Figure 3.

Working model of a two-hit mechanism of cell death induced by VDAC opening. VDAC-tubulin antagonists and potentially other VDAC openers increase the flux of metabolites into and out of mitochondria. VDAC opening increases mitochondrial metabolism, promotes high cytosolic ATP/ADP ratios, increases oxygen consumption, and decreases glycolysis (anti-Warburg). VDAC opening also increases mitochondrial ROS formation causing oxidative stress and mitochondrial dysfunction. Images are from confocal fluorescence microscopy of SNU-449 hepatocarcinoma cells loaded with chloromethyl-20,70–dichlorodihydrofluorescein diacetate (ROS), and tetramethyl rhodamine methyl ester (ΔΨ).