Hypoxia-induced damage to the adult and immature brain: Molecular mechanism of oxidative damage and the need for targeted therapeutic intervention

Christian A. Reynolds, Maik Hüttemann, Karin Przyklenk, Thomas H. Sanderson

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

Restriction of oxygen delivery to the brain resulting from cerebral hypoxia and/or ischemia is the cause of substantial neurologic trauma in patients suffering from stroke or cardiac arrest. Similarly, among newborn infants exposed to hypoxic events during the perinatal period, pathologic decreases in cerebral oxygen availability results in subsequent hypoxic-ischemic encephalopathy (HIE). While cerebral re-oxygenation is the ultimate goal in the management of these patients, it is now evident that the reintroduction of oxygen can be detrimental and potentiate brain injury. This phenomenon, termed reperfusion injury, has been attributed to the excessive production of reactive oxygen species (ROS), which in turn promote oxidative damage leading to delayed cell death. Here we propose a model of ischemia/reperfusion-induced cerebral damage, where ischemic alterations to the mitochondrial oxidative phosphorylation system (OxPhos) initiate a deleterious chain of events, culminating in cell death. Specifically, we discuss novel findings which indicate that recently-identified posttranslational modifications of mitochondrial electron transport chain (ETC) proteins, specifically complex IV, can alter cellular bioenergetics during ischemia/reperfusion. These modifications lead to abnormal mitochondrial respiration and promote excessive mitochondrial ROS production during early reperfusion. Following this reperfusioninduced 'burst' of ROS, redox signalling cascades further alter mitochondrial function and initiate widespread oxidative damage and apoptotic signalling culminating in neural cell death. Therefore, we propose that treatment strategies aimed at modulating ETC complex function may prove efficacious in mitigating the extent of oxidative damage observed following adult and neonatal cerebral ischemia/reperfusion.

Original languageEnglish
Title of host publicationHypoxia
Subtitle of host publicationCauses, Types and Management
PublisherNova Science Publishers, Inc.
Pages3-20
Number of pages18
ISBN (Print)9781620817698
StatePublished - Jan 2013

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