Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Medical School, Southeast University, Nanjing, China.
Key Laboratory of Environmental Medicine Engineering of Ministry of Education, Medical School, Southeast University, Nanjing, China; Shenzhen Ruipuxun Academy for Stem Cell & Regenerative Medicine, Shenzhen, China.
Sci Total Environ. 2024 Dec 1;954:176275. doi: 10.1016/j.scitotenv.2024.176275. Epub 2024 Sep 13.
6-PPD quinone (6-PPDQ) exists widely in water environment media, causing acute lethality to some aquatic species. Long-term exposure to 6-PPDQ reduced the lifespan of Caenorhabditis elegans. However, the molecular basis for mitochondrial control of 6-PPDQ toxicity remains largely unclear. Using HSP-6 as marker of mitochondrial unfolded protein response (mt UPR), we observed activation of mt UPR by 0.1 and 1 μg/L 6-PPDQ and inhibition in mt UPR by 10 μg/L 6-PPDQ. Additionally, increased atfs-1, ubl-5, and dve-1 expressions were caused by 0.1 and 1 μg/L 6-PPDQ and decreased expressions of these genes were induced by 10 μg/L 6-PPDQ. Neuronal and intestinal RNA interference (RNAi) of hsp-6 caused susceptibility to 6-PPDQ toxicity on longevity, and atfs-1, ubl-5, and dve-1 acted in neurons and intestine to modulate mt UPR and 6-PPDQ toxicity on longevity. Meanwhile, 6-PPDQ (1 and 10 μg/L) increased expressions of histone methyltransferase genes met-2 and set-6, and decreased expressions of histone demethylase genes jmjd-1.2 and jmjd-3.1. Neuronal RNAi of set-6 and intestinal RNAi of met-2 accelerated hsp-6, atfs-1, ubl-5, and dve-1 expressions and extended lifespan of 6-PPDQ exposed nematodes. In contrast, neuronal RNAi of jmjd-1.2 and jmjd-3.1 and intestinal RNAi of jmjd-1.2 suppressed these 4 gene expressions and reduced lifespan of 6-PPDQ exposed nematodes o. In nematodes, RNAi of hsp-6 could also enhance mitochondrial dysfunction and mitochondrial reactive oxygen species (ROS) induced by 6-PPDQ. Therefore, 6-PPDQ caused damage on longevity was associated with suppression in mt UPR, which was under regulation of certain histone methylation related signals.
6-对苯二酚醌（6-PPDQ）广泛存在于水环境介质中，对一些水生生物具有急性致死性。长期暴露于 6-PPDQ 会降低秀丽隐杆线虫的寿命。然而，线粒体控制 6-PPDQ 毒性的分子基础在很大程度上仍不清楚。使用 HSP-6 作为线粒体未折叠蛋白反应（mt UPR）的标志物，我们观察到 0.1 和 1μg/L 6-PPDQ 激活了 mt UPR，而 10μg/L 6-PPDQ 抑制了 mt UPR。此外，0.1 和 1μg/L 6-PPDQ 引起了 atfs-1、ubl-5 和 dve-1 的表达增加，而 10μg/L 6-PPDQ 则诱导这些基因的表达减少。神经元和肠道的 hsp-6 RNAi 导致线虫对 6-PPDQ 毒性的寿命易感性增加，atfs-1、ubl-5 和 dve-1 在神经元和肠道中作用于调节 mt UPR 和线虫对 6-PPDQ 毒性的寿命。同时，6-PPDQ（1 和 10μg/L）增加了组蛋白甲基转移酶基因 met-2 和 set-6 的表达，降低了组蛋白去甲基化酶基因 jmjd-1.2 和 jmjd-3.1 的表达。set-6 的神经元 RNAi 和 met-2 的肠道 RNAi 加速了 hsp-6、atfs-1、ubl-5 和 dve-1 的表达，并延长了暴露于 6-PPDQ 的线虫的寿命。相比之下，神经元 RNAi 的 jmjd-1.2 和 jmjd-3.1 和肠道 RNAi 的 jmjd-1.2 抑制了这 4 个基因的表达，减少了暴露于 6-PPDQ 的线虫的寿命。在线虫中，hsp-6 的 RNAi 也可以增强 6-PPDQ 诱导的线粒体功能障碍和线粒体活性氧（ROS）。因此，6-PPDQ 对寿命造成的损害与 mt UPR 的抑制有关，而 mt UPR 的抑制受某些组蛋白甲基化相关信号的调节。
