Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency

Hum Mol Genet. 2013 Oct 1;22(19):3819-27. doi: 10.1093/hmg/ddt232. Epub 2013 May 31.


Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid β-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency. In this study, we show that moderately decreased CoQ10 levels in fibroblasts from six unrelated RR-MADD patients were associated with increased levels of mitochondrial reactive oxygen species (ROS). Treatment with CoQ10, but not with riboflavin, could normalize the CoQ10 level and decrease the level of ROS in the patient cells. Additionally, riboflavin-depleted control fibroblasts showed moderate CoQ10 deficiency, but not increased mitochondrial ROS, indicating that variant ETF-QO proteins and not CoQ10 deficiency are the causes of mitochondrial ROS production in the patient cells. Accordingly, the corresponding variant Rhodobacter sphaeroides ETF-QO proteins, when overexpressed in vitro, bind a CoQ10 pseudosubstrate, Q10Br, less tightly than the wild-type ETF-QO protein, suggesting that molecular oxygen can get access to the electrons in the misfolded ETF-QO protein, thereby generating superoxide and oxidative stress, which can be reversed by CoQ10 treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Ataxia / metabolism
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cells, Cultured
  • Electron-Transferring Flavoproteins / genetics*
  • Electron-Transferring Flavoproteins / metabolism*
  • Fibroblasts / metabolism*
  • Genetic Variation
  • Humans
  • Iron-Sulfur Proteins / genetics*
  • Iron-Sulfur Proteins / metabolism*
  • Mitochondria / metabolism
  • Mitochondrial Diseases / metabolism
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / complications
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / drug therapy
  • Multiple Acyl Coenzyme A Dehydrogenase Deficiency / metabolism*
  • Muscle Weakness / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / metabolism*
  • Reactive Oxygen Species / metabolism
  • Rhodobacter sphaeroides / genetics
  • Rhodobacter sphaeroides / metabolism
  • Riboflavin / metabolism
  • Riboflavin / pharmacology
  • Ubiquinone / analogs & derivatives*
  • Ubiquinone / deficiency
  • Ubiquinone / metabolism
  • Ubiquinone / pharmacology
  • Ubiquinone / therapeutic use


  • Acyl Coenzyme A
  • Bacterial Proteins
  • Electron-Transferring Flavoproteins
  • Iron-Sulfur Proteins
  • Reactive Oxygen Species
  • Ubiquinone
  • Oxidoreductases Acting on CH-NH Group Donors
  • electron-transferring-flavoprotein dehydrogenase
  • coenzyme Q10
  • Riboflavin

Supplementary concepts

  • Coenzyme Q10 Deficiency