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- Title
Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.
- Authors
Dadsena, Shashank; Cuevas Arenas, Rodrigo; Vieira, Gonçalo; Brodesser, Susanne; Melo, Manuel N.; García-Sáez, Ana J.
- Abstract
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. BAX and BAK are proapoptotic proteins that directly mediate mitochondrial outer membrane permeabilization (MOMP). Here, lipidomics and other data provide insight on how local lipid environment affects BAX and BAK function during apoptosis, suggesting that unsaturated lipids promote BAX pore activity.
- Subjects
FATTY acid desaturase; APOPTOSIS; BILAYER lipid membranes; UNSATURATED fatty acids; MEMBRANE lipids; LIPIDS; MOLECULAR dynamics
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-49067-6