The Oxygen Free Radicals Originating from Mitochondrial Complex I Contribute to Oxidative Brain Injury Following Hypoxia–Ischemia in Neonatal Mice
Open Access
- 29 February 2012
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 32 (9), 3235-3244
- https://doi.org/10.1523/jneurosci.6303-11.2012
Abstract
Oxidative stress and Ca2+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 H2O2emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to the Ca2+-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% O2which exacerbated brain injury only in vehicle-treated mice.In vitro, intact brain mitochondria dramatically increased H2O2emission in response to hyperoxia, resulting in substantial loss of Ca2+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 Ca2+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.Keywords
This publication has 59 references indexed in Scilit:
- Isoflurane Differentially Modulates Mitochondrial Reactive Oxygen Species Production via Forward versus Reverse Electron Transport FlowAnesthesiology, 2011
- Mitochondrial oxidant stress triggers cell death in simulated ischemia–reperfusionBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2011
- Mitochondrial calcium and the permeability transition in cell deathBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2009
- How mitochondria produce reactive oxygen speciesBiochemical Journal, 2008
- Mitochondrial-mediated suppression of ROS production upon exposure of neurons to lethal stress: Mitochondrial targeted preconditioningAdvanced Drug Delivery Reviews, 2008
- Brief Exposure to Hyperoxia Depletes the Glial Progenitor Pool and Impairs Functional Recovery after Hypoxic-Ischemic Brain InjuryJournal of Cerebral Blood Flow & Metabolism, 2008
- Delayed neuronal preconditioning by NS1619 is independent of calcium activated potassium channelsJournal of Neurochemistry, 2007
- Mitochondria Are a Major Source of Paraquat-induced Reactive Oxygen Species Production in the BrainOnline Journal of Public Health Informatics, 2007
- Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell deathNature, 2005
- Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell deathNature, 2005