title: Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice.
abstract: A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.
authors.affiliation: Department of Cell Biology and Anatomy, University of Miami School of Medicine, Miami, Florida 33136, USA.
authors.forename: Ilias G
authors.initials: IG
authors.lastname: Kirkinezos
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Bacman
authors.forename: Dayami
authors.initials: D
authors.lastname: Hernandez
authors.forename: Jose
authors.initials: J
authors.lastname: Oca-Cossio
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Arias
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Perez-Pinzon
authors.forename: Walter G
authors.initials: WG
authors.lastname: Bradley
authors.forename: Carlos T
authors.initials: CT
authors.lastname: Moraes
mesh_terms: D000375:Aging / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D001205:Ascorbic Acid / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D045304:Cytochromes c / Q000378:metabolism*; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D015227:Lipid Peroxidation / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013772:Tetramethylphenylenediamine / Q000378:metabolism
chemical_list: C000606290:SOD1 protein, human; D045304:Cytochromes c; D019001:Nitric Oxide Synthase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003576:Electron Transport Complex IV; D013772:Tetramethylphenylenediamine; D001205:Ascorbic Acid