Parthanatos cascade

The Parthanatos cascade is a caspase-independent form of programmed cell death triggered by severe DNA damage from genotoxic stress, excitotoxicity, or oxidative insults, leading to hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1). PARP1 synthesizes poly(ADP-ribose) (PAR) polymers, which translocate from the nucleus to mitochondria, binding and releasing apoptosis-inducing factor (AIF) for nuclear translocation, where it causes large-scale (~50 kb) DNA fragmentation, chromatin condensation, and cell demise without apoptotic bodies or caspase reliance. This pathway depletes cellular NAD+ and ATP through PARP1's consumption of NAD+, disrupting glycolysis and bioenergetics, and may involve calcium influx via channels like TRPM2. Distinct from apoptosis (caspase/cytochrome c-dependent, small DNA fragments) and necrosis (uncontrolled), parthanatos contributes to pathologies like stroke, neurodegeneration (e.g., Parkinson's), ischemia-reperfusion injury, cancer progression, and sepsis by promoting excessive neuronal or tissue cell loss. While no approved drugs directly target the cascade, PARP1 inhibitors (e.g., for cancer) indirectly modulate it by blocking PAR formation, and research explores AIF or PARG (PAR glycohydrolase) as intervention points, though challenges include distinguishing protective DNA repair from lethal overactivation. Ongoing studies clarify roles of PAR structural heterogeneity, MIF binding to AIF, and metabolic feedbacks like NAD+ salvage costs.

Other names

ParthanatosPAR-dependent cell deathPARP1/AIF-dependent cell death