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Oxidative stress as a modulator of BAX apoptotic activity
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2019 (English)In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 48, p. S170-S170Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Apoptosis is a regulated process of cell death that plays an important role in embryonic development, regulation of tissue homeostasis or removal of harmful cells in multicellular organisms. A failure in apoptosis can lead to severe pathological disorders including cancer, autoimmunity or neurodegenerative diseases. Mitochondria play a key role in the intrinsic apoptotic pathway, which is tightly regulated by Bcl-2 protein family. In response to cytotoxic stress, these proteins initiate cell death by permeabilization of the mitochondrial outer membrane (MOM) followed by the release of apoptotic factors, such as cytochrome c, which represents a point of no return in apoptotic progression. BAX protein, a member of the pro-apoptotic Bcl-2 family with a pore forming activity, is a critical effector of the mitochondrial cell death pathway. Upon interaction with BH3-only proteins, cytosolic BAX undergoes conformational activation and translocation resulting in MOM permeabilization. However, the underlying mechanism controlling this membrane-associated BAX action is still poorly understood. Recent findings suggest that the activity of BAX protein is significantly regulated by the lipid composition of the MOM. In particular, oxidized phospholipids (OxPL) that are generated under oxidative stress conditions seem to directly influence BAX membrane penetration and its activity [1,2].

By employing single molecule fluorescence spectroscopy techniques and various dye leakage assays we study the BAX membrane interactions and its activity in in vitro system that makes use of synthetic giant unilamellar vesicles (GUVs) and large unilamellar vesicles (LUVs) doped with varying amounts of OxPL species, which mimics oxidative stress conditions. Dye leakage assays revealed that BAX activity is sensitive to the type and concentration of different OxPL species in the MOM-mimicking vesicles. Higher levels of oxidized phospholipids in MOM mimicking model lipid bilayer significantly enhance membrane affinity and partial penetration of full length BAX. In addition, solid state NMR studies and calorimetric experiments on the lipid vesicles revealed that the presence of OxPL disrupts the membrane organization enabling BAX to penetrate into the membrane.

Place, publisher, year, edition, pages
Springer, 2019. Vol. 48, p. S170-S170
National Category
Biophysics
Identifiers
URN: urn:nbn:se:umu:diva-161702DOI: 10.1007/s00249-019-01373-4ISI: 000473420400554OAI: oai:DiVA.org:umu-161702DiVA, id: diva2:1340450
Conference
Joint 12th EBSA European Biophysics Congress / 10th IUPAP International Conference on Biological Physics (ICBP), Madrid, Spain, July 20-24, 2019
Note

Supplement: 1

Meeting Abstract: P-366

Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved

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Lidman, MartinDingeldein, Artur P. G.Gröbner, Gerhard

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