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

Clifton, Luke A.SIS Pulsed Neutron and Muon Source, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UK (author)

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.

Wacklin-Knecht, Hanna P.Lund University,Lunds universitet,Fysikalisk kemi,Enheten för fysikalisk och teoretisk kemi,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Physical Chemistry,Physical and theoretical chemistry,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH,European Spallation Source ERIC, ESS, Lund, Sweden; Department of Chemistry, Division of Physical Chemistry, Lund University, Lund, Sweden(Swepub:lu)fkem-hwn (author)
Ådén, Jörgen,1980-Umeå universitet,Umeå University,Kemiska institutionen(Swepub:umu)jonadn02 (author)
Ul Mushtaq, AmeeqUmeå universitet,Umeå University,Kemiska institutionen(Swepub:umu)amul0005 (author)
Sparrman, TobiasUmeå universitet,Umeå University,Kemiska institutionen(Swepub:umu)tosp0001 (author)
Gröbner, GerhardUmeå universitet,Umeå University,Kemiska institutionen(Swepub:umu)gegr0001 (author)
SIS Pulsed Neutron and Muon Source, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot, Oxfordshire, UKFysikalisk kemi (creator_code:org_t)

In:Science Advances: American Association for the Advancement of Science (AAAS)9:222375-2548

By the author/editor: Clifton, Luke A.; Wacklin-Knecht, ...; Ådén, Jörgen, 19 ...; Ul Mushtaq, Amee ...; Sparrman, Tobias; Gröbner, Gerhard

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biophysics

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

NATURAL SCIENCES: NATURAL SCIENCES; and Chemical Science ...; and Physical Chemist ...

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