Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in Polg mutator mice.
Somatic stem cell (SSC) dysfunction is typical for different progeroid phenotypes in mice with genomic DNA repair defects. MtDNA mutagenesis in mice with defective Polg exonuclease activity also leads to progeroid symptoms, by an unknown mechanism. We found that Polg-Mutator mice had neural (NSC) and hematopoietic progenitor (HPC) dysfunction already from embryogenesis. NSC self-renewal was decreased in vitro, and quiescent NSC amounts were reduced in vivo. HPCs showed abnormal lineage differentiation leading to anemia and lymphopenia. N-acetyl-L-cysteine treatment rescued both NSC and HPC abnormalities, suggesting that subtle ROS/redox changes, induced by mtDNA mutagenesis, modulate SSC function. Our results show that mtDNA mutagenesis affected SSC function early but manifested as respiratory chain deficiency in nondividing tissues in old age. Deletor mice, having mtDNA deletions in postmitotic cells and no progeria, had normal SSCs. We propose that SSC compartment is sensitive to mtDNA mutagenesis, and that mitochondrial dysfunction in SSCs can underlie progeroid manifestations.
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.
Kati J
KJ
Ahlqvist
Riikka H
RH
Hämäläinen
Shuichi
S
Yatsuga
Marko
M
Uutela
Mügen
M
Terzioglu
Alexandra
A
Götz
Saara
S
Forsström
Petri
P
Salven
Alexandre
A
Angers-Loustau
Outi H
OH
Kopra
Henna
H
Tyynismaa
Nils-Göran
NG
Larsson
Kirmo
K
Wartiovaara
Tomas
T
Prolla
Aleksandra
A
Trifunovic
Anu
A
Suomalainen
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004579:Electron Transport; D004920:Erythropoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D038041:Lymphopoiesis; D051379:Mice; D008817:Mice, Mutant Strains; D028361:Mitochondrial Diseases / Q000473:pathology; D016296:Mutagenesis; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D000111:Acetylcysteine