THE ANTI-APOPTOTIC PROTEIN BCL-XL ENHANCES NEURONAL METABOLISM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Within a developing presynaptic terminal, maturation of vesicle pools and synaptic stabilization occur shortly after contact with the postsynaptic target cell, but little is known about the intracellular molecules that control these processes. We have shown that the major brain anti-apoptotic mitochondrial protein BCL-xL acts presynaptically in cultured hippocampal neurons to increase the number and size of vesicle clusters, and to increase spontaneous vesicle fusion events. Normal mitochondrial function is necessary for the augmentation in spontaneous synaptic events because inhibition of mitochondrial function eliminates the increase. BCL-xL transfection increases the number of mitochondria and improves mitochondrial localization to synaptic sites in part through its effects on the GTPase DRP-1. Conversly, a reduction in endogenous BCL-xL decreases synaptogenesis without attenuating cell viability. Not only does BCL-xL direct newly divided mitochondria to synaptic sites, it also enhances ATP availability within the cytosol while decreasing oxygen flux across neuronal membranes. Thus, in addition to preventing cell death in neurons, we suggest that BCL-xL enhances mitochondrial efficiency and changes mitochondrial location, and may thereby produce synaptic maturation.