β-RA reduces DMQ/CoQ ratio and recues the encephalopathic phenotype in Coq9R239X mice

Coenzyme Q (CoQ) deficiency has been associated to 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 of fatal mitochondrial encephalopathy due to CoQ deficiency, we have tested the therapeutic potential of β-Resorcylic Acid (β-RA), a structural analog of the CoQ precursor 4-hydroxybenzoic acid and the anti-inflammatory salicylic acid. β-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 and 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 β-RA administration were superior to those after CoQ10 supplementation, its use in the clinic should be considered in CoQ deficiencies. Physiological, biochemical and gene expression (RNA-Seq) analysis of the mitochondrial encephalopathy and the therapeutic effect of the β-Resorcylic Acid