6-PPD quinone at environmentally relevant concentrations induced damage on longevity in C. elegans: Mechanistic insight from inhibition in mitochondrial UPR response.

Abstract

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.