Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins

Marina A. Schwab , Sven W. Sauer , Jürgen G. Okun , Leo G. J. Nijtmans , Richard J. T. Rodenburg , Lambert P. van den Heuvel , Stefan Dröse , Ullrich Brandt , Georg F. Hoffmann , Henk ter Laak , Stefan Kölker , Jan A. M. Smeitink , Stefan Kölker (1)

1 Department of General Pediatrics

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-Coenzyme A (CoA) and metabolites of alternative propionate oxidation. Here we demonstrate uncompetitive inhibition of pyruvate dehydrogenase complex (PDHc) 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 homologous monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast to CoA esters, free fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid enzymes also revealed an inhibition of propionyl-CoA on respiratory chain complex III and {alpha}-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 microorganisms.

Mots clés: Life Sciences

Marina A. Schwab, Sven W. Sauer, Jürgen G. Okun, Leo G. J. Nijtmans, Richard J. T. Rodenburg, et al.. Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochemical Journal, 2006, 398 (1), pp.107-112. ⟨10.1042/BJ20060221⟩. ⟨hal-00478532⟩