Somatic Cells with a Heavy Mitochondrial DNA Mutational Load Render Induced Pluripotent Stem Cells with Distinct Differentiation Defects

• Published in: Stem cells (Dayton, Ohio) Ohio), 2014-05, Vol.32 (5), p.1173-1182
• Main Authors: Wahlestedt, Martin, Ameur, Adam, Moraghebi, Roksana, Norddahl, Gudmundur L., Sten, Gerd, Woods, Niels‐Bjarne, Bryder, David
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Cell Differentiation - genetics; Cells, Cultured; Cellular Reprogramming - genetics; Deoxyribonucleic acid; DNA; DNA mutations; DNA Polymerase gamma; DNA, Mitochondrial - genetics; DNA-Directed DNA Polymerase - genetics; Genomes; Glycolysis - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Interleukin Receptor Common gamma Subunit - deficiency; Interleukin Receptor Common gamma Subunit - genetics; Kruppel-Like Transcription Factors - genetics; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Microscopy, Electron, Transmission; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - ultrastructure; Mitochondrial DNA; Mutation; Octamer Transcription Factor-3 - genetics; Reprogramming Aging; Reverse Transcriptase Polymerase Chain Reaction; SOXB1 Transcription Factors - genetics; Stem cells
• ISSN: 1066-5099; 1549-4918; 1549-4918
• DOI: 10.1002/stem.1630

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