Bcl-x _L induces Drp1-dependent synapse formation in cultured hippocampal neurons

Abstract

Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-xL, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-xL or inhibiting it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-xL appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-xL coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-xL protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-xL positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation.Bcl-2 ͉ synaptic transmission ͉ mitochondria ͉ cell death ͉ ABT-737

The mitochondrial dynamics in cancer and immune-surveillance

“…However, Mfn-1 KO MEFs are resistant to apoptotic stimuli. This apparent contradiction is due to the consequent hyperfragmented phenotype of mitochondria in these cells, which does not allow Bax accumulation into OMMs because of an incorrect OMM curvature of the hyperfragmented organelles [50]. These data suggest that an optimal OMM curvature, induced by partial hemi-fission more than complete mitochondrial fragmentation, is essential to promote cytC release.…”

Mitochondrial fission/fusion dynamics and apoptosis

“…Expression of Bcl-xL has also been linked with elevated numbers of neuronal synapses due to enhanced mitochondrial localisation at synaptic sites (Li et al, 2008). These effects are thought to be mediated by mitochondrial fission in a Drp1-dependent manner.…”

“…cell types, which may explain the fission and fusion phenotypes seen with overexpression of Bcl-xL (Berman et al, 2008;Delivani et al, 2006;Li et al, 2008;Sheridan et al, 2008). Bak has been shown to interact with Mfn1 and Mfn2, while Bax promotes the activity of Mfn2 (Brooks et al, 2007, Karbowski et al, 2006.…”

Mitochondrial outer-membrane permeabilization and remodelling in apoptosis

“…Bax binds Mfn-2 in its GTP-bound state, regulates its assembly in large complexes and changes its sub-mitochondrial distribution and membrane motility, resulting in a change in mitochondrial morphology. Finally, Bcl-2, Bcl-xL and the Caenorhabditis elegans homolog of Bcl-2 Ced-9 were also shown to interact with Mfn2 and regulate mitochondrial morphology (Delivani et al, 2006;Li et al, 2008). Bcl-xL has also been reported to regulate mitochondrial morphology and mitochondrial biomass in neurones by modulating fusion and fission (Berman et al, 2009).…”