Peer Reviewed

1

Document Type

Article

Publication Date

2012

Keywords

Excitotoxicity, Energy Depletion, AMPK, BH3-Only Protein BIM, FOXO3, Computational Modeling, Network Motifs.

Funder/Sponsor

Marie Curie IEF (PIEF-GA-2009-237765), Science Foundation Ireland (08/ IN1/ 1949), and the Health Research Board in Ireland (PHD/2007/11).

Comments

This article is also available at http://www.nature.com/cdd/focus/computational_cell_death/index.html

Abstract

Cerebral ischemia and excitotoxic injury induce transient or permanent bioenergetic failure, and may result in neuronal apoptosis or necrosis. We have previously shown that ATP depletion and activation of AMP-activated protein kinase (AMPK) during excitotoxic injury induces neuronal apoptosis by transcription of the proapoptotic BH3 only protein, Bim. AMPK, however, also exerts pro-survival functions in neurons. The molecular switches that determine these differential outcomes are not well understood. Using an approach combining biochemistry, single cell imaging and computational modeling, we here demonstrate that excitotoxic injury activated the bim promoter in a FOXO3-dependent manner. The activation of AMPK reduced AKT activation, and led to dephosphorylation and nuclear translocation of FOXO3. Subsequent mutation studies indicated that bim gene activation during excitotoxic injury required direct FOXO3 phosphorylation by AMPK in the nucleus as a second activation step. Inhibition of this phosphorylation prevented Bim expression and protected neurons against excitotoxic and oxygen/glucose deprivation-induced injury. Systems analysis and computational modeling revealed that these two activation steps defined a coherent feedforward loop; a network motif capable of filtering any effects of short-term AMPK activation on bim gene induction. This may prevent unwanted AMPK-mediated Bim expression and apoptosis during transient or physiological bioenergetic stress.

Disciplines

Physics | Physiology

Citation

Davila D, Connolly NMC, Bonner H, Weisova P, Dussman H, Concannon CG, Huber HJ, Prehn JHM. Two step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate. Cell Death and Differentiation. 2012;19:1677–1688.

PubMed ID

22539004

DOI Link

10.1038/cdd.2012.49

Creative Commons License

Creative Commons License
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