Rauthan Manish, Pilon Marc
Department of Chemistry and Molecular Biology; University of Gothenburg ; Gothenburg, Sweden.
Worm. 2015 Oct 2;4(4):e1096490. doi: 10.1080/21624054.2015.1096490. eCollection 2015 Oct-Dec.
We previously showed that inhibition of the mevalonate pathway in C. elegans causes inhibition of protein prenylation, developmental arrest and lethality. We also showed that constitutive activation of the mitochondrial unfolded protein response, UPR(mt), is an effective way for C. elegans to become resistant to the negative effects of mevalonate pathway inhibition. This was an important finding since statins, a drug class prescribed to lower cholesterol levels in patients, act by inhibiting the mevalonate pathway, and it is therefore possible that some of their undesirable side effects could be alleviated by activating the UPR(mt). Here, we screened a chemical library and identified 4 compounds that specifically activated the UPR(mt). One of these compounds, methacycline hydrochloride (a tetracycline antibiotic) also protected C. elegans and mammalian cells from statin toxicity. Methacycline hydrochloride and ethidium bromide, a known UPR(mt) activator, were also tested in mice: only ethidium bromide significantly activate the UPR(mt) in skeletal muscles.
我们之前表明，秀丽隐杆线虫中甲羟戊酸途径的抑制会导致蛋白质异戊二烯化的抑制、发育停滞和致死。我们还表明，线粒体未折叠蛋白反应（UPR(mt)）的组成型激活是秀丽隐杆线虫对甲羟戊酸途径抑制的负面影响产生抗性的有效方式。这是一个重要发现，因为他汀类药物（一类用于降低患者胆固醇水平的药物）通过抑制甲羟戊酸途径起作用，因此有可能通过激活UPR(mt)来减轻它们的一些不良副作用。在此，我们筛选了一个化学文库并鉴定出4种特异性激活UPR(mt)的化合物。其中一种化合物盐酸美他环素（一种四环素抗生素）也保护秀丽隐杆线虫和哺乳动物细胞免受他汀类药物毒性的影响。盐酸美他环素和已知的UPR(mt)激活剂溴化乙锭也在小鼠中进行了测试：只有溴化乙锭能显著激活骨骼肌中的UPR(mt)。
