Mitochondrial contributions to tissue damage in stroke.
Tissue infarction, involving death of essentially all cells within a part of the brain, is a common pathology resulting from stroke and an important determinant of the long-term consequences of this disorder. The cell death that leads to infarct formation is likely to be the result of multiple interacting pathological processes. A range of factors, including the severity of the ischemic insult and whether this is permanent or reversed, determine which mechanisms predominate. Although evaluating mitochondrial properties in intact brain is difficult, evidence for several potentially deleterious responses to cerebral ischemia or post-ischemic reperfusion have been obtained from investigations using animal models of stroke. Marked changes in ATP and related energy metabolites develop quickly in response to occlusion of a cerebral artery, as expected from limitations in the delivery of oxygen and glucose. However, these alterations are often only partially reversed on reperfusion despite improved substrate delivery. Ischemia-induced decreases in the mitochondrial capacity for respiratory activity probably contribute to the ongoing impairment of energy metabolism during reperfusion and possibly also to the magnitude of changes seen during ischemia. Conditions during reperfusion are likely to be conducive to the induction of the permeability transition in mitochondria. There are as yet no well-characterized techniques to identify this change in the intact brain. However, the protective effects of some agents that block formation of the transition pore are consistent with both the induction of the permeability transition during early recirculation and a role for this in the development of tissue damage. Release of cytochrome c into the cytoplasm of cells has been observed with both permanent and reversed ischemia and could trigger the death of some cells by apoptosis, a process which probably contributes to the expansion of the ischemic lesion. Mitochondria are also likely to contribute to the widely-accepted role of nitric oxide in the development of ischemic damage. These organelles are a probable target for the deleterious effects of this substance and can also act as a source of superoxide for reaction with the nitric oxide to produce the damaging species, peroxynitrite. Further characterization of these mitochondrial responses should help to elucidate the mechanisms of cell death due to cerebral ischemia and possibly point to novel sites for therapeutic interventions in stroke.
Sims
Neil R
NR
Department of Medical Biochemistry, Center for Neuroscience, School of Medicine, Flinders Medical Research Institute, Flinders University, G.P.O. Box 2100, Adelaide, SA 5001, Australia. neil.sims@flinders.edu.au
Anderson
Michelle F
MF
D000818:Animals; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D010101:Oxygen Consumption / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology; D020521:Stroke / Q000473:pathology*
D005609:Free Radicals