Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling.
Different cell-death mechanisms control many physiological and pathological processes in humans. Mitochondria play important roles in cell death through the release of pro-apoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF), which activate caspase-dependent and caspase-independent cell death, respectively. Poly(ADP-ribose) polymerase 1 (PARP-1) is emerging as an important activator of caspase-independent cell death. PARP-1 generates the majority of long, branched poly(ADP-ribose) (PAR) polymers following DNA damage. Overactivation of PARP-1 initiates a nuclear signal that propagates to mitochondria and triggers the release of AIF. AIF then shuttles from mitochondria to the nucleus and induces peripheral chromatin condensation, large-scale fragmentation of DNA and, ultimately, cytotoxicity. Identification of the pro-death and pro-survival signals in the PARP-1-mediated cell-death program might provide novel therapeutic targets in human diseases.
Hong
Suk Jin
SJ
Institute for Cell Engineering and Department of Neurology, Johns Hopkins University School of Medicine, 733 North Broadway Street, Suite 731, Baltimore, MD 21205, USA.
Dawson
Ted M
TM
Dawson
Valina L
VL
D051033:Apoptosis Inducing Factor; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D016923:Cell Death / Q000502:physiology*; D005420:Flavoproteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases