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J. Biol. Chem., Vol. 280, Issue 23, 21830-21836, June 10, 2005

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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 M. Koeller¶, and Stefan Kölker||

From the Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital of Heidelberg, D-69120 Heidelberg, Germany, the Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, and the ^¶Departments of Pediatrics, and Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon 97201

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 -ketoglutarate dehydrogenase complex activity. Notably, reduced activity of -ketoglutarate dehydrogenase activity has recently been demonstrated in other neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases. In contrast to -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.

Received for publication, March 15, 2005 , and in revised form, April 11, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant KO 2010/2-1. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This study is dedicated to Dr. Linda Crnic, Ph.D., who was instrumental in developing and characterizing the glutaryl-CoA dehydrogenase-deficient mouse. She was the director of the Mental Retardation and Developmental Disabilities Research Center at the University of Colorado Health Sciences Center, and an internationally known researcher in mouse models of human mental retardation syndromes. Her work and passion for science will be missed.

^|| To whom correspondence should be addressed: Dept. of General Pediatrics, Division of Inborn Metabolic Diseases, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany. Tel.: 49-6221-561714; Fax: 49-6221-565565; E-mail: Stefan_Koelker{at}med.uni-heidelberg.de.

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