title: Bax interacting factor-1 promotes survival and mitochondrial elongation in neurons.
abstract: Bax-interacting factor 1 (Bif-1, also known as endophilin B1) is a multifunctional protein involved in the regulation of apoptosis, mitochondrial morphology, and autophagy. Previous studies in non-neuronal cells have shown that Bif-1 is proapoptotic and promotes mitochondrial fragmentation. However, the role of Bif-1 in postmitotic neurons has not been investigated. In contrast to non-neuronal cells, we now report that in neurons Bif-1 promotes viability and mitochondrial elongation. In mouse primary cortical neurons, Bif-1 knockdown exacerbated apoptosis induced by the DNA-damaging agent camptothecin. Neurons from Bif-1-deficient mice contained fragmented mitochondria and Bif-1 knockdown in wild-type neurons also resulted in fragmented mitochondria which were more depolarized, suggesting mitochondrial dysfunction. During ischemic stroke, Bif-1 expression was downregulated in the penumbra of wild-type mice. Consistent with Bif-1 being required for neuronal viability, Bif-1-deficient mice developed larger infarcts and an exaggerated astrogliosis response following ischemic stroke. Together, these data suggest that, in contrast to non-neuronal cells, Bif-1 is essential for the maintenance of mitochondrial morphology and function in neurons, and that loss of Bif-1 renders neurons more susceptible to apoptotic stress. These unique actions may relate to the presence of longer, neuron-specific Bif-1 isoforms, because only these forms of Bif-1 were able to rescue deficiencies caused by Bif-1 suppression. This finding not only demonstrates an unexpected role for Bif-1 in the nervous system but this work also establishes Bif-1 as a potential therapeutic target for the treatment of neurological diseases, especially degenerative disorders characterized by alterations in mitochondrial dynamics.
authors: Departments of Neurological Surgery and Neurology, University of Washington School of Medicine, Seattle, Washington 98195-6470, and Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.
authors: David B
authors: DB
authors: Wang
authors: Takuma
authors: T
authors: Uo
authors: Chizuru
authors: C
authors: Kinoshita
authors: Bryce L
authors: BL
authors: Sopher
authors: Rona J
authors: RJ
authors: Lee
authors: Sean P
authors: SP
authors: Murphy
authors: Yoshito
authors: Y
authors: Kinoshita
authors: Gwenn A
authors: GA
authors: Garden
authors: Hong-Gang
authors: HG
authors: Wang
authors: Richard S
authors: RS
authors: Morrison
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002470:Cell Survival; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D020033:Protein Isoforms; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020033:Protein Isoforms; C486100:Sh3glb1 protein, mouse
keywords: Bax interacting factor 1; Bif-1; apoptosis; endophilin B1; ischemia; mitochondrial dynamics