An environmentally relevant concentration of 6-PPD quinone inhibits two types of mitophagy to cause mitochondrial dysfunction and lifespan reduction in <i>Caenorhabditis elegans</i>

<i>N</i>-(1,3-Dimethylbutyl)-<i>N</i>'-phenyl-<i>p</i>-phenylenediamine quinone (6-PPDQ) is widely distributed in the environment and bioavailable to organisms. Exposure to 6-PPDQ can impair the mitochondrial function. However, the underlying mechanisms for 6-PPDQ-induced mitochondrial dysfunction remain largely unclear. Mitophagy is important for organisms to maintain normal mitochondrial function. In the current study, <i>Caenorhabditis elegans</i> was employed as model to determine the role of mitophagy suppression in 6-PPDQ-induced toxicity. After exposure to 6-PPDQ, it was found that, although mitophagy was increased by 0.1-1 μg L^-1 6-PPDQ, 10 μg L^-1 6-PPDQ downregulated the expression of genes involved in PINK1/Parkin-dependent mitophagy (<i>pink</i>-1, <i>pdr</i>-1, and <i>sqst</i>-1) and receptor-mediated mitophagy (<i>fndc</i>-1 and <i>dct</i>-1). RNAi of these mitophagy-related genes enhanced the 6-PPDQ toxicity on mitochondrial function and lifespan. Moreover, after 6-PPDQ (10 μg L^-1) exposure, 6-PPDQ could be accumulated in the nucleus and affected the expressions of some transcription factor (TF) genes (<i>daf</i>-5, <i>elt</i>-2, <i>atf</i>-7, <i>daf</i>-16, <i>bar</i>-1, and <i>skn</i>-1) thereby inducing the inhibition of these two types of mitophagy. Inhibition in both mitophagy and the mitochondrial unfolded protein response (mt UPR) caused more severe 6-PPDQ toxicity on the mitochondrial function and lifespan. Our results demonstrate the crucial role of mitophagy suppression in mediating the toxicity of 6-PPDQ, which is useful for predicting the environmental exposure risk of 6-PPDQ on organisms.