Lipid composition of the membrane governs the oligomeric organization of VDAC1

Abstract

Mitochondrial physiology is intricately linked to the oligomerization of voltage-dependent anion channels (VDAC), acting as gatekeepers to mitochondria. However, the molecular determinants of VDAC oligomerization remain poorly understood. Here, we used atomic force microscopy to investigate the effects of three lipids of the Mitochondrial Outer Membrane (MOM) on VDAC assemblies. We observed that VDAC forms lipid-sensitive clusters, termed honeycombs, and their compaction is regulated by cholesterol. Molecular dynamics simulations revealed VDAC’s affinity for cholesterol and phosphatidylethanolamine, both of which affect the formation of these honeycombs. Although we identified honeycomb-like assemblies akin to those in the native MOM, deviations from the physiological lipid composition resulted in varying degrees of disruption of these native-like structures. This emphasizes the profound impact of the lipid environment on VDAC organization. These findings underscore the physiological significance of lipid heterogeneity and changes within biological membranes arising from membrane contacts or pathologies in modulating VDAC behavior.