β-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice
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Hidalgo Gutiérrez, Agustín; Barriocanal Casado, Eliana; Bakkali, Mohammed; Díaz-Casado, Elena; Sánchez-Maldonado, Laura; Romero Pérez, Miguel; Sayed, Ramy K. A.; Prehn, Cornelia; Escames Rosa, Germaine; Duarte Pérez, Juan Manuel; Acuña Castroviejo, Darío; López García, Luis CarlosEditorial
European Molecular Biology Organization (EMBO)
Materia
Genetics Gene Therapy & Genetic Disease Pharmacology & Drug Discovery
Date
2018-11-27Referencia bibliográfica
Hidalgo-Gutiérrez, Agustín; et. al. β-RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice. EMBO Mol Med (2018) e9466 [http://hdl.handle.net/10481/53973]
Sponsorship
This work was supported by grants from Ministerio de Economía y Competitividad, Spain, and the ERDF (grant numbers SAF2013-47761-R and SAF2015-65786-R), from the NIH (P01HD080642), and from the University of Granada (grant reference “UNETE”, UCE-PP2017-06). A.H.-G. is a “FPU fellow” from the Ministerio de Educación Cultura y Deporte, Spain. E.B.-C- and M.E.D.-C. were supported by the Junta de Andalucía. L.C.L. was supported by the “Ramón y Cajal” National Programme, Ministerio de Economía y Competitividad, Spain (RYC- 2011-07643).Abstract
Coenzyme Q (CoQ) deficiency has been associated with primary
defects in the CoQ biosynthetic pathway or to secondary events. In
some cases, the exogenous CoQ supplementation has limited efficacy.
In the Coq9R239X mouse model with fatal mitochondrial
encephalopathy due to CoQ deficiency, we have tested the therapeutic
potential of b-resorcylic acid (b-RA), a structural analog of
the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory
salicylic acid. b-RA noticeably rescued the phenotypic,
morphological, and histopathological signs of the encephalopathy,
leading to a significant increase in the survival. Those effects were
due to the decrease of the levels of demethoxyubiquinone-9
(DMQ9) and the increase of mitochondrial bioenergetics in peripheral
tissues. However, neither CoQ biosynthesis nor mitochondrial
function changed in the brain after the therapy, suggesting that
some endocrine interactions may induce the reduction of the
astrogliosis, spongiosis, and the secondary down-regulation of
astrocytes-related neuroinflammatory genes. Because the therapeutic
outcomes of b-RA administration were superior to those
after CoQ10 supplementation, its use in the clinic should be considered
in CoQ deficiencies.