title: In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space.
abstract: Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 causes a complex array of pathological events, through toxic gain of function mechanisms, leading to selective motor neuron degeneration. Mitochondrial dysfunction is among the well established toxic effects of mutant SOD1, but its mechanisms are just starting to be elucidated. A portion of mutant SOD1 is localized in mitochondria, where it accumulates mostly on the outer membrane and inside the intermembrane space (IMS). Evidence in cultured cells suggests that mutant SOD1 in the IMS causes mitochondrial dysfunction and compromises cell viability. Therefore, to test its pathogenic role in vivo we generated transgenic mice expressing G93A mutant or wild-type (WT) human SOD1 targeted selectively to the mitochondrial IMS (mito-SOD1). We show that mito-SOD1 is correctly localized in the IMS, where it oligomerizes and acquires enzymatic activity. Mito-G93ASOD1 mice, but not mito-WTSOD1 mice, develop a progressive disease characterized by body weight loss, muscle weakness, brain atrophy, and motor impairment, which is more severe in females. These symptoms are associated with reduced spinal motor neuron counts and impaired mitochondrial bioenergetics, characterized by decreased cytochrome oxidase activity and defective calcium handling. However, there is no evidence of muscle denervation, a cardinal pathological feature of ALS. Together, our findings indicate that mutant SOD1 in the mitochondrial IMS causes mitochondrial dysfunction and neurodegeneration, but per se it is not sufficient to cause a full-fledged ALS phenotype, which requires the participation of mutant SOD1 localized in other cellular compartments.
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors: Anissa
authors: A
authors: Igoudjil
authors: Jordi
authors: J
authors: Magrané
authors: Lindsey R
authors: LR
authors: Fischer
authors: Hyun Jeong
authors: HJ
authors: Kim
authors: Isabel
authors: I
authors: Hervias
authors: Magali
authors: M
authors: Dumont
authors: Czrina
authors: C
authors: Cortez
authors: Jonathan D
authors: JD
authors: Glass
authors: Anatoly A
authors: AA
authors: Starkov
authors: Giovanni
authors: G
authors: Manfredi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000473:pathology / Q000648:ultrastructure*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D006321:Heart; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology / Q000648:ultrastructure*; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D009419:Nerve Tissue Proteins; C000606290:SOD1 protein, human; C470429:SOD1 G37R protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002118:Calcium