title: Deleterious role of superoxide dismutase in the mitochondrial intermembrane space.
abstract: This work demonstrates how increased activity of copper-zinc superoxide dismutase (SOD1) paradoxically boosts production of toxic reactive oxygen species (ROS) in the intermembrane space (IMS) of mitochondria. Even though SOD1 is a cytosolic enzyme, a fraction of it is found in the IMS, where it is thought to provide protection against oxidative damage. We found that SOD1 controls cytochrome c-catalyzed peroxidation in vitro when superoxide is available. The presence of SOD1 significantly increased the rate of ROS production in mitoplasts, which are devoid of outer membrane and IMS. In response to inhibition of respiration with antimycin A, isolated mouse wild-type mitochondria increased ROS production, but the mitochondria from mice lacking SOD1 (SOD1(-/-)) did not. Also, lymphocytes isolated from SOD1(-/-) mice produced significantly less ROS than did wild-type cells and were more resistant to apoptosis induced by inhibition of respiration. Moreover, an increased amount of the toxic mutant G93A SOD1 in the IMS increased ROS production. The mitochondrial dysfunction and cell damage paradoxically induced by SOD1-mediated ROS production may be implicated in chronic degenerative diseases.
authors.affiliation: Department of Neurobiology, A I Virtanen Institute for Molecular Sciences, University of Kuopio, Finland. gundars.goldsteins@uku.fi
authors.forename: Gundars
authors.initials: G
authors.lastname: Goldsteins
authors.forename: Velta
authors.initials: V
authors.lastname: Keksa-Goldsteine
authors.forename: Toni
authors.initials: T
authors.lastname: Ahtoniemi
authors.forename: Merja
authors.initials: M
authors.lastname: Jaronen
authors.forename: Egils
authors.initials: E
authors.lastname: Arens
authors.forename: Karl
authors.initials: K
authors.lastname: Akerman
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
mesh_terms: D000818:Animals; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D017353:Gene Deletion; D006861:Hydrogen Peroxide / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics; D051336:Mitochondrial Membranes / Q000201:enzymology*; D009154:Mutation / Q000235:genetics; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000201:enzymology; D013379:Substrate Specificity; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D017382:Reactive Oxygen Species; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1