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The mitochondrial H+-ATP synthase and the lipogenic switch

New core components of metabolic reprogramming in induced pluripotent stem (iPS) cells

, , , , , , , & show all
Pages 207-218 | Published online: 15 Jan 2012
 

Abstract

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

Acknowledgments

We are indebted to Prof. Carlos Lopez-Otin and his team [Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain] for providing most of the reagents and descriptions of the procedures used in this work. Soraphen A, purified from the myxobacterium S. cellulosum, was provided by Drs. Klaus Gerth and Rolf Jansen (Hemholtz Zentrum für Infektionsforschung GmbH). This work was financially supported by the Instituto de Salud Carlos III [Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), grants CP05-00090, PI06-0778 and RD06-0020-0028], the Fundación Científica de la Asociación Española Contra el Cáncer (AECC) and the Ministerio de Ciencia e Innovación (SAF2009-11579, Plan Nacional de I+D+ I, MICINN). A.V.-M. received a Sara Borrell post-doctoral contract (CD08/00283, Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria -FIS-). S.C. received a research fellowship (Formación de Personal Investigador, FPI) from the Ministerio de Ciencia e Innovación (MICINN).

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