Mitochondria oxidative metabolism and cell death in stroke

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, Mitochondria oxidative metabolism and cell death in stroke. Neil R Sims Hakan Muyderman,PII S0925 4439 09 00214 2. DOI doi 10 1016 j bbadis 2009 09 003,Reference BBADIS 63006. To appear in BBA Molecular Basis of Disease,Received date 19 July 2009. Revised date 28 August 2009,Accepted date 8 September 2009.
Please cite this article as Neil R Sims Hakan Muyderman Mitochondria oxida . tive metabolism and cell death in stroke BBA Molecular Basis of Disease 2009 . doi 10 1016 j bbadis 2009 09 003, This is a PDF le of an unedited manuscript that has been accepted for publication . As a service to our customers we are providing this early version of the manuscript . The manuscript will undergo copyediting typesetting and review of the resulting proof. before it is published in its nal form Please note that during the production process. errors may be discovered which could a ect the content and all legal disclaimers that. apply to the journal pertain , ACCEPTED MANUSCRIPT. Mitochondria oxidative metabolism and cell death in stroke. Neil R Sims and Hakan Muyderman, Centre for Neuroscience and Discipline of Medical Biochemistry Flinders. Medical Science and Technology School of Medicine Flinders University . Adelaide South Australia Australia,Address for Correspondence NU. Professor Neil Sims,Discipline of Medical Biochemistry .
School of Medicine Flinders University ,GPO Box 2100 . Adelaide S A 5001 Australia,Email Neil Sims flinders edu au. Telephone 61 8 8204 4242,Fax 61 8 8374 0139, Running Title Mitochondria oxidative metabolism and cell death in stroke. Key words Mitochondria stroke focal ischemia energy metabolism necrosis apoptosis. Abbreviations AIF apoptosis inducing factor AKAP121 A kinase anchor protein 121 APAF 1 . apoptotic protease activating factor 1 IAPs inhibitor of apoptosis proteins JNK c Jun N terminal. kinase MCA middle cerebral artery Omi HtrA2 Omi stress regulated endoprotease high. temperature requirement protein A2 PARP poly ADP ribose polymerase Smac DIABLO second. mitochondria derived activator of caspase direct IAP binding protein of low pI t Bid truncated Bid. ACCEPTED MANUSCRIPT, Stroke most commonly results from occlusion of a major artery in the brain and typically leads to the. death of all cells within the affected tissue Mitochondria are centrally involved in the development of. this tissue injury due to modifications of their major role in supplying ATP and to changes in their. properties that can contribute to the development of apoptotic and necrotic cell death In animal models. of stroke the limited availability of glucose and oxygen directly impairs oxidative metabolism in severely. ischemic regions of the affected tissue and leads to rapid changes in ATP and other energy related. metabolites In the less severely ischemic penumbral tissue more moderate alterations develop in. these metabolites associated with near normal glucose use but impaired oxidative metabolism This. tissue remains potentially salvageable for at least the first few hours following stroke onset Early. restoration of blood flow can result in substantial recovery of energy related metabolites throughout the. affected tissue However glucose oxidation is markedly decreased due both to lower energy. requirements in the post ischemic tissue and limitations on the mitochondrial oxidation of pyruvate A. secondary deterioration of mitochondrial function subsequently develops that may contribute to. progression to cell loss Mitochondrial release of multiple apoptogenic proteins has been identified in. ischemic and post ischemic brain mostly in neurons Pharmacological interventions and genetic. modifications in rodent models strongly implicate caspase dependent and caspase independent apoptosis. and the mitochondrial permeability transition as important contributors to tissue damage particularly. when induced by short periods of temporary focal ischemia . ACCEPTED MANUSCRIPT,1 Introduction, Stroke is the primary cause of adult disability in developed countries and ranks only behind cancer and.
cardiac disease as a cause of death 1 2 Focal ischemia that results from occlusion of an artery in the. brain ischemic stroke accounts for more than 80 of all strokes 1 Unless rapidly reversed the. occlusion of a major artery usually produces tissue infarction in which affected parts of the brain exhibit. a non selective loss of all cells including neurons astrocytes oligodendrocytes microglia and endothelial. cells The size and location of these infarcts are important determinants of the long term functional. deficits resulting from ischemic stroke Mitochondria have been implicated as central players in the. development of ischemic cell death both through impairment of their normal role in generating much of. the ATP for neural cell function and as key mediators in cell death pathways This article reviews the. current understanding of the mitochondrial responses to focal cerebral ischemia and the contributions of. these organelles to tissue damage Additional aspects of this topic and further discussion of some of the. earlier studies can be found in previous reviews 3 6 . 2 Tissue damage in response to ischemic stroke, Occlusion of a major artery within the brain produces complex cellular changes that depend in part on the. severity of the ischemia that is generated and whether the occlusion is temporary or permanent Because. of the limited overlap in the perfusion territories of cerebral arteries severe ischemia develops in the. tissue immediately surrounding the occluded vessel Blood flow usually falls to less than 20 of normal. in this core or focal tissue 7 9 The resultant disruption to delivery of glucose and oxygen leads to. a greatly reduced ATP generation see section 4 1 1 Ionic gradients across the plasma membrane. quickly dissipate resulting in marked losses of intracellular potassium and large shifts of calcium into. cells 2 10 11 Because of contributions to perfusion from adjacent vessels a lesser ischemia develops. in tissue surrounding the core This penumbral or perifocal tissue typically exhibits reductions to. approximately 20 to 40 of normal flow 8 9 12 Neurons in the penumbra are electrically silent for. long periods a response associated with hyperpolarization of the plasma membrane 8 12 Note For. simplicity the term penumbra has been used throughout this review to describe tissue identified as. ACCEPTED MANUSCRIPT, receiving moderate ischemia even though criteria other than direct measurement of blood flow or plasma. membrane potential have commonly been used , Following permanent arterial occlusion infarcts initially develop in the core tissue but progress to. encompass both core and penumbral regions 13 14 The differences in the severity of the ischemia in. the core and penumbra mean that different mechanisms contribute to cell death Much of our. understanding of the cellular changes induced by focal ischemia comes from animal models of stroke and. from the effects of pharmacological treatments or genetic modifications on the damage that develops . Permanent or temporary occlusion of the middle cerebral artery MCA in rats or mice has commonly. been used for these investigations The present review focuses primarily on insights derived from such. animal models into changes in energy metabolism and mitochondrial properties within the first few hours. of stroke and their involvement in cell death , Many interventions during the initial few hours following the onset of stroke in these models can reduce. infarct volume particularly in the penumbra 2 15 Thus irreversible damage develops relatively. slowly in this region Consistent with this conclusion early restoration of blood flow can reduce the. tissue damage and functional deficits in animal models of stroke 16 17 and following a stroke in. humans 13 18 Indeed treatment with a thrombolytic agent to reverse arterial occlusion within the first. three hours following stroke onset provides the only approach in routine clinical use for limiting the acute. effects of this disorder in humans 13 18 Unfortunately because of the narrow therapeutic window . only a small proportion of those affected by stroke are currently treated with thrombolysis Spontaneous. reversal of arterial occlusion occurs within the first six hours in approximately 17 of ischemic stroke. patients and in approximately 40 to 50 by four days 19 Reperfusion beginning later than six hours. probably has limited effects on the tissue damage that develops Thus animal models involving. permanent arterial occlusion although less commonly investigated than temporary occlusion are likely to. be more relevant to the majority of ischemic stroke cases in humans . Treatments targeting a diverse range of cellular properties have been found to ameliorate tissue damage. and improve functional deficits in animal models of stroke 2 15 This suggests that the mechanisms. for cell loss involve interactions between multiple deleterious processes such that initial changes in one of. ACCEPTED MANUSCRIPT, these processes leads to more severe alterations in others Interruption of one of these initial responses is.
apparently able to disrupt or in some instances greatly delay the spiral of increasingly abnormal changes. that culminate in cell death Intriguingly treatments that reduce damage including those targeting. properties of specific cell populations preserve essentially all cells in the tissue that is salvaged A. smaller but still well demarcated infarct results Such a uniform demise of different cell populations is. not seen with many other insults and suggests a close interdependence of the different cell populations in. their responses to ischemia , Early studies demonstrated that pharmacological blockade of ionotropic glutamate receptors markedly. reduced ischemic damage 2 15 20 This effect is commonly ascribed to the involvement of an. excitotoxic process in which increases in glutamate release from neurons and astrocytes induced by the. ischemia cause an excessive calcium entry via these receptors and triggers other intracellular changes. leading to cell death However alternative mechanisms have also been suggested to explain the. protection by glutamate receptor antagonists including interference with the propogation of potentially. harmful spreading depression like depolarizations that develop in the penumbral tissue during arterial. occlusion 15 21 Abnormal intracellular calcium accumulations arising from calcium entry via ion. channels or transporters in addition to the ionotropic glutamate receptors have also been implicated in. triggering cell death 20 , Other changes identified as important in ischemia induced cell loss include oxidative stress particularly. involving nitric oxide and peroxynitrite and abnormal activation of enzymes such as poly ADP ribose. polymerase PARP and the calpains 2 15 Early reperfusion can limit the effects of some of these. changes but also adds to the complexity of the cellular responses that develop Oxidative stress is. promoted under these conditions and inflammatory responses arising both from resident microglia and. astrocytes as well as blood derived cells also become important 2 15 . 3 The nature of cell death in focal ischemia, Cell death resulting from cerebral ischemia was originally considered to be almost exclusively due to the. process of necrosis in which catastrophic events initiated by ischemia led to cellular changes culminating. in organelle swelling disruption of the plasma membrane and release of intracellular contents These. ACCEPTED MANUSCRIPT, features of cell death are usually seen in the vast majority of cells throughout the developing infarct 22 . Nonetheless a more complex picture began to emerge in the mid 1990 s with the identification of cells. that exhibited features of apoptosis including DNA fragmentation and the production of membrane. enclosed apoptotic bodies 23 24 Such changes are common features of cell death mediated by the. activation of caspases either via the intrinisic pathway or the extrinsic pathway 3 25 26 . Mitochondrial changes resulting in the release of proteins are central to the intrinsic pathway Fig 1 . These proteins lead to the activation of caspases particularly caspase 3 in brain which in turn induces. cellular changes including internucleosomal chromatin condensation and DNA fragmentation 3 25 27 . The role of the intrinsic pathway in focal ischemia is discussed in section 5 2 The extrinsic pathway is. triggered by the binding of specific ligands to plasma membrane cell death receptors This leads to. intracellular activation of caspase 8 and then of executioner capsases involved in cell death In the. extrinsic pathway the executioner caspase activation can occur without involvement of mitochondria 3 . 26 However caspase 8 activation can also cleave Bid to produce truncated Bid t Bid which initiates. the release of apoptogenic proteins from mitochondria under some conditions Caspase independent. forms of apoptosis Fig 1 which result from mitochondrial release of apoptosis inducing factor AIF . and perhaps other proteins 3 25 26 have also been implicated in focal ischemic damage see section. Cells exhibiting features of apoptosis typically peak in number at 24 hours or longer after stroke onset. 23 24 28 They are found scattered throughout the infarct following temporary or permanent occlusion. ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Mitochondria oxidative metabolism and cell death in stroke Neil R Sims and Hakan Muyderman Centre for Neuroscience and Discipline of Medical Biochemistry Flinders

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