Ranji Parmida, Rauthan Manish, Pitot Christophe, Pilon Marc
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden.
PLoS One. 2014 Jun 11;9(2):e100033. doi: 10.1371/journal.pone.0100033. eCollection 2014.
HMG-CoA reductase is the rate-limiting enzyme in the mevalonate pathway and the target of cholesterol-lowering statins. We characterized the C. elegans hmgr-1(tm4368) mutant, which lacks HMG-CoA reductase, and show that its phenotypes recapitulate that of statin treatment, though in a more severe form. Specifically, the hmgr-1(tm4368) mutant has defects in growth, reproduction and protein prenylation, is rescued by exogenous mevalonate, exhibits constitutive activation of the UPRer and requires less mevalonate to be healthy when the UPRmt is activated by a constitutively active form of ATFS-1. We also show that different amounts of mevalonate are required for different physiological processes, with reproduction requiring the highest levels. Finally, we provide evidence that the mevalonate pathway is required for the activation of the UPRmt.
HMG-CoA还原酶是甲羟戊酸途径中的限速酶，也是降胆固醇他汀类药物的作用靶点。我们对缺乏HMG-CoA还原酶的秀丽隐杆线虫hmgr-1(tm4368)突变体进行了表征，结果表明其表型重现了他汀类药物治疗的表型，只是更为严重。具体而言，hmgr-1(tm4368)突变体在生长、繁殖和蛋白质异戊二烯化方面存在缺陷，可被外源性甲羟戊酸挽救，表现出未折叠蛋白反应内质网（UPRer）的组成型激活，并且当通过组成型活性形式的ATFS-1激活线粒体未折叠蛋白反应（UPRmt）时，维持健康所需的甲羟戊酸较少。我们还表明，不同的生理过程需要不同量的甲羟戊酸，繁殖所需的水平最高。最后，我们提供证据表明甲羟戊酸途径是激活UPRmt所必需的。
