title: The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice.
abstract: Oxidative stress and Ca(2+) toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI brain by limiting a generation of oxidative radicals during reperfusion. HI insult was produced in p10 mice treated with complex I (C-I) inhibitor, pyridaben, or vehicle. Administration of P significantly decreased the extent of HI injury. Mitochondria isolated from the ischemic hemisphere in pyridaben-treated animals showed reduced H(2)O(2) emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca(2+)-triggered opening of the permeability transition pore. A protective effect of pyridaben administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O(2) which exacerbated brain injury only in vehicle-treated mice. In vitro, intact brain mitochondria dramatically increased H(2)O(2) emission in response to hyperoxia, resulting in substantial loss of Ca(2+) buffering capacity. However, in the presence of the C-I inhibitor, rotenone, or the antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I-dependent mitochondrial respiration contributes not only to the cellular survival, but also causes oxidative damage to the mitochondria, potentiating a loss of Ca(2+) buffering capacity. This highlights a novel neuroprotective strategy against HI brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion.
authors.affiliation: Department of Pediatrics, Columbia University, New York, New York 10032, USA.
authors.forename: Zoya V
authors.initials: ZV
authors.lastname: Niatsetskaya
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Dzmitry
authors.initials: D
authors.lastname: Matsiukevich
authors.forename: Irina V
authors.initials: IV
authors.lastname: Utkina-Sosunova
authors.forename: Veniamin I
authors.initials: VI
authors.lastname: Ratner
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.forename: Vadim S
authors.initials: VS
authors.lastname: Ten
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D042967:Electron Transport Complex I / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005609:Free Radicals / Q000378:metabolism* / Q000633:toxicity; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism* / Q000633:toxicity
chemical_list: D005609:Free Radicals; D042967:Electron Transport Complex I; D010100:Oxygen