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Oxidative Medicine and Cellular Longevity Volume 2019 ,2019-07-10
Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6
Research Article
Manuel J. Acosta Lopez 1 , 2 Eva Trevisson 1 , 2 Marcella Canton 2 , 3 Luis Vazquez-Fonseca 1 , 2 Valeria Morbidoni 1 , 2 Elisa Baschiera 1 , 2 Chiara Frasson 2 Ludovic Pelosi 4 Bérengère Rascalou 4 Maria Andrea Desbats 1 , 2 María Alcázar-Fabra 5 José Julián Ríos 6 Alicia Sánchez-García 6 Giuseppe Basso 2 , 7 Placido Navas 5 Fabien Pierrel 4 Gloria Brea-Calvo 5 Leonardo Salviati 1 , 2
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DOI:10.1155/2019/3904905
Received 2019-02-03, accepted for publication 2019-05-26, Published 2019-05-26
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摘要

Coenzyme Q (CoQ), a redox-active lipid, is comprised of a quinone group and a polyisoprenoid tail. It is an electron carrier in the mitochondrial respiratory chain, a cofactor of other mitochondrial dehydrogenases, and an essential antioxidant. CoQ requires a large set of enzymes for its biosynthesis; mutations in genes encoding these proteins cause primary CoQ deficiency, a clinically and genetically heterogeneous group of diseases. Patients with CoQ deficiency often respond to oral CoQ10 supplementation. Treatment is however problematic because of the low bioavailability of CoQ10 and the poor tissue delivery. In recent years, bypass therapy using analogues of the precursor of the aromatic ring of CoQ has been proposed as a promising alternative. We have previously shown using a yeast model that vanillic acid (VA) can bypass mutations of COQ6, a monooxygenase required for the hydroxylation of the C5 carbon of the ring. In this work, we have generated a human cell line lacking functional COQ6 using CRISPR/Cas9 technology. We show that these cells cannot synthesize CoQ and display severe ATP deficiency. Treatment with VA can recover CoQ biosynthesis and ATP production. Moreover, these cells display increased ROS production, which is only partially corrected by exogenous CoQ, while VA restores ROS to normal levels. Furthermore, we show that these cells accumulate 3-decaprenyl-1,4-benzoquinone, suggesting that in mammals, the decarboxylation and C1 hydroxylation reactions occur before or independently of the C5 hydroxylation. Finally, we show that COQ6 isoform c (transcript NM_182480) does not encode an active enzyme. VA can be produced in the liver by the oxidation of vanillin, a nontoxic compound commonly used as a food additive, and crosses the blood-brain barrier. These characteristics make it a promising compound for the treatment of patients with CoQ deficiency due to COQ6 mutations.

授权许可

Copyright © 2019 Manuel J. Acosta Lopez et al. 2019
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

通讯作者

1. Gloria Brea-Calvo.Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide and CIBERER, Sevilla, Spain, upo.es.gbrecal@upo.es
2. Leonardo Salviati.Clinical Genetics Unit, Department of Women’s and Children’s Health, University of Padova, Italy, unipd.it;Istituto di Ricerca Pediatrica (IRP) Città della Speranza, Padova, Italy, cittadellasperanza.org.leonardo.salviati@unipd.it

推荐引用方式

Manuel J. Acosta Lopez,Eva Trevisson,Marcella Canton,Luis Vazquez-Fonseca,Valeria Morbidoni,Elisa Baschiera,Chiara Frasson,Ludovic Pelosi,Bérengère Rascalou,Maria Andrea Desbats,María Alcázar-Fabra,José Julián Ríos,Alicia Sánchez-García,Giuseppe Basso,Placido Navas,Fabien Pierrel,Gloria Brea-Calvo,Leonardo Salviati. Vanillic Acid Restores Coenzyme Q Biosynthesis and ATP Production in Human Cells Lacking COQ6. Oxidative Medicine and Cellular Longevity ,Vol.2019(2019)

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