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Accumulation of excess ROSRNS can oxidize cellular components; including lipids, proteins, and DNA, leading to impaired function and eventually cell death.Oxidative stress damage in vivo has been attributed to HO or superoxide reacting with divalent metal ions to form hydroxyl radicals.Hydroxyl radicals, however, are such highly reactive species that they probably are not the proximate mediators of tissue damage.More likely, two electronbased reactive species like HO react with proteincysteine residues to mediate the damage that leads to cell death.Thus, emphasis in this review is focused on disruption of protein thiol homeostasis, which is mostly mediated by nonradical reactions, as a major basis of neurodegenerative disease.This point of view is reinforced by a compelling analysis of how covalent modifications of cysteine resides can more effectively account for tissue damage due to oxidative stress in human diseases than free radicalmediated reactions. Thus, thiol homeostasis involving GSH is a major theme of this review.An alternative perspective based on studies with yeast was recently presented, where GSH was suggested to be more important for iron metabolism than thiol homeostasis.However, this provocative viewpoint warrants further investigation in broader contexts.The magnitude to which ROS play a role in neurodegenerative diseases may be due in part to the extensive production of ROS in the brain.Although small, the brain uses about of the bodys oxygen supply, and a considerable amount is converted to ROS.Moreover, relative to other organs the brain has lower levels of ROS scavenging enzymes and a richer supply of unsaturated lipids that can propagate damage through reactive aldehyde products of lipid peroxidation. ROS generation in the brain comes from multiple sources.Leakage of electrons to molecular oxygen at various points in the Mofezolac mitochondrial electron transport chain is the main source of ROS. Complex I produce superoxide and consequently peroxide as byproducts of their enzymatic activities. Additionally, HO in the brain is a natural product of monoamine oxidase reactions.The MAO enzymes catalyze the oxidation of neurotransmitters, thereby terminating their activity.For example, dopamine is oxidized by MAOB with the concomitant conversion of O to HO. Besides sources of ROS generation, the brain also has an abundant supply of nitric oxide. Like ROS, ONOO leads to the oxidation of proteins, lipids, and DNA, but also mediates nitration of tyrosine residues.Additional ROS generation is from flavoproteins, represented by MAOB in this diagram.The mitochondrial GSH accounts for approximately of cellular glutathione.In general the mitochondrial GSH:GSSG ratio is greater than that of the cytosol, resulting in a more reducing environment. One study of the GSH and GSSG levels in rat mitochondria Mofezolac reported that liver GSH concentration was. However, in brain mitochondria the GSH was reported to be. The reason for this difference in redox ratio between tissues is not known, and should be investigated further.It is unclear currently as to which of these transport mechanisms is the predominant system for importing GSH into neuronal tissue.Additionally, they reported loss of the glutathione when cortical mitochondria were treated with a dicarboxylate carrier inhibitor; whereas only loss was observed with a oxoglutarate carrier inhibitor. These results demonstrate that the dicarboxylate carrier is the major transporter of GSH into the cortical mitochondria.

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