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The present work shows that the rate of free respiration of liver mitochondria (in the absence of ATP synthesis (state 4) during the oxidation of succinate is 1.7 times higher than during the oxidation of glutamate with malate. In turn, in the case of oxidation of ferrocyanide with ascorbate, this value is 3.1 times greater than in the case of succinate oxidation. A similar pattern is also observed upon stimulation of free respiration by low concentrations (5 and 10 μM) of the protonophore uncoupler 2,4-dinitrophenol (DNP). It is found that the passive leakage rate of protons in state 4 is the same if the H

Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction in the skeletal muscles of dystrophin-deficient

Effect of alisporivir (a mitochondrial permeability transition pore inhibitor) on the development of mitochondrial dysfunction under hyperglycemic conditions in the primary culture of mouse lung endothelial cells was investigated in this work. We demonstrated that hyperglycemia (30 mM glucose for 24 h) leads to the decrease in viability of the pulmonary endotheliocytes, causes mitochondrial dysfunction manifested by the drop in membrane potential and increase in superoxide anion generation as well as facilitates opening of the mitochondrial permeability transition pore (MPT pore). Incubation of endothelial cells with 5 µM alisporivir under hyperglycemic conditions leads to the increase in cell viability, restoration of the membrane potential level and of the MPT pore opening activity to control values. Hyperglycemia causes increased mitophagy in the lung endothelial cells: we observed increase in the degree of colocalization of mitochondria and lysosomes and upregulation of the Parkin gene expression. Alisporivir restores these parameters back to the levels observed in the control cells. Hyperglycemia results in the increase in the expression of the Drp1 gene in endotheliocytes responsible for synthesis of the protein involved in the process of mitochondria fission. Alisporivir does not significantly alter expression of the genes. The paper discusses mechanisms of the effect of alisporivir on mitochondrial dysfunction in murine pulmonary endotheliocytes under conditions of hyperglycemia.

Duchenne muscular dystrophy is caused by the loss of functional dystrophin that secondarily causes systemic metabolic impairment in skeletal muscles and cardiomyocytes. The nutraceutical approach is considered as a possible complementary therapy for this pathology. In this work, we have studied the effect of pyrimidine nucleoside uridine (30 mg/kg/day for 28 days, i.p.), which plays an important role in cellular metabolism, on the development of DMD in the skeletal muscles of dystrophin deficient mdx mice, as well as its effect on the mitochondrial dysfunction that accompanies this pathology. We found that chronic uridine administration reduced fibrosis in the skeletal muscles of mdx mice, but it had no effect on the intensity of degeneration/regeneration cycles and inflammation, pseudohypetrophy, and muscle strength of the animals. Analysis of TEM micrographs showed that uridine also had no effect on the impaired mitochondrial ultrastructure of mdx mouse skeletal muscle. The administration of uridine was found to lead to an increase in the expression of the Drp1 and Parkin genes, which may indicate an increase in the intensity of organelle fission and the normalization of mitophagy. Uridine had little effect on OXPHOS dysfunction in mdx mouse mitochondria, and moreover, it was suppressed in the mitochondria of wild type animals. At the same time, uridine restored the transport of potassium ions and reduced the production of reactive oxygen species; however, this had no effect on the impaired calcium retention capacity of mdx mouse mitochondria. The obtained results demonstrate that the used dose of uridine only partially prevents mitochondrial dysfunction in skeletal muscles during Duchenne dystrophy, though it mitigates the development of destructive processes in skeletal muscles.

Dapagliflozin (DAPA), a selective inhibitor of sodium/glucose cotransporter SGLT2, is currently used as a hypoglycemic agent in the treatment of diabetes mellitus. In this work, we have assessed the effect of DAPA treatment (1 mg/kg/day) on the ultrastructure and functions of the liver mitochondria of C57BL/6NCrl mice with type 2 diabetes mellitus (T2DM) induced by a high-fat diet combined with low-dose streptozotocin injections. An electron microscopy study showed that DAPA prevented the mitochondrial swelling and normalized the average mitochondrial size in hepatocytes of diabetic animals. The treatment with DAPA reversed the decline in the mtDNA copy number in the liver of diabetic mice. DAPA-treated T2DM mice showed increased expression of the Ppargc1a, Mfn2 and Drp1 in the liver tissue. The treatment of diabetic animals with DAPA normalized the mitochondrial respiratory control ratio, significantly decreased the level of lipid peroxidation products in liver mitochondria, and decreased their resistance to the opening of the mitochondrial permeability transition pore. At the same time, DAPA had no effects on the studied parameters of control animals. The paper discusses the possible mechanisms of the effect of dapagliflozin on mitochondrial dysfunction in the liver of diabetic animals.

This study examines the effect of glucocorticoid deflazacort on the functioning of rat liver mitochondria. Deflazacort at concentrations up to 100 μM has been shown to have no effect on respiration and oxidative phosphorylation of rat liver mitochondria, energized both in the presence of glutamate/malate (substrates of complex I of the respiratory chain) and succinate (substrate of complex II of the respiratory chain), and also does not affect activity of complexes of the respiratory chain of organelles. It was found that deflazacort does not affect the permeability of the inner membrane of liver mitochondria, but reduces the resistance of organelles to the induction of calcium-dependent MPT pore. In addition, we have found that this glucocorticoid is able to induce a decrease in the level of mitochondrial NAD(P)H, as well as inhibit the production of hydrogen peroxide by organelles. The paper discusses how the effects of deflazacort on mitochondrial function may be related to the therapeutic effects of this agent.

The paper shows that natural α,ω-dioic acid, α,ω-hexadecanedioic acid (HDA), is able to stimulate the respiration of succinate-fueled rat liver mitochondria in state 4 without induction of proton conductivity of the inner membrane. This effect of HDA is less pronounced in glutamate/malate-fueled mitochondria, as well as in the case of ascorbate/TMPD or ascorbate/ferrocyanide substrate systems, which transfer electrons directly to cytochrome c. It is noted that HDA-induced stimulation of respiration is not associated with damage to the inner membrane in a part of mitochondria and with shunting of electrons through the bc1 complex. Therefore, HDA can be considered as a natural decoupling agent. Specific inhibitors of the bc1 complex (antimycin A and myxothiazole) as well as malonate and dithionitrobenzoate were used in the inhibitory analysis. These and other experiments have shown that during the oxidation of succinate in liver mitochondria, the decoupling effect of HDA is mainly carried out at the level of the bc1 complex. We hypothesized that HDA is capable of promoting the cyclic transport of protons within the bc1 complex and thus switch this complex to the idle mode of operation (intrinsic uncoupling of the bc1 complex). Induction of free respiration in liver mitochondria by HDA at the level of the bc1 complex is considered as one of the "rescue pathways" of hepatocytes in various pathological conditions, accompanied by disorders of carbohydrate and lipid metabolism and increased oxidative stress.

Itaconic acid (methylene-succinic acid, ItA) is an unsaturated dicarboxylic acid that is secreted by mammalian macrophages in response to a pro-inflammatory stimulus and shows an anti-inflammatory/antibacterial effect. Being a mitochondrial metabolite, it exhibits an inhibitory activity on succinate dehydrogenase and subsequently induces mitochondrial dysfunction. The present study has shown that ItA dose-dependently inhibited ADP- and DNP-stimulated (uncoupled) respiration of rat liver mitochondria energized with succinate. This effect of ItA could be related to the suppression of the activity of complex II and the combined activity of complexes II + III of the respiratory chain. At the same time, ItA had no effect on the activity of the dicarboxylate carrier, which catalyzes the transport of succinate across the inner mitochondrial membrane. It was found that 4 mM ItA diminished the rates of ADP- and DNP-stimulated mitochondrial respiration supported by the substrates of complex I glutamate and malate. A study of the effect of ItA on the activity of complexes of the respiratory chain showed that it significantly decreases the activity of complex IV. It was observed that 4 mM ItA inhibited the rate of H2O2 production by mitochondria. At the same time, ItA promoted the opening of the cyclosporin A-sensitive Ca2+-dependent permeability transition pore. The latter was revealed as the decrease in the calcium retention capacity of mitochondria and the stimulation of release of cytochrome c from the organelles. ItA by itself promotes the cytochrome c release from mitochondria. Possible mechanisms of the effect of ItA on mitochondrial function are discussed.

Theoretical and experimental studies have revealed that that in the liver mitochondria an increase in the rate of free respiration in state 3 induced by protonophore uncouplers 2,4-dinitrophenol and сarbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone is equal to or slightly greater than the increase in respiration rate in state 4 induced by these uncouplers. In contrast to these protonophore uncouplers, the decoupler α,ω-tetradecanedioic acid, increasing the rate of respiration in state 4, does not significantly affect the rate of free respiration in state 3. We have proposed quantitative indicators that allow determining the constituent part of the rate of respiration in state 4, associated with the decoupling effect of the uncoupler. Using the example of palmitic acid, we have found out the fundamental possibility of the simultaneous functioning of uncouplers by two mechanisms: as protonophores and as decouplers. The data obtained contradict the delocalized version of Mitchell’s chemiosmotic theory, but are in complete agreement with its local version. It can be assumed that the F0F1-ATP synthase and nearby respiratory chain complexes form a local zone of coupled respiration and oxidative ATP synthesis (zones of oxidative phosphorylation). The uncoupler-induced stimulation of mitochondrial free respiration of mitochondria in state 3 is mainly due to the return of protons to the matrix in local zones, where the generation of a proton motive force (Δр) by respiratory chain complexes is associated with various transport processes, but not with ATP synthesis (zones of protonophore uncoupling). In contrast, respiratory stimulation in state 4 by decouplers is realized in local zones of oxidative phosphorylation by switching the respiratory chain complexes to the idle mode of operation in the absence of ATP synthesis.

Microbial antibiotic resistance is an important global world health problem. Recently, an interest in nanoparticles (NPs) of silver oxides as compounds with antibacterial potential has significantly increased. From a practical point of view, composites of silver oxide NPs and biocompatible material are of interest. A borosiloxane (BS) can be used as one such material. A composite material combining BS and silver oxide NPs has been synthesized. Composites containing BS have adjustable viscoelastic properties. The silver oxide NPs synthesized by laser ablation have a size of ~65 nm (half-width 60 nm) and an elemental composition of Ag2O. The synthesized material exhibits strong bacteriostatic properties against E. coli at a concentration of nanoparticles of silver oxide more than 0.01%. The bacteriostatic effect depends on the silver oxide NPs concentration in the matrix. The BS/silver oxide NPs have no cytotoxic effect on a eukaryotic cell culture when the concentration of nanoparticles of silver oxide is less than 0.1%. The use of the resulting composite based on BS and silver oxide NPs as a reusable dry disinfectant is due to its low toxicity and bacteriostatic activity and its characteristics are not inferior to the medical alloy nitinol.

Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with mitochondrial permeability transition (MPT) pore opening being recognized as one of its pathogenic mechanisms. Alisporivir has been recently identified as a non-immunosuppressive analogue of the MPT pore blocker cyclosporin A and has broad therapeutic potential. The purpose of the present work was to study the effect of alisporivir (2.5 mg/kg/day i.p.) on the ultrastructure and functions of the skeletal muscle mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections. The glucose tolerance tests indicated that alisporivir increased the rate of glucose utilization in diabetic mice. An electron microscopy analysis showed that alisporivir prevented diabetes-induced changes in the ultrastructure and content of the mitochondria in myocytes. In diabetes, the ADP-stimulated respiration, respiratory control, and ADP/O ratios and the level of ATP synthase in the mitochondria decreased, whereas alisporivir treatment restored these indicators. Alisporivir eliminated diabetes-induced increases in mitochondrial lipid peroxidation products. Diabetic mice showed decreased mRNA levels of Atp5f1a, Ant1, and Ppif and increased levels of Ant2 in the skeletal muscles. The skeletal muscle mitochondria of diabetic animals were sensitized to the MPT pore opening. Alisporivir normalized the expression level of Ant2 and mitochondrial susceptibility to the MPT pore opening. In parallel, the levels of Mfn2 and Drp1 also returned to control values, suggesting a normalization of mitochondrial dynamics. These findings suggest that the targeting of the MPT pore opening by alisporivir is a therapeutic approach to prevent the development of mitochondrial dysfunction and associated oxidative stress in the skeletal muscles in diabetes.

Mitigation of calcium-dependent destruction of skeletal muscle mitochondria is considered as a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). In this work, we study the effect of intraperitoneal administration of a non-immunosuppressive inhibitor of calcium-dependent mitochondrial permeability transition (MPT) pore alisporivir on the state of skeletal muscles and the functioning of mitochondria in dystrophin-deficient mdx mice. We show that treatment with alisporivir reduces inflammation and improves muscle function in mdx mice. These effects of alisporivir were associated with an improvement in the ultrastructure of mitochondria, normalization of respiration and oxidative phosphorylation, and a decrease in lipid peroxidation, due to suppression of MPT pore opening and an improvement in calcium homeostasis. The action of alisporivir was associated with suppression of the activity of cyclophilin D and a decrease in its expression in skeletal muscles. This was observed in both mdx mice and wild-type animals. At the same time, alisporivir suppressed mitochondrial biogenesis, assessed by the expression of Ppargc1a, and altered the dynamics of organelles, inhibiting both DRP1-mediated fission and MFN2-associated fusion of mitochondria. The article discusses the effects of alisporivir administration and cyclophilin D inhibition on mitochondrial reprogramming and networking in DMD and the consequences of this therapy on skeletal muscle health.

Simple Summary Diabetes mellitus as a systemic metabolic disease is one of the most serious threats to global health in this century. Diabetic cardiomyopathy is increasingly recognized as one of the most important complications of the disease, which is associated with impaired cell energy metabolism and damage to mitochondria in cardiomyocytes. Therefore, targeting mitochondrial dysfunction by pharmacological agents can be used as a therapeutic strategy in diabetic heart disease. The aim of the work was to study the effect of the mitochondria-targeted agent alisporivir on the development of mitochondrial dysfunction in the heart of mice with experimental diabetes mellitus. Alisporivir has been recently identified as a non-immunosuppressive analogue of cyclosporin A, a selective inhibitor of cyclophilin D and the mitochondrial permeability transition pore opening, with a potential in a wide range of therapeutic indications. Our results indicated that alisporivir alleviates diabetes-induced abnormalities in the ultrastructure and functions of mitochondria in cardiomyocytes and increases the rate of glucose utilization in diabetic mice. The data suggest that alisporivir acts as a mitochondria-targeted metabolic reprogramming agent and attenuates oxidative damage to the heart tissue of diabetic mice. Abstract Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with the mitochondrial permeability transition (MPT) pore opening being considered as one of its possible mechanisms. The effect of alisporivir, a non-immunosuppressive cyclosporin derivative and a selective inhibitor of the MPT pore opening, on the ultrastructure and functions of the heart mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections was studied. The treatment of diabetic animals with alisporivir (2.5 mg/kg ip for 20 days) increased the rate of glucose clearance during the glucose tolerance test. The blood glucose level and the indicator of heart rate in alisporivir-treated diabetic mice tended to restore. An electron microscopy analysis showed that alisporivir prevented mitochondrial swelling and ultrastructural alterations in cardiomyocytes of diabetic mice. Alisporivir canceled the diabetes-induced increases in the susceptibility of heart mitochondria to the MPT pore opening and the level of lipid peroxidation products, but it did not affect the decline in mitochondrial oxidative phosphorylation capacity. The mRNA expression levels of Pink1 and Parkin in the heart tissue of alisporivir-treated diabetic mice were elevated, suggesting the stimulation of mitophagy. In parallel, alisporivir decreased the level of mtDNA in the heart tissue. These findings suggest that targeting the MPT pore opening by alisporivir alleviates the development of mitochondrial dysfunction in the diabetic heart. The cardioprotective effect of the drug in diabetes can be mediated by the induction of mitophagy and the inhibition of lipid peroxidation in the organelles.

The effects of palmitic acid (PA) and the products of its ω-oxidation–ω-hydroxypalmitic acid (HPA) and α,ω-hexadecanedioic acid (HDA)—on respiration in the absence of ATP synthesis and on the H2O2 generation were studied on isolated liver mitochondria energized by oxidation of succinate. It was shown that HPA stimulates respiration and reduces the difference in electrical potentials (Δψ) in mitochondria to the same extent as is typical for PA and classical protonophore uncouplers. Under similar conditions, the stimulation of mitochondrial respiration by HDA is not accompanied by a decrease in Δψ and is suppressed by 10 μM cyclosporin A. In this regard, HDA is considered as a “decoupling” agent that switches the complexes of the mitochondrial respiratory chain to the idle mode. It was established that in the presence of 20 mM potassium chloride in the sucrose incubation medium, stimulation of respiration by HPA (in contrast to PA and HDA) is suppressed by 60% in the case of pre-incubation with 3 mM magnesium chloride. We found that under these conditions, HPA at a concentration of 25 μM and above induces mitochondrial swelling, which is completely suppressed by magnesium chloride. HPA as an inducer of mitochondrial swelling is less efficient in the absence of potassium chloride than in its presence. We assume that, in contrast to PA and HDA, HPA produces its activating influence on free respiration in mitochondria owing to a combination of its ionophore and protonophore effects. It was established that PA, HDA, and HPA in concentrations equally stimulating respiration of mitochondria in state 2 are equally efficient in inhibiting the H2O2 generation. We conclude that the effects of these fatty acids as inhibitors of H2O2 generation in isolated liver mitochondria are due to stimulation of respiration in various ways and are not associated with a decrease in Δψ.

The effects of ω-hydroxypalmitic acid as an inducer of Ca2+-dependent membrane permeabilization were studied on isolated rat liver mitochondria energized by succinate oxidation and lecithin liposomes. These Ca2+-dependent effects of ω-hydroxypalmitic acid on mitochondria and liposomes were compared with similar well-studied effects of palmitic acid. It was found that ω-hydroxypalmitic acid induced significantly more intensive mitochondrial swelling than palmitic acid in the presence of cyclosporin A and, therefore, was a more effective inducer of Ca2+-dependent cyclosporin A-insensitive permeabilization of the inner membrane of the organelles. At the same time, ω-hydroxypalmitic acid was a much less effective inducer of Ca2+-dependent release of sulforhodamine B from liposomes compared to palmitic acid. It has been shown that, in contrast to palmitic acid, the action of ω-hydroxypalmitic acid as an inducer of Ca2+-dependent pore in the liver mitochondria was completely blocked by inorganic phosphate in the presence of cyclosporin A. It was found that in this case inorganic phosphate cannot be replaced by vanadate, a permeable anion with similar properties. These results are considered as evidence of significant difference in the mechanisms of action of ω-hydroxypalmitic acid and palmitic acid as inducers of the Ca2+-dependent permeabilization of liver mitochondria. While the Ca2+-dependent effect of palmitic acid can be considered to be due the formation of a lipid pore, the Ca2+-dependent effect of ω-hydroxypalmitic acid in the presence of inorganic phosphate can be due to the formation of a cyclosporin A-sensitive mitochondrial permeability transition pore. The effect of inorganic phosphate as an inhibitor of ω-hydroxypalmitic acid-induced Ca2+-dependent cyclosporin A-sensitive pore in liver mitochondria is discussed.

Dodecyltriphenylphosphonium (C12TPP) is a membrane-bound penetrating cation with a delocalized charge widely used for creating and delivering of antioxidants, spin traps, and other chemical probes into mitochondria. The ability of C12TPP to induce permeabilization of the inner membrane of rat liver mitochondria at micromolar concentrations was investigated. It was found that C12TPP in a dose-dependent manner (10–30 µM) caused swelling of rat liver mitochondria in the incubation medium, the osmolarity of which was maintained with KCl. At the same time, C12TPP induced the reduction of the volume of rat liver mitochondria in the isotonic sucrose medium. It was shown that mitochondrial swelling induced by C12TPP was not inhibited by cyclosporin A, but it was suppressed by glibenclamide and ATP, the inhibitors of the ATP-sensitive potassium channel. It was also found that the C12TPP-induced mitochondrial swelling was inhibited by free saturated fatty acids. In turn, C12TPP prevented mitochondrial swelling induced by palmitic acid and Ca2+, which was insensitive to cyclosporin A. A possible mechanism of the C12TPP-induced permeabilization of the inner mitochondrial membrane is discussed.

—The characteristics of the ultrastructure and functioning of mitochondria in the liver of Sprague Dawley rats in the experimental model of type I diabetes mellitus have been investigated. It has been found that diabetes mellitus induced in response to streptozotocin administration at a dose of 75 mg/kg body weight was accompanied by disturbances in the structural organization of mitochondrial cristae and a decrease in the size of the organelles compared to the control. It has been also demonstrated that in type I diabetes the respiratory rates of liver mitochondria in metabolic states 2, 3, and 4 increase. This may be associated with an increase in the total content of fatty acids in liver mitochondria of diabetic rats. At the same time, streptozotocin-induced diabetes mellitus in rats did not affect the indices of oxidative phosphorylation efficiency (ADP/O, respiratory control ratio, and phosphorylation time) in liver mitochondria.

Mitochondria play an important role in the regulation of intracellular Ca2+ homeostasis in Eukaryotes. Progress in the development of molecular and genetic methods for the study of living systems made it possible to identify the structures that carry specific Ca2+ transport in mitochondria, including Ca2+ uniporter (MCU), Na+/Ca2+ exchanger (NCLX) and Ca2+/H+ antiporter (Letm1). The study of the architecture and functioning of these systems at different levels of the organization of living organisms can provide insight into the origin and evolution of the systems of Ca2+ homeostasis and also reveal general mechanisms of regulation and control of these systems in normal and pathological conditions. This review is focused on the taxonomic features of the structure and functioning of specific calcium transport systems in eukaryotic mitochondria and provides evidence of the presence of homologous structures in prokaryotic organisms.

Mitochondria are among the most important cell organelles involved in the regulation of intracellular calcium homeostasis. During the last decade, a number of molecular structures responsible for the mitochondrial calcium transport have been identified including the mitochondrial Ca2+ uniporter (MCU), Na+/Ca2+ exchanger (NCLX), and Ca2+/H+ antiporter (Letm1). The review summarizes the data on the structure, regulation, and physiological role of such structures. The pathophysiological mechanism of Ca2+ transport through the cyclosporine A-sensitive mitochondrial permeability transition pore is discussed. An alternative mechanism for the mitochondrial pore opening, namely, formation of the lipid pore induced by saturated fatty acids, and its role in Ca2+ transport are described in detail.

The article considers the comparative analysis of the functional activity of mitochondria isolated from the liver of grass snakes, Natrix natrix (Linnaeus, 1758) that were kept at different temperatures (23–26 °C and 4-5 °C). It was found that liver mitochondria of hypothermia-exposed grass snakes are characterized by weak coupling of oxidative phosphorylation as compared to mitochondria of active animals which is caused by inhibition of succinate-fuelled respiration in ADP-stimulated state, as well as by activation of basal non-phosphorylating rate. Inhibition of mitochondrial respiration in hibernating animals is associated with a decrease in the activity of the respiratory chain complexes of organelles. A significant decrease in the rate of K+ transport in the liver mitochondria of hibernating animals has been established. Under these conditions, a decrease in the calcium capacity of the organelles was also revealed, which indicates a decrease in the resistance of the mitochondria of hibernating animals to the induction of the Ca2+-dependent mitochondrial pore. All these changes in the functional activity of mitochondria are observed on the background of increasing H2O2 production as well as increasing the proportion of polyunsaturated fatty acids in phospholipid composition of mitochondrial membranes, which are the targets of reactive oxygen species. It can lead to increased formation of lipid peroxides and activation of destructive processes associated with the induction of Ca2+-dependent mitochondrial pore.

Bedaquiline (BDQ) is a new drug from the family of diarylquinolines, which has a potent bactericidal activity against Mycobacterium tuberculosis. This paper has examined the interaction of BDQ with model membranes (liposomes and BLM) and rat erythrocytes. It was shown that BDQ (1–10 mol%) changed the thermotropic phase behavior of DMPC liposomes, leading to the lateral phase separation in the lipid bilayer and the formation of membrane microdomains. BDQ (10–50 μM) was also demonstrated to cause permeabilization of lecithin liposomes loaded with the fluorescent dye sulforhodamine B. At the same time, it did not alter the ionic conductivity of BLM. A dynamic light scattering study showed that BDQ led to the emergence of two populations of light-scattering particles in the suspension of lecithin liposomes, suggesting that an aggregation of the vesicles took place. In rat erythrocytes, BDQ was found to induce changes in their size and shape, as well as aggregation and lysis of the cells.

Long-term hyperglycemia in diabetes mellitus is associated with complex damage to cardiomyocytes and the development of mitochondrial dysfunction in the myocardium. Uridine, a pyrimidine nucleoside, plays an important role in cellular metabolism and is used to improve cardiac function. Herein, the antidiabetic potential of uridine (30 mg/kg/day for 21 days, i.p.) and its effect on mitochondrial homeostasis in the heart tissue were examined in a high-fat diet–streptozotocin-induced model of diabetes in C57BL/6 mice. We found that chronic administration of uridine to diabetic mice normalized plasma glucose and triglyceride levels and the heart weight/body weight ratio and increased the rate of glucose utilization during the intraperitoneal glucose tolerance test. Analysis of TEM revealed that uridine prevented diabetes-induced ultrastructural abnormalities in mitochondria and sarcomeres in ventricular cardiomyocytes. In diabetic heart tissue, the mRNA level of Ppargc1a decreased and Drp1 and Parkin gene expression increased, suggesting the disturbances of mitochondrial biogenesis, fission, and mitophagy, respectively. Uridine treatment of diabetic mice restored the mRNA level of Ppargc1a and enhanced Pink1 gene expression, which may indicate an increase in the intensity of mitochondrial biogenesis and mitophagy, and as a consequence, mitochondrial turnover. Uridine also reduced oxidative phosphorylation dysfunction and suppressed lipid peroxidation, but it had no significant effect on the impaired calcium retention capacity and potassium transport in the heart mitochondria of diabetic mice. Altogether, these findings suggest that, along with its hypoglycemic effect, uridine has a protective action against diabetes-mediated functional and structural damage to cardiac mitochondria and disruption of mitochondrial quality-control systems in the diabetic heart.

The paper considers the effect of the MPT pore inhibitor cyclosporin A (CsA) and its non-immunosuppressive analogue alisporivir (Ali) on the functioning of rat skeletal muscle mitochondria. We have shown that both agents at a standard in vitro concentration of 1 μM increase the calcium capacity of organelles and have no effect on the parameters of oxidative phosphorylation. However, an increase in their concentration to 5 μM leads to the suppression of oxygen consumption by mitochondria, which is more pronounced in the case of Ali. This effect is accompanied by a decrease in the membrane potential of organelles and, apparently, is based on the inhibition of electron transport along the mitochondrial respiratory chain due to limited mobility of coenzyme Q. We have noted that both agents do not affect the production of hydrogen peroxide by isolated mitochondria. NMR spectroscopy and molecular dynamics simulation did not reveal significant differences in the structure and backbone flexibility of CsA and Ali. Both agents decrease the overall fluidity of the membrane of DPPC liposomes, inducing an increase in laurdan generalized polarization parameter. A similar effect was also found in the case of mitochondrial membranes. We suggested that these effects of CsA and Ali, associated with their lipophilic nature and the ability to accumulate in the lipid phase of membranes, may cause a decrease in the efficiency of electron transport in the respiratory chain of mitochondria and suppression of the bioenergetics of these organelles.

The present study describes the in vivo effect of triclosan on the frog Xenopus laevis (Daudin, 1802). We have found a dose-dependence of the effect of triclosan on the survival of frogs. At a dose of 2 mg/L, the death of frogs was observed already on the 4th day of the experiment, while at a concentration of 0.5 mg/L, the frogs remained viable for 11 days. Triclosan caused damage to the liver tissue, which was expressed in an increase in the area of hemorrhage and the number of melanomacrophage centers. 0.5 mg/L of this agent did not affect the number of frog red blood cells, but reduced their osmotic resistance. Keeping animals in water containing triclosan (0.5 mg/L for 96 h) led to the suppression of the state 3 respiration rate of frog liver mitochondria. This effect was accompanied by suppression of the combined activity of complexes II and III of the mitochondrial respiratory chain. In parallel with this, we observed a reduction in the Ca

The paper examines the molecular mechanisms of the cytotoxicity of conjugates of betulinic acid with the penetrating cation F16. The in vitro experiments on rat thymocytes revealed that all the obtained F16-betulinic acid derivatives showed more than 10-fold higher cytotoxicity as compared to betulinic acid and F16. In this case, 0.5–1 μM of all conjugates showed mitochondria-targeted action, inducing superoxide overproduction and reducing the mitochondrial potential of cells. Experiments on isolated rat liver mitochondria revealed the ability of conjugates to dose-dependently reduce the membrane potential of organelles, as well as the intensity of respiration and oxidative phosphorylation, which is also accompanied by an increase in the production of hydrogen peroxide by mitochondria. It was shown that these actions of derivatives may be due to several effects: the reversion of ATP synthase, changes in the activity of complexes of the respiratory chain and permeabilization of the inner mitochondrial membrane. All compounds also demonstrated the ability to induce aggregation of isolated rat liver mitochondria. Using the model of lecithin liposomes, we found that the F6 conjugate (2 μM) induces the permeability of vesicle membranes for the fluorescent probe sulforhodamine B. High concentrations (25 μM) of the F6 derivative have been found to induce dynamic processes in the liposome membrane leading to aggregation and/or fusion of vesicle membranes. The paper discusses the relationship between the mitochondria-targeted effects of F16-betulinic acid conjugates and their cytotoxicity.

Duchenne muscular dystrophy (DMD) is a severe hereditary disease caused by a lack of dystrophin, a protein essential for myocyte integrity. Mitochondrial dysfunction is reportedly responsible for DMD. This study examines the effect of glucocorticoid deflazacort on the functioning of the skeletal-muscle mitochondria of dystrophin-deficient mdx mice and WT animals. Deflazacort administration was found to improve mitochondrial respiration of mdx mice due to an increase in the level of ETC complexes (complexes III and IV and ATP synthase), which may contribute to the normalization of ATP levels in the skeletal muscle of mdx animals. Deflazacort treatment improved the rate of Ca2+ uniport in the skeletal muscle mitochondria of mdx mice, presumably by affecting the subunit composition of the calcium uniporter of organelles. At the same time, deflazacort was found to reduce the resistance of skeletal mitochondria to MPT pore opening, which may be associated with a change in the level of ANT2 and CypD. In this case, deflazacort also affected the mitochondria of WT mice. The paper discusses the mechanisms underlying the effect of deflazacort on the functioning of mitochondria and contributing to the improvement of the muscular function of mdx mice.

Background Disorders of mitochondrial Ca2+ homeostasis play a key role in the glutamate excitotoxicity of brain neurons. DS16570511 (DS) is a new penetrating inhibitor of mitochondrial Ca2+ uniporter complex (MCUC). The paper examines the effects of DS on the cultivated cortical neurons and isolated mitochondria of the rat brain. Methods The functions of neurons and mitochondria were examined using fluorescence microscopy, XF24 microplate-based сell respirometry, ion-selective microelectrodes, spectrophotometry, and polarographic technique. Results At the doses of 30 and 45 μM, DS reliably slowed down the onset of glutamate-induced delayed calcium deregulation of neurons and suppressed their death. 30 μM DS caused hyperpolarization of mitochondria of resting neurons, and 45 μM DS temporarily depolarized neuronal mitochondria. It was also demonstrated that 30–60 μM DS stimulated cellular respiration. DS was shown to suppress Ca2+ uptake by isolated brain mitochondria. In addition, DS inhibited ADP-stimulated mitochondrial respiration and ADP-induced decrease in the mitochondrial membrane potential. It was found that DS inhibited the activity of complex II of the respiratory chain. In the presence of Ca2+, high DS concentrations caused a collapse of the mitochondrial membrane potential. Conclusions The data obtained indicate that, in addition to the inhibition of MCUC, DS affects the main energy-transducing functions of mitochondria. General significance The using DS as a tool for studying MCUC and its functional role in neuronal cells should be done with care, bearing in mind multiple effects of DS, a proper evaluation of which would require multivariate analysis.

Diabetes mellitus is one of the most common metabolic diseases in the developed world, and is associated either with the impaired secretion of insulin or with the resistance of cells to the actions of this hormone (type I and type II diabetes, respectively). In both cases, a common pathological change is an increase in blood glucose—hyperglycemia, which eventually can lead to serious damage to the organs and tissues of the organism. Mitochondria are one of the main targets of diabetes at the intracellular level. This review is dedicated to the analysis of recent data regarding the role of mitochondrial dysfunction in the development of diabetes mellitus. Specific areas of focus include the involvement of mitochondrial calcium transport systems and a pathophysiological phenomenon called the permeability transition pore in the pathogenesis of diabetes mellitus. The important contribution of these systems and their potential relevance as therapeutic targets in the pathology are discussed.