Figure 8.

Proposed model of TGHQ-induced PARP-1-mediated non-apoptotic cell death in HK-2 cells. TGHQ, a potent nephrotoxic and carcinogenic metabolite of HQ, induces the robust generation of ROS, which leads to DNA damage and the hyperactivation of PARP-1. Activated PARP-1 subsequently depletes NAD⁺ to create PAR polymers, which translocate from the nucleus to the cytosol, thus PARylating proteins that may lead to activation of SOCs (CRAC channels). Activation of CRAC channels may also occur directly through ROS or direct PARylation. The subsequent iCa²⁺ increases may lead to non-apoptotic cell death. Green lightning represents ROS-induced DNA damage, pink spheres represent Ca²⁺, PAR is represented by orange spheres in chains, and red ovals represent possible PARylated proteins involved in TGHQ-mediated cell death.