β‐RA reduced DMQ/CoQ ration and rescues the encephalopathic phenotype in Coq9R239X mice

RNA-Seq data were generated as described above. The files have been uploaded in the repository Gene Expression Omnibus. The accession number is GSE120287. All data can be found at https:// www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE120287.

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.

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).