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Journal Article

Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in polg mutator mice.

MPS-Authors

Ahlqvist, Kati J
Max Planck Society;

Hämäläinen, Riikka H
Max Planck Society;

Yatsuga, Shuichi
Max Planck Society;

Uutela, Marko
Max Planck Society;

Terzioglu, Mügen
Max Planck Society;

Götz, Alexandra
Max Planck Society;

Forsström, Saara
Max Planck Society;

Salven, Petri
Max Planck Society;

Angers-Loustau, Alexandre
Max Planck Society;

Kopra, Outi H
Max Planck Society;

Tyynismaa, Henna
Max Planck Society;

Larsson, Nils-Göran
Max Planck Society;

Wartiovaara, Kirmo
Max Planck Society;

Prolla, Tomas
Max Planck Society;

Trifunovic, Aleksandra
Max Planck Society;

Suomalainen, Anu
Max Planck Society;

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Citation

Ahlqvist, K. J., Hämäläinen, R. H., Yatsuga, S., Uutela, M., Terzioglu, M., Götz, A., et al. (2012). Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in polg mutator mice. Cell Metab, 15(1), 100-109.

Abstract

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.