A Membrane-Disruptive Action of VBIT-4 Challenges Its Role as a Widely Used VDAC Oligomerization Inhibitor.

ABSTRACT: VDAC, the most abundant protein in the outer mitochondrial membrane, plays a central role in mitochondrial physiology. Its oligomerization has been contemplated to be involved in critical processes such as mtDNA release and apoptosis, yet the underlying molecular mechanisms remain poorly defined. VBIT-4, a small molecule widely used as a VDAC1 oligomerization inhibitor, has seen extensive applications over the past five years without proper mechanistic characterization. Using high-speed atomic force microscopy, we directly visualized VDAC1 oligomerization in planar lipid membranes and examined the effects of VBIT-4. Unexpectedly, VBIT-4 partitioned into lipid bilayers at micromolar concentrations and disrupted membrane structure even in the absence of VDAC1. Complementary approaches-includ

SUBMITTER: Ravishankar V 

PROVIDER: S-EPMC12312184 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature