During the course of accomplishing the previous specific aims, we found that a relatively brief expression of a mitochondrial targeted restriction endonuclease, ubiquitously in mice, generates double strand breaks (DSB) in the mtDNA of the different tissues. MtDNA levels recovered from this transient event and no abnormal phenotypes were observed in the weeks following the molecular insult. However, later in life mice developed a phenotype resembling accelerated aging. Initial characterization showed a reduction in progenitor cell pools. These observations, together with other recent reports led us to hypothesize that progenitor cells are targets of mtDNA damage. We also obtained preliminary data showing that p53-associated pathways are involved in the mechanism leading to a reduction of progenitor cell pools after mtDNA transient insults. We propose a series of experiments to rigorously test this hypothesis in mouse and cultured cells. We will also develop a valuable model of mice with heteroplasmic mtDNA deletions, which will be used to unveil the role of mtDNA deletions in aging. These models will be shared with the research community. We expect that these studies will increase our understanding the role of mtDNA damage in aging.
The role of mitochondrial DNA (mtDNA) damage to the aging process is poorly understood. This project will explore whether stem/progenitor cells pools are reduced when mtDNA is damaged. We will also study the molecular mechanisms involved. This reduction in stem/progenitor cells pools would lead to accelerated aging. In addition, we will develop a mouse model that accumulates mtDNA deletions with age. A better understanding of this process could lead to interventions to promote healthy aging.
Showing the most recent 10 out of 43 publications
