AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis

Concannon, CG; Tuffy, LP; Weisova, P; Bonner, HP; Davila, D; Bonner, C; Devocelle, MC; Strasser, A; Ward, MW; Prehn, JHM

Author(s): Concannon, CG; Tuffy, LP; Weisova, P; Bonner, HP; Davila, D; Bonner, C; Devocelle, MC; Strasser, A; Ward, MW; Prehn, JHM;
Details: Publication Year 2010-04-05,Volume 189,Issue #1,Page 83-U122
Journal Title: JOURNAL OF CELL BIOLOGY
Publication Type: Journal Article
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.
Publisher: ROCKEFELLER UNIV PRESS
Keywords: N-TERMINAL KINASE; PROMOTES NEURONAL SURVIVAL; CYTOCHROME-C RELEASE; METHYL-D-ASPARTATE; CELL-DEATH; GLUTAMATE NEUROTOXICITY; MITOCHONDRIAL DYSFUNCTION; TRANSCRIPTION FACTOR; SIGNALING PATHWAYS; CORTICAL-NEURONS
Publisher's Version: https://doi.org/10.1083/jcb.200909166
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-04-05 12:00:00