Somatic Progenitor Cell Vulnerability to Mitochondrial DNA Mutagenesis Underlies Progeroid Phenotypes in Polg Mutator Mice

Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, 00290 Helsinki, Finland.
Cell metabolism (Impact Factor: 17.57). 01/2012; 15(1):100-9. DOI: 10.1016/j.cmet.2011.11.012
Source: PubMed


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.

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    • "The sensitivity of the stem cell pool to subtle changes in ROS levels makes SSCs also sensitive to antioxidants. While n-acetyl-l-cysteine treatment rescued both the NSC and HPC phenotypes in mtDNA Mutator embryos in vivo [23], treatment with mitochondria-targeted ubiquinone (MitoQ) had contradictory effects on SSCs, and rescued the Mutator HPC phenotype but was harmful to NSCs, both Mutator and wild-type, in the same embryos [39]. MitoQ, a strong antioxidant that accumulates several hundred-fold within mitochondria, was more potent than NAC in ameliorating self-renewal of Mutator stem cells in vitro but showed dose-dependent toxicity to both NSCs and iPSCs also in vitro, with NSCs being most vulnerable [39]. "
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    • "No statistical difference in mtDNA copy number could be observed between COX pos cells from mutant and control animals at both checked time points. Point mutation rates remain as yet unknown in the context of our study, but previous Twinkle mouse models showed no increased incidence of point mutations in heart, muscle, and neural progenitor cells (Ahlqvist et al., 2012; Tyynismaa et al., 2005). Moreover, quantification of the total deletion loads in three different pools from COX pos and COX neg cells of 18-month-old K320E- Twinkle Myo mice by single-molecule PCR revealed percentages of 85% ± 18% of mutated mtDNA in the COX neg cells and 2.3% ± 0.6% in the COX pos cells (p < 0.05). "
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    • "imals have aberrant mitochondria in the brain , concomitant with oxidative damage to proteins and a progressive glial activation that induces neuronal death ( Quintana et al . , 2010 ) . In the Pol - gamma - Mutator mice , the animal model for Alper ' s syndrome , ROS production induced by mtDNA mutagenesis triggers neural stem cells dysfunction ( Ahlqvist et al . , 2012 ) . Moreover , a newly described animal model for LHON exhibits smaller caliber optic nerve fibers with neuronal accumulation of abnormal mitochondria , axo - nal swelling , and demyelination . It is worth noting that in these animals , oxidative stress , rather than energy deficiency , appears to be the key factor in the pathogenesis s"
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