VDAC-Kinase Electrogenic Complexes as Direct Generators of Mitochondrial Membrane Potentials

Abstract

The voltage dependent anion channel (VDAC) is a main metabolic pathway between mitochondria and the cytosol. Although VDAC's electrical characteristics are well known, VDAC is still considered as a constantly open pore in physiological conditions, or as regulated with “molecular corks” of various types. On the other hand, one of the unresolved problems, according to Colombini and Mannella (BBA, vol. 1818, 2012), remains the role of VDAC's highly conserved voltage gating properties. Earlier, we have proposed several possible mechanisms of generation of the mitochondrial outer membrane potential (OMP). According to one of them, the OMP might result from the application in part of the inner membrane potential (IMP) to the outer membrane through the intermembrane contact sites ANT (adenine nucleotide translocator)-VDAC, or AND-VDAC-HK (hexokinase). Even VDAC-HK electrogenic complex has been considered to function as a direct generator of the OMP, using the Gibbs free energy of the HK reaction. Here, we further developed this concept showing with a simple computational model that the creatine kinase (CK) reaction might also contribute to the OMP generation applying its Gibbs free energy to the ANT-CK-VDAC contact sites, or to the CK-VDAC complex, similarly to that suggested earlier for the ANT-VDAC-HK or VDAC-HK complexes. The OMP might influence the distribution of adenine nucleotides and calcium between the intermembrane space and the cytosol, thus influencing mitochondrial metabolic state and permeability transition. One of the results of the developed concept is a new, non-Mitchell mechanism of the IMP generation under hypoxic/anoxic conditions. Thus, VDAC seems to function as an electrical metabolic interface playing fundamental role in various physiological processes by controlling the metabolic state of mitochondria and cell resistance to death.