Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death

Sean P. Cregan, Andre Fortin, Jason G. MacLaurin, Steven M. Callaghan, Francesco Cecconi, Seong Woon Yu, Ted M. Dawson, Valina L. Dawson, David S. Park, Guido Kroemer, Ruth S. Slack

Research output: Contribution to journalArticlepeer-review

Abstract

Caspase-independent death mechanisms have been shown to execute apoptosis in many types of neuronal injury. P53 has been identified as a key regulator of neuronal cell death after acute injury such as DNA damage, ischemia, and excitotoxicity. Here, we demonstrate that p53 can induce neuronal cell death via a caspase-mediated process activated by apoptotic activating factor-1 (Apaf1) and via a delayed onset caspase-independent mechanism. In contrast to wild-type cells, Apaf1-deficient neurons exhibit delayed DNA fragmentation and only peripheral chromatin condensation. More importantly, we demonstrate that apoptosis-inducing factor (AIF) is an important factor involved in the regulation of this caspase-independent neuronal cell death. Immunofluorescence studies demonstrate that AIF is released from the mitochondria by a mechanism distinct from that of cytochrome-c in neurons undergoing p53-mediated cell death. The Bcl-2 family regulates this release of AIF and subsequent caspase-independent cell death. In addition, we show that enforced expression of AIF can induce neuronal cell death in a Bax- and caspase-independent manner. Microinjection of neutralizing antibodies against AIF significantly decreased injury-induced neuronal cell death in Apaf1-deficient neurons, indicating its importance in caspase-independent apoptosis. Taken together, our results suggest that AIF may be an important therapeutic target for the treatment of neuronal injury.

Original languageEnglish (US)
Pages (from-to)507-517
Number of pages11
JournalJournal of Cell Biology
Volume158
Issue number3
DOIs
StatePublished - 2002

Keywords

  • Apoptosis
  • Bax
  • Neurodegeneration
  • Neurons
  • p53

ASJC Scopus subject areas

  • Cell Biology

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