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Neuropharmacology. 2010 Jun;58(8):1258-67. doi: 10.1016/j.neuropharm.2010.03.008. Epub 2010 Mar 20.

Mitochondrial fragmentation and neuronal cell death in response to the Bcl-2/Bcl-x(L)/Bcl-w antagonist ABT-737.

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MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.


Inhibition of pro-survival Bcl-2 family proteins by BH3-only proteins is a key initial step leading to apoptotic cell death. In neurons, investigating cell death pathways is often hampered by the multi-factorial nature of the stress stimuli employed. Here we investigate the action of ABT-737, a small molecule inhibitor which specifically targets the BH3-protein binding domain of pro-survival Bcl-2, Bcl-X(L) and Bcl-w. ABT-737 produced a time- and concentration-dependent neuronal cell death which displayed the classical hallmarks of apoptosis. Cell death was maximal by around 4 h ABT-737 treatment, and the effect of ABT-737 could be delayed by the broad spectrum caspase inhibitor zVADfmk. Examining, using real-time confocal microscopy, the molecular basis for the onset of response demonstrated recruitment of pro-apoptotic Bax to specific mitochondrial foci, followed by mitochondrial fragmentation. Treatment of neurons with ABT-737 also produced cleavage of Bid, a BH3-only protein known to be a caspase substrate. Interestingly, cleaved Bid translocated to mitochondria but did not colocalise with Bax foci. zVADfmk inhibited Bid cleavage and slowed the rate of fragmentation, suggesting a role for cleaved Bid in the amplification of the apoptotic response. siRNA-mediated knockdown of Bax significantly inhibited ABT-737 induced cell death, whereas knockdown of the BH3-only proteins Bid or Bim had no effect. ABT-737 therefore appears to be a useful tool with which to examine neuronal apoptotic pathways. Our data suggests that caspase-dependent cleavage of Bid may be a downstream amplification event which enhances the rate of mitochondrial fragmentation.

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