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

Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death 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. neurodegeneration; neurons; apoptosis; p53; Bax Footnotes ↵ * Abbreviations used in this paper: AIF, apoptosis-inducing factor; Apaf1, apoptotic activating factor-1; BAF, Boc-aspartyl (OMe)-fluoromethylketone; MOI, multiplicity of infection. Submitted: 27 February 2002 Accepted: 24 June 2002 Revision received 22 May 2002 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

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

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Publisher
Rockefeller University Press
Copyright
© 2002 Rockefeller University Press
ISSN
0021-9525
eISSN
1540-8140
D.O.I.
10.1083/jcb.200202130
Publisher site
See Article on Publisher Site

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. neurodegeneration; neurons; apoptosis; p53; Bax Footnotes ↵ * Abbreviations used in this paper: AIF, apoptosis-inducing factor; Apaf1, apoptotic activating factor-1; BAF, Boc-aspartyl (OMe)-fluoromethylketone; MOI, multiplicity of infection. Submitted: 27 February 2002 Accepted: 24 June 2002 Revision received 22 May 2002

Journal

The Journal of Cell BiologyRockefeller University Press

Published: Aug 5, 2002

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