Regulation of mitochondrial respiration by controlling the permeability of the outer membrane through the mitochondrial channel, VDAC.

Mitochondrial functions depend not only on the properties of the particular enzyme systems, but also on the continual flux of metabolites between the cytoplasm and mitochondrial spaces. We report the results of experiments that strongly indicate that a soluble mitochondrial protein can regulate mitochondrial respiration by reducing the permeability of the outer membrane. This protein is known as the VDAC modulator because it induces the outer mitochondrial membrane channel, VDAC, to close. When added to intact mitochondria, the modulator reduces the ADP-stimulated respiration. This inhibition can be prevented by damaging the outer membrane prior to modulator addition. Another mitochondrial activity, adenylate kinase, is reduced by 40% by the addition of the VDAC modulator to intact mitochondria. Again, damaging the outer membrane removed the modulator effect. Dextran sulfate, an artificial polyanion that acts on VDAC channels in a similar way to the VDAC modulator, has the same effects on intact mitochondria. The findings correlate well with observations of the actions of the VDAC modulator on reconstituted VDAC channels, in which the modulator induces the channel to enter a very low conductive state. The ability of a mitochondrial protein to regulate mitochondrial activities by reducing the permeability of the outer membrane further fuels the hypothesis that this membrane participates in the overall regulation of mitochondrial functions.