mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling.

TitlemtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling.
Publication TypeJournal Article
Year of Publication2015
AuthorsHämäläinen, RH, Ahlqvist, KJ, Ellonen, P, Lepistö, M, Logan, A, Otonkoski, T, Murphy, MP, Suomalainen, A
JournalCell Rep
Volume11
Issue10
Pagination1614-24
Date Published2015 Jun 16
ISSN2211-1247
KeywordsAnimals, Cell Differentiation, DNA, Mitochondrial, Female, Male, Mice, Mutagenesis, Oxidation-Reduction, Pluripotent Stem Cells, Reactive Oxygen Species, Signal Transduction
Abstract

mtDNA mutagenesis in somatic stem cells leads to their dysfunction and to progeria in mouse. The mechanism was proposed to involve modification of reactive oxygen species (ROS)/redox signaling. We studied the effect of mtDNA mutagenesis on reprogramming and stemness of pluripotent stem cells (PSCs) and show that PSCs select against specific mtDNA mutations, mimicking germline and promoting mtDNA integrity despite their glycolytic metabolism. Furthermore, mtDNA mutagenesis is associated with an increase in mitochondrial H2O2, reduced PSC reprogramming efficiency, and self-renewal. Mitochondria-targeted ubiquinone, MitoQ, and N-acetyl-L-cysteine efficiently rescued these defects, indicating that both reprogramming efficiency and stemness are modified by mitochondrial ROS. The redox sensitivity, however, rendered PSCs and especially neural stem cells sensitive to MitoQ toxicity. Our results imply that stem cell compartment warrants special attention when the safety of new antioxidants is assessed and point to an essential role for mitochondrial redox signaling in maintaining normal stem cell function.

DOI10.1016/j.celrep.2015.05.009
Alternate JournalCell Rep
Citation Key10.1016/j.celrep.2015.05.009
PubMed ID26027936
PubMed Central IDPMC4509707
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom