Figure 1.

Necrostatin-1 downregulates rotenone-activated necroptosis and mitophagy.

Through the inhibition of mitochondrial complex I, rotenone triggers ROS generation, which leads to the activation of the necrosome complex (RIP1-RIP3-MLKL) and necroptosis. Meanwhile, RIP3 activates the serine/threonine phosphatase protein PGAM5. The latter recruits into mitochondria and dephosphorylates DRP1 to promote the mitochondrial fission and turnover. However, necrostatin-1 inhibits both rotenone-induced necroptosis and mitophagy and enhances necrosis and apoptotic cell death. DRP1: Dynamin-related protein 1; MLKL: mixed lineage kinase domain-like protein; PGAM5: phosphoglycerate mutase 5; RIP: receptor-interacting protein; ROS: reactive oxygen species.