Matakovic 2015 Abstract MiP2015

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Cofactor deficiency in mitochondrial diseases.


Matakovic L, Feichtinger R, Sperl W, Holzerova E, Prokisch H, Haack T, Mayr J (2015)

Event: MiP2015

The mitochondrial energy metabolism consists of numerous enzymatic reactions and transport processes. Several of these mitochondrial reactions depend on cofactors. Cofactors are small molecules that can be associated or covalently bound to enzymes. Cofactors are either synthesized de novo or from precursors, several of these precursors are vitamins. Furthermore, cofactors or their precursors have to be transported into appropriate compartments in the cells (e.g. mitochondria). To date, 39 different genes in the synthesis and transport of cofactors have been reported that manifest clinically as disorders in the mitochondrial energy metabolism. Therefore, the analysis of cofactors and cofactor dependent enzymes is crucial to gain a better understanding of the pathomechanism of these diseases and set the basis for therapeutic interventions.

Thiamin pyrophosphate (TPP) is an essential cofactor for mitochondrial enzyme complexes like pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase and requires thiamin pyrophosphokinase (TPK, EC for its formation [1]. Here we report on two patients with TPK1 mutations providing novel clinical and biological insights into the condition. Two novel homozygous mutations were found c.664G>C (p.Asp222His) leading to decreased TPK1 protein stability, but a high residual enzymatic activity and c.479C>T (p.Ser160Leu) that interferes with TPK dimerization, leading to drastically decreased enzymatic activity [2]. Recombinant mutant or wild type TPK was investigated concerning substrate and Mg2+ concentrations. A clear dependence of TPK activity on thiamine and Mg2+ was found in both mutant and the wild type TPK. These results hold promise for the clinical use of vitamins/cofactors as pharmacological chaperones in TPK deficient patients harboring thiamine/Mg2+ responsive mutations.

O2k-Network Lab: AT Salzburg Sperl W

Labels: MiParea: Respiration, mtDNA;mt-genetics, mt-Medicine, Patients 

Stress:Mitochondrial disease  Organism: Human 

Enzyme: Complex II;succinate dehydrogenase 

Event: A1, Oral, Poster, P-flash  MiP2015 


1-Dept Pediatrics, Paracelsus Med Univ. Salzburg, Austria; 2-Inst Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. - [email protected]

Abstract continued

The interaction between riboflavin metabolism and the mitochondrial respiratory chain is reported in a large number of human diseases. Our research currently focuses on an important enzyme flavin adenine dinucleotide synthetase (FLAD1, EC, involved in intracellular metabolism of riboflavin. FLAD1 catalyzes the adenylation of flavin mononucleotide (FMN) to form flavin adenine dinucleotide (FAD), which is an essential cofactor of e.g. pyruvate dehydrogenase, succinate dehydrogenase, electron transferring flavoprotein dehydrogenase (ETFDH) and many different ETFDH dependent dehydrogenases involved in fatty acid oxidation and branched chain- amino acid metabolism [3]. During these ongoing investigations, we measured the concentrations of riboflavin, FMN, and FAD in different tissues and the distribution in subcellular compartments in patient and control samples. Further functional studies are on the way to elucidate the disease mechanism. Our results point to the importance of exogenous supplementation with cofactor (or vitamin), which can compensate for deficiencies in cofactor biosynthesis/availability.

References and acknowledgements

  1. Mayr JA, Freisinger P, Schlachter K, Rolinski B, Zimmermann FA, Scheffner T, Haack TB, Koch J, Ahting U, Prokisch H, Sperl W (2007) Thiamine Pyrophosphokinase deficiency in encephalopathic children with defects in the pyruvate oxidation pathway. American J Hum Genet 89:806–12.
  2. Banka S, de Goede C, Yue WW, Morris MAA, von Bremen B, Chandler EK, Feichtinger GR, Hart C, Khan N, Lunzer V, Mataković L, Marquardt T, Makowski C, Prokisch H, Debus O, Nosaka K, Sonwalkar H, Zimmermann FA, Sperl W, Mayr JA (2014) Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: A treatable neurological disorder caused by TPK1 mutations. Mol Genet Metab 113:301-6.
  3. Joosten V, van Berkel WJ (2007) Flavoenzymes. Curr Opin Chem Biol 11:195-202.