Lafargue Elodie, Duneau Jean-Pierre, Buzhinsky Nicolas, Ornelas Pamela, Ortega Alexandre, Ravishankar Varun, Sturgis James, Casuso Ignacio, Bergdoll Lucie
Turing Centre for Living System, Aix-Marseille Université, U1325 INSERM, DyNaMo, Marseille, France.
Laboratoire d'Ingénierie des Systèmes Macromoléculaires, CNRS - Aix Marseille Université, Marseille, France.
Commun Biol. 2025 Jun 17;8(1):936. doi: 10.1038/s42003-025-08311-5.
VDACs, the most abundant proteins in the outer mitochondrial membrane (MOM), are crucial for mitochondrial physiology. VDAC regulate metabolite and ion exchange, modulate calcium homeostasis, and play roles in numerous cellular events such as apoptosis, mitochondrial DNA (mtDNA) release, and different diseases. Mitochondrial function is closely tied to VDAC oligomerization, influencing key processes like mtDNA release and apoptosis, but the molecular drivers of this oligomerization remain unclear. In this study, we investigate the effects of three major MOM lipids on VDAC assemblies using atomic force microscopy and molecular dynamics simulations. Our results show that phosphatidylethanolamine and cholesterol regulate VDAC assembly, with the formation of stable lipid-protein organization of various size and compaction. Deviations from physiological lipid content disrupted native-like VDAC assemblies, highlighting the importance of lipid environment in VDAC organization. These findings underscore how lipid heterogeneity and changes in membranes influence VDAC function.
电压依赖性阴离子通道（VDACs）是线粒体外膜（MOM）中含量最丰富的蛋白质，对线粒体生理学至关重要。VDAC调节代谢物和离子交换，调节钙稳态，并在许多细胞事件中发挥作用，如细胞凋亡、线粒体DNA（mtDNA）释放和不同疾病。线粒体功能与VDAC寡聚化密切相关，影响mtDNA释放和细胞凋亡等关键过程，但这种寡聚化的分子驱动因素仍不清楚。在本研究中，我们使用原子力显微镜和分子动力学模拟研究了三种主要的线粒体外膜脂质对VDAC组装的影响。我们的结果表明，磷脂酰乙醇胺和胆固醇调节VDAC组装，形成各种大小和致密程度的稳定脂质-蛋白质组织。生理脂质含量的偏差破坏了类似天然的VDAC组装，突出了脂质环境在VDAC组织中的重要性。这些发现强调了脂质异质性和膜变化如何影响VDAC功能。
