Mitochondria UPR stimulation by pelargonidin-3-glucoside contributes to ameliorating lipid accumulation under copper exposure.

Intensification of copper pollution in the environment has led to its excessive accumulation in humans, causing oxidative stress and lipid metabolism disorders. It is necessary to look for effective targets and safe methods to alleviate copper toxicity. Pelargonidin-3-glucoside (Pg3G) is a natural anthocyanin with metal ion chelating ability and multiple physiological activities. In this study, lipid accumulation was investigated under copper exposure in Caenorhabditis elegans which can be improved by Pg3G. Transcriptome analysis revealed that differentially expressed genes are enriched in lipid metabolism and protein folding/degradation. Pg3G activated mitochondrial unfold protein response (UPR) to mitigate mitochondrial damage caused by copper and regulated the expression of genes involved in lipid absorption, transport, and synthesis, thereby reducing lipid levels in C. elegans. This improvement disappeared in the ubl-5 knockout strain, indicating that ubl-5 is one target of Pg3G. Meanwhile, in HepG2 cells, Pg3G enhanced the cellular antioxidant capacity by activating UPR for maintaining mitochondrial homeostasis, followed by inhibition of excessive lipid accumulation. Overall, these results suggested that UPR activation can be a strategy for mitigating lipid disorders induced by copper and Pg3G with excellent ability to resist oxidative stress specially targeted for ubl-5 has a promising application in controlling copper contamination.