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The Journal of Neuroscience, February 9, 2005, 25(6):1324-1334; doi:10.1523/JNEUROSCI.4261-04.2005

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Neurobiology of Disease
Apoptosis-Inducing Factor Is a Key Factor in Neuronal Cell Death Propagated by BAX-Dependent and BAX-Independent Mechanisms

Eric C. C. Cheung,¹ Lysanne Melanson-Drapeau,² Sean P. Cregan,¹ Jacqueline L. Vanderluit,¹ Kerry L. Ferguson,¹ William C. McIntosh,¹ David S. Park,¹ Steffany A. L. Bennett,² and Ruth S. Slack¹

¹Ottawa Health Research Institute, Neuroscience Center and Department of Cellular and Molecular Medicine, and ²Neural Regeneration Laboratory, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5

Mitochondria release proteins that propagate both caspase-dependent and caspase-independent cell death pathways. AIF (apoptosis-inducing factor) is an important caspase-independent death regulator in multiple neuronal injury pathways. Presently, there is considerable controversy as to whether AIF is neuroprotective or proapoptotic in neuronal injury, such as oxidative stress or excitotoxicity. To evaluate the role of AIF in BAX-dependent (DNA damage induced) and BAX-independent (excitotoxic) neuronal death, we used Harlequin (Hq) mice, which are hypomorphic for AIF. Neurons carrying double mutations for Hq/Apaf1^-/- (apoptosis proteases-activating factor) are impaired in both caspase-dependent and AIF-mediated mitochondrial cell death pathways. These mutant cells exhibit extended neuroprotection against DNA damage, as well as glutamate-induced excitotoxicity. Specifically, AIF is involved in NMDA- and kainic acid- but not AMPA-induced excitotoxicity. In vivo excitotoxic studies using kainic acid-induced seizure showed that Hq mice had significantly less hippocampal damage than wild-type littermates. Our results demonstrate an important role for AIF in both BAX-dependent and BAX-independent mechanisms of neuronal injury.

Key words: AIF; excitotoxicity; neuron; caspase independent; kainic acid; apoptosis

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Received Oct 13, 2004; revised December 17, 2004; accepted December 17, 2004.

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