β‐RA reduces DMQ/CoQ ratio and rescues the encephalopathic phenotype in Coq9R239X mice

This study proposes a powerful therapy for COQ9 or COQ7 deficiencies. The novel therapeutic strategy is based on oral administration of β‐RA, showing superior outcomes to those obtained after oral CoQ10 supplementation, as demonstrated in the mitochondrial encephalopathyCoq9R239X mouse model. AbstractCoenzyme 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 theCoq9R239X mouse model with 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 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 β‐RA administration were superior to those after CoQ10 supplementation, its u...
Source: EMBO Molecular Medicine - Category: Molecular Biology Authors: Tags: Research Article Source Type: research