title: mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling.
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.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Riikka H
authors.initials: RH
authors.lastname: Hämäläinen
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Ahlqvist
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.affiliation: Institute for Molecular Medicine Finland, FIMM, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Lepistö
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, 00290 Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.affiliation: Medical Research Council Mitochondrial Biology Unit, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland; Department of Neurology, Helsinki University Central Hospital, 00290 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00290 Helsinki, Finland. Electronic address: anu.wartiovaara@helsinki.fi.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D016296:Mutagenesis; D010084:Oxidation-Reduction; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species