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Abstract
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 (β-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 Coq9R239X mice. As a consequence, β-RA rescued the phenotype of Coq9R239X mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with β-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 β-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.
Highlights
This article is an open access articleMitochondria are the primary sites of cellular energy production and have a broad range of metabolic functions
These results suggest that metabolism in the kidneys and, to a lesser extent, the liver contributed to the reduced white adipose tissue (WAT) that was induced by β-Resorcylic acid (β-RA) in wild-type animals
Because other hydroxybenzoic acid derivatives (HBAs), e.g., salicylic acid or vanillic acid, can activate AMPK [40,41], which is an enzyme that plays a key role in cellular energy homeostasis [42,43], we investigated whether the observed effects of β-RA in WAT were due to the activation of AMPK through its phosphorylation
Summary
Mitochondria are the primary sites of cellular energy production and have a broad range of metabolic functions. One particular case of mitochondrial disease is coenzyme Q10 (CoQ10 ) deficiency syndrome, which can be primarily caused by mutations in genes that encode proteins that are involved in the CoQ10 biosynthetic pathway (primary CoQ10 deficiency). Wang and colleagues reported that β-RA decreased the body weight of wild-type mice and increased survival in animals at the middle-age and elderly stages of life, but the mechanisms behind these observations remain to be elucidated. These results in the Coq and Adck mouse models and in wild-type mice suggest that β-RA may work through additional unidentified mechanisms. We tested whether β-RA could be a useful agent to treat the fat accumulation that is linked to aging
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