Mutations of the mitochondrial DNA (mtDNA) have been identified in several neuro-ophthalmological, neurological and, in neuromuscular diseases. However, the detailed molecular events associated with the pathology of these untreatable disorders are still poorly understood. These mutations occur in protein coding, tRNA or rRNA genes and have the common feature of impairing energy production in affected tissues. In the last three years we produced and characterized a large number of established cell lines containing different pathogenic mtDNA mutation, most of which affect tRNA genes. We propose to continue to characterize disease-related mtDNA alterations and use this collection of cell lines as a paradigm to study genotype-phenotype correlations. We will compare the activity of individual respiratory complexes, potential oxidative damage, and RNA and DNA metabolism in fourteen cell lines containing either wild-type mtDNA or one of nine different mtDNA alterations. We also propose to develop new approaches to ameliorate the phenotypic consequences of mtDNA mutations. This will be attempted by expressing modulatory genes into the nucleus of cells harboring pathogenic mtDNA mutations. These genes include: aminoacyl tRNA synthetase, re-coded mitochondrial genes and putative second-site functional suppressors currently under investigation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010804-07
Application #
6384413
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Hunter, Chyren
Project Start
1994-12-01
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
7
Fiscal Year
2001
Total Cost
$244,891
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Miami
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
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
Peralta, Susana; Garcia, Sofia; Yin, Han Yang et al. (2016) Sustained AMPK activation improves muscle function in a mitochondrial myopathy mouse model by promoting muscle fiber regeneration. Hum Mol Genet 25:3178-3191
Pinto, Milena; Nissanka, Nadee; Peralta, Susana et al. (2016) Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuroinflammation. Mol Neurodegener 11:25

Showing the most recent 10 out of 88 publications