Abstract
We observed that the transient induction of mtDNA double strand breaks (DSBs) in cultured cells led to activation of cell cycle arrest proteins (p21/p53 pathway) and decreased cell growth, mediated through reactive oxygen species (ROS). To investigate this process in vivo we developed a mouse model where we could transiently induce mtDNA DSBs ubiquitously. This transient mtDNA damage in mice caused an accelerated aging phenotype, preferentially affecting proliferating tissues. One of the earliest phenotypes was accelerated thymus shrinkage by apoptosis and differentiation into adipose tissue, mimicking age-related thymic involution. This phenotype was accompanied by increased ROS and activation of cell cycle arrest proteins. Treatment with antioxidants improved the phenotype but the knocking out of p21 or p53 did not. Our results demonstrate that transient mtDNA DSBs can accelerate aging of certain tissues by increasing ROS. Surprisingly, this mtDNA DSB-associated senescence phenotype does not require p21/p53, even if this pathway is activated in the process.
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Abbreviations
- mtDNA:
-
mitochondrial DNA
- DSBs:
-
double strand breaks
- ROS:
-
reactive oxygen species
- OXPHOS:
-
oxidative phosphorylation
- COX8:
-
cytochrome c oxidase subunit VIII
- Cdkn1a :
-
cyclin-dependent kinase Inhibitor 1 A (p21/Cip1)
- MDM2:
-
Mouse double minute 2
- NAC:
-
N-acetyl-cysteine
- TUNEL:
-
terminal deoxynucleotidyl transferase dUTP nick end labeling
- DOX:
-
doxycycline
- DEXA:
-
dual-energy X-ray absorptiometry
- DN:
-
double negative, CD4−/CD8−
- DP:
-
double positive CD4+/CD8+
- PGC:
-
peroxisome proliferator activated receptor gamma coactivators
- PPARγ:
-
peroxisome proliferator activated receptor gamma
- ADRP:
-
adipose differentiation related protein
- SystemicIndmito-PstI:
-
systemic-inducible mitochondrial-targeted PstI
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Acknowledgements
We would like to thank Dr. Wayne E. Balkan from the University of Miami for the access to and the use of the DEXA scan; Dr. Norman H. Altman VMD for consultation on thymus pathology, Dr. Ying Wang, and Dr. Ge Tao from the University of Miami for antibodies and technical assistance. We also thank the University of Miami Comparative Pathology Laboratory for the blood work analysis. This work was supported primarily by the US National Institutes of Health Grant 1R01AG036871. The following grants also helped support this work: NIH 1R01NS079965, 5R01EY010804; the Muscular Dystrophy Association and the United Mitochondrial Disease Foundation. We acknowledge support from the NEI center grant P30-EY014801 from the National Institutes of Health (NIH).
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Pinto, M., Pickrell, A., Wang, X. et al. Transient mitochondrial DNA double strand breaks in mice cause accelerated aging phenotypes in a ROS-dependent but p53/p21-independent manner. Cell Death Differ 24, 288–299 (2017). https://doi.org/10.1038/cdd.2016.123
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DOI: https://doi.org/10.1038/cdd.2016.123
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