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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG036871-09
Application #
9643986
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Fridell, Yih-Woei
Project Start
2010-06-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Nissanka, Nadee; Moraes, Carlos T (2018) Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease. FEBS Lett 592:728-742
Pinto, Milena; Nissanka, Nadee; Moraes, Carlos T (2018) Lack of Parkin Anticipates the Phenotype and Affects Mitochondrial Morphology and mtDNA Levels in a Mouse Model of Parkinson's Disease. J Neurosci 38:1042-1053
Pereira, Claudia V; Bacman, Sandra R; Arguello, Tania et al. (2018) mitoTev-TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels. EMBO Mol Med 10:
Peralta, Susana; Goffart, Steffi; Williams, Sion L et al. (2018) ATAD3 controls mitochondrial cristae structure in mouse muscle, influencing mtDNA replication and cholesterol levels. J Cell Sci 131:
Garcia, Sofia; Nissanka, Nadee; Mareco, Edson A et al. (2018) Overexpression of PGC-1? in aging muscle enhances a subset of young-like molecular patterns. Aging Cell 17:
Arguello, Tania; Köhrer, Caroline; RajBhandary, Uttam L et al. (2018) Mitochondrial methionyl N-formylation affects steady-state levels of oxidative phosphorylation complexes and their organization into supercomplexes. J Biol Chem 293:15021-15032
Madsen, Pernille M; Pinto, Milena; Patel, Shreyans et al. (2017) Mitochondrial DNA Double-Strand Breaks in Oligodendrocytes Cause Demyelination, Axonal Injury, and CNS Inflammation. J Neurosci 37:10185-10199
Pinto, Milena; Pickrell, Alicia M; Wang, Xiao et al. (2017) 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
Tengan, Celia H; Moraes, Carlos T (2017) NO control of mitochondrial function in normal and transformed cells. Biochim Biophys Acta Bioenerg 1858:573-581
Guarás, Adela; Perales-Clemente, Ester; Calvo, Enrique et al. (2016) The CoQH2/CoQ Ratio Serves as a Sensor of Respiratory Chain Efficiency. Cell Rep 15:197-209

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