title: VDAC electronics: 1. VDAC-hexo(gluco)kinase generator of the mitochondrial outer membrane potential.
abstract: The simplest mechanism of the generation of the mitochondrial outer membrane potential (OMP) by the VDAC (voltage-dependent anion channel)-hexokinase complex (VHC), suggested earlier, and by the VDAC-glucokinase complex (VGC), was computationally analyzed. Even at less than 4% of VDACs bound to hexokinase, the calculated OMP is high enough to trigger the electrical closure of VDACs beyond the complexes at threshold concentrations of glucose. These results confirmed our previous hypothesis that the Warburg effect is caused by the electrical closure of VDACs, leading to global restriction of the outer membrane permeability coupled to aerobic glycolysis. The model showed that the inhibition of the conductance and/or an increase in the voltage sensitivity of a relatively small fraction of VDACs by factors like tubulin potentiate the electrical closure of the remaining free VDACs. The extrusion of calcium ions from the mitochondrial intermembrane space by the generated OMP, positive inside, might increase cancer cell resistance to death. Within the VGC model, the known effect of induction of ATP release from mitochondria by accumulated glucose-6-phosphate in pancreatic beta cells might result not only of the known effect of GK dissociation from the VDAC-GK complex, but also of a decrease in the free energy of glucokinase reaction, leading to the OMP decrease and VDAC opening. We suggest that the VDAC-mediated electrical control of the mitochondrial outer membrane permeability, dependent on metabolic conditions, is a fundamental physiological mechanism of global regulation of mitochondrial functions and of cell death.
authors.affiliation: Escuela de Física, Facultad de Ciencias, Universidad Nacional de Colombia, sede Medellín, Calle 59A, No 63-20, Medellín, Colombia. Electronic address: vvasilie@unal.edu.co.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Lemeshko
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002463:Cell Membrane Permeability / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D006593:Hexokinase / Q000378:metabolism / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D014404:Tubulin / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D014404:Tubulin; D050994:Voltage-Dependent Anion Channels; D019298:Glucose-6-Phosphate; D000255:Adenosine Triphosphate; D006593:Hexokinase; D005947:Glucose; D002118:Calcium
keywords: Aerobic glycolysis; Cancer; Computational model; Hexokinase; Mitochondrial outer membrane potential; VDAC