Increased superoxide accumulation in pyruvate dehydrogenase complex deficient fibroblasts

Mol Genet Metab. 2011 Nov;104(3):255-60. doi: 10.1016/j.ymgme.2011.07.023. Epub 2011 Jul 28.


The pyruvate dehydrogenase complex (PDC) oxidizes pyruvate to acetyl CoA and is critically important in maintaining normal cellular energy homeostasis. Loss-of-function mutations in PDC give rise to congenital lactic acidosis and to progressive cellular energy failure. However, the subsequent biochemical consequences of PDC deficiency that may contribute to the clinical manifestations of the disorder are poorly understood. We postulated that altered flux through PDC would disrupt mitochondrial electron transport, resulting in oxidative stress. Compared to cells from 4 healthy subjects, primary cultures of skin fibroblasts from 9 patients with variable mutations in the gene encoding the alpha subunit (E1α) of pyruvate dehydrogenase (PDA1) demonstrated reduced growth and viability. Superoxide (O(2)(.-)) from the Qo site of complex III of the electron transport chain accumulated in these cells and was associated with decreased activity of manganese superoxide dismutase. The expression of uncoupling protein 2 was also decreased in patient cells, but there were no significant changes in the expression of cellular markers of protein or DNA oxidative damage. The expression of hypoxia transcription factor 1 alpha (HIF1α) also increased in PDC deficient fibroblasts. We conclude that PDC deficiency is associated with an increase in O(2)(.-) accumulation coupled to a decrease in mechanisms responsible for its removal. Increased HIF1α expression may contribute to the increase in glycolytic flux and lactate production in PDC deficiency and, by trans-activating pyruvate dehydrogenase kinase, may further suppress residual PDC activity through phosphorylation of the E1α subunit.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cells, Cultured
  • DNA Damage
  • Electron Transport Chain Complex Proteins / metabolism
  • Fibroblasts / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Ion Channels / metabolism
  • Mitochondrial Proteins / metabolism
  • Oxidative Stress / physiology*
  • Pyruvate Dehydrogenase (Lipoamide) / genetics*
  • Pyruvate Dehydrogenase Complex Deficiency Disease / metabolism*
  • Reactive Oxygen Species / metabolism
  • Skin / cytology
  • Superoxide Dismutase / metabolism
  • Superoxides / metabolism*
  • Uncoupling Protein 2


  • Electron Transport Chain Complex Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ion Channels
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • UCP2 protein, human
  • Uncoupling Protein 2
  • Superoxides
  • Superoxide Dismutase
  • Pyruvate Dehydrogenase (Lipoamide)
  • pyruvate dehydrogenase E1alpha subunit