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J Neurosci. 2014 Feb 12;34(7):2674-83. doi: 10.1523/JNEUROSCI.4074-13.2014.

Bax interacting factor-1 promotes survival and mitochondrial elongation in neurons.

Author information

1
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.

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.

KEYWORDS:

Bax interacting factor 1; Bif-1; apoptosis; endophilin B1; ischemia; mitochondrial dynamics

PMID:
24523556
PMCID:
PMC3921432
DOI:
10.1523/JNEUROSCI.4074-13.2014
[Indexed for MEDLINE]
Free PMC Article

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