Nuclear and mitochondrial conversations in cell death: PARP-1 and AIF signaling

Trends Pharmacol Sci. 2004 May;25(5):259-64. doi: 10.1016/


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Apoptosis Inducing Factor
  • Caspases / metabolism*
  • Caspases / physiology
  • Cell Death / physiology*
  • Flavoproteins / physiology*
  • Humans
  • Membrane Proteins / physiology*
  • Mitochondria* / enzymology
  • Mitochondria* / metabolism
  • Mitochondria* / physiology
  • Poly(ADP-ribose) Polymerases / physiology*


  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • Flavoproteins
  • Membrane Proteins
  • Poly(ADP-ribose) Polymerases
  • Caspases