterized instrumental events that, coupling Warburg effect anabolic metabolism, enable de-differentiation