beta-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight
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AuthorHidalgo Gutiérrez, Agustín; Barriocanal Casado, Eliana; Díaz Casado, María Elena; González García, Pilar; Acuña Castroviejo, Darío; López García, Luis Carlos
Mitochondrial diseaseEncephalopathyAstrogliosisSpongiosisObesityWhite adipose tissueMitochondrial proteome3T3-L1Mouse modelHepatic steatosis
Hidalgo-Gutiérrez, A... [et al.]. beta -RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight. Biomedicines 2021, 9, 1457. [https://doi.org/10.3390/biomedicines9101457]
SponsorshipSpanish Government; European Commission RTI2018-093503-B-100; Muscular Dystrophy Association MDA602322; Junta de Andalucia P20_00134; University of Granada UCE-PP2017-06; EPIC-XS - Horizon 2020 program of the European Union 823839; Muscular Dystrophy Association; Junta de Andalucia; Spanish Government; University of Granada
Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the 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 remain challenging. Here, we show that beta-resorcylic acid (beta-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9(R239X) mice. As a consequence, beta-RA rescued the phenotype of Coq9(R239X) mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with beta-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that beta-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis.