Lipid unsaturation promotes BAX and BAK pore activity during apoptosis

• DOI: 10.1038/s41467-024-49067-6
• Publication Date: 2024-06-03T12:02:14Z
• Authors: Shashank Dadsena; Rodrigo Cuevas Ar...; Gonçalo Vieira; Susanne Brodesser; Manuel N. Melo; Ana J. García-Sáez
• Keywords: 0303 health sciences; Science; Q; Apoptosis; Molecular Dynamics Simulation; Article; Mitochondria; 03 medical and health sciences; bcl-2 Homologous Antagonist-Killer Protein; SDG 3 - Good Health and Well-being; Cell Line, Tumor; Mitochondrial Membranes; Fatty Acids, Unsaturated; Humans; Animals; bcl-2-Associated X Protein

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, molecular architecture apoptotic pore remains key open question especially little is known about contribution lipids to MOMP. By performing comparative lipidomics analysis proximal environment isolated lipid nanodiscs, we find significant enrichment unsaturated species nearby conditions. We then demonstrate promote activity model membranes, mitochondria cellular systems, which further supported by dynamics simulations. Accordingly, fatty acid desaturase FADS2 not only enhances sensitivity, but also activation cGAS/STING pathway downstream mtDNA release. The correlation levels with sensitization different lung kidney cancer cell lines co-treatment acids supports relevance our findings. Altogether, work provides an insight on how local affects function during apoptosis.