Mitochondrial Bcl-xL promotes brain synaptogenesis by controlling non-lethal caspase activation

Non-lethal caspase activation (NLCA) has been linked to neurodevelopmental processes. However, how neurons control NLCA remains elusive. Here, we focused on Bcl-xL, a Bcl-2 homolog regulating caspase activation through the mitochondria. We generated a mouse model, referred to as ER-xL, in which Bcl-xL is absent in the mitochondria, yet present in the endoplasmic reticulum. Unlike bclx knockout mice that died at E13.5, ER-xL mice survived embryonic develop-ment but died post-partum because of altered feeding behavior. Enhanced caspase-3 activity was observed in the brain and the spinal cord white matter, but not the gray matter. No increase in cell death was observed in ER-xL cortical neurons, suggesting that the observed caspase-3 activation was apoptosis-inde-pendent. ER-xL neurons displayed increased caspase-3 activity in the neurites, resulting in impaired axon arborescence and synaptogenesis. Together, our find-ings suggest that mitochondrial Bcl-xL finely tunes caspase-3 through Drp-1-dependent mitochondrial fission, which is critical to neural network design.

Automated summary

This study found that the absence of Bcl-xL protein in mitochondria leads to increased caspase-3 activation in the brain and spinal cord white matter, resulting in impaired axon arborescence and synaptogenesis. It suggests that Bcl-xL finely tunes caspase-3 activity through mitochondrial fission, which is critical for neural network design.