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Mitochondria, composed of two membranes, play a key role in energy production in eukaryotic cells. The main function of the inner membrane is oxidative phosphorylation, while the mitochondrial outer membrane (MOM) seems to control the energy flux and exchange of various charged metabolites between mitochondria and the cytosol. Metabolites cross MOM via the various isoforms of voltage-dependent anion channel (VDAC). In turn, VDACs interact with some enzymes, other proteins and molecules, including drugs. This work aimed to analyze various literature experimental data related to targeting mitochondrial VDACs and VDAC-kinase complexes on the basis of the hypothesis of generation of the outer membrane potential (OMP) and OMP-dependent reprogramming of cell energy metabolism. Our previous model of the VDAC-hexokinase-linked generation of OMP was further complemented in this study with an additional regulation of the MOM permeability by the OMP-dependent docking of cytosolic proteins like tubulin to VDACs. Computational analysis of the model suggests that OMP changes might be involved in the mechanisms of apoptosis promotion through the so-called transient hyperpolarization of mitochondria. The high concordance of the performed computational estimations with many published experimental data allows concluding that OMP generation under physiological conditions is highly probable and VDAC might function as an OMP-dependent gatekeeper of mitochondria, controlling cell life and death. The proposed model of OMP generation allows understanding in more detail the mechanisms of cancer death resistance and anticancer action of various drugs and treatments influencing VDAC voltage-gating properties, VDAC content, mitochondrial hexokinase activity and VDAC-kinase interactions in MOM. [Display omitted] • Kinase-linked generation of the outer membrane potential (OMP) in mitochondria • Dependence of OMP generation on the VDAC blockage by proteins like tubulin • OMP generation depends on VDAC and hexokinase overexpression or knockdown. • Glucose-dependent OMP generation in the mechanism of cell death resistance • Possible involvement of OMP changes in various diseases targeting VDAC [ABSTRACT FROM AUTHOR]

Abstract Glycolysis plays a key role in brain energy metabolism. The initial and rate-limiting step of brain glycolysis is catalyzed mainly by hexokinase I (HKI), the majority of which is bound to the mitochondrial outer membrane (MOM), mostly through the mitochondrial inter-membrane contact sites formed by the voltage-dependent anion channel (VDAC, outer membrane) and the adenine nucleotide translocator (ANT, inner membrane). Earlier, we proposed a mechanism for the generation of the mitochondrial outer membrane potential (OMP) as a result of partial application of the inner membrane potential (IMP) to MOM through the electrogenic ANT-VDAC-HK inter-membrane contact sites. According to this previous mechanism, the Gibbs free energy of the hexokinase reaction might modulate the generated OMP (Lemeshko, Biophys. J., 2002). In the present work, a new computational model was developed to perform thermodynamic estimations of the proposed mechanism of IMP-HKI-mediated generation of OMP. The calculated OMP was high enough to electrically regulate MOM permeability for negatively charged metabolites through free, unbound VDACs in MOM. On the other hand, the positive-inside polarity of OMP generated by the IMP-HKI-mediated mechanism is expected to protect mitochondria against elevated concentrations of cytosolic Ca2+. This computational analysis suggests that metabolically-dependent generation of OMP in the brain mitochondria, controlled by many factors that modulate VDAC1-HKI interaction, VDAC's voltage-gating properties and permeability, might represent one of the physiological mechanisms of regulation of the brain energy metabolism and of neuronal death resistance, and might also be involved in various neurodegenerative disorders, such as Alzheimer's disease. Graphical abstract Unlabelled Image Highlights • Generation of the outer membrane potential in brain mitochondria • Computational thermodynamic analysis of the proposed mechanism • Fast electrical coordination of mitochondrial oxidative phosphorylation and glycolysis • The positive outer membrane potential in Ca2+-resistance of brain mitochondria • Possible involvement of the outer membrane potential in neurodegenerative disorders [ABSTRACT FROM AUTHOR]

Mitochondrial energy in cardiac cells has been reported to be channeled into the cytosol through the intermembrane contact sites formed by the adenine nucleotide translocator, creatine kinase and VDAC. Computational analysis performed in this study showed a high probability of the outer membrane potential (OMP) generation coupled to such a mechanism of energy channeling in respiring mitochondria. OMPs, positive inside, calculated at elevated concentrations of creatine are high enough to restrict ATP release from mitochondria, to significantly decrease the apparent K m,ADP for state 3 respiration and to maintain low concentrations of Ca 2 + in the mitochondrial intermembrane space. An inhibition by creatine of Ca 2 + -induced swelling of isolated mitochondria and other protective effects of creatine reported in the literature might be explained by generated positive OMP. We suggest that VDAC-creatine kinase-dependent generation of OMP represents a novel physiological factor controlling metabolic state of mitochondria, cell energy channeling and resistance to death. [ABSTRACT FROM AUTHOR]

Recently reported kinase-linked mild depolarization of mitochondria, which prevents the generation of the reactive oxygen species (ROS) and disappears in various organs of the old mice, has been assumed to represent a crucial component of the mitochondrial anti-aging program. To measure mitochondrial inner membrane potential (IMP), the authors used fluorescent probe safranin O+. It is widely accepted that the accumulation of such cationic probes in the mitochondrial matrix depends exclusively on IMP, thus completely ignoring the possibility of the outer membrane potential (OMP) generation. However, computational analysis performed in the presented work suggests that the kinase-linked generation of the positive OMP might take place under the described conditions, because the measured potential includes the algebraic sum of both IMP and OMP. Alternatively to the suggested mild depolarization of mitochondria, the reported experimental data might reflect mainly a change of the positive OMP generated by the VDAC-kinase complexes. We also demonstrate that the reported in the literature mitochondrial hyperpolarization induced by erastin (known to prevent VDAC-tubulin interactions) and the depolarization caused by the mitochondrial VDAC knockdowns in the cancer cells might actually represent a decrease or increase, respectively, of the magnitude of the kinase-linked positive OMP. This is consistent with our hypothesis that VDAC voltage gating by the kinase-linked metabolically-dependent OMP plays a very important physiological role in regulating the cell energy metabolism under normal and pathological conditions, in the maintenance of the cell death resistance and even in the genetic aging program. [Display omitted] • Kinase-linked generation of the positive outer membrane potential in mitochondria • Alternative explanations of an apparent hyperpolarization-depolarization of mitochondria • VDAC knockdowns increase kinase-linked outer membrane potential in mitochondria. • Role of the positive outer membrane potential of mitochondria in cell death protection • Possible aging program at the level of the mitochondrial outer membrane [ABSTRACT FROM AUTHOR]

Energy, generated by the mitochondrial oxidative phosphorylation system, is transferred to the cytosol across the mitochondrial outer membrane (MOM), through the voltage-dependent anion channels (VDACs). The role of the VDAC's voltage-gating process to control the transfer of ATP, creatine phosphate and other negatively charged metabolites across MOM might be crucial for the cell energy metabolism regulation. However, it depends on the probability of the outer membrane potential (OMP) generation by a currently undefined mechanism that has usually been considered doubtful, based on the assumption that VDACs always stay in the electrically open state. Nevertheless, computational analysis of various possible metabolically-dependent mechanisms of OMP generation suggests that MOM is not a "coarse sieve", but in fact it functions as an electrical gatekeeper of cell energy metabolism, due to a probable OMP-dependent VDAC's gating. OMP generation could also be involved in the control of cell death resistance and mechanisms of various diseases. Unlabelled Image • Active mechanisms of generation of the mitochondrial outer membrane potential • VDAC-hexokinase and VDAC-creatine kinase as biological batteries • VDAC-mediated electrical regulation of the cell energy metabolism • Outer membrane potential-dependent decrease in K m,ADP for mitochondrial respiration • Outer membrane potential-dependent resistance to Ca2+ and cell death [ABSTRACT FROM AUTHOR]