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

Trang Thi Minh Nguyen (1) , Rudy Gadet (1) , Marine Lanfranchi (2) , Romane Lahaye (3) , Sozerko Yandiev (2) , Olivier Lohez (1) , Ivan Mikaelian (1) , Lea Jabbour (1) , Ruth Rimokh (1) , Julien Courchet (2) , Frédéric Saudou (3) , Nikolay Popgeorgiev (1, 4) , Germain Gillet (1)

1 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
2 PGNM - Pathophysiologie et génétique du neurone et du muscle
3 GIN - [GIN] Grenoble Institut des Neurosciences
4 IUF - Institut universitaire de France

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.

Domaines: Neurobiologie; Biologie du développement

Trang Thi Minh Nguyen, Rudy Gadet, Marine Lanfranchi, Romane Lahaye, Sozerko Yandiev, et al.. Mitochondrial Bcl-xL promotes brain synaptogenesis by controlling non-lethal caspase activation. iScience, 2023, 26 (5), pp.106674. ⟨10.1016/j.isci.2023.106674⟩. ⟨hal-04121358⟩