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 Ward, Jochen H.M. Prehn

    Research output: Contribution to journalArticlepeer-review

    110 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 Ca 2+ 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

    ASJC Scopus subject areas

    • Cell Biology

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