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

Caoimhín G. Concannon, Liam P. Tuffy, Petronela Weisová, Helena P. Bonner, David Dávila, Caroline Bonner, Marc C. Devocelle, Andreas Strasser, Manus W. Ward, Jochen H.M. Prehn

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

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 Ca2+ deregulation, mitochondrial depolarization, and apoptosisinducing 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.

Original languageEnglish (US)
Pages (from-to)83-94
Number of pages12
JournalJournal of Cell Biology
Volume189
Issue number1
DOIs
StatePublished - Apr 5 2010
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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