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) an...

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Published inCell metabolism Vol. 15; no. 1; pp. 100 - 109
Main Authors Ahlqvist, Kati J., Hämäläinen, Riikka H., Yatsuga, Shuichi, Uutela, Marko, Terzioglu, Mügen, Götz, Alexandra, Forsström, Saara, Salven, Petri, Angers-Loustau, Alexandre, Kopra, Outi H., Tyynismaa, Henna, Larsson, Nils-Göran, Wartiovaara, Kirmo, Prolla, Tomas, Trifunovic, Aleksandra, Suomalainen, Anu
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 04.01.2012
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Summary: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. ► Somatic stem cells are vulnerable to increased mitochondrial DNA mutagenesis ► Subtle changes in physiological ROS/redox signaling modulate NSC and HPC function ► MtDNA mutagenesis in SSCs contributes to premature aging in mice
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ISSN:1550-4131
1932-7420
1932-7420
DOI:10.1016/j.cmet.2011.11.012