Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis

Umeå universitet, Kemiska institutionen 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 2023

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.

Biophysics; Biofysik; Article in journal; info:eu-repo/semantics/article; text

10.1126.sciadv.adg7940

English

UPE oai:DiVA.org:umu-209321
0000-0002-4480-1219
0000-0002-5636-2567
0000-0001-7380-8797
doi:10.1126/sciadv.adg7940
PMID 37267355
ISI:001009737900018
Scopus 2-s2.0-85160903390
1400067878

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