Increased S-adenosyl methionine strengthens the suppression in mitochondrial unfolded protein response induced by 6-PPD quinone at environmentally relevant concentrations in Caenorhabditis elegans

Exposure to 6-PPD quinone (6-PPDQ) caused mitochondrial dysfunction; however, underlying mechanisms remain largely unclear. In cells, S-adenosylmethionine (SAM) can be generated from methionine. In nematodes, 6-PPDQ (0.1-10 μg/L) reduced methionine content by decreasing expression of msra-1 encoding methionine sulfoxide reductase. 6-PPDQ further increased SAM content by enhancing expressions of sams-1 and sams-5 encoding methionine adenosyltransferases, which activated expressions of mitochondrial slc-25A26 encoding SAM transporter and trmt-10C.2 encoding tRNA methyltransferase. The 6-PPDQ induced mitochondrial dysfunction was inhibited by slc-25A26 and trmt-10C.2 RNAi. Additionally, slc-25A26 and trmt-10C.2 RNAi inhibited 6-PPDQ caused suppression in mitochondrial unfolded protein response (mt UPR) by increasing expressions of haf-1 and clpp-1, two mitochondrial genes governing mt UPR. Moreover, after treatment with methionine to reduce SAM content, 6-PPDQ induced mitochondrial dysfunction and suppression in mt UPR were inhibited. Therefore, 6-PPDQ caused increase in SAM could strengthen mitochondrial dysfunction by enhancing mt UPR suppression, which suggested a metabolic regulatory mechanism of 6-PPDQ toxicity on mitochondrial function.