Arginine metabolism disruption mediates 6-PPD quinone-induced mitochondrial toxicity at environmentally relevant concentrations in Caenorhabditis elegans

The 6-PPD quinone (6-PPDQ) is frequently detected in environment. However, the possible effect of 6-PPDQ on amino acid metabolism and corresponding mechanisms remain unclear. In Caenorhabditis elegans, we examined effect of 6-PPDQ exposure on the absorption and catabolism of arginine. In nematodes, 6-PPDQ exposure reduced arginine content, and decreased expression of amino acid transporter 1 (aat-1) and C50D2.2 encoding intestinal transporters. Intestinal RNA interference (RNAi) of aat-1 and C50D2.2 reduced arginine content. Additionally, 6-PPDQ increased the expression of slc-25A29, which governs arginine import into the mitochondria, and argn-1, which governs mitochondrial arginine catabolism. Arginine content was increased by slc-25A29 and argn-1 RNAi. 6-PPDQ-induced mitochondrial dysfunction was strengthened by aat-1 and C50D2.2 RNAi and suppressed by slc-25A29 and argn-1 RNAi. The expression of slc-25A29 and argn-1 was further increased by RNAi of aat-1 and C50D2.2, and in the mitochondria, gas-1, mev-1, sod-3, and hsp-6 were identified as targets of argn-1 for controlling 6-PPDQ toxicity. Therefore, exposure risk of 6-PPDQ in disrupting arginine absorption and catabolism was suggested, which was associated with 6-PPDQ-induced mitochondrial dysfunction.