The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the cell death machinery, including Bcl-2 homologs, was reported to be essential for the central nervous system (CNS), notably with respect to synaptic transmission and axon pruning. Here we focused on Bcl-xL, a close Bcl-2 homolog, which plays a major role in neuronal development, as bclx knock out mice prematurely die at embryonic day 13.5, showing massive apoptosis in the CNS. In addition, we present evidence that Bcl-xL fosters ATP generation by the mitochondria to fuel high energy needs by neurons, and its contribution to synaptic transmission. We discuss how Bcl-xL might control local and transient activation of caspases in neurons without causing cell death. Consistently, Bcl-xL may contribute to morphological changes, such as sprouting and retractation of axon branches, in the context of CNS plasticity. Regarding degenerative diseases and aging, a better understanding of the numerous roles of the cell death machinery in neurons may have future clinical implications.

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