Pathological Alterations in Heart Mitochondria in a Rat Model of Isoprenaline-Induced Myocardial Injury and Their Correction with Water-Soluble Taxifolin.

Mitochondrial damage and associated oxidative stress are considered to be major contributory factors in cardiac pathology. One of the most potent naturally occurring antioxidants is taxifolin, especially in its water-soluble form. Herein, the effect of a 14-day course of the peroral application of the water-soluble taxifolin (aqTAX, 15 mg/kg of body weight) on the progression of ultrastructural and functional disorders in mitochondria and the heart's electrical activity in a rat model of myocardial injury induced with isoprenaline (ISO, 150 mg/kg/day for two consecutive days, ) was studied.

The Protective Effect of Uridine in a Rotenone-Induced Model of Parkinson's Disease: The Role of the Mitochondrial ATP-Dependent Potassium Channel.

The effect of the modulators of the mitochondrial ATP-dependent potassium channel (mitoK) on the structural and biochemical alterations in the substantia nigra and brain tissues was studied in a rat model of Parkinson's disease induced by rotenone. It was found that, in experimental parkinsonism accompanied by characteristic motor deficits, both neurons and the myelin sheath of nerve fibers in the substantia nigra were affected. Changes in energy and ion exchange in brain mitochondria were also revealed.

Protective Effect of Uridine on Structural and Functional Rearrangements in Heart Mitochondria after a High-Dose Isoprenaline Exposure Modelling Stress-Induced Cardiomyopathy in Rats.

The pyrimidine nucleoside uridine and its phosphorylated derivates have been shown to be involved in the systemic regulation of energy and redox balance and promote the regeneration of many tissues, including the myocardium, although the underlying mechanisms are not fully understood. Moreover, rearrangements in mitochondrial structure and function within cardiomyocytes are the predominant signs of myocardial injury. Accordingly, this study aimed to investigate whether uridine could alleviate acute myocardial injury induced by isoprenaline (ISO) exposure, a rat model of stress-induced cardiomyopathy, and to elucidate the mechanisms of its action related to mitochondrial dysfunction.

Uridine as a Regulator of Functional and Ultrastructural Changes in the Brain of Rats in a Model of 6-OHDA-Induced Parkinson's Disease.

Using a model of Parkinson's disease (PD) induced by the bilateral injection of neurotoxin 6-hydroxydopamine (6-OHDA) into rat brain substantia nigra (SN), we showed uridine to exert a protective effect associated with activation of the mitochondrial ATP-dependent potassium (mitoK-ATP) channel. Injection of 4 µg neurotoxin evoked a 70% decrease in the time the experimental animal spent on the rod in the RotaRod test, an increase in the amount of lipid peroxides in blood serum and cerebral-cortex mitochondria and the rate of reactive oxygen species formation, and a decrease in Ca retention in mitochondria. Herewith, lymphocytes featured an increase in the activity of lactate dehydrogenase, a cytosolic enzyme of glycolysis, without changes in succinate-dehydrogenase activity.

Effect of Chronic Treatment with Uridine on Cardiac Mitochondrial Dysfunction in the C57BL/6 Mouse Model of High-Fat Diet-Streptozotocin-Induced Diabetes.

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.

The Short-Term Opening of Cyclosporin A-Independent Palmitate/Sr-Induced Pore Can Underlie Ion Efflux in the Oscillatory Mode of Functioning of Rat Liver Mitochondria.

Mitochondria are capable of synchronized oscillations in many variables, but the underlying mechanisms are still unclear. In this study, we demonstrated that rat liver mitochondria, when exposed to a pulse of Sr ions in the presence of valinomycin (a potassium ionophore) and cyclosporin A (a specific inhibitor of the permeability transition pore complex) under hypotonia, showed prolonged oscillations in K and Sr fluxes, membrane potential, pH, matrix volume, rates of oxygen consumption and HO formation. The dynamic changes in the rate of HO production were in a reciprocal relationship with the respiration rate and in a direct relationship with the mitochondrial membrane potential and other indicators studied.

Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice.

Here, we found that functionally active mitochondria isolated from the brain of NMRI donor mice and administrated intranasally to recipient mice penetrated the brain structures in a dose-dependent manner. The injected mitochondria labeled with the MitoTracker Red localized in different brain regions, including the neocortex and hippocampus, which are responsible for memory and affected by degeneration in patients with Alzheimer's disease. In behavioral experiments, intranasal microinjections of brain mitochondria of native NMRI mice improved spatial memory in the olfactory bulbectomized (OBX) mice with Alzheimer's type degeneration.

Uridine treatment prevents myocardial injury in rat models of acute ischemia and ischemia/reperfusion by activating the mitochondrial ATP-dependent potassium channel.

The effect of uridine on the myocardial ischemic and reperfusion injury was investigated. A possible mechanism of its cardioprotective action was established. Two rat models were used: (1) acute myocardial ischemia induced by occlusion of the left coronary artery for 60 min; and (2) myocardial ischemia/reperfusion with 30-min ischemia and 120-min reperfusion.

Mitochondrial Cyclosporine A-Independent Palmitate/Ca-Induced Permeability Transition Pore (PA-mPT Pore) and Its Role in Mitochondrial Function and Protection against Calcium Overload and Glutamate Toxicity.

A sharp increase in the permeability of the mitochondrial inner membrane known as mitochondrial permeability transition (or mPT) occurs in mitochondria under the conditions of Ca and ROS stress. Permeability transition can proceed through several mechanisms. The most common mechanism of mPT is based on the opening of a cyclosporine A (CSA)-sensitive protein channel in the inner membrane.

Energy metabolism and oxidative status of rat liver mitochondria in conditions of experimentally induced hyperthyroidism.

The aim of the present work was to investigate the energy metabolism and antioxidant status of rat liver mitochondria using a model of hyperthyroidism. In experimental animals, the level of triiodothyronine and thyroxine was increased 3- and 4-fold, respectively, in comparison with that in the control group, indicating the development of hyperthyroidism in these animals. Oxygen consumption was found to be higher in rats with experimentally induced hyperthyroidism (from 20 to 60% depending on the experimental scheme used), with a slight decrease in the efficiency of oxidative phosphorylation and respiratory state ratio.

Effect of hypoxia on mitochondrial enzymes and ultrastructure in the brain cortex of rats with different tolerance to oxygen shortage.

The mitochondrial structure and the contents of subunits (NDUFV2, SDHA, Cyt b, COX1) of mitochondrial respiratory complexes I-IV as well as of the hypoxia-inducible factor (HIF-1α) in the brain cortex (BC) of rats with high resistance (HR) and low resistance (LR) to hypoxia were studied for the first time depending on the severity of hypoxia. Different regimes of 30-min hypobaric hypoxia (pO 14, 10, and 8%) were used. It was found that cortical mitochondria responded to 30-min hypobaric hypoxia of different severity with typical and progressing changes in mitochondrial structure and function of mitochondrial enzymes.

Uridine as a protector against hypoxia-induced lung injury.

The effect of the activation of the mitochondrial ATP-dependent potassium channel (mitoK) on the ultrastructure of rat lung in acute hypoxic hypoxia (7% of oxygen in nitrogen, exposure 30 min) was studied. It was shown that uridine, a precursor of the mitoK activator UDP, exerted a protective effect against hypoxic damage to the lung. The administration of uridine to animals prior to hypoxia decreased the number of mitochondria with altered ultrastructure and prevented the hypoxia-induced mitochondrial swelling.

The role of mitochondrial KATP channel in anti-inflammatory effects of uridine in endotoxemic mice.

In this study, we examined the effects of uridine on plasma cytokine levels, heat shock protein (HSP) 72 expression, and nuclear factor (NF)-κB signaling in spleen lymphocytes after exposure of male BALB/c mice to Escherichia coli lipopolysaccharide (LPS). Mice were treated with uridine (30 mg/kg body weight, intraperitoneal injection [i.p.

Formation of lamellar bodies in rat liver mitochondria in hyperthyroidism.

In the present work, ultrastructural changes of rat liver mitochondria in hyperthyroidism were studied. Hyperthyroidism was induced in male Wistar rats by daily administration of 100 μg thyroxin per 100 g body weight for 5 days. The level of triiodothyronine and thyroxine increased 3- and 4-fold, respectively, in comparison with the same parameters in the control group, indicating the development of hyperthyroidism in experimental animals.

Energetic, oxidative and ionic exchange in rat brain and liver mitochondria at experimental audiogenic epilepsy (Krushinsky-Molodkina model).

The role of brain and liver mitochondria at epileptic seizure was studied on Krushinsky-Molodkina (KM) rats which respond to sound with an intensive epileptic seizure (audiogenic epilepsy). We didn't find significant changes in respiration rats of brain and liver mitochondria of KM and control rats; however the efficiency of АТР synthesis in the KM rat mitochondria was 10% lower. In rats with audiogenic epilepsy the concentration of oxidative stress marker malondialdehyde in mitochondria of the brain (but not liver) was 2-fold higher than that in the control rats.

Effect of surface-potential modulators on the opening of lipid pores in liposomal and mitochondrial inner membranes induced by palmitate and calcium ions.

The effect of surface-potential modulators on palmitate/Ca2+-induced formation of lipid pores was studied in liposomal and inner mitochondrial membranes. Pore formation was monitored by sulforhodamine B release from liposomes and swelling of mitochondria. ζ-potential in liposomes was determined from electrophoretic mobility.

Involvement of palmitate/Ca2+(Sr2+)-induced pore in the cycling of ions across the mitochondrial membrane.

The palmitate/Ca2+-induced (Pal/Ca2+) pore, which is formed due to the unique feature of long-chain saturated fatty acids to bind Ca2+ with high affinity, has been shown to play an important role in the physiology of mitochondria. The present study demonstrates that the efflux of Ca2+ from rat liver mitochondria induced by ruthenium red, an inhibitor of the energy-dependent Ca2+ influx, seems to be partly due to the opening of Pal/Ca2+ pores. Exogenous Pal stimulates the efflux.

Ca(2+)-dependent permeabilization of mitochondria and liposomes by palmitic and oleic acids: a comparative study.

In the present work, we examine and compare the effects of saturated (palmitic) and unsaturated (oleic) fatty acids in relation to their ability to cause the Ca(2+)-dependent membrane permeabilization. The results obtained can be summarized as follows. (1) Oleic acid (OA) permeabilizes liposomal membranes at much higher concentrations of Ca(2+) than palmitic acid (PA): 1mM versus 100μM respectively.

Functioning of the mitochondrial ATP-dependent potassium channel in rats varying in their resistance to hypoxia. Involvement of the channel in the process of animal's adaptation to hypoxia.

The mechanism of tissue protection from ischemic damage by activation of the mitochondrial ATP-dependent K(+) channel (mitoK(ATP)) remains unexplored. In this work, we have measured, using various approaches, the ATP-dependent mitochondrial K(+) transport in rats that differed in their resistance to hypoxia. The transport was found to be faster in the hypoxia-resistant rats as compared to that in the hypoxia-sensitive animals.

Palmitic acid induces the opening of a Ca2+-dependent pore in the plasma membrane of red blood cells: the possible role of the pore in erythrocyte lysis.

Earlier we found that in the presence of Ca(2+) palmitic acid (Pal) increases the nonspecific permeability of artificial (planar and liposomal) membranes and causes permeabilization of the inner mitochondrial membrane. An assumption was made that the mechanism of Pal/Ca(2+)-induced membrane permeabilization relates to the Ca(2+)-induced phase separation of Pal and can be considered as formation of fast-tightening lipid pores due to chemotropic phase transition in the lipid bilayer. In this article, we continue studying this pore.

Physiological aspects of the mitochondrial cyclosporin A-insensitive palmitate/Ca2+-induced pore: tissue specificity, age profile and dependence on the animal's adaptation to hypoxia.

Earlier we found that being added to rat liver mitochondria, palmitic acid (Pal) plus Ca(2+) opened a cyclosporin A-insensitive pore, which remained open for a short time. Apparently, this pore is involved in the Pal-induced apoptosis and may also take part in the mitochondrial Ca(2+) recycling as a Ca(2+) efflux system (Belosludtsev et al. J Bioenerg Biomembr 38:113-120, 2006; Mironova et al.

Mitochondrial Ca2+ cycle mediated by the palmitate-activated cyclosporin A-insensitive pore.

Earlier we found that in isolated rat liver mitochondria the reversible opening of the mitochondrial cyclosporin A-insensitive pore induced by low concentrations of palmitic acid (Pal) plus Ca(2+) results in the brief loss of Deltapsi [Mironova et al., J Bioenerg Biomembr (2004), 36:171-178]. Now we report that Pal and Ca(2+), increased to 30 and 70 nmol/mg protein respectively, induce a stable and prolonged (10 min) partial depolarization of the mitochondrial membrane, the release of Ca(2+) and the swelling of mitochondria.

Ca2+-induced phase separation in the membrane of palmitate-containing liposomes and its possible relation to membrane permeabilization.

A Ca(2+)-induced phase separation of palmitic acid (PA) in the membrane of azolectin unilamellar liposomes has been demonstrated with the fluorescent membrane probe nonyl acridine orange (NAO). It has been shown that NAO, whose fluorescence in liposomal membranes is quenched in a concentration-dependent way, can be used to monitor changes in the volume of lipid phase. The incorporation of PA into NAO-labeled liposomes increased fluorescence corresponding to the expansion of membrane.

On the mechanism of palmitic acid-induced apoptosis: the role of a pore induced by palmitic acid and Ca2+ in mitochondria.

Palmitic acid (Pal) is known to promote apoptosis (Sparagna G et al (2000) Am J Physiol Heart Circ Physiol 279: H2124-H2132) and its amount in blood and mitochondria increases under some pathological conditions. Yet, the mechanism of the proapoptotic action of Pal has not been elucidated. We present evidence for the involvement of the mitochondrial cyclosporin A-insensitive pore induced by Pal/Ca(2+) complexes in the apoptotic process.