Universität zu Köln

Dadsena, Shashank ORCID: 0000-0002-0227-5900, Cuevas Arenas, Rodrigo ORCID: 0000-0002-2354-1286, Vieira, Gonçalo ORCID: 0000-0003-4093-525X, Brodesser, Susanne ORCID: 0000-0001-5631-0663, Melo, Manuel N. ORCID: 0000-0001-6567-0513 and García-Sáez, Ana J. ORCID: 0000-0002-3894-5945 (2024). Lipid unsaturation promotes BAX and BAK pore activity during apoptosis. Nature Communications, 15 (1). pp. 1-16. Springer Nature. ISSN 2041-1723

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Abstract

[Artikel-Nr.: 4700] BAX and BAK are proapoptotic members of the BCL2 family that directly mediate mitochondrial outer membrane permeabilition (MOMP), a central step in apoptosis execution. However, the molecular architecture of the mitochondrial apoptotic pore remains a key open question and especially little is known about the contribution of lipids to MOMP. By performing a comparative lipidomics analysis of the proximal membrane environment of BAK isolated in lipid nanodiscs, we find a significant enrichment of unsaturated species nearby BAK and BAX in apoptotic conditions. We then demonstrate that unsaturated lipids promote BAX pore activity in model membranes, isolated mitochondria and cellular systems, which is further supported by molecular dynamics simulations. Accordingly, the fatty acid desaturase FADS2 not only enhances apoptosis sensitivity, but also the activation of the cGAS/STING pathway downstream mtDNA release. The correlation of FADS2 levels with the sensitization to apoptosis of different lung and kidney cancer cell lines by co-treatment with unsaturated fatty acids supports the relevance of our findings. Altogether, our work provides an insight on how local lipid environment affects BAX and BAK function during apoptosis.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Dadsena, Shashank UNSPECIFIED https://orcid.org/0000-0002-0227-5900 UNSPECIFIED Cuevas Arenas, Rodrigo UNSPECIFIED https://orcid.org/0000-0002-2354-1286 UNSPECIFIED Vieira, Gonçalo UNSPECIFIED https://orcid.org/0000-0003-4093-525X UNSPECIFIED Brodesser, Susanne UNSPECIFIED https://orcid.org/0000-0001-5631-0663 UNSPECIFIED Melo, Manuel N. UNSPECIFIED https://orcid.org/0000-0001-6567-0513 UNSPECIFIED García-Sáez, Ana J. UNSPECIFIED https://orcid.org/0000-0002-3894-5945 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-814768
Identification Number:	10.1038/s41467-024-49067-6
Journal or Publication Title:	Nature Communications
Volume:	15
Number:	1
Page Range:	pp. 1-16
Number of Pages:	16
Date:	3 June 2024
Publisher:	Springer Nature
ISSN:	2041-1723
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81476