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Somatic Cells with a Heavy Mitochondrial DNA Mutational Load Render Induced Pluripotent Stem Cells with Distinct Differentiation Defects
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.ORCID iD: 0000-0001-6085-6749
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2014 (English)In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 32, no 5, 1173-1182 p.Article in journal (Refereed) Published
Abstract [en]

It has become increasingly clear that several age-associated pathologies associate with mutations in the mitochondrial genome. Experimental modeling of such events has revealed that acquisition of mitochondrial DNA (mtDNA) damage can impair respiratory function and, as a consequence, can lead to widespread decline in cellular function. This includes premature aging syndromes. By taking advantage of a mutator mouse model with an error-prone mtDNA polymerase, we here investigated the impact of an established mtDNA mutational load with regards to the generation, maintenance, and differentiation of induced pluripotent stem (iPS) cells. We demonstrate that somatic cells with a heavy mtDNA mutation burden were amenable for reprogramming into iPS cells. However, mutator iPS cells displayed delayed proliferation kinetics and harbored extensive differentiation defects. While mutator iPS cells had normal ATP levels and glycolytic activity, the induction of differentiation coincided with drastic decreases in ATP production and a hyperactive glycolysis. These data demonstrate the differential requirements of mitochondrial integrity for pluripotent stem cell self-renewal versus differentiation and highlight the relevance of assessing the mitochondrial genome when aiming to generate iPS cells with robust differentiation potential. Stem Cells 2014;32:1173-1182

Place, publisher, year, edition, pages
2014. Vol. 32, no 5, 1173-1182 p.
Keyword [en]
DNA mutations, Mitochondria, Reprogramming Aging
National Category
Cell Biology Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-225013DOI: 10.1002/stem.1630ISI: 000334597200012OAI: oai:DiVA.org:uu-225013DiVA: diva2:719600
Available from: 2014-05-26 Created: 2014-05-26 Last updated: 2017-12-05Bibliographically approved

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Ameur, Adam

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