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

• Published in: iScience Vol. 26; no. 5; p. 106674
• Main Authors: Nguyen, Trang Thi Minh, Gadet, Rudy, Lanfranchi, Marine, Lahaye, Romane A., Yandiev, Sozerko, Lohez, Olivier, Mikaelian, Ivan, Jabbour, Lea, Rimokh, Ruth, Courchet, Julien, Saudou, Frédéric, Popgeorgiev, Nikolay, Gillet, Germain
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-05-2023; Elsevier
• Subjects: Cell biology; Development Biology; Life Sciences; Molecular biology; Neurobiology; Neurons and Cognition; Neuroscience; Cell biology; Molecular biology; Neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.106674

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 development 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-independent. ER-xL neurons displayed increased caspase-3 activity in the neurites, resulting in impaired axon arborescence and synaptogenesis. Together, our findings suggest that mitochondrial Bcl-xL finely tunes caspase-3 through Drp-1-dependent mitochondrial fission, which is critical to neural network design.
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•The exclusive loss of mitochondrial Bcl-xL does not prevent mouse development and birth•KI mice expressing ER-based Bcl-xL die soon postpartum, evoking the 22q11DS syndrome•Bcl-xL fosters synaptogenesis through non-lethal caspase activation
Molecular biology; Neuroscience; Cell biology