6-PPD quinone at environmentally relevant concentrations activates feedback response of electron transport chain to mediate damage on mitochondrial function and longevity in Caenorhabditis elegans
Xin Hua, Dayong Wang
Abstract
6-PPD quinone (6-PPDQ) could cause mitochondrial dysfunction; however, response of entire electron transport chain to 6-PPDQ remains largely unclear. In Caenorhabditis elegans , activity of mitochondrial complex IV was inhibited by 6-PPDQ (1–10 μg/L), and expressions of cco-1 , cox-4 and cox-7c encoding complex IV components were increased by 6-PPDQ (1–10 μg/L). 6-PPDQ induced mitochondrial dysfunction was suppressed by cco-1 , cox-4 and cox-7c RNAi, and 6-PPDQ induced mitochondrial UPR was strengthened by cco-1 , cox-4 and cox-7c RNAi. The 6-PPDQ caused decrease in complex IV activity and increase in cco-1 , cox-4 and cox-7c expressions were enhanced by RNAi of gas-1 and mev-1 encoding components of complex I and II, and inhibited by RNAi of clk-1 and isp-1 encoding components of complex III. Moreover, after 6-PPDQ exposure, activities of complex I-III and expressions of gas-1 and mev-1 were increased by cco-1 , cox-4 , and/or cox-7c RNAi, and isp-1 expression was decreased by cco-1 , cox-4 and cox-7c RNAi. Additionally, CCO-1, COX-4, and COX-7c functioned in intestine, germline, and/or neurons to control 6-PPDQ induced mitochondrial dysfunction and lifespan reduction by affecting certain insulin ligands in these tissues. Therefore, 6-PPDQ could induce response of entire electron transfer chain, which was related to induction of mitochondrial dysfunction and lifespan reduction. • Exposure to 6-PPDQ at ERCs could decreased the activity of mitochondrial complex IV. • CCO-1, COX-4 and COX-7C changes mediated 6-PPDQ toxicity on mitochondrial function. • Alteration of components on complex IV formed a feedback regulation to other complexes. • CCO-1/COX-4/COX-7C acted upstream of insulin ligands in controlling 6-PPDQ toxicity.