title: Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitochondria of transgenic mice.
abstract: A growing body of evidence suggests that impaired mitochondrial energy production and increased oxidative radical damage to the mitochondria could be causally involved in motor neuron death in amyotrophic lateral sclerosis (ALS) and in familial ALS associated with mutations of Cu,Zn superoxide dismutase (SOD1). For example, morphologically abnormal mitochondria and impaired mitochondrial histoenzymatic respiratory chain activities have been described in motor neurons of patients with sporadic ALS. To investigate further the role of mitochondrial alterations in the pathogenesis of ALS, we studied mitochondria from transgenic mice expressing wild type and G93A mutated hSOD1. We found that a significant proportion of enzymatically active SOD1 was localized in the intermembrane space of mitochondria. Mitochondrial respiration, electron transfer chain, and ATP synthesis were severely defective in G93A mice at the time of onset of the disease. We also found evidence of oxidative damage to mitochondrial proteins and lipids. On the other hand, presymptomatic G93A transgenic mice and mice expressing the wild type form of hSOD1 did not show significant mitochondrial abnormalities. Our findings suggest that G93A-mutated hSOD1 in mitochondria may cause mitochondrial defects, which contribute to precipitating the neurodegenerative process in motor neurons.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Mattiazzi
authors.forename: Marilena
authors.initials: M
authors.lastname: D'Aurelio
authors.forename: Carl D
authors.initials: CD
authors.lastname: Gajewski
authors.forename: Katherine
authors.initials: K
authors.lastname: Martushova
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
authors.forename: Giovanni
authors.initials: G
authors.lastname: Manfredi
mesh_terms: D000818:Animals; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D013482:Superoxide Dismutase; D010100:Oxygen