Hidalgo-Gutiérrez Agustín, Barriocanal-Casado Eliana, Díaz-Casado María Elena, González-García Pilar, Zenezini Chiozzi Riccardo, Acuña-Castroviejo Darío, López Luis Carlos
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, 18016 Granada, Spain.
Centro de Investigación Biomédica, Instituto de Biotecnología, Universidad de Granada, 18016 Granada, Spain.
Biomedicines. 2021 Oct 13;9(10):1457. doi: 10.3390/biomedicines9101457.
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 mice. As a consequence, β-RA rescued the phenotype of 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.
原发性线粒体疾病由线粒体或核基因的突变引起，导致特定线粒体途径的功能异常。线粒体功能障碍在更常见的病理生理状况（如肥胖和代谢综合征）中也是一个继发性事件。在这两种情况下，线粒体稳态的改善和管理仍然具有挑战性。在此，我们表明，作为一种天然酚类化合物的β-间苯二酚酸（β-RA）在体内与辅酶Q生物合成的天然前体4-羟基苯甲酸竞争。这导致去甲氧基泛醌减少，去甲氧基泛醌是辅酶Q生物合成的一种中间代谢产物，在小鼠中异常积累。结果，β-RA挽救了原发性线粒体脑病模型小鼠的表型。此外，我们观察到，长期用β-RA治疗还减少了野生型小鼠衰老过程中正常积累的白色脂肪组织（WAT）的大小和含量，从而预防了肝脂肪变性，并提高了老年阶段的存活率。WAT含量的减少是由于脂肪生成减少、肾脏线粒体蛋白质组的适应性变化以及糖酵解和乙酰辅酶A代谢的刺激。因此，我们的结果表明，β-RA通过不同的细胞机制发挥作用，对线粒体代谢产生影响；因此，它可用于治疗原发性辅酶Q缺乏、超重和肝脂肪变性。
