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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 01; 22(19):3819-27.HM

Abstract

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.

Authors

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Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23727839

Citation

Cornelius, Nanna, et al. "Secondary Coenzyme Q10 Deficiency and Oxidative Stress in Cultured Fibroblasts From Patients With Riboflavin Responsive Multiple Acyl-CoA Dehydrogenation Deficiency." Human Molecular Genetics, vol. 22, no. 19, 2013, pp. 3819-27.
Cornelius N, Byron C, Hargreaves I, et al. Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency. Hum Mol Genet. 2013;22(19):3819-27.
Cornelius, N., Byron, C., Hargreaves, I., Guerra, P. F., Furdek, A. K., Land, J., Radford, W. W., Frerman, F., Corydon, T. J., Gregersen, N., & Olsen, R. K. (2013). Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency. Human Molecular Genetics, 22(19), 3819-27. https://doi.org/10.1093/hmg/ddt232
Cornelius N, et al. 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. PubMed PMID: 23727839.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency. AU - Cornelius,Nanna, AU - Byron,Colleen, AU - Hargreaves,Iain, AU - Guerra,Paula Fernandez, AU - Furdek,Andrea K, AU - Land,John, AU - Radford,Weston W, AU - Frerman,Frank, AU - Corydon,Thomas J, AU - Gregersen,Niels, AU - Olsen,Rikke K J, Y1 - 2013/05/31/ PY - 2013/6/4/entrez PY - 2013/6/4/pubmed PY - 2014/3/19/medline SP - 3819 EP - 27 JF - Human molecular genetics JO - Hum Mol Genet VL - 22 IS - 19 N2 - 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. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/23727839/Secondary_coenzyme_Q10_deficiency_and_oxidative_stress_in_cultured_fibroblasts_from_patients_with_riboflavin_responsive_multiple_Acyl_CoA_dehydrogenation_deficiency_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddt232 DB - PRIME DP - Unbound Medicine ER -