The Mitochondrial Outer Membrane Potential as an Electrical Feedback Control of Cell Energy Metabolism

Abstract

Computational models were developed to demonstrate possible generation of mitochondrial outer membrane potential (OMP) due to a sustained transfer of negatively charged phosphoryl groups through the electrogenic complexes formed by the voltage-dependent anion channel (VDAC) and hexokinase (HK), VDAC and adenine nucleotide translocator (ANT), or VDAC and creatine kinase (CK) together with ANT. The thermodynamic estimations showed a high probability of generation of OMP (positive in the intermembrane space) by VDAC-HK complexes using the Gibbs free energy of the HK reaction. OMP, generated by the ANT-VDAC and ANT-CK-VDAC bi-transmembrane contact sites together with the inner membrane potential, may be positive or negative, depending on metabolic conditions, thus justifying the functionality of the essentially symmetrical bell-shaped VDAC’s voltage-gating properties. A decrease in the conductance and/or an increase in the voltage sensitivity of VDACs by various effectors potentiate OMP generation. On the other hand, the factors that prevent formation of VDAC-HK complexes could decrease OMP, causing an anti-Warburg effect. The computational analysis demonstrates the possibility of a combined, voltage gating and “molecular corking up” modulation of VDAC and, consequently, of the mitochondrial outer membrane permeability. It also predicts an influence of OMP on apparent values of the inner membrane potential measured with membrane-permeable charged fluorescent probes. The presented models suggest novel physiological mechanisms of OMP generation, as an electrical feedback control of the mitochondrial energy flux through the outer membrane, with possible implications in cell death resistance and electrical suppression of mitochondrial energetics in cancer cells, thus underlying the Warburg and Crabtree effects.