Deleterious role of superoxide dismutase in the mitochondrial intermembrane space.
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.
Goldsteins
Gundars
G
Department of Neurobiology, A I Virtanen Institute for Molecular Sciences, University of Kuopio, Finland. gundars.goldsteins@uku.fi
Keksa-Goldsteine
Velta
V
Ahtoniemi
Toni
T
Jaronen
Merja
M
Arens
Egils
E
Akerman
Karl
K
Chan
Pak H
PH
Koistinaho
Jari
J
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
D017382:Reactive Oxygen Species; D045304:Cytochromes c; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1