Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1 |
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| Institution: | 1. DFG-Centre of Molecular Physiology of the Brain, Institute of Neuro- and Sensory Physiology, Georg-August-University, Göttingen 37073, Germany;2. DFG-Centre of Molecular Physiology of the Brain, Department of Neurology, Georg-August-University, Göttingen 37073, Germany;1. NSW Centre for Rett Syndrome Research, Western Sydney Genetics Program, Children''s Hospital at Westmead, Sydney, Australia;2. Discipline of Paediatrics & Child Health, University of Sydney, Australia;3. Neurometabolic Unit, National Hospital and Department of Molecular Neuroscience, Institute of Neurology, London, United Kingdom;4. Embryology Unit, Children''s Medical Research Institute, Sydney, Australia;5. Discipline of Medicine, Sydney Medical School, University of Sydney, Australia;6. Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Australia |
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| Abstract: | Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects. |
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| Keywords: | Rett syndrome Mitochondrial dysfunction Oxidative stress Reactive oxygen species Energy metabolism Free radicals |
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