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Both aims are based on extensive published and unpublished preliminary data.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 #
5R01AG036871-04
Application #
8466269
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
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$284,898
Indirect Cost
$98,690
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
Pinto, Milena; Moraes, Carlos T (2014) Mitochondrial genome changes and neurodegenerative diseases. Biochim Biophys Acta 1842:1198-207
Bacman, Sandra R; Williams, Sion L; Pinto, Milena et al. (2014) The use of mitochondria-targeted endonucleases to manipulate mtDNA. Methods Enzymol 547:373-97
Moraes, Carlos T; Bacman, Sandra R; Williams, Sion L (2014) Manipulating mitochondrial genomes in the clinic: playing by different rules. Trends Cell Biol 24:209-11
Peralta, Susana; Torraco, Alessandra; Wenz, Tina et al. (2014) Partial complex I deficiency due to the CNS conditional ablation of Ndufa5 results in a mild chronic encephalopathy but no increase in oxidative damage. Hum Mol Genet 23:1399-412
Wang, Xiao; Peralta, Susana; Moraes, Carlos T (2013) Mitochondrial alterations during carcinogenesis: a review of metabolic transformation and targets for anticancer treatments. Adv Cancer Res 119:127-60
Pickrell, Alicia M; Pinto, Milena; Moraes, Carlos T (2013) Mouse models of Parkinson's disease associated with mitochondrial dysfunction. Mol Cell Neurosci 55:87-94
Pinto, Milena; Pickrell, Alicia M; Fukui, Hirokazu et al. (2013) Mitochondrial DNA damage in a mouse model of Alzheimer's disease decreases amyloid beta plaque formation. Neurobiol Aging 34:2399-407
Moraes, Carlos T (2013) Adrenoleukodystrophy and the mitochondrial connection: clues for supplementing Lorenzo's oil. Brain 136:2339-41
Bacman, Sandra R; Williams, Sion L; Pinto, Milena et al. (2013) Specific elimination of mutant mitochondrial genomes in patient-derived cells by mitoTALENs. Nat Med 19:1111-3
Wang, Xiao; Pickrell, Alicia M; Rossi, Susana G et al. (2013) Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool. Hum Mol Genet 22:3976-86

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