Poly(ADP-ribose) polymerase-1 mediated caspase-independent cell death after ischemia/reperfusion.
In ischemia/reperfusion (I/R) injury increased intracellular Ca(2+) and production of reactive oxygen species (ROS) may cause cell death by intrinsic apoptotic pathways or by necrosis. In this review, an alternative intrinsic cell death pathway, mediated by poly(ADP-ribose) polymerase-1 (PARP-1) and apoptosis-inducing factor (AIF), is described. ROS-induced DNA strand breaks lead to overactivation of the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30), causing excessive use of energetic substrates such as NAD(+) and ATP, inducing cell death either by apoptosis or by necrosis. Recently, it was demonstrated that activation of PARP-1 induces translocation of apoptosis-inducing factor from the mitochondria to the nucleus, causing DNA condensation and fragmentation, and subsequent cell death. This pathway seems to be triggered by depletion of NAD(+) and appears to be caspase independent. Several lines of evidence suggest that this pathway plays a role in I/R injury, although some studies indicate that mitochondrial dysfunction may also trigger AIF translocation and cell death. At present, the exact mechanisms linking PARP-1 and AIF in the induction of the ROS-induced cell death are still unclear. Therefore, it appears that further investigations will yield valuable information on underlying mechanisms and potential interventions to reduce caspase-independent cell death during ischemia-reperfusion.
van Wijk
Sjoerd J L
SJ
Department of Health Risk Analysis and Toxicology, University of Maastricht, The Netherlands.
Hageman
Geja J
GJ
D000818:Animals; D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation; D005420:Flavoproteins / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology*
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases