Cellular and Molecular Life Sciences

, Volume 75, Issue 16, pp 3009–3026 | Cite as

Folding and assembly defects of pyruvate dehydrogenase deficiency-related variants in the E1α subunit of the pyruvate dehydrogenase complex

  • Srdja Drakulic
  • Jay Rai
  • Steen Vang Petersen
  • Monika M. Golas
  • Bjoern Sander
Original Article


The pyruvate dehydrogenase complex (PDC) bridges glycolysis and the citric acid cycle. In human, PDC deficiency leads to severe neurodevelopmental delay and progressive neurodegeneration. The majority of cases are caused by variants in the gene encoding the PDC subunit E1α. The molecular effects of the variants, however, remain poorly understood. Using yeast as a eukaryotic model system, we have studied the substitutions A189V, M230V, and R322C in yeast E1α (corresponding to the pathogenic variants A169V, M210V, and R302C in human E1α) and evaluated how substitutions of single amino acid residues within different functional E1α regions affect PDC structure and activity. The E1α A189V substitution located in the heterodimer interface showed a more compact conformation with significant underrepresentation of E1 in PDC and impaired overall PDC activity. The E1α M230V substitution located in the tetramer and heterodimer interface showed a relatively more open conformation and was particularly affected by low thiamin pyrophosphate concentrations. The E1α R322C substitution located in the phosphorylation loop of E1α resulted in PDC lacking E3 subunits and abolished overall functional activity. Furthermore, we show for the E1α variant A189V that variant E1α accumulates in the Hsp60 chaperonin, but can be released upon ATP supplementation. Our studies suggest that pathogenic E1α variants may be associated with structural changes of PDC and impaired folding of E1α.


PDHA1 Genetic disorder Mutation Brain development Single-particle electron microscopy Mitochondria 



This work has been supported by the Centre for Stochastic Geometry and Advanced Bioimaging (CSGB; supported by the Villum Foundation), the Danish Council for Independent Research to BS as well as the Lundbeck Foundation, the Danish Council for Independent Research, Danish Center for Scientific Computing (DCSC), and the Carlsberg Foundation to MMG.

Supplementary material

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Supplementary material 1 (PDF 1311 kb)


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiomedicineAarhus UniversityAarhus CDenmark
  2. 2.Centre for Stochastic Geometry and Advanced BioimagingAarhus UniversityAarhus CDenmark
  3. 3.Institute of PathologyHannover Medical School30625 HannoverGermany
  4. 4.Department of Human GeneticsHannover Medical School30625 HannoverGermany

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