Peer Reviewed

1

Document Type

Article

Publication Date

5-4-2010

Keywords

Adenylate Kinase, Animals, Apoptosis, Apoptosis Regulatory Proteins, Cell Death, Cells, Cultured, Membrane Proteins, Mice, Mice, Transgenic, Microscopy, Confocal, Neurons, Proto-Oncogene Proteins, Rats

Comments

The original article is available at http://jcb.rupress.org/content/189/1/83.full

Abstract

Excitotoxicity after glutamate receptor overactivation induces disturbances in cellular ion gradients, resulting in necrosis or apoptosis. Excitotoxic necrosis is triggered by rapid, irreversible ATP depletion, whereas the ability to recover cellular bioenergetics is suggested to be necessary for the activation of excitotoxic apoptosis. In this study, we demonstrate that even a transient decrease in cellular bioenergetics and an associated activation of adenosine monophosphate-activated protein kinase (AMPK) is necessary for the activation of excitotoxic apoptosis. We show that the Bcl-2 homology domain 3 (BH3)-only protein Bim, a proapoptotic Bcl-2 family member, is activated in multiple excitotoxicity paradigms, mediates excitotoxic apoptosis, and inhibits delayed Ca(2+) deregulation, mitochondrial depolarization, and apoptosis-inducing factor translocation. We demonstrate that bim activation required the activation of AMPK and that prolonged AMPK activation is sufficient to induce bim gene expression and to trigger a bim-dependent cell death. Collectively, our data demonstrate that AMPK activation and the BH3-only protein Bim couple transient energy depletion to stress-induced neuronal apoptosis.

Disciplines

Physics | Physiology

Citation

Concannon CG, Tuffy LP, Weisová P, Bonner HP, Dávila D, Bonner C, Devocelle MC, Strasser A, Ward MW, Prehn JH. AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis. J Cell Biol. 2010 Apr 5;189(1):83-94.

PubMed ID

20351066

DOI Link

10.1083/jcb.200909166

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