Treatment of CoQ10 Deficient Fibroblasts with Ubiquinone, CoQ Analogs, and Vitamin C: Time- and Compound-Dependent Effects
and Vitamin C:
Time- and Compound-Dependent Effects. PLoS ONE 5(7): e11897. doi:10.1371/journal.pone.0011897
Treatment of CoQ10 Deficient Fibroblasts with Ubiquinone, CoQ Analogs, and Vitamin C: Time- and Compound-Dependent Effects
Luis C. Lo pez 0
Catarina M. Quinzii 0
Estela Area 0
Ali Naini 0
Shamima Rahman 0
Markus Schuelke 0
Leonardo Salviati 0
Salvatore DiMauro 0
Michio Hirano 0
Antoni L. Andreu, Hospital Vall d'Hebron, Spain
0 1 Department of Neurology, Columbia University Medical Center , New York , New York, United States of America, 2 Clinical and Molecular Genetics Unit, University College London Institute of Child Health , London , United Kingdom , 3 Department of Neuropediatrics, Charite Virchow University Hospital , Berlin, Germany , 4 Servizio di Genetica Clinica ed Epidemiologica, Department of Pediatrics, University of Padova , Padova , Italy
Background: Coenzyme Q10 (CoQ10) and its analogs are used therapeutically by virtue of their functions as electron carriers, antioxidant compounds, or both. However, published studies suggest that different ubiquinone analogs may produce divergent effects on oxidative phosphorylation and oxidative stress. Methodology/Principal Findings: To test these concepts, we have evaluated the effects of CoQ10, coenzyme Q2 (CoQ2), idebenone, and vitamin C on bioenergetics and oxidative stress in human skin fibroblasts with primary CoQ10 deficiency. A final concentration of 5 mM of each compound was chosen to approximate the plasma concentration of CoQ10 of patients treated with oral ubiquinone. CoQ10 supplementation for one week but not for 24 hours doubled ATP levels and ATP/ADP ratio in CoQ10 deficient fibroblasts therein normalizing the bioenergetics status of the cells. Other compounds did not affect cellular bioenergetics. In COQ2 mutant fibroblasts, increased superoxide anion production and oxidative stress-induced cell death were normalized by all supplements. Conclusions/Significance: These results indicate that: 1) pharmacokinetics of CoQ10 in reaching the mitochondrial respiratory chain is delayed; 2) short-tail ubiquinone analogs cannot replace CoQ10 in the mitochondrial respiratory chain under conditions of CoQ10 deficiency; and 3) oxidative stress and cell death can be counteracted by administration of lipophilic or hydrophilic antioxidants. The results of our in vitro experiments suggest that primary CoQ10 deficiencies should be treated with CoQ10 supplementation but not with short-tail ubiquinone analogs, such as idebenone or CoQ2. Complementary administration of antioxidants with high bioavailability should be considered if oxidative stress is present.
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Funding: This work was supported by U.S. National Institutes of Health (NIH) grants HD32062 and NS11766, by grants from the Muscular Dystrophy Association
(MDA), and by the Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF). LCL was supported by a post-doctoral fellowship from the Ministerio de
Educacio n y Ciencia, Spain. CMQ is supported by the MDA. LS is supported by Telethon grant GGP09207. The funders had no role in study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: Santhera Pharmaceuticals (Switzerland) Ltd supplied idebenone for this study. In addition, Dr. Hirano has a research contract with
Santhera for a clinical trial of idebenone for a mitochondrial disease (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-like episode [MELAS]). Dr.
Hirano receives no salary support from Santhera. Other than supplying idebenone, Santhera was not involved in the research described in this manuscript. The
work of Dr. Hirano and colleagues was performed independently of Santhera. In fact, the results of this study may be viewed as negative for Santhera, because the
findings suggest that idebenone cannot replace coenzyme Q10 in the mitochondrial respiratory chain.
. These authors contributed equally to this work.
Coenzyme Q10 (CoQ10; ubiquinone) and its analogs have been
evaluated as antioxidant agents and enhancers of mitochondrial
functions in patients with mitochondrial disorders and clinical
trials of neurodegenerative diseases including Parkinson disease,
amyotrophic lateral sclerosis, Huntington disease, Friedreich
ataxia, and Alzheimers disease with modest or no objective
benefits [16]. The use of CoQ10 therapy and its analogs in
primary CoQ10 deficiency, an autosomal recessive syndrome due
to defects of ubiquinone biosynthesis, could provide valuable data
to evaluate the effectiveness of these compounds in restoring
respiratory chain activities and preventing oxidative stress. The
disorder manifests clinically with four major phenotypes: 1) an
encephalomyopathy with brain involvement and recurrent
myoglobinuria [7]; 2) an infantile multisystem disorder with
encephalopathy usually associated with nephropathy and variable
involvement of other organs [8,9]; 3) ataxic syndrome with
cerebellar atrophy [10, (...truncated)