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.


Available from: Outi Kopra
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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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    ABSTRACT: Decline in metabolism and regenerative potential of tissues are common characteristics of aging. Regeneration is maintained by somatic stem cells (SSCs), which require tightly controlled energy metabolism and genomic integrity for their homeostasis. Recent data indicate that mitochondrial dysfunction may compromise this homeostasis, and thereby contribute to tissue degeneration and aging. Progeroid Mutator mouse, accumulating random mtDNA point mutations in their SSCs, showed disturbed SSC homeostasis, emphasizing the importance of mtDNA integrity for stem cells. The mechanism involved changes in cellular redox-environment, including subtle increase in reactive oxygen species (H2O2 and superoxide anion), which did not cause oxidative damage, but disrupted SSC function. Mitochondrial metabolism appears therefore to be an important regulator of SSC fate determination, and defects in it in SSCs may underlie premature aging. Here we review the current knowledge of mitochondrial contribution to SSC dysfunction and aging. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; 1847(11). DOI:10.1016/j.bbabio.2015.05.014 · 4.66 Impact Factor
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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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    ABSTRACT: Aging is a progressive decline of body function, during which many tissues accumulate few cells with high levels of deleted mitochondrial DNA (mtDNA), leading to a defect of mitochondrial functions. Whether this mosaic mitochondrial deficiency contributes to organ dysfunction is unknown. To investigate this, we generated mice with an accelerated accumulation of mtDNA deletions in the myocardium, by expressing a dominant-negative mutant mitochondrial helicase. These animals accumulated few randomly distributed cardiomyocytes with compromised mitochondrial function, which led to spontaneous ventricular premature contractions and AV blocks at 18 months. These symptoms were not caused by a general mitochondrial dysfunction in the entire myocardium, and were not observed in mice at 12 months with significantly lower numbers of dysfunctional cells. Therefore, our results suggest that the disposition to arrhythmia typically found in the aged human heart might be due to the random accumulation of mtDNA deletions and the subsequent mosaic respiratory chain deficiency. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 05/2015; 21(5):667-77. DOI:10.1016/j.cmet.2015.04.005 · 17.57 Impact Factor
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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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    ABSTRACT: Defects of mitochondrial respiration and function had been proposed as a major culprit in the most common neurodegenerative diseases, including prototypic diseases of central nervous system (CNS) white matter such as multiple sclerosis. The importance of mitochondria for white matter is best exemplified in a group of defects of the mitochondria oxidative metabolism called mitochondria leukoencephalopathies or encephalomyopathies. These diseases are clinically and genetically heterogeneous, given the dual control of the respiratory chain by nuclear and mitochondrial DNA, which makes the precise diagnosis and classification challenging. Our understanding of disease pathogenesis is nowadays still limited. Here, we review current knowledge on pathogenesis and genetics, outlining diagnostic clues for the various forms of mitochondria disease. In particular, we underscore the value of magnetic resonance imaging (MRI) for the differential diagnosis of specific types of mitochondrial leukoencephalopathies, such as genetic defects on SDHFA1. The use of novel technologies for gene identification, such as whole-exome sequencing studies, is expected to shed light on novel molecular etiologies, broadening prenatal diagnosis, disease understanding, and therapeutic options. Current treatments are mostly palliative, but very promising novel gene and pharmacologic therapies are emerging, which may also benefit a growing list of secondary mitochondriopathies, such as the peroxisomal disease adrenoleukodystrophy. GLIA 2014.
    Glia 11/2014; 62(11). DOI:10.1002/glia.22670 · 6.03 Impact Factor
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