title: Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials.
abstract: Recent studies suggest that the toxicity of familial amyotrophic lateral sclerosis mutant Cu, Zn superoxide dismutase (SOD1) arises from its selective recruitment to mitochondria. Here we demonstrate that each of 12 different familial ALS-mutant SOD1s with widely differing biophysical properties are associated with mitochondria of motoneuronal cells to a much greater extent than wild-type SOD1, and that this effect may depend on the oxidation of Cys residues. We demonstrate further that mutant SOD1 proteins associated with the mitochondria tend to form cross-linked oligomers and that their presence causes a shift in the redox state of these organelles and results in impairment of respiratory complexes. The observation that such a diverse set of mutant SOD1 proteins behave so similarly in mitochondria of motoneuronal cells and so differently from wild-type SOD1 suggests that this behavior may explain the toxicity of ALS-mutant SOD1 proteins, which causes motor neurons to die.
authors.affiliation: Institute of Neuroscience, Department of Psychobiology and Psychopharmacology, Consiglio Nazionale delle Ricerche, 00100 Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ferri
authors.forename: Mauro
authors.initials: M
authors.lastname: Cozzolino
authors.forename: Claudia
authors.initials: C
authors.lastname: Crosio
authors.forename: Monica
authors.initials: M
authors.lastname: Nencini
authors.forename: Arianna
authors.initials: A
authors.lastname: Casciati
authors.forename: Edith Butler
authors.initials: EB
authors.lastname: Gralla
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rotilio
authors.forename: Joan Selverstone
authors.initials: JS
authors.lastname: Valentine
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Carrì
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D009046:Motor Neurons / Q000201:enzymology* / Q000648:ultrastructure; D009154:Mutation; D010084:Oxidation-Reduction; D013482:Superoxide Dismutase / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003545:Cysteine