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  • It is important to highlight that glucose dependent generati

    2021-09-14

    It is important to highlight that glucose-dependent generation of OMP of high magnitudes occurs due to the voltage-gating properties of VDACs, because only small magnitudes of OMP were obtained when the VDAC voltage sensitivity was zero (Fig. 5). These results indicate a possible physiological role of the VDAC voltage-gating properties discussed in detail by Colombini and Mannella [58]. The proposed ANT-VDAC1-HKI mechanism of OMP generation (Fig. 1) showed a very interesting phenomenon of a relatively weak dependence of the metabolic flux Ics through the ANT-VDAC1-HKI contact sites on generated OMP (Figs. 3, e and d, 4D–F, and 5D, E). This result suggests a relatively weak negative feedback control of the rate of the mitochondrial hexokinase reaction by generated OMP. At the same time, permeability to Pi− through free VDACs in MOM (MPPi in Eq. (4)) showed strong dependence on OMP (Fig. 3, Fig. 5). Moreover, the modulation of MOM permeability to ATP by OMP seems to be even greater, because the electrically closed VDAC is almost impermeable to ATP [59]. Two types of hexokinase AZ3146 sale in brain mitochondria, A and B, differing in their access to the mitochondrial ATP, have been reported in the literature [29,39,54], allowing assumption that hexokinase might bind not only to the ANT-VDAC inter-membrane contact sites, but also to the non-contact site VDACs in MOM, thus forming a fraction of VDAC-HK complexes. According to the previously suggested mechanism, the VDAC-HK complexes in MOM should generate OMP, contributing to the generation of positive OMP mediated by the ANT-VDAC1-HKI mechanism and to the maintenance of a relatively low concentration of Ca2+ in MIMS [42]. Enhanced binding of HKII to mitochondria in the ischemic brain has been reported to protect neurons from hypoxic cell death [60]. This protection might be due to the formation of VDAC-HKII complexes and its contribution in the generation of positive OMP of higher magnitude. Many neurodegenerative disorders have been linked in the last decade to brain mitochondrial VDACs [30,[36], [37], [38], [39]]. For the earlier stage of Alzheimer's disease, for example, it has been reported a pronounced increase in amount of some proteins, such as ANT, VDAC and HKI, responsible for utilization of mitochondrial ATP to phosphorylate cytosolic glucose [61]. On the other hand, one of the most important features of Alzheimer's disease is an increased level of cytosolic Ca2+, caused by the amyloid beta protein [62], which accelerates the aging process and increases the probability of Ca2+-activated mitochondrial permeability transition, leading to neuronal cell death. It is very interesting that the Warburg type metabolism (cancer type) is developed in some neurons as a mechanism of cell death resistance in Alzheimer's disease [50,51]. The Warburg type metabolism has been suggested to be the result of a possible electrical suppression of mitochondria [28,42,43,63], due to the VDAC-HK-mediated generation of OMP. Metabolically-dependent generation of positive OMP in brain mitochondria by the ANT-VDAC1-HKI (Fig. 1A) or by the combined ANT-VDAC1-HKI/VDAC-HK mechanisms might maintain a relatively low concentration of Ca2+ in MIMS, thus protecting mitochondria against calcium overload and the permeability transition. This hypothesis, supported by our computational model, is in strong accordance with the observations that both HKI binding to mitochondria and hexokinase activity are important for an anti-apoptotic effect [9,11,22]. Interestingly, an inverse association between the probabilities of cancer and Alzheimer's disease has been reported in the literature [64,65]. This inverse association raises the question of, could it possible that at least some cancer chemical therapies might increase the probability of Alzheimer's disease and vice versa? In this context, the proposed model of generation of OMP (positive inside) and its consequent enhancement of OMP-dependent cell resistance against Ca2+-activated mitochondrial permeability transition might be helpful to understand in more detail the molecular mechanisms of various neurodegenerative disorders.