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  • According to the experimental data HKI preferentially binds

    2021-09-15

    According to the experimental data, HKI preferentially binds to the mitochondrial inter-membrane contact sites formed by ANT and VDAC [[5], [6], [7],27], mainly via the VDAC1 isoform [7,8]. These electrogenic contact sites allow application of a part of IMP to MOM by transferring phosphoryl groups from the mitochondrial matrix ATP to the cytosolic glucose, as suggested earlier [26,28]. In addition, the free energy of the hexokinase reaction of ANT-VDAC1-HKI contact sites might modulate OMP generation [28], as shown in Fig. 1. The proposed IMP-HKI-dependent mechanism (Fig. 1A) was modeled as an equivalent electrical circuit (Fig. 1B) to perform thermodynamic estimations of a possible range of changes of generated OMP. The known thermodynamic properties of the hexokinase reaction, the typical value of IMP, and physiological range of cytosolic concentrations of glucose and glucose-6-phosphate in the neuronal Pertussis Toxin were used for the computational analysis. The performed calculations demonstrated the possibility for the generation of OMP of relatively high magnitudes (Fig. 3). This OMP was dependent on the glucose concentration, the presence of the VDAC3 isoform (10% or 15% of all VDACs in MOM), and the depth of the electrical closure of free voltage-sensitive VDACs in MOM (Pc = 0.2 or Pc = 0.1). Additionally, OMP was greatly enhanced by an increase in the percentage of VDACs forming ANT-VDAC1-HKI contact sites (Fig. 4A). This result indicates that factors influencing VDAC1-HKI interaction, as for example those controlling phosphorylation-dephosphorylation of VDAC1 [32,33], might significantly modulate the magnitude of OMP generated by the ANT-VDAC1-HKI mechanism (Fig. 1). The calculated OMP was lower in hypo-polarized mitochondria (Fig. 4B), and even in normal mitochondria at enhanced level of cytosolic glucose-6-phosphate (Fig. 4C). The magnitudes of calculated OMP were high enough to modulate MOM permeability to Pi− by the VDAC voltage-gating mechanism (Fig. 4G). At the same time, the proposed model showed a very slight OMP-dependent negative feedback control of the steady-state flux of phosphoryl groups through the ANT-VDAC1-HKI contact sites (Fig. 3, curves d in comparison to curves e, as well as Fig. 4D in comparison to Fig. 4F, for the options of voltage-sensitive and voltage-insensitive VDACs, respectively). Interestingly, the trans-positive OMP has been shown to increase VDAC “corking up” by proteins such as tubulin and alpha-synuclein in experiments with VDACs incorporated into artificial lipid bilayer [41]. In turn, the “corking up” of free VDACs in MOM or inhibition of VDAC's permeability by any other factors [52,53], should increase the probability of generation of OMP (Fig. 5A–C). These thermodynamic estimations suggest that factors controlling the quantity of free, unbound VDACs in MOM, or/and factors modulating their permeability by “corking up” or by chemical modifications might regulate brain energy metabolism through fast, OMP-dependent modulation of the MOM permeability to ATP, ADP and other charged metabolites. A sharp increase in generated OMP at threshold concentrations of the cytosolic glucose (Fig. 5G, H) allows switching the neuronal cell energy metabolism to higher glycolytic production of ATP, thus explaining the possible physiological role of HKI binding to the brain mitochondria [29,54]. The model demonstrates that the glucose-dependent increase of the magnitude of generated OMP greatly depends on the VDAC voltage-gating properties (Fig. 5A–C), which are known to be modulated by NADH [55], tubulin and alfa-synuclein [41], by chemical modifications of various VDAC's isoforms [32,56,57], and by many other factors [53]. On the other hand, an increased level of glucose-6-phosphate in the cytosol has been shown to induce solubilization of mitochondrially-bound HKI [54], antagonized by inorganic phosphate [6], while Mg2+ ions favor HKI binding to the brain mitochondria [30], thus decreasing and enhancing, respectively, the probability of OMP generation according to the suggested mechanism (Fig. 1).