title: Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition.
abstract: Mitochondrial uptake of calcium in excitotoxicity is associated with subsequent increase in reactive oxygen species (ROS) generation and delayed cellular calcium deregulation in ischemic and neurodegenerative insults. The mechanisms linking mitochondrial calcium uptake and ROS production remain unknown but activation of the mitochondrial permeability transition (mPT) may be one such mechanism. In the present study, calcium increased ROS generation in isolated rodent brain and human liver mitochondria undergoing mPT despite an associated loss of membrane potential, NADH and respiration. Unspecific permeabilization of the inner mitochondrial membrane by alamethicin likewise increased ROS independently of calcium, and the ROS increase was further potentiated if NAD(H) was added to the system. Importantly, calcium per se did not induce a ROS increase unless mPT was triggered. Twenty-one cyclosporin A analogs were evaluated for inhibition of calcium-induced ROS and their efficacy clearly paralleled their potency of inhibiting mPT-mediated mitochondrial swelling. We conclude that while intact respiring mitochondria possess powerful antioxidant capability, mPT induces a dysregulated oxidative state with loss of GSH- and NADPH-dependent ROS detoxification. We propose that mPT is a significant cause of pathological ROS generation in excitotoxic cell death.
authors.affiliation: Department of Clinical Sciences, Lund University, SE-221 84 Lund, Sweden. magnus.hansson@med.lu.se
authors.forename: Magnus J
authors.initials: MJ
authors.lastname: Hansson
authors.forename: Roland
authors.initials: R
authors.lastname: Månsson
authors.forename: Saori
authors.initials: S
authors.lastname: Morota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchino
authors.forename: Thérese
authors.initials: T
authors.lastname: Kallur
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sumi
authors.forename: Nagao
authors.initials: N
authors.lastname: Ishii
authors.forename: Motohide
authors.initials: M
authors.lastname: Shimazu
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Keep
authors.forename: Alexandr
authors.initials: A
authors.lastname: Jegorov
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D008933:Mitochondrial Swelling / Q000502:physiology; D009249:NADP / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D009249:NADP; D002118:Calcium