Figure 1.

Caspase-Independent Cell Death Cascade. Ischemia causes calcium influx through multiple channels including, NMDA, ASIC, and TRPM7, which leads to increased neuronal nitric oxide synthase (nNOS), and generation of peroxynitrite (ONOO−) from nitric oxide (NO) and superoxide (O2−), damagings DNA. O2− is generated from NMDA receptor activation of NADPH oxidase. The DNA repair enzyme PARP-1 is activated utilizing cellular NAD+ forming PAR polymers, which cause nuclear translocation of AIF further damaging DNA. Cell death occurs from AIF-mediated DNA degradation and NAD+ depletion causing energy failure. What plays the role of executioner?