Preferential glutamine uptake in rat brain synaptic mitochondria

Steib, Anita; Rendón, Álvaro; Mark, J.; Borg, Jacques

doi:10.1016/0014-5793(86)80013-8

Cited by 20 publications

(9 citation statements)

References 18 publications

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“…The bulk (>75%) of glutamine derived from ammonia is then transported into mitochondria (Sonnewald et al, 1996;Yudkoff et al, 1988) by a specific carrier-mediated process (Minn, 1982;Steib et al, 1986) and then hydrolyzed by PAG, yielding ammonia and glutamate (Kvamme et al, 1982). Given the fact that glutamine levels are highly elevated in hyperammonemic conditions, and that ammonia has been shown to increase glutamine transport into mitochondria (Dolinska et al, 1996), such increase in mitochondrial glutamine following its hydrolysis may result in the generation of very high levels of ammonia in the mitochondrial compartment.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

Pichili

Rao

Jayakumar

et al. 2007

Glia

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Hepatic encephalopathy (HE) is a major neurological complication that occurs in the setting of severe liver failure. Ammonia is a key neurotoxin implicated in this condition, and astrocytes are the principal neural cells histopathologically and functionally affected. Although the mechanism by which ammonia causes astrocyte dysfunction is incompletely understood, glutamine, a by-product of ammonia metabolism, has been strongly implicated in many of the deleterious effects of ammonia on astrocytes. Inhibiting mitochondrial glutamine hydrolysis in astrocytes mitigates many of the toxic effects of ammonia, suggesting the involvement of mitochondrial glutamine metabolism in the mechanism of ammonia neurotoxicity. To determine whether mitochondriaare indeed the organelle where glutamine exerts its toxic effects, we examined the effect of L-histidine, an inhibitor of mitochondrial glutamine transport, on ammonia-mediated astrocyte defects. Treatment of cultured astrocytes with L-histidine completely blocked or significantly attenuated ammonia-induced reactive oxygen species production, cell swelling, mitochondrial permeability transition, and loss of ATP. These findings implicate mitochondrial glutamine transport in the mechanism of ammonia neurotoxicity.

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Section: Discussionmentioning

confidence: 98%

Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

Pichili

Rao

Jayakumar

et al. 2007

Glia

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“…The relatively avid synaptosomal utilization of glutamine may also mean that mitochondria1 aspartate aminotransferase is either more active than its cytosolic counterpart or that it has preferential access to glutaminase. Glutamine uptake into mitochondria is extremely active (Steib et al, 1986) and many enzymes are known to form multienzyme complexes within the protein-rich matrix of these organelles (Srivastava and Bernhard, 1986;Srere, 1987), an environment that favors direct metabolite transfer. This possibility implies that uptake of glutamine into mitochondria is faster than that of glutamate and/or that glutamate so transported is not channelled preferentially to aspartate aminotransferase.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Glutamine Utilization: Pathways of Nitrogen Transfer tudied with [¹⁵N]Glutamine

Yudkoff¹,

Zaleska

Nissim³

et al. 1989

Journal of Neurochemistry

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Gas chromatography-mass spectrometry was used to evaluate the metabolism of [15N]glutamine in isolated rat brain synaptosomes. In the presence of 0.5 mM glutamine, synaptosomes accumulated this amino acid to a level of 25-35 nmol/mg protein at an initial rate greater than 9 nmol/min/mg of protein. The metabolism of [15N]glutamine generated 15N-labelled glutamate, aspartate, and gamma-aminobutyric acid (GABA). An efflux of both [15N]glutamate and [15N]aspartate from synaptosomes to the medium was observed. Enrichment of 15N in alanine could not be detected because of a limited pool size. Elimination of glucose from the incubation medium substantially increased the rate and amount of [15N]aspartate formed. It is concluded that: (1) With 0.5 mM external glutamine, the glutaminase reaction, and not glutamine transport, determines the rate of metabolism of this amino acid. (2) The primary route of glutamine catabolism involves aspartate aminotransferase which generates 2-oxoglutarate, a substrate for the tricarboxylic acid cycle. This reaction is greatly accelerated by the omission of glucose. (3) Glutamine has preferred access to a population of synaptosomes or to a synaptosomal compartment that generates GABA. (4) Synaptosomes maintain a constant internal level of glutamate plus aspartate of about 70-80 nmol/mg protein. As these amino acids are produced from glutamine in excess of this value, they are released into the medium. Hence synaptosomal glutamine and glutamate metabolism are tightly regulated in an interrelated manner.

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“…it is partly activated by an electrochemical proton gradient (34,56), and inhibited by Glu, tricarboxylic acid intermediates (34) and His and leucine (Leu) (33). Inhibition by Glu plus the fact that the uptake is more active in synaptic than in nonsynaptic mitochondria (54,56) is in agreement with Gln being primarily metabolized in the neurons. Whether Gln uptake to mitochondria is directly coupled with, and a prerequisite of, its intramitochondrial degradation by PAG is a matter of dispute.…”

Section: Gln Transport In Mitochondriamentioning

confidence: 66%

“…Experiments with isolated mitochondria revealed that mitochondrial Gln uptake consists of an active (saturable) and a diffusive (non-saturable) component, whereby the former appears to dominate (22,(53)(54)(55). The saturable component is concentrative, osmosensitive and largely stereospecific (56).…”

Section: Gln Transport In Mitochondriamentioning

confidence: 99%

Glutamine in the central nervous system: function and dysfunction

Albrecht¹

2007

Front Biosci

143

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Glutamine (Gln) abounds in the central nervous system (CNS), and its interstitial and cerebrospinal fluid (CSF) concentrations are at least one order of magnitude higher than of any other amino acid. Gln transport from blood to the brain is insufficient to meet the demand of the brain tissues for this amino acid. This demand is met by intracerebral Gln synthesis from glutamate (Glu), a reaction carried out by glutamine synthetase (GS), an enzyme residing in astrocytes. A major proportion of astroglia-derived Gln is shuttled to neurons where it is degraded by phosphate-activated glutaminase (PAG) giving rise to the excitatory neurotransmitter amino acid Glu, which is also a precursor of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Glu released from neurons is taken up by astrocytes, and reconverted to Gln, closing the so called "glutamate-glutamine" cycle. A portion of Gln serves as an energy metabolite, and part of it leaves the brain to blood. Gln efflux from astrocytes, its neuronal uptake and egress to the blood via the cerebral capillary endothelial cells is mediated by different amino acid carriers showing i) considerable preference for Gln, ii) distribution between astrocytes and neurons that favors astrocyte-to-neuron fluxes of the amino acid. The Gln-specific carriers also largely contribute to Gln efflux from the brain to the vascular bed. Excessive accumulation of Gln in brain cells may be deleterious to brain function. In hyperammonemia associated with acute liver failure, excess Gln leads to cerebral edema, which largely results from its interference with mitochondrial function and partly from its osmotic action. Future analyses of the roles of Gln in both normal and abnormal cerebral metabolism and function will have to account for its newly recognized direct involvement in the regulation of gene transcription and/or translation.

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Preferential glutamine uptake in rat brain synaptic mitochondria

Cited by 20 publications

References 18 publications

Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

Neuronal Glutamine Utilization: Pathways of Nitrogen Transfer tudied with [¹⁵N]Glutamine

Glutamine in the central nervous system: function and dysfunction

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Preferential glutamine uptake in rat brain synaptic mitochondria

Cited by 20 publications

References 18 publications

Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity

Neuronal Glutamine Utilization: Pathways of Nitrogen Transfer tudied with [15N]Glutamine

Glutamine in the central nervous system: function and dysfunction

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Neuronal Glutamine Utilization: Pathways of Nitrogen Transfer tudied with [¹⁵N]Glutamine