Glutamate neurotoxicity is associated with nitric oxide-mediated mitochondrial dysfunction and glutathione depletion (original) (raw)
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Glutamate neurotoxicity, oxidative stress and mitochondria
FEBS Letters, 2001
The excitatory neurotransmitter glutamate plays a major role in determining certain neurological disorders. This situation, referred to as`glutamate neurotoxicity' (GNT), is characterized by an increasing damage of cell components, including mitochondria, leading to cell death. In the death process, reactive oxygen species (ROS) are generated. The present study describes the state of art in the field of GNT with a special emphasis on the oxidative stress and mitochondria. In particular, we report how ROS are generated and how they affect mitochondrial function in GNT. The relationship between ROS generation and cytochrome c release is described in detail, with the released cytochrome c playing a role in the cell defense mechanism against neurotoxicity. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
Journal of Biological Chemistry, 2009
The finding that upon neuronal activation glutamate is transported postsynaptically from synaptic clefts and increased lactate availability for neurons suggest that brain mitochondria (BM) utilize a mixture of substrates, namely pyruvate, glutamate, and the tricarboxylic acid cycle metabolites. We studied how glutamate affected oxidative phosphorylation and reactive oxygen species (ROS) production in rat BM oxidizing pyruvate ؉ malate or succinate. Simultaneous oxidation of glutamate ؉ pyruvate ؉ malate increased state 3 and uncoupled respiration by 52 and 71%, respectively. The state 4 ROS generation increased 100% over BM oxidizing pyruvate ؉ malate and 900% over that of BM oxidizing glutamate ؉ malate. Up to 70% of ROS generation was associated with reverse electron transport. These effects of pyruvate ؉ glutamate ؉ malate were observed only with BM and not with liver or heart mitochondria. The effects of glutamate ؉ pyruvate on succinate-supported respiration and ROS generation were not organ-specific and depended only on whether mitochondria were isolated with or without bovine serum albumin. With the non-bovine serum albumin brain and heart mitochondria oxidizing succinate, the addition of pyruvate and glutamate abrogated inhibition of Complex II by oxaloacetate. We conclude that (i) during neuronal activation, simultaneous oxidation of glutamate ؉ pyruvate temporarily enhances neuronal mitochondrial ATP production, and (ii) intrinsic inhibition of Complex II by oxaloacetate is an inherent mechanism that protects against ROS generation during reverse electron transport. Recently, it has emerged that mitochondrial dysfunctions play an important role in the pathogenesis of degenerative diseases of the central nervous system (1-3). The processes underlying neuronal degeneration are complex, and some authors suggest that several genetic alterations are involved (4). How-* This work was supported, in whole or in part, by National Institutes of Health Grant DK RO1 38825 (to H. L. B.). This work was also supported by the Carolinas HealthCare Foundation. Some of the data in this work have been presented at scientific meetings and published as abstracts (35, 36).
Glutamate-induced differential mitochondrial response in young and adult rats
Neurochemistry International, 2004
Excitatory amino acid glutamate is involved in neurotransmission in the nervous system but it becomes a potent neurotoxin under variety of conditions. However, the molecular mechanism of excitotoxicity is not known completely. We have studied the influence of glutamate on intracellular calcium and mitochondrial functions in cortical slices from young and adult rats. The slices from both the age groups exhibited comparable intracellular calcium changes upon glutamate stimulation. Glutamate treatment caused a decrease in adenosine 5-diphosphate/adenosine 5-triphosphate (ADP/ATP) and an increase in nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide reduced form (NAD/NADH) ratio in both the age groups but the magnitude and the nature of temporal change was different. Glutamate-induced decrease in ATP/ADP and increase in NAD/NADH ratio was significantly higher in slices from the adult as compared to the young rats. The slices from young rats elicited slightly higher mitochondrial depolarization than adult rats. However, the formation of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) release were significantly higher in adult rats as compared to young rats. Glutamate-induced mitochondrial depolarization, ROS formation and LDH release were highly dependent on the presence of Ca 2+ in the extracellular medium. The treatment of slices with mitochondrial inhibitors rotenone and oligomycin inhibited ROS formation and LDH release substantially. Our results suggest that the glutamate-induced increase in intracellular calcium is not the only factor responsible for neuronal cell death but the mitochondrial functions could be crucial in excitotoxicity.
A new vicious cycle involving glutamate excitotoxicity, oxidative stress and mitochondrial dynamics
Cell death & disease, 2011
Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1(enu/+) mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1(enu/+) mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide ...
Glutamate and Mitochondria: Two Prominent Players in the Oxidative Stress-Induced Neurodegeneration
The aetiology of major neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) is still unknown, but increasing evidences suggest that glutamate and mitochondria are two prominent players in the oxidative stress (OS) process that underlie these illnesses. Although AD and PD have distinct pathological and clinical features, OS is a common mechanism contributing to neuronal damage. Glutamate is an important neurotransmitter in neurons and glial cells and is strongly dependent on calcium homeostasis and on mitochondrial function. In the present work we focused on glutamate- induced calcium signaling and its relation to the mitochondrial dysfunction with cell death processes. In addition, we have discussed how alterations in this pathway may lead or aggravate the neurodegenerative diseases. Finally, this review aims to stimulate further studies on this issue and thereby engage a new perspective regarding the design of possible therapeutic agents or the identification of biomarkers
Glutamate receptors modulate oxidative stress in neuronal cells. A mini-review
Neurotoxicity Research, 2004
Under extreme conditions, these molecules induce oxidative stress, which may stimulate (or accompany) a number of neurodegenerative processes. In the glutamatergic system, ROS levels are under control of ionotropic and metabotropic glutamate receptors, which modulate ion fluxes through the neuronal membrane. The Na + /K + -pump is also one of the important participants affecting stationary ROS levels through several distinct mechanisms. This review describes the involvement of the Na + /K + -pump in intracellular signaling mechanisms via cross-talk between the pump and glutamate receptors in cerebellum granule cells. Selective dysfunction of mGlu II receptors may also lead to abnormal protein phosphorylation (i.e., tau phosphorylation), culminating in neurodegenerative disorders (i.e., Alzheimer disease). Also, unregulated production of intracellular ROS resulting from an imbalance of ionotropic and metabotropic receptors may activate one or more protein kinases. In summary, Glu receptor dysfunction, leading to a deficit in glutamate-mediated signal transduction may represent one of the earliest stages of neurodegenerative disorders. The Na + /K + -pump is able to prevent over-production of intracellular ROS, thus increasing oxidative stability of neuronal cells.
Journal of Neurochemistry, 2002
To gain some insight into the mechanism by which glutamate neurotoxicity takes place in cerebellar granule cells, two steps of glucose oxidation were investigated: the electron flow via respiratory chain from certain substrates to oxygen and the transfer of extramitochondrial reducing equivalents via the mitochondrial shuttles. However, cytochrome c release from intact mitochondria was found to occur in glutamate-treated cells as detected photometrically in the supernatant of the cell homogenate suspension. As a result of cytochrome c release, an increase of the oxidation of externally added NADH was found, probably occurring via the NADH-b 5 oxidoreductase of the outer mitochondrial membrane. When the two mitochondrial shuttles glycerol 3-phosphate/dihydroxyacetone phosphate and malate/oxaloacetate, devoted to oxidizing externally added NADH, were reconstructed, both were found to be impaired under glutamate neurotoxicity. Consistent early activation in two NADH oxidizing mechanisms, i.e., lactate production and plasma membrane NADH oxidoreductase activity, was found in glutamate-treated cells. In spite of this, the increase in the cell NADH fluorescence was found to be time-dependent, an index of the progressive damage of the cell.
Journal of Neurochemistry, 2002
Within the CNS and under normal conditions, nitric oxide ('NO) appears to be an important physiological signalling molecule. Its ability to increase cyclic GMP concentration suggests that 'No is implicated in the regulation of important metabolic pathways in the brain. Under certain circumstances N0 synthesis may be excessive and N0 may become neurotoxic. Excessive glutamatereceptor stimulation may lead to neuronal death through a mechanism implicating synthesis of both 'No and superoxide (02') and hence peroxynitrite (ONOO ) formation. In response to lipopolysaccharide and cytokines, glial cells may also be induced to synthesize large amounts of 'No, which may be deleterious to the neighbouring neurones and oligodendrocytes. The precise mechanism of 'No neurotoxicity is not fully understood. One possibility is that it may involve neuronal energy deficiency. This may occur by ONOO interfering with key enzymes of the tricarboxylic acid cycle, the mitochondrial respiratory chain, mitochondrial calcium metabolism, or DNA damage with subsequent activation of the energy-consuming pathway involving poly(ADPribose) synthetase. Possible mechanisms whereby ONOO impairs the mitochondrial respiratory chain and the relevance for neurotoxicity are discussed. The intracellular content of reduced glutathione also appears important in determining the sensitivity of cells to ONOOproduction. lt is concluded that neurotoxicity elicited by excessive 'NO production may be mediated by mitochondrial dysfunction leading to an energy deficiency state.