title: Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.
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.
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Roma, Italy. Electronic address: bianca.defilippis@iss.it.
authors.forename: Bianca
authors.initials: B
authors.lastname: De Filippis
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valenti
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: de Bari
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: De Rasmo
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Musto
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Ricceri
authors.affiliation: Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Fiorentini
authors.affiliation: Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy. Electronic address: r.vacca@ibbe.cnr.it.
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Vacca
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004579:Electron Transport; D042963:Electron Transport Complex II / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D005609:Free Radicals / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015518:Rett Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D005609:Free Radicals; D051783:Methyl-CpG-Binding Protein 2; D017382:Reactive Oxygen Species; C478189:respiratory complex II; C060296:cytotoxic necrotizing factor type 1; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II
keywords: Energy metabolism; Free radicals; Mitochondrial dysfunction; Oxidative stress; Reactive oxygen species; Rett syndrome