A progressive decline in mitochondrial oxidative phosphorylation function during life is a likely contributor to neurodegeneration. However, the understanding of the mechanisms involved in the mitochondrial defects is still rudimentary and practical approaches to mitigate this problem are not available. Our project will study these two aspects of mitochondrial involvement in neurodegeneration and aging. In the first part, we propose to study the role of mitochondrial DNA (mtDNA) deletions in the aging of the brain. We will use a novel mouse developed in our laboratory in which a mitochondria targeted restriction endonuclease (Mito-PstI) is expressed in a tissue-specific and inducible fashion. The double-strand breaks elicited by Mito-PstI lead to recombination and deletion formation. We will generate mtDNA deletions in the CNS or ubiquitously. The role of the mitochondrial polymerase gamma in repairing these double-strand breaks will also be analyzed. The goal of this aim is to study the functional consequences of accumulating different levels of mtDNA deletions during neurodegeneration and aging. In the second part of the proposal, we will develop approaches to mitigate the aging of CNS and other tissues by increasing the expression of PGC-1a, either in skeletal muscle or ubiquitously. This will be achieved by stable and inducible expression. The effect of PGC-1a will be tested both in normal aging mice and in the proof-reading deficient polymerase gamma """"""""mutator mouse"""""""". The latter is a model of accelerated aging.
Both aims are based on extensive published and unpublished preliminary data. We are confident that the accomplishment of these two aims will lead to not only a better understanding of the role of mitochondrial defects in age-related neurodegeneration but also to novel approaches to counteract these effects.

Public Health Relevance

Mitochondria is believed to play a major role in neurodegeneration and aging. By better understanding the mechanisms involved in this process and by developing approaches to counteract these effects, the debilitating effects of the neurodegenerative process could be mitigated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG036871-01
Application #
7867471
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Finkelstein, David B
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$314,675
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
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
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:
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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