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  • br Materials and methods br Results

    2022-06-23


    Materials and methods
    Results Estimations of OMP generated by the proposed mechanism (Fig. 1) were first performed for the range of 0.001–2 mM of taselisib concentration in the cytosol. It was assumed that only 5% of all VDACs in MOM form the ANT-VDAC1-HKI contact sites, and that the fraction of the VDAC3 isoform represents 10% of all VDACs in MOM, i.e. NV3 = 0.10 (in Eq. (1)). The VDAC3 isoform was considered a permanently open channel. The system of Eqs. (1), (2), (4), (5), (6), (7), (8) was solved for mitochondria at Δψi = −140 mV, [ATP]m/[ADP]m = 3, 0.15 mM glucose-6-phosphate in the cytosol (Eq. (6)) and VDAC voltage-gating properties described by Eq. (2) (Fig. 3A, C, E) or Eq. (3) (Fig. 3B, D, F), with Pc = 0.2 (Fig. 3A–D) or Pc = 0.1 (Fig. 3E, F). The model showed significantly different dependencies of the calculated OMP on the glucose concentration in the cytosol (Fig. 3, curves a) for the cases of VDAC voltage-gating properties described by Eq. (2) (Fig. 3A, C) and Eq. (3) (Fig. 3B, D), both at Pc = 0.2. For the case described by Eq. (3), at 10% fraction of VDAC3 (NV3 = 0.10) in MOM (Fig. 3B), there were observed a sharp increase in calculated OMP (Fig. 3B, a) and a sharp OMP-dependent restriction of the MOM permeability to Pi− (Fig. 3B, b) at the threshold concentrations of glucose. Relatively smooth changes were demonstrated for the case described by Eq. (2) (Fig. 3A, a and b, respectively). On the other hand, the magnitudes of calculated positive OMP for both cases were high enough (Fig. 3A, a and B, a, respectively) to completely close the fraction Nv of voltage-sensitive VDACs in MOM, at glucose concentrations higher than 1.3 mM (Fig. 3A, b), or higher than 0.4 mM (Fig. 3B, b). Lower values of OMP were calculated assuming a higher content of the VDAC3 fraction (NV3 = 0.15) in MOM (Fig. 3C, D, curves a), taselisib showing monotonic increase in generated OMP with an increase in the glucose concentration for the case of the VDAC voltage-gating properties described by Eq. (2) (Fig. 3C, a). Nonetheless, for the case described by Eq. (3), a sharp increase in generated OMP was still observed at threshold levels of glucose (Fig. 3D, a). As a result, only for the last case, the model showed a sharp OMP-dependent decrease in MOM permeability to Pi− (Fig. 3D, b) in comparison to relatively monotonic changes obtained for the case described by Eq. (2) (Fig. 3C, b). Assuming a more profound electrical closure of VDACs for Pi− permeability, i.e. Pc = 0.1 in Eqs. (2), (3), the model demonstrated significantly higher sharpness in the glucose-dependent increase of calculated OMP even at NV3 = 0.15, for both cases described by Eq. (2) (Fig. 3E, a) and Eq. (3) (Fig. 3F, a). The mentioned increased sharpness in the glucose-dependent increase of OMP at Pc = 0.1 and the voltage sensitivity parameter S = 30 V−1 also resulted in a very sharp decrease in the MOM permeability to Pi− (Fig. 3E, b and F, b, respectively). No glucose-dependent restriction of MOM permeability to Pi− was obtained assuming zero voltage sensitivity of VDAC's, S = 0 V−1, for all the cases considered above (curves c in Fig. 3A–F). The proposed model also demonstrated an almost hyperbolic increase in the steady-state metabolic flux Ics through the ANT-VDAC1-HKI contact sites with an increase in the glucose concentration (curves d in Fig. 3A–F). Interestingly, only slight OMP-dependent restrictions of Ics were shown even at the highest values of calculated OMP (curves d in Fig. 3A–F) in comparison to the case of zero voltage sensitivity of free VDAC's in MOM, i.e. at S = 0 V−1 (curves e in Fig. 3A–F). The next analysis of the model was performed varying the percentage of VDACs forming ANT-VDAC1-HKI contact sites (AVH, % in Fig. 4) from 2% to 6% of all VDACs in MOM (Ncs = 0.02–0.06). The system of Eqs. (1), (2), (4), (5), (6), (7), (8) was solved for the range of glucose concentrations of 0.001–1 mM at Δψi = −140 mV, Pc = 0.2, S = 30 V−1 and the VDAC3 fraction in MOM NV3 = 0.15 (15%) (Fig. 4A, D, G). The calculated positive OMP was relatively low at 2–4% of VDACs forming ANT-VDAC1-HKI contact sites, and significantly increased at a percentage greater than 5% (Fig. 4A).