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N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death.

ABSTRACT: Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ?N-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited ?N-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for ?N-Bcl-x(L), we generated knock-in mice expressing a caspase-resistant form of Bcl-x(L). The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x(L) could be a potentially important therapeutic target in ischemic brain injury.

SUBMITTER: Ofengeim D

PROVIDER: S-EPMC3862259 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death.

Ofengeim Dimitry D Chen Ying-Bei YB Miyawaki Takahiro T Li Hongmei H Sacchetti Silvio S Flannery Richard J RJ Alavian Kambiz N KN Pontarelli Fabrizio F Roelofs Brian A BA Hickman John A JA Hardwick J Marie JM Zukin R Suzanne RS Jonas Elizabeth A EA

Nature neuroscience 20120226 4

Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x(L) is ...[more]

PMID: 22366758

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Project description:Bcl-xL is a pro-survival protein of the Bcl2 family found in the mitochondrial membrane. Bcl-xL supports growth, development, and maturation of neurons, and it also prevents neuronal death during neurotoxic stimulation. This article reviews the mechanisms and upstream signaling that regulate the activity and abundance of Bcl-xL. Our team and others have reported that oxidative stress is a key regulator of intracellular Bcl-xL balance in neurons. Oxidative stress regulates synthesis, degradation, and activity of Bcl-xL and therefore neuronal function. During apoptosis, pro-apoptotic Bcl2 proteins such as Bax and Bak translocate to and oligomerize in the mitochondrial membrane. Formation of oligomers causes release of cytochrome c and activation of caspases that lead to neuronal death. Bcl-xL binds directly to pro-apoptotic Bcl2 proteins to block apoptotic signaling. Although anti-apoptotic roles of Bcl-xL have been well documented, an increasing number of studies in recent decades show that protein binding partners of Bcl-xL are not limited to Bcl2 proteins. Bcl-xL forms a complex with F1Fo ATP synthase, DJ-1, DRP1, IP3R, and the ryanodine receptor. These proteins support physiological processes in neurons such as growth and development and prevent neuronal damage by regulating mitochondrial ATP production, synapse formation, synaptic vesicle recycling, neurotransmission, and calcium signaling. However, under conditions of oxidative stress, Bcl-xL undergoes proteolytic cleavage thus lowering the abundance of functional Bcl-xL in neurons. Additionally, oxidative stress alters formation of Bcl-xL-mediated multiprotein complexes by regulating post-translational phosphorylation. Finally, oxidative stress regulates transcription factors that target the Bcl-x gene and alter accessibility of microRNA to mRNA influencing mRNA levels of Bcl-xL. In this review, we discussed how Bcl-xL supports the normal physiology of neurons, and how oxidative stress contributes to pathology by manipulating the dynamics of Bcl-xL production, degradation, and activity.

Project description:ABT-737 is a pharmacological inhibitor of the anti-apoptotic activity of B-cell lymphoma-extra large (Bcl-xL) protein; it promotes apoptosis of cancer cells by occupying the BH3-binding pocket. We have shown previously that ABT-737 lowers cell metabolic efficiency by inhibiting ATP synthase activity. However, we also found that ABT-737 protects rodent brain from ischemic injury in vivo by inhibiting formation of the pro-apoptotic, cleaved form of Bcl-xL, ?N-Bcl-xL. We now report that a high concentration of ABT-737 (1??M), or a more selective Bcl-xL inhibitor WEHI-539 (5??M) enhances glutamate-induced neurotoxicity while a low concentration of ABT-737 (10?nM) or WEHI-539 (10?nM) is neuroprotective. High ABT-737 markedly increased ?N-Bcl-xL formation, aggravated glutamate-induced death and resulted in the loss of mitochondrial membrane potential and decline in ATP production. Although the usual cause of death by ABT-737 is thought to be related to activation of Bax at the outer mitochondrial membrane due to sequestration of Bcl-xL, we now find that low ABT-737 not only prevents Bax activation, but it also inhibits the decline in mitochondrial potential produced by glutamate toxicity or by direct application of ?N-Bcl-xL to mitochondria. Loss of mitochondrial inner membrane potential is also prevented by cyclosporine A, implicating the mitochondrial permeability transition pore in death aggravated by ?N-Bcl-xL. In keeping with this, we find that glutamate/?N-Bcl-xL-induced neuronal death is attenuated by depletion of the ATP synthase c-subunit. C-subunit depletion prevented depolarization of mitochondrial membranes in ?N-Bcl-xL expressing cells and substantially prevented the morphological change in neurites associated with glutamate/?N-Bcl-xL insult. Our findings suggest that low ABT-737 or WEHI-539 promotes survival during glutamate toxicity by preventing the effect of ?N-Bcl-xL on mitochondrial inner membrane depolarization, highlighting ?N-Bcl-xL as an important therapeutic target in injured brain.

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N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death.

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N-terminally cleaved Bcl-xL mediates ischemia-induced neuronal death.

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