Fig. 6.

The core molecular mechanisms of parthanatos. The activation of NMDA receptors stimulates NO synthase (nNOS). The abundant levels of NO and superoxide spontaneously generate peroxynitrite (ONOO⁻). Along with other ROS, this strong prooxidant damages DNA strands and thereby causes the activation of PARP-1. When DNA damage is high, the consequent overactivation of PARP-1 leads to abundant PAR polymer formation in the nucleus; some of the PARy lated carrier proteins exit the nucleus and cause the release of AIF from a pool on the outer mitochondrial membrane. Once in the cytosol, AIF can bind to MIF. Together, these proteins enter the nucleus and cause large-scale DNA degradation and cell death. Abbreviations: ROS, reactive oxygen species; NO, nitric oxide; NMDA, N-methyl-D-aspartic acid receptor; nNOS, nitric oxide synthase; ONOO⁻, peroxynitrite; PARP-1, poly-ADP-ribosome-polymerase 1; NAD⁺, nicotinamide adenine dinucleotide; PAR, poly-ADP-ribose; AIF, apoptosis-inducing factor; MIF, macrophage migration inhibitory factor