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Article first published online: 19 AUG 2011
Copyright © 2011 AlphaMed Press
Volume 29, Issue 9, pages 1338–1348, September 2011
How to Cite
Prigione, A., Lichtner, B., Kuhl, H., Struys, E. A., Wamelink, M., Lehrach, H., Ralser, M., Timmermann, B. and Adjaye, J. (2011), Human Induced Pluripotent Stem Cells Harbor Homoplasmic and Heteroplasmic Mitochondrial DNA Mutations While Maintaining Human Embryonic Stem Cell–like Metabolic Reprogramming. STEM CELLS, 29: 1338–1348. doi: 10.1002/stem.683
Author contributions: A.P.: conception and design, data collection, analysis and interpretation, manuscript writing; B.L., H.K., E.A.S., and M.W.: data collection; H.L.: infrastructure support; M.R.: data interpretation; B.T.: data collection and interpretation; J.A.: data interpretation, manuscript editing.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS July 5, 2011.
- Issue published online: 19 AUG 2011
- Article first published online: 19 AUG 2011
- Accepted manuscript online: 5 JUL 2011 04:13PM EST
- Manuscript Accepted: 15 JUN 2011
- Manuscript Received: 2 FEB 2011
- BMBF. Grant Number: 01GN0807
- Max Planck Society
- Induced pluripotent stem cells;
- Mitochondrial DNA;
- Pyruvate dehydrogenase kinase 1
Human induced pluripotent stem cells (iPSCs) have been recently found to harbor genomic alterations. However, the integrity of mitochondrial DNA (mtDNA) within reprogrammed cells has yet to be investigated. mtDNA mutations occur at a high rate and contribute to the pathology of a number of human disorders. Furthermore, the lack of mtDNA integrity may alter cellular bioenergetics and limit efficient differentiation. We demonstrated previously that the derivation of iPSCs is associated with mitochondrial remodeling and a metabolic switch towards glycolysis. Here, we have discovered that alterations of mtDNA can occur upon the induction of pluripotency. Massively parallel pyrosequencing of mtDNA revealed that human iPSCs derived from young healthy donors harbored single base mtDNA mutations (substitutions, insertions, and deletions), both homoplasmic (in all mtDNA molecules) and heteroplasmic (in a fraction of mtDNAs), not present in the parental cells. mtDNA modifications were mostly common variants and not disease related. Moreover, iPSC lines bearing different mtDNA mutational loads maintained a consistent human embryonic stem cell–like reprogramming of energy metabolism. This involved the upregulation of glycolytic enzymes, increased glucose-6-phosphate levels, and the over-expression of pyruvate dehydrogenase kinase 1 protein, which reroutes the bioenergetic flux toward glycolysis. Hence, mtDNA mutations within iPSCs may not necessarily impair the correct establishment of pluripotency and the associated metabolic reprogramming. Nonetheless, the occurrence of pathogenic mtDNA modifications might be an important aspect to monitor when characterizing iPSC lines. Finally, we speculate that this random rearrangement of mtDNA molecules might prove beneficial for the derivation of mutation-free iPSCs from patients with mtDNA disorders. STEM CELLS 2011; 29:1338–1348