Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been associated with various primary mitochondrial diseases as well as with neurodegenerative disorders. Such disorders can be caused by defects in nuclear or mitochondrial DNA (mtDNA). We propose to take advantage of existing and new mouse models created in our lab to manipulate the mtDNA to study fundamental mechanisms of the role of mtDNA mutations in neurodegeneration. We will also use DNA editing enzymes to further modulate mtDNA heteroplasmy in vivo. We will analyze the ability of different neuronal types (glutamatergic and dopaminergic) to accumulate mtDNA deletions (aim#1) and a pathogenic point mutation in a tRNA gene (aim#2). With these models in place, we will also study the susceptibility of glutamatergic and dopaminergic neuronal subtypes to OXPHOS defects.
Mitochondrial diseases affect mostly brain and muscles. Many age-related neurodegenerative disorders are also believed to be caused by mitochondrial dysfunction. Mitochondria are unique because they have their own DNA (mtDNA). In this project we will study the accumulation and functional consequences of deletions and point mutations in the mtDNA in the central nervous system, both of which have been shown to cause mitochondrial diseases and neurodegeneration.
|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|
|Pinto, Milena; Vempati, Uma D; Diaz, Francisca et al. (2018) Ablation of Cytochrome c in Adult Forebrain Neurons Impairs Oxidative Phosphorylation Without Detectable Apoptosis. Mol Neurobiol :|
|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|
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