β-RA targets mitochondrial metabolism and adipogenesis, leading to therapeutic benefits against CoQ deficiency and age-related overweight [article]

Agustín Hidalgo-Gutiérrez, Eliana Barriocanal-Casado, María Elena Díaz-Casado, Pilar González-García, Riccardo Zenezini Chiozzi, Darío Acuña-Castroviejo, Luis Carlos López
2021 bioRxiv   pre-print
AbstractPrimary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remains challenging. Here, we show that beta-resorcylic acid (β-RA), a natural phenolic compound, competes in vivo with
more » ... droxybenzoic acid, the natural precursor of Coenzyme Q biosynthesis. This leads to a decrease of demethoxyubiquinone, an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, β-RA rescues the phenotype of Coq9R239X mice, a model of primary mitochondrial encephalopathy. Moreover, we observe that long-term treatment with β-RA also reduces the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to a prevention of hepatic steatosis and an increase in survival at the old stage of life. The reduction in WAT content is due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and a stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that β-RA acts through different cellular mechanisms, with effects on mitochondrial metabolism, and it may be used for the treatment of primary Coenzyme Q deficiency, overweight, and hepatic steatosis.
doi:10.1101/2021.04.13.438670 fatcat:v5kvwyixvjckliefysys53afgq