J Clin Invest 113(7): 960-962

Bim, Bad, and Bax: a deadly combination in epileptic seizures

^{Epilepsy Research Laboratory, Veteran’s Administration Greater Los Angeles Healthcare System, West Los Angeles, California, USA.}^{Department of Neurology and}^{Brain Research Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.}

Address correspondence to: Jerome Niquet, Epilepsy Research Laboratory, Research 151, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Boulevard, West Los Angeles, California 90073, USA. Phone: (310) 478-3711 ext. 41974; Fax: (310) 268-4856; E-mail: ude.alcu@teuqinj.

Abstract

Several Bcl-2 family members, including Bim, may contribute to programmed cell death by inducing mitochondrial cytochrome c release, which activates caspase-9 and then caspase-3, the “executioner” of the cell. In this issue of the JCI, Shinoda and collaborators show the key role of Bim in epileptic seizure–induced neuronal injury and identify the contribution of transcription factors responsible for seizure-induced Bim upregulation .

Abstract

Neuronal death following brain insults often results from the execution of cellular programs that resemble those involved in developmentally programmed cell death. Cell demise is often brought about by the activation of caspases, a family of cysteine proteases. When what is usually called the “extrinsic” pathway of programmed cell death is induced, the first step involves the activation of extracellular cell death receptors of the TNF superfamily, which recruit other proteins to form a complex that activates caspase-8, which in turn activates caspase-3 (Figure (Figure1)1) (1). This “executioner” caspase kills the cell through its widespread proteolytic effects, activating DNA breakdown, inactivating DNA repair enzymes, and attacking the cytoskeleton, among other activities. In the “intrinsic” pathway of programmed cell death, the mitochondrion plays a critical role by releasing cytochrome c from its intermembrane space to the cytosol, where, in association with apoptotic protease-activating factor-1 and dATP, it forms the apoptosome complex, activating caspase-9, which in turn activates caspase-3 (Figure (Figure1)1) (1). Cytochrome c release is regulated by the Bcl-2 family of proteins, which are pro- or antiapoptotic, depending on their ability to promote or suppress its release. The balance between proapoptotic factors (BH3-interacting domain death agonist [Bid], Bcl-2–associated death protein [Bad], Bcl-2–interacting mediator of cell death [Bim], Bcl-2–associated X protein [Bax], and Bcl-2 homologous antagonist killer [Bak]) and antiapoptotic factors (Bcl-2, Bcl-x, and Bcl-w) determines cytochrome c release and the fate of the cell (1). This balance depends not only on the respective levels of expression of these factors but also on their post-translational modifications and interactions (1).

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Figure 1

Putative neuronal death pathways induced by epileptic seizures. In the “extrinsic” pathway of programmed cell death, activation of extracellular cell death receptors of the TNF superfamily (Fas and tumor necrosis factor receptor 1 [TNFR1]) induces activation of catalytic enzymes caspase-8 and caspase-3, causing widespread proteolytic damage and cell death. Mitochondria have a central role in the other forms of programmed cell death. In the “intrinsic” pathway, cytochrome c release is triggered by translocation of the proapoptotic factor Bax to the mitochondria. Seizures induce dephosphorylation of transcription factors FKHR and FKHRL-1, leading to the upregulation of the proapoptotic factor Bim, which forms an oligomer with Bcl-w, triggering Bax activation. Seizures may also induce dissociation of Bad from chaperone protein 14-3-3. Released Bad binds to Bcl-xl, provoking dissociation of Bax–Bcl-xl and Bax release. Bax penetrates the mitochondrial outer membrane and triggers cytochrome c release from the intermembrane space to the cytosol, where it activates caspase-9, which then activates caspase-3. Alternatively, cytochrome c release may be induced after Bid truncation by active caspase-8, linking the “extrinsic” and “intrinsic” pathways. In “programmed necrosis,” seizures deplete energy reserves, leading to mitochondrial calcium overloading, opening of the mitochondrial transition pore, and/or mitochondrial swelling and rupture of the outer membrane. Subsequent cytochrome c release activates the caspase cascade and leads to cell demise.

Footnotes

See the related Commentary beginning on page 1059.

Nonstandard abbreviations used: apoptopsis-inducing factor (AIF); Bcl-2–associated death promoter (Bad); Bcl-2–associated X protein (Bax); Bcl-2–interacting mediator of cell death (Bim); BH3 interacting domain death agonist (Bid); forkhead in rhabdomyosarcoma (FKHR); FKHR-like-1 (FKHRL-1); kainic acid (KA); status epilepticus (SE).

Conflict of interest: The authors have declared that no conflict of interest exists.

Footnotes

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