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  • br Introduction Glycolysis plays a

    2022-05-27


    Introduction Glycolysis plays a key role in hiv protease inhibitor energy metabolism [[1], [2], [3]]. It is initiated mainly by hexokinase I (HKI), the major hexokinase isoform of the brain ([3,4] and references therein). Up to 90% of brain HKI is bound to the mitochondrial outer membrane (MOM) through the voltage-dependent anion channel (VDAC) [[5], [6], [7]], via its most abundant isoform VDAC1 [7,8]. In contrast to the human isoform HVDAC1, the isoform HVDAC2 does not bind HKI [8]. The binding of HKI to VDAC1, reconstructed into planar lipid bilayer, significantly decreases the channel conductance [[9], [10], [11]]. On the other hand, MOM-bound hexokinase greatly facilitates access of the mitochondrial matrix ATP to engage into phosphorylation of the external glucose [[12], [13], [14], [15]], starting brain glycolysis by selectively utilizing ATP produced by the mitochondrial oxidative phosphorylation [4,5,8,13]. The coupling of mitochondrial HKI activity to oxidative phosphorylation is so tight that the addition of glucose to isolated brain mitochondria at state 4 respiration, after conversion of relatively small quantity of ADP into ATP, greatly increases the respiration rate, up to state 3 activity [16,17]. Such glucose-dependent acceleration of oxidative phosphorylation has also been observed in the mitochondria of some cancer cells, but not in normal liver mitochondria [18,19]. Both HKI binding to mitochondria and its activity in the presence of glucose have been demonstrated to remarkably increase mitochondrial resistance to the opening of the Ca2+-activated permeability transition pore [9,11], thus hiv protease inhibitor modulating the mitochondrial phase of apoptosis [[20], [21], [22]]. Similarly, creatine kinase activity in the presence of creatine was needed to inhibit Ca2+-activated permeability transition in mitochondria isolated from the liver of transgenic mice expressing human ubiquitous mitochondrial creatine kinase [23,24]. This puzzling protective effect was recently attributed to the generation of the metabolically-derived mitochondrial outer membrane potential (OMP), positive inside, allowing OMP-dependent extrusion of Ca2+ from the mitochondrial inter-membrane space (MIMS) to the external medium [25,26], therefore maintaining relatively low Ca2+ concentration near the inner membrane Ca2+-uniporter. The main target for HKI binding to the outer membrane of brain mitochondria is the fraction of VDACs that forms the inter-membrane contact sites with the adenine nucleotide translocator (ANT) of the inner membrane [[5], [6], [7],14,16,27]. Hence, the formed ANT-VDAC1-HKI contact sites allow the application of a part of the inner membrane potential (IMP), generated by the respiratory chain, to MOM through the transfer of negative phosphoryl groups from the mitochondrial matrix ATP to the cytosolic glucose [6,27]. Thereby it provides a possible mechanism of OMP generation [28]. The generated OMP in this case should be also modulated by the Gibbs free energy of the hexokinase reaction catalyzed by the HK bound to the ANT-VDAC complexes [26,28]. However, a quantitative analysis of such a combined mechanism has never been performed. The most important physiological aspect of the proposed mechanism of OMP generation is that many factors controlling VDAC1-HKI interactions [[29], [30], [31], [32], [33]] can influence the value of generated OMP and OMP-dependent integration of the mitochondrial and cell energy metabolism. For example, it is known that phosphorylation of VDAC1 impaired VDAC1-HKI interaction [32,33]. In addition, the binding of HKI to VDAC1 decreases channel phosphorylation by glycogen synthase kinase 3 beta (GSK3β) [32]. Moreover, understanding the mechanisms and physiological role of regulation of the VDAC1-HKI interactions in the brain mitochondria has recently been considered very important for the development of new therapeutic strategies for the treatment of various neurological disorders [[34], [35], [36], [37], [38]]. In this respect, OMP generation in the brain mitochondria might present great interest as a new possible factor controlling mitochondrial metabolic state and cell death resistance.