title: Partial complex I deficiency due to the CNS conditional ablation of Ndufa5 results in a mild chronic encephalopathy but no increase in oxidative damage.
abstract: Deficiencies in the complex I (CI; NADH-ubiquinone oxidoreductase) of the respiratory chain are frequent causes of mitochondrial diseases and have been associated with other neurodegenerative disorders, such as Parkinson's disease. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex subunit 5 (NDUFA5) is a nuclear-encoded structural subunit of CI, located in the peripheral arm. We inactivated Ndufa5 in mice by the gene-trap methodology and found that this protein is required for embryonic survival. Therefore, we have created a conditional Ndufa5 knockout (KO) allele by introducing a rescuing Ndufa5 cDNA transgene flanked by loxP sites, which was selectively ablated in neurons by the CaMKIIα-Cre. At the age of 11 months, mice with a central nervous system knockout of Ndufa5 (Ndufa5 CNS-KO) showed lethargy and loss of motor skills. In these mice cortices, the levels of NDUFA5 protein were reduced to 25% of controls. Fully assembled CI levels were also greatly reduced in cortex and CI activity in homogenates was reduced to 60% of controls. Despite the biochemical phenotype, no oxidative damage, neuronal death or gliosis were detected in the Ndufa5 CNS-KO brain at this age. These results showed that a partial defect in CI in neurons can lead to late-onset motor phenotypes without neuronal loss or oxidative damage.
authors.affiliation: Departments of Neurology and.
authors.forename: Susana
authors.initials: S
authors.lastname: Peralta
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.forename: Tina
authors.initials: T
authors.lastname: Wenz
authors.forename: Sofia
authors.initials: S
authors.lastname: Garcia
authors.forename: Francisca
authors.initials: F
authors.lastname: Diaz
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
mesh_terms: D000818:Animals; D001925:Brain Damage, Chronic / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism*; D004249:DNA Damage; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000172:deficiency / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009245:NADH Dehydrogenase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: C000592702:NDUFA5 protein, mouse; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I