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

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.

MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction

“…For example, Deletor mice 12 carry a mutation in the nuclear-encoded replicative Twinkle helicase, leading to subtle progressive accumulation of secondary multiple mtDNA deletions after 1 year of age. These mice only show mtDNA mutagenesis in postmitotic tissues, not in SSCs, and accordingly do not develop anaemia 9 .…”

“…In Mutators, the redox-active antioxidant N-Acetyl-L-cysteine (NAC) rescued the erythroid and lymphoid differentiation in embryonal haematopoiesis, indicating that subtle increases in ROS signalling by mtDNA mutagenesis disturbed SSC homoeostasis 9 .…”

“…These mice show aberrant hematopoiesis that initiates in embryogenesis and is progressive, developing anaemia and leucopenia after 6 months of age ultimately restricting their lifespan to about 50 weeks of age 9 . However, even on terminalstage anaemia the Mutator bone marrow contains all the different erythroid progenitor populations and the total cellularity is not decreased 9,10 . Therefore, exhaustion of the haematopoietic stem cell (HSC) pool does not account for the severe anaemia of these mice.…”

“…Similar to patients with Pearson's syndrome, mice carrying a heteroplasmic primary single mtDNA deletion (Mitomice) develop anaemia and kidney dysfunction, and die at 6 months of age 5,6 . Anaemia is also a manifestation of the progeroid mtDNA mouse model known as the 'Mutator', which harbours a proof-reading deficient mtDNA polymerase gamma (PolG) that leads to increased random mtDNA mutagenesis in all cell types, including somatic stem cells (SSCs) [7][8][9] . These mice show aberrant hematopoiesis that initiates in embryogenesis and is progressive, developing anaemia and leucopenia after 6 months of age ultimately restricting their lifespan to about 50 weeks of age 9 .…”

“…Anaemia is also a manifestation of the progeroid mtDNA mouse model known as the 'Mutator', which harbours a proof-reading deficient mtDNA polymerase gamma (PolG) that leads to increased random mtDNA mutagenesis in all cell types, including somatic stem cells (SSCs) [7][8][9] . These mice show aberrant hematopoiesis that initiates in embryogenesis and is progressive, developing anaemia and leucopenia after 6 months of age ultimately restricting their lifespan to about 50 weeks of age 9 . However, even on terminalstage anaemia the Mutator bone marrow contains all the different erythroid progenitor populations and the total cellularity is not decreased 9,10 .…”