Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and α-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I–IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms.
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August 2006
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Research Article|
July 27 2006
Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins
Marina A. Schwab
;
Marina A. Schwab
*Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany
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Sven W. Sauer
;
Sven W. Sauer
*Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany
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Jürgen G. Okun
;
Jürgen G. Okun
*Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany
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Leo G. J. Nijtmans
;
Leo G. J. Nijtmans
†Department of Pediatrics, Radboud University Nijmegen Medical Center – NCMD (Nijmegen Center for Mitochondrial Disorders), Geert Grooteplein 10, NL-6500 HB Nijmegen, The Netherlands
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Richard J. T. Rodenburg
;
Richard J. T. Rodenburg
†Department of Pediatrics, Radboud University Nijmegen Medical Center – NCMD (Nijmegen Center for Mitochondrial Disorders), Geert Grooteplein 10, NL-6500 HB Nijmegen, The Netherlands
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Lambert P. van den Heuvel
;
Lambert P. van den Heuvel
†Department of Pediatrics, Radboud University Nijmegen Medical Center – NCMD (Nijmegen Center for Mitochondrial Disorders), Geert Grooteplein 10, NL-6500 HB Nijmegen, The Netherlands
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Stefan Dröse
;
Stefan Dröse
‡Molecular Bioenergetics Group, Gustav-Embden-Zentrum der Biologischen Chemie, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
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Ulrich Brandt
;
Ulrich Brandt
‡Molecular Bioenergetics Group, Gustav-Embden-Zentrum der Biologischen Chemie, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany
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Georg F. Hoffmann
;
Georg F. Hoffmann
*Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany
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Henk Ter Laak
;
Henk Ter Laak
†Department of Pediatrics, Radboud University Nijmegen Medical Center – NCMD (Nijmegen Center for Mitochondrial Disorders), Geert Grooteplein 10, NL-6500 HB Nijmegen, The Netherlands
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Stefan Kölker
;
*Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 150, D-69120 Heidelberg, Germany
2To whom correspondence should be addressed (email Stefan_Koelker@med.uni-heidelberg.de).
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Jan A. M. Smeitink
Jan A. M. Smeitink
1
†Department of Pediatrics, Radboud University Nijmegen Medical Center – NCMD (Nijmegen Center for Mitochondrial Disorders), Geert Grooteplein 10, NL-6500 HB Nijmegen, The Netherlands
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Biochem J (2006) 398 (1): 107–112.
Article history
Received:
February 07 2006
Revision Received:
April 26 2006
Accepted:
May 09 2006
Accepted Manuscript online:
May 09 2006
Citation
Marina A. Schwab, Sven W. Sauer, Jürgen G. Okun, Leo G. J. Nijtmans, Richard J. T. Rodenburg, Lambert P. van den Heuvel, Stefan Dröse, Ulrich Brandt, Georg F. Hoffmann, Henk Ter Laak, Stefan Kölker, Jan A. M. Smeitink; Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 15 August 2006; 398 (1): 107–112. doi: https://doi.org/10.1042/BJ20060221
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