Department of Biology and the Environment, Faculty of Natural Sciences, University of Haifa, Oranim, Tivon 36006, Israel.
Department of Biology and the Environment, Faculty of Natural Sciences, University of Haifa, Oranim, Tivon 36006, Israel
Genetics. 2018 Jun;209(2):457-473. doi: 10.1534/genetics.118.300863. Epub 2018 Mar 29.
The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway's enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPR, can protect yeast, , and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins. The mechanistic basis for this protection, however, remains unknown. Using , we found that the UPR does not directly affect the levels of the statin target HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway in mammals. Instead, in the UPR upregulates the first dedicated enzyme of the pathway, HMG-CoA synthase (HMGS-1). A targeted RNA interference (RNAi) screen identified two UPR transcription factors, ATFS-1 and DVE-1, as regulators of HMGS-1 A comprehensive analysis of the pathway's enzymes found that, in addition to HMGS-1, the UPR upregulates enzymes involved with the biosynthesis of electron carriers and geranylgeranylation intermediates. Geranylgeranylation, in turn, is requisite for the full execution of the UPR 3response. Thus, the UPR acts in at least three coordinated, compensatory arms to upregulate specific branches of the mevalonate pathway, thereby alleviating mitochondrial stress. We propose that statin-mediated inhibition of the mevalonate pathway blocks this compensatory system of the UPR and consequentially impedes mitochondrial homeostasis. This effect is likely one of the principal bases for the adverse side effects of statins.
甲羟戊酸途径是降胆固醇药物他汀类药物的主要靶点，他汀类药物是有史以来应用最广泛的药物之一。该途径的酶不仅催化胆固醇的合成，还催化多种代谢物的合成，如线粒体电子载体和异戊烯基。最近，已经表明一种线粒体应激反应，UPR，可以保护酵母、和培养的人类细胞免受他汀类药物抑制甲羟戊酸途径的有害影响。然而，这种保护的机制基础仍然未知。使用，我们发现 UPR 不会直接影响他汀类药物的靶标 HMG-CoA 还原酶的水平，HMG-CoA 还原酶是哺乳动物中甲羟戊酸途径的限速酶。相反，在酵母中，UPR 上调途径的第一个专用酶 HMG-CoA 合酶（HMGS-1）。靶向 RNA 干扰（RNAi）筛选鉴定出两个 UPR 转录因子 ATFS-1 和 DVE-1 作为 HMGS-1 的调节剂。对途径酶的全面分析发现，除了 HMGS-1 之外，UPR 还上调参与电子载体和香叶基香叶基化中间体生物合成的酶。香叶基香叶基化反过来又是 UPR 3 反应完全执行所必需的。因此，UPR 通过至少三个协调的补偿臂来上调甲羟戊酸途径的特定分支，从而减轻线粒体应激。我们提出，他汀类药物抑制甲羟戊酸途径阻断了 UPR 的这种补偿系统，从而阻碍了线粒体的动态平衡。这种影响可能是他汀类药物产生不良反应的主要基础之一。
