Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis
Clifton, Luke A. ; Wacklin-Knecht, Hanna P. LU
; Ådén, Jörgen
; Ul Mushtaq, Ameeq
; Sparrman, Tobias
and Gröbner, Gerhard
(2023)
In Science Advances
9(22).
- Abstract
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 whichwere critically dependent on cardiolipin levels. The initially fast adsorption of Bax on the mitochondrial... (More)
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 whichwere 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.
(Less)
- author
- Clifton, Luke A.
; Wacklin-Knecht, Hanna P.
LU
; Ådén, Jörgen
; Ul Mushtaq, Ameeq
; Sparrman, Tobias
and Gröbner, Gerhard
- organization
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Science Advances
- volume
- 9
- issue
- 22
- article number
- eadg7940
- publisher
- American Association for the Advancement of Science (AAAS)
- external identifiers
-
- pmid:37267355
- scopus:85160903390
- ISSN
- 2375-2548
- DOI
- 10.1126/sciadv.adg7940
- language
- English
- LU publication?
- yes
- id
- 8f4a2340-6f54-4bce-9740-c22f2fc15d6e
- date added to LUP
- 2023-08-17 10:10:34
- date last changed
- 2024-04-20 01:51:00
@article{8f4a2340-6f54-4bce-9740-c22f2fc15d6e,
abstract = {{<p>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 whichwere 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.</p>}},
author = {{Clifton, Luke A. and Wacklin-Knecht, Hanna P. and Ådén, Jörgen and Ul Mushtaq, Ameeq and Sparrman, Tobias and Gröbner, Gerhard}},
issn = {{2375-2548}},
language = {{eng}},
number = {{22}},
publisher = {{American Association for the Advancement of Science (AAAS)}},
series = {{Science Advances}},
title = {{Creation of distinctive Bax-lipid complexes at mitochondrial membrane surfaces drives pore formation to initiate apoptosis}},
url = {{http://dx.doi.org/10.1126/sciadv.adg7940}},
doi = {{10.1126/sciadv.adg7940}},
volume = {{9}},
year = {{2023}},
}