Bcl-xL Is Required by Primary Hippocampal Neurons during Development to Support Local Energy Metabolism at Neurites

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dc.contributor.authorJansen, Joseph
dc.contributor.authorScott, Madison
dc.contributor.authorAmjad, Emma
dc.contributor.authorStumpf, Allison
dc.contributor.authorLackey, Kimberly H.
dc.contributor.authorCaldwell, Kim A.
dc.contributor.authorPark, Han-A
dc.contributor.otherUniversity of Alabama Tuscaloosa
dc.date.accessioned2023-10-02T15:15:15Z
dc.date.available2023-10-02T15:15:15Z
dc.date.issued2021
dc.description.abstractSimple Summary B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic protein that regulates energy metabolism in neurons. In this study, we found that primary hippocampal neurons transduced with Bcl-xL shRNA or treated with a pharmacological inhibitor of Bxl-xL had a decrease in the population of motile mitochondria. Primary hippocampal neurons lacking Bcl-xL failed to retain ATP at their neurites, which hindered the formation of complex neurite arbors, and ultimately had enhanced vulnerability to excitotoxic challenge. B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial protein known to inhibit mitochondria-dependent intrinsic apoptotic pathways. An increasing number of studies have demonstrated that Bcl-xL is critical in regulating neuronal energy metabolism and has a protective role in pathologies associated with an energy deficit. However, it is less known how Bcl-xL regulates physiological processes of the brain. In this study, we hypothesize that Bcl-xL is required for neurite branching and maturation during neuronal development by improving local energy metabolism. We found that the absence of Bcl-xL in rat primary hippocampal neurons resulted in mitochondrial dysfunction. Specifically, the ATP/ADP ratio was significantly decreased in the neurites of Bcl-xL depleted neurons. We further found that neurons transduced with Bcl-xL shRNA or neurons treated with ABT-263, a pharmacological inhibitor of Bcl-xL, showed impaired mitochondrial motility. Neurons lacking Bcl-xL had significantly decreased anterograde and retrograde movement of mitochondria and an increased stationary mitochondrial population when Bcl-xL was depleted by either means. These mitochondrial defects, including loss of ATP, impaired normal neurite development. Neurons lacking Bcl-xL showed significantly decreased neurite arborization, growth and complexity. Bcl-xL depleted neurons also showed impaired synapse formation. These neurons showed increased intracellular calcium concentration and were more susceptible to excitotoxic challenge. Bcl-xL may support positioning of mitochondria at metabolically demanding regions of neurites like branching points. Our findings suggest a role for Bcl-xL in physiological regulation of neuronal growth and development.en_US
dc.format.mediumelectronic
dc.format.mimetypeapplication/pdf
dc.identifier.citationJansen, J., Scott, M., Amjad, E., Stumpf, A., Lackey, K., Caldwell, K., & Park, H.-A. (2021). Bcl-xL Is Required by Primary Hippocampal Neurons during Development to Support Local Energy Metabolism at Neurites. In Biology (Vol. 10, Issue 8, p. 772). MDPI AG. https://doi.org/10.3390/biology10080772
dc.identifier.doi10.3390/biology10080772
dc.identifier.orcidhttps://orcid.org/0000-0001-5563-5255
dc.identifier.orcidhttps://orcid.org/0000-0003-4377-4893
dc.identifier.urihttps://ir.ua.edu/handle/123456789/12500
dc.languageEnglish
dc.language.isoen_US
dc.publisherMDPI
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectBcl-xL
dc.subjectmitochondria
dc.subjectmotility
dc.subjectATP
dc.subjectneurite
dc.subjectMITOCHONDRIAL PERMEABILITY TRANSITION
dc.subjectC-SUBUNIT RING
dc.subjectINNER MEMBRANE
dc.subjectATP SYNTHASE
dc.subjectCELL-DEATH
dc.subjectREGULATOR
dc.subjectBCL-X(L)
dc.subjectFAMILY
dc.subjectCOMPLEX
dc.subjectINHIBITION
dc.subjectBiology
dc.titleBcl-xL Is Required by Primary Hippocampal Neurons during Development to Support Local Energy Metabolism at Neuritesen_US
dc.typeArticle
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