Glutamate and aspartate transport in rat brain mitochondria

Brand, Martin D.; Chappell, Joseph

doi:10.1042/bj1400205

Cited by 51 publications

(21 citation statements)

References 16 publications

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“…One of the primary ways is a transfer of electrons from NADH to mitochondria by glycerol-phosphate or malate-aspartate shuttles. In the malate-aspartate shuttle, which has been shown to be operative in brain (16)(17)(18), electrons are transferred from NADH in the cytosol to oxaloacetate, forming malate, which traverses the inner mitochondrial membrane and is then reoxidized by NAD ϩ in the matrix to form NADH. The resulting oxaloacetate does not readily cross the inner mitochondrial membrane, so a transamination reaction is needed to form aspartate, which can be transported to the cytosolic side (10).…”

Section: Discussionmentioning

confidence: 99%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

133

104

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The factors regulating cerebral blood flow (CBF) changes in physiological activation remain the subject of great interest and debate. Recent experimental studies suggest that an increase in cytosolic NADH mediates increased blood flow in the working brain. Lactate injection should elevate NADH levels by increasing the lactate͞ pyruvate ratio, which is in near equilibrium with the NADH͞NAD ؉ ratio. We studied CBF responses to bolus lactate injection at rest and in visual stimulation by using positron-emission tomography in seven healthy volunteers. Bolus lactate injection augmented the CBF response to visual stimulation by 38 -53% in regions of the visual cortex but had no effect on the resting CBF or the wholebrain CBF. These lactate-induced CBF increases correlated with elevations in plasma lactate͞pyruvate ratios and in plasma lactate levels but not with plasma pyruvate levels. Our observations support the hypothesis that an increase in the NADH͞NAD ؉ ratio activates signaling pathways to selectively increase CBF in the physiologically stimulated brain regions.T he nature of the link between cerebral blood flow (CBF) and energy metabolism is of great interest and importance but remains controversial despite decades of research and debate. Although CBF augmentation is still considered to be a hallmark of intensified neural activity, previous assumptions that behaviorally induced increases in local blood flow reflect similar local increases in oxidative metabolism (1) have been contradicted by brain imaging studies with positron-emission tomography (PET) (2, 3) and functional MRI (4). Fox and his colleagues (2, 3) demonstrated that in normal, awake adult humans, stimulation of the visual or somatosensory cortex results in dramatic increases in CBF but minimal increases in oxygen consumption. Increases in glucose utilization are similar to changes in CBF (3, 5). Although it is often assumed that the increase in CBF in neural activation is driven by a need for increased delivery of oxygen or glucose, it has been demonstrated in human subjects that the CBF response to physiological activation is not altered by either stepped hypoglycemia (6) or hypoxia (7). These results suggest that increased CBF during physiological brain activation does not occur to prevent a shortage of these metabolic substrates. Ido et al. (8) recently reported that CBF in activated rat brain is modified by changes in the plasma lactate͞pyruvate ratio: CBF was augmented when lactate͞pyruvate ratios were raised and attenuated when the ratios were lowered. Specifically, immediately after lactate bolus injection, the magnitude of the CBF increase associated with sensory stimulation approximately doubled. Based on the near equilibrium between the ratios of lactate͞pyruvate and cytosolic free NADH͞NAD ϩ (which reflects the local environment redox state) (9), they suggested that cytosolic free NADH is an important trigger or sensor of blood flow. The reoxidation of NADH to NAD ϩ is a step of vital importance for brain cells, especially in the acti...

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Section: Discussionmentioning

confidence: 99%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

133

104

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show abstract

“…Unfortunately, this is not without inconsistency when compared with the available knowledge. For example, the possible absence of the glutamate/hydroxyl carrier (GC) in brain mitochondria would require rigid coupling between AGC1 and mitochondrial AAT (mAAT) [41]. Indeed, to maintain mitochondrial aspartate level necessary for MAS activity, the entry of glutamate through AGC1 must be followed by transamination with oxalacetate by mAAT.…”

Section: Glutamate Metabolism In Neurons and Astrocytesmentioning

confidence: 99%

Metabolic Pathways and Activity-Dependent Modulation of Glutamate Concentration in the Human Brain

2012

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Glutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for γ-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies.

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“…Hindfelt et al ( 1977) have proposed that ammonia may be toxic to the CNS by interfering with the transfer of reducing equivalents from the cytosol into the mitochondria. The malate-aspartate shuttle appears to be an important route for the transport of reducing equivalents in liver (Anderson et al, 1971;Williamson et al, 197 1;Alderman and Schiller, 198 l), kidney (Rognstad and Katz, 1970;Ross et al, 1981), heart (LaNoue et al, 1970LaNoue and Williamson, 197 l), and brain (Brand and Chappell, 1974;Dennis et al, 1976Dennis et al, , 1977Minn and Gayet, 1977; Dennis and Clark, 1978). P-Methylene-D,L-aspartate is a selective and irreversible inhibitor of aspartate aminotransferase, a key enzyme of the malate-aspartate shuttle .…”

mentioning

confidence: 99%

Brain α‐Ketoglutarate Dehydrogenase Complex: Kinetic Properties, Regional Distribution, and Effects of Inhibitors

Lai

Cooper

1986

Journal of Neurochemistry

297

157

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The substrate and cofactor requirements and some kinetic properties of the alpha-ketoglutarate dehydrogenase complex (KGDHC; EC 1.2.4.2, EC 2.3.1.61, and EC 1.6.4.3) in purified rat brain mitochondria were studied. Brain mitochondrial KGDHC showed absolute requirement for alpha-ketoglutarate, CoA and NAD, and only partial requirement for added thiamine pyrophosphate, but no requirement for Mg2+ under the assay conditions employed in this study. The pH optimum was between 7.2 and 7.4, but, at pH values below 7.0 or above 7.8, KGDHC activity decreased markedly. KGDHC activity in various brain regions followed the rank order: cerebral cortex greater than cerebellum greater than or equal to midbrain greater than striatum = hippocampus greater than hypothalamus greater than pons and medulla greater than olfactory bulb. Significant inhibition of brain mitochondrial KGDHC was noted at pathological concentrations of ammonia (0.2-2 mM). However, the purified bovine heart KGDHC and KGDHC activity in isolated rat heart mitochondria were much less sensitive to inhibition. At 5 mM both beta-methylene-D,L-aspartate and D,L-vinylglycine (inhibitors of cerebral glucose oxidation) inhibited the purified heart but not the brain mitochondrial enzyme complex. At approximately 10 microM, calcium slightly stimulated (by 10-15%) the brain mitochondrial KGDHC. At concentrations above 100 microM, calcium (IC50 = 1 mM) inhibited both brain mitochondrial and purified heart KGDHC. The present results suggest that some of the kinetic properties of the rat brain mitochondrial KGDHC differ from those of the purified bovine heart and rat heart mitochondrial enzyme complexes. They also suggest that the inhibition of KGDHC by ammonia and the consequent effect on the citric acid cycle fluxes may be of pathophysiological and/or pathogenetic importance in hyperammonemia and in diseases (e.g., hepatic encephalopathy, inborn errors of urea metabolism, Reye's syndrome) where hyperammonemia is a consistent feature. Brain accumulation of calcium occurs in a number of pathological conditions. Therefore, it is possible that such a calcium accumulation may have a deleterious effect on KGDHC activity.

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Glutamate and aspartate transport in rat brain mitochondria

Cited by 51 publications

References 16 publications

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Metabolic Pathways and Activity-Dependent Modulation of Glutamate Concentration in the Human Brain

Brain α‐Ketoglutarate Dehydrogenase Complex: Kinetic Properties, Regional Distribution, and Effects of Inhibitors

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