Our long-term goal is to develop genetic approaches that could be used for the treatment of mitochondrial disorders associated with mitochondrial DNA (mtDNA) mutations. Although some of the approaches tested in the past showed some promise, they are inefficient and unlikely to reach clinical trials. We propose to develop approaches that are more efficient in improving oxidative phosphorylation in cells harboring heteroplasmic mtDNA mutations (i.e. a mixture of wild-type and mutated mtDNA). The approach is based on the """"""""mtDNA heteroplasmy shift"""""""" concept, where, by genetic manipulation, levels of the wild-type genome are increased in relation to the mutated genome. In the previous funding period we showed that mitochondria-targeted specific endonucleases are powerful tools to achieve mtDNA heteroplasmy shift. The present proposal will continue to develop this approach. We will deliver mitochondria targeted restriction endonucleases systemically to muscle of a mouse model of mtDNA heteroplasmy and expect to see a generalized shift in mtDNA heteroplasmy in skeletal muscle. To expand the use of mitochondria nucleases, we will create novel zinc finger protein nucleases that can target common mtDNA mutations associated with mitochondrial disorders. When this approach moves into the clinical arena, it will be important to avoid secondary effects with potential clinical relevance, such as transient mtDNA depletion. To this end, we will test a model whereby the levels of mtDNA are increased (per cell) before the action of the specific mitochondrial restriction endonuclease. This should minimize a potential bioenergetic crisis associated with partial mtDNA depletion.
Mitochondrial disorders are devastating diseases affecting the central nervous system, eyes, muscle and several other organ systems. At present, there are no treatments for mitochondrial disorders. We propose to develop a genetic approach that could be used as a therapy for a sub-group of mitochondrial disorders.
|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|
|Tengan, Celia H; Moraes, Carlos T (2017) NO control of mitochondrial function in normal and transformed cells. Biochim Biophys Acta 1858:573-581|
|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|
|Luo, Xueting; Ribeiro, Marcio; Bray, Eric R et al. (2016) Enhanced Transcriptional Activity and Mitochondrial Localization of STAT3 Co-induce Axon Regrowth in the Adult Central Nervous System. Cell Rep 15:398-410|
|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|
|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; Moraes, Carlos T (2015) Mechanisms linking mtDNA damage and aging. Free Radic Biol Med 85:250-8|
|Reddy, Pradeep; Ocampo, Alejandro; Suzuki, Keiichiro et al. (2015) Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 161:459-469|
|(2015) Retraction Notice to: mTERF2 Regulates Oxidative Phosphorylation by Modulating mtDNA Transcription. Cell Metab 22:751|
|Hashimoto, Masami; Bacman, Sandra R; Peralta, Susana et al. (2015) MitoTALEN: A General Approach to Reduce Mutant mtDNA Loads and Restore Oxidative Phosphorylation Function in Mitochondrial Diseases. Mol Ther 23:1592-9|
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