Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency: A role for glutaryl-coenzyme A

Sven W. Sauer, Jürgen G. Okun, Marina A. Schwab, Linda R. Crnic, Georg F. Hoffmann, Stephen I. Goodman, David Koeller, Stefan Kölker

Research output: Contribution to journalArticle

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Abstract

Inherited deficiency of glutaryl-CoA dehydrogenase results in an accumulation of glutaryl-CoA, glutaric, and 3-hydroxyglutaric acids. If untreated, most patients suffer an acute encephalopathic crisis and, subsequently, acute striatal damage being precipitated by febrile infectious diseases during a vulnerable period of brain development (age 3 and 36 months). It has been suggested before that some of these organic acids may induce excitotoxic cell damage, however, the relevance of bioenergetic impairment is not yet understood. The major aim of our study was to investigate respiratory chain, tricarboxylic acid cycle, and fatty acid oxidation in this disease using purified single enzymes and tissue homogenates from Gcdh-deficient and wild-type mice. In purified enzymes, glutaryl-CoA but not glutaric or 3-hydroxyglutaric induced an uncompetitive inhibition of α-ketoglutarate dehydrogenase complex activity. Notably, reduced activity of α-ketoglutarate dehydrogenase activity has recently been demonstrated in other neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases. In contrast to α-ketoglutarate dehydrogenase complex, no direct inhibition of glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid was found in other enzymes tested. In Gcdh-deficient mice, respiratory chain and tricarboxylic acid activities remained widely unaffected, virtually excluding regulatory changes in these enzymes. However, hepatic activity of very long-chain acyl-CoA dehydrogenase was decreased and concentrations of long-chain acylcarnitines increased in the bile of these mice, which suggested disturbed oxidation of long-chain fatty acids. In conclusion, our results demonstrate that bioenergetic impairment may play an important role in the pathomechanisms underlying neurodegenerative changes in glutaryl-CoA dehydrogenase deficiency.

Original languageEnglish (US)
Pages (from-to)21830-21836
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number23
DOIs
StatePublished - Jun 10 2005

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Glutaryl-CoA Dehydrogenase
Energy Metabolism
Ketoglutarate Dehydrogenase Complex
Enzymes
Electron Transport
Long-Chain Acyl-CoA Dehydrogenase
Fatty Acids
Tricarboxylic Acids
Neurodegenerative diseases
Corpus Striatum
Oxidation
Citric Acid Cycle
Organic acids
Huntington Disease
Bile
Neurodegenerative Diseases
Communicable Diseases
Parkinson Disease
Brain
Alzheimer Disease

ASJC Scopus subject areas

  • Biochemistry

Cite this

Sauer, S. W., Okun, J. G., Schwab, M. A., Crnic, L. R., Hoffmann, G. F., Goodman, S. I., ... Kölker, S. (2005). Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency: A role for glutaryl-coenzyme A. Journal of Biological Chemistry, 280(23), 21830-21836. https://doi.org/10.1074/jbc.M502845200

Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency : A role for glutaryl-coenzyme A. / Sauer, Sven W.; Okun, Jürgen G.; Schwab, Marina A.; Crnic, Linda R.; Hoffmann, Georg F.; Goodman, Stephen I.; Koeller, David; Kölker, Stefan.

In: Journal of Biological Chemistry, Vol. 280, No. 23, 10.06.2005, p. 21830-21836.

Research output: Contribution to journalArticle

Sauer, SW, Okun, JG, Schwab, MA, Crnic, LR, Hoffmann, GF, Goodman, SI, Koeller, D & Kölker, S 2005, 'Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency: A role for glutaryl-coenzyme A', Journal of Biological Chemistry, vol. 280, no. 23, pp. 21830-21836. https://doi.org/10.1074/jbc.M502845200
Sauer SW, Okun JG, Schwab MA, Crnic LR, Hoffmann GF, Goodman SI et al. Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency: A role for glutaryl-coenzyme A. Journal of Biological Chemistry. 2005 Jun 10;280(23):21830-21836. https://doi.org/10.1074/jbc.M502845200
Sauer, Sven W. ; Okun, Jürgen G. ; Schwab, Marina A. ; Crnic, Linda R. ; Hoffmann, Georg F. ; Goodman, Stephen I. ; Koeller, David ; Kölker, Stefan. / Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency : A role for glutaryl-coenzyme A. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 23. pp. 21830-21836.
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