Abnormalities of mitochondrial enzymes in hereditary ataxias

Sorbi, Sandro; Piacentini, Silvia; Fani, Carla; Tonini, Stefano; Marini, P.; Amaducci, L.

doi:10.1111/j.1600-0404.1989.tb03849.x

Cited by 17 publications

(11 citation statements)

References 41 publications

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“…At least one study suggests GDH deficiency may be an epiphenomenon. In this report, decreased activities of other mitochondrial enzymes were found but not to the same degree as that of GDH [Sorbi et al, 1989]. Finally, despite the findings of GDH deficiency, mutations of GDH have yet to be reported in OPCA.…”

Section: Olivopontocerebellar Atrophy-loss Of Gdh Activity Proposedcontrasting

confidence: 62%

Disorders of glutamate metabolism

Kelly

Stanley

2001

Ment. Retard. Dev. Disabil. Res. Rev.

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The significant role the amino acid glutamate assumes in a number of fundamental metabolic pathways is becoming better understood. As a central junction for interchange of amino nitrogen, glutamate facilitates both amino acid synthesis and degradation. In the liver, glutamate is the terminus for release of ammonia from amino acids, and the intrahepatic concentration of glutamate modulates the rate of ammonia detoxification into urea. In pancreatic beta-cells, oxidation of glutamate mediates amino acid-stimulated insulin secretion. In the central nervous system, glutamate serves as an excitatory neurotransmittor. Glutamate is also the precursor of the inhibitory neurotransmittor GABA, as well as glutamine, a potential mediator of hyperammonemic neurotoxicity. The recent identification of a novel form of congenital hyperinsulinism associated with asymptomatic hyperammonemia assigns glutamate oxidation by glutamate dehydrogenase a more important role than previously recognized in beta-cell insulin secretion and hepatic and CNS ammonia detoxification. Disruptions of glutamate metabolism have been implicated in other clinical disorders, such as pyridoxine-dependent seizures, confirming the importance of intact glutamate metabolism. This article will review glutamate metabolism and clinical disorders associated with disrupted glutamate metabolism.

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Section: Olivopontocerebellar Atrophy-loss Of Gdh Activity Proposedcontrasting

confidence: 62%

Disorders of glutamate metabolism

Kelly

Stanley

2001

Ment. Retard. Dev. Disabil. Res. Rev.

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“…Studies several years ago suggested that loss of mitochondrial enzyme activities including PDHC and KGDHC is commonly found in SCAs, 76,77 but extensive studies in patients whose defects have been defined at the gene level have not been done. The “toxin gain of function” of the Q n repeats may be mediated at least in part by aberrant transglutaminase‐catalyzed reactions.…”

Section: Kgdhc In Neurodegenerative Diseasesmentioning

confidence: 99%

The α‐Ketoglutarate Dehydrogenase Complex

Sheu

Blass

1999

Annals of the New York Academy of Sciences

102

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The alpha-ketoglutarate dehydrogenase complex (KGDHC) is an important mitochondrial constituent, and deficiency of KGDHC is associated with a number of neurological disorders. KGDHC is composed of three proteins, each encoded on a different and well-characterized gene. The sequences of the human proteins are known. The organization of the proteins into a large, ordered multienzyme complex (a "metabolon") has been well studied in prokaryotic and eukaryotic species. KGDHC catalyzes a critical step in the Krebs tricarboxylic acid cycle, which is also a step in the metabolism of the potentially excitotoxic neurotransmitter glutamate. A number of metabolites modify the activity of KGDHC, including inactivation by 4-hydroxynonenal and other reactive oxygen species (ROS). In human brain, the activity of KGDHC is lower than that of any other enzyme of energy metabolism, including phosphofructokinase, aconitase, and the electron transport complexes. Deficiencies of KGDHC are likely to impair brain energy metabolism and therefore brain function, and lead to manifestations of brain disease. In general, the clinical manifestations of KGDHC deficiency relate to the severity of the deficiency. Several such disorders have been recognized: infantile lactic acidosis, psychomotor retardation in childhood, intermittent neuropsychiatric disease with ataxia and other motor manifestations, Friedreich's and other spinocerebellar ataxias, Parkinson's disease, and Alzheimer's disease (AD). A KGDHC gene has been associated with the first two and last two of these disorders. KGDHC is not uniformly distributed in human brain, and the neurons that appear selectively vulnerable in human temporal cortex in AD are enriched in KGDHC. We hypothesize that variations in KGDHC that are not deleterious during reproductive life become deleterious with aging, perhaps by predisposing this mitochondrial metabolon to oxidative damage.

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“…Glutamate is also the precursor of GABA, an inhibitory neurotransmitter. Interestingly, a loss of GDH activity was reported in a multiple system atrophy condition called olivopontocerebellar atropy where GDH activity was decreased to a greater extent than other mitochondrial enzymes (52), suggesting that GDH is more sensitive to insults. Our study showed that it is, however, not inhibited by hydrogen peroxide from 10 -220 M concentration.…”

Section: Nadmentioning

confidence: 99%

A Mechanism of Sulfite Neurotoxicity

Zhang

Vincent

Halliwell

et al. 2004

Journal of Biological Chemistry

123

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Exposure of Neuro-2a and PC12 cells to micromolar concentrations of sulfite caused an increase in reactive oxygen species and a decrease in ATP. Likewise, the biosynthesis of ATP in intact rat brain mitochondria from the oxidation of glutamate was inhibited by micromolar sulfite. Glutamate-driven respiration increased the mitochondrial membrane potential (MMP), and this was abolished by sulfite but the MMP generated by oxidation of malate and succinate was not affected. The increased rate of production of NADH from exogenous NAD ؉ and glutamate added to rat brain mitochondrial extracts was inhibited by sulfite, and mitochondria preincubated with sulfite failed to reduce NAD ؉ . Glutamate dehydrogenase (GDH) in rat brain mitochondrial extract was inhibited dose-dependently by sulfite as was the activity of a purified enzyme. An increase in the K m (glutamate) and a decrease in V max resulting in an attenuation in V max /K m (glutamate) at 100 M sulfite suggest a mixed type of inhibition. However, uncompetitive inhibition was noted with decreases in both K m (NAD ؉ ) and V max , whereas V max /K m (NAD ؉ ) remained relatively constant. We propose that GDH is one target of action of sulfite, leading to a decrease in ␣-ketoglutarate and a diminished flux through the tricarboxylic acid cycle accompanied by a decrease in NADH through the mitochondrial electron transport chain, a decreased MMP, and a decrease in ATP synthesis. Because glutamate is a major metabolite in the brain, inhibition of GDH by sulfite could contribute to the severe phenotype of sulfite oxidase deficiency in human infants.

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Abnormalities of mitochondrial enzymes in hereditary ataxias

Cited by 17 publications

References 41 publications

Disorders of glutamate metabolism

Disorders of glutamate metabolism

The α‐Ketoglutarate Dehydrogenase Complex

A Mechanism of Sulfite Neurotoxicity

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