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Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis
SIS Pulsed Neutron and Muon Source, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UK.
European Spallation Source ERIC, ESS, Lund, Sweden; Department of Chemistry, Division of Physical Chemistry, Lund University, Lund, Sweden.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-4480-1219
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-5636-2567
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2023 (English)In: Science Advances, E-ISSN 2375-2548, Vol. 9, no 22, article id eadg7940Article in journal (Refereed) Published
Abstract [en]

Apotosis is an essential process tightly regulated by the Bcl-2 protein family where proapoptotic Bax triggers cell death by perforating the mitochondrial outer membrane. Although intensively studied, the molecular mechanism by which these proteins create apoptotic pores remains elusive. Here, we show that Bax creates pores by extracting lipids from outer mitochondrial membrane mimics by formation of Bax/lipid clusters that are deposited on the membrane surface. Time-resolved neutron reflectometry and Fourier transform infrared spectroscopy revealed two kinetically distinct phases in the pore formation process, both of which were critically dependent on cardiolipin levels. The initially fast adsorption of Bax on the mitochondrial membrane surface is followed by a slower formation of pores and Bax-lipid clusters on the membrane surface. Our findings provide a robust molecular understanding of mitochondrial membrane perforation by cell-killing Bax protein and illuminate the initial phases of programmed cellular death. Bax initiates apoptosis by perforating mitochondrial membranes via formation of pores and extramembranous Bax-lipid complexes.

Place, publisher, year, edition, pages
American Association for the Advancement of Science (AAAS), 2023. Vol. 9, no 22, article id eadg7940
National Category
Biophysics
Identifiers
URN: urn:nbn:se:umu:diva-209321DOI: 10.1126/sciadv.adg7940ISI: 001009737900018PubMedID: 37267355Scopus ID: 2-s2.0-85160903390OAI: oai:DiVA.org:umu-209321DiVA, id: diva2:1763957
Conference
2023/06/07
Funder
Swedish Research Council, 2021-00167Swedish Research Council, 2016-06963The Kempe Foundations, JCK-132Available from: 2023-06-08 Created: 2023-06-08 Last updated: 2023-09-05Bibliographically approved

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Ådén, JörgenUl Mushtaq, AmeeqSparrman, TobiasGröbner, Gerhard

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