Peer Reviewed

1

Document Type

Article

Publication Date

28-1-2015

Keywords

Animals, Anoxia, Calcium, Calcium Signaling, Cell Death, Cell Line, Tumor, Cells, Cultured, Embryo, Mammalian, Endoplasmic Reticulum, Excitatory Amino Acid Agonists, Extracellular Fluid, Glucose, Homeostasis, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, N-Methylaspartate, Neocortex, Neurons, bcl-2-Associated X Protein

Comments

This article is available from the Society of Neuroscience at http://www.jneurosci.org/.

Abstract

Excessive Ca(2+) entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation.

Disciplines

Physics | Physiology

Citation

D’Orsi, B, Kilbride, SM, Chen G, Alvarez SP, Bonner HP, Pfeiffer S, Plesnila N, Engel T, Henshall DC, Dussmann H, Prehn JHM. Bax Regulates Neuronal Ca2 Homeostasis. Journal of Neuroscience. 2015; 35(4):1706-22.

PubMed ID

25632145

DOI Link

10.1523/JNEUROSCI.2453-14.2015

Creative Commons License

Creative Commons License
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