Abstract

The 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme of the mevalonate pathway for the synthesis of cholesterol in mammals (ergosterol in fungi), is inhibited by statins, a class of cholesterol lowering drugs. Indeed, statins are in a wide medical use, yet statins treatment could induce side effects as hepatotoxicity and myopathy in patients. We used Saccharomyces cerevisiae as a model to investigate the effects of statins on mitochondria. We demonstrate that statins are active in S.cerevisiae by lowering the ergosterol content in cells and interfering with the attachment of mitochondrial DNA to the inner mitochondrial membrane. Experiments on murine myoblasts confirmed these results in mammals. We propose that the instability of mitochondrial DNA is an early indirect target of statins.

 抽象的

3-羟基-3-甲基戊二酰辅酶A还原酶是哺乳动物中合成胆固醇（真菌中的麦角甾醇）的甲羟戊酸途径的关键酶，可被他汀类药物（一类降胆固醇药物）抑制。事实上，他汀类药物具有广泛的医疗用途，但他汀类药物治疗可能会引起患者肝毒性和肌病等副作用。我们使用酿酒酵母作为模型来研究他汀类药物对线粒体的影响。我们证明他汀类药物通过降低细胞中麦角甾醇含量并干扰线粒体 DNA 与线粒体内膜的附着而在酿酒酵母中发挥活性。对小鼠成肌细胞的实验证实了哺乳动物中的这些结果。我们认为线粒体 DNA 的不稳定性是他汀类药物的早期间接靶标。