Toxic vs Therapeutic: The Dose-Dependent Effects of beta-RA Depends on CoQ Metabolism

Hydroxybenzoic acids derivatives (HBAs) are natural phenolic compounds that are being used for medical purposes. Some of these compounds (e.g. salicylic acid), however, have reported toxicity in particular conditions but the mechanisms of this effect remain obscure. In this study, we used multiple approaches to evaluate the effect of a high dose of beta-resorcylic acid (beta-RA), an HBA potentially useful for the treatment of Coenzyme Q (CoQ) deficiencies, in wild-type animals. We also test the therapeutic potential of a lower dose of beta-RA in both wild-type and a mouse model (Coq9R239X) of mitochondrial encephalopathy caused by CoQ deficiency. We show that the high dose of beta-RA induces hepatic, renal and cerebral toxicity in wild-type animals, similar to those produced in Reye's syndrome, with a disruption in transcriptomic profiles and mitochondrial proteomes. Those toxic effects are dependent of the metabolic capability to use beta-RA in the CoQ biosynthetic pathway. Accordingly, the low dose of beta-RA dramatically reduces the toxicological potential in wild-type animals, preserving the therapeutic capability in Coq9R239X mice by modulating CoQ metabolism. Collectively, our results highlight novel toxic mechanisms of HBAs and provide a safe translational perspective for the use the beta-RA in the treatment of CoQ deficiencies.