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1.
Basic Res Cardiol ; 118(1): 39, 2023 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-37775647

RESUMO

Giant mitochondria are frequently observed in different disease models within the brain, kidney, and liver. In cardiac muscle, these enlarged organelles are present across diverse physiological and pathophysiological conditions including in ageing and exercise, and clinically in alcohol-induced heart disease and various cardiomyopathies. This mitochondrial aberration is widely considered an early structural hallmark of disease leading to adverse organ function. In this thematic paper, we discuss the current state-of-knowledge on the presence, structure and functional implications of giant mitochondria in heart muscle. Despite its demonstrated reoccurrence in different heart diseases, the literature on this pathophysiological phenomenon remains relatively sparse since its initial observations in the early 60s. We review historical and contemporary investigations from cultured cardiomyocytes to human tissue samples to address the role of giant mitochondria in cardiac health and disease. Finally, we discuss their significance for the future development of novel mitochondria-targeted therapies to improve cardiac metabolism and functionality.


Assuntos
Cardiomiopatias , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/metabolismo , Dilatação Mitocondrial , Mitocôndrias/metabolismo , Miocárdio/metabolismo , Mitocôndrias Cardíacas/metabolismo
2.
Toxicon ; 233: 107259, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37595687

RESUMO

Immune system hyperactivation is involved with clinical severity and pathological alterations during scorpion envenomation. In a murine model, mice inoculated with a lethal dose of Tityus serrulatus scorpion venom presented mitochondrial swelling in cardiomyocytes, with other structures such as sarcomeres and intercalated disks preserved. Treatment with dexamethasone or knockout animals to the interleukin-1ß receptor do not undergo mitochondrial changes in cardiomyocytes during envenomation.


Assuntos
Picadas de Escorpião , Venenos de Escorpião , Animais , Camundongos , Miócitos Cardíacos , Dilatação Mitocondrial , Modelos Animais de Doenças , Venenos de Escorpião/toxicidade , Escorpiões
3.
Liver Int ; 43(11): 2365-2378, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37615254

RESUMO

This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal cells. Their presence and accumulation are considered to be a major pathological hallmark of the health and fate of liver parenchymal cells that leads to overall tissue deterioration and eventually results in organ failure. The first description on giant mitochondria dates back to the 1960s, coinciding with the availability of the first generation of electron microscopes in clinical diagnostic laboratories. Detailed accounts on their ultrastructure have mostly been described in patients suffering from alcoholic liver disease, chronic hepatitis, hepatocellular carcinoma and non-alcoholic fatty liver disease. Interestingly, from this extensive literature survey, it became apparent that giant mitochondria or megamitochondria present themselves with or without highly organised crystal-like intramitochondrial inclusions. The origin, formation and potential role of giant mitochondria remain to-date largely unanswered. Likewise, the biochemical composition of the well-organised crystal-like inclusions and their possible impact on mitochondrial function is unclear. Herein, concepts about the possible mechanism of their formation and three-dimensional architecture will be approached. We will furthermore discuss their importance in diagnostics, including future research outlooks and potential therapeutic interventions to cure liver disease where giant mitochondria are implemented.


Assuntos
Hepatopatias Alcoólicas , Hepatopatia Gordurosa não Alcoólica , Humanos , Dilatação Mitocondrial , Mitocôndrias Hepáticas/patologia , Hepatopatias Alcoólicas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatite Crônica/patologia , Fígado/patologia
6.
Mitochondrion ; 71: 64-75, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37276954

RESUMO

As the cell's energy factory and metabolic hub, mitochondria are critical for ATP synthesis to maintain cellular function. Mitochondria are highly dynamic organelles that continuously undergo fusion and fission to alter their size, shape, and position, with mitochondrial fusion and fission being interdependent to maintain the balance of mitochondrial morphological changes. However, in response to metabolic and functional damage, mitochondria can grow in size, resulting in a form of abnormal mitochondrial morphology known as megamitochondria. Megamitochondria are characterized by their considerably larger size, pale matrix, and marginal cristae structure and have been observed in various human diseases. In energy-intensive cells like hepatocytes or cardiomyocytes, the pathological process can lead to the growth of megamitochondria, which can further cause metabolic disorders, cell damage and aggravates the progression of the disease. Nonetheless, megamitochondria can also form in response to short-term environmental stimulation as a compensatory mechanism to support cell survival. However, extended stimulation can reverse the benefits of megamitochondria leading to adverse effects. In this review, we will focus on the findings of the different roles of megamitochondria, and their link to disease development to identify promising clinical therapeutic targets.


Assuntos
Doenças Metabólicas , Mitocôndrias , Humanos , Dilatação Mitocondrial , Mitocôndrias/metabolismo , Hepatócitos/metabolismo , Membranas Mitocondriais/metabolismo , Dinâmica Mitocondrial
7.
Cell Biol Toxicol ; 39(2): 435-450, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-35606662

RESUMO

Mitochondrial metabolism and function are modulated by changes in matrix Ca2+. Small increases in the matrix Ca2+ stimulate mitochondrial bioenergetics, whereas excessive Ca2+ leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca2+ overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and FOF1-ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANTM), cytosolic (ANTC), and pore (ANTP) states of the transporter. Then, the ANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca2+ overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca2+ and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca2+ response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca2+, enabled the model to simulate Ca2+ release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.


Assuntos
Nucleotídeos de Adenina , Proteínas de Transporte da Membrana Mitocondrial , Nucleotídeos de Adenina/metabolismo , Dilatação Mitocondrial , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Cálcio/metabolismo
8.
Hepatology ; 77(1): 159-175, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-35698731

RESUMO

BACKGROUND AND AIMS: Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms by which alcohol consumption increases megamitochondria formation in the pathogenesis of ALD. APPROACH AND RESULTS: Human alcoholic hepatitis (AH) liver samples were used for electron microscopy, histology, and biochemical analysis. Liver-specific dynamin-related protein 1 (DRP1; gene name DNM1L, an essential gene regulating mitochondria fission ) knockout (L-DRP1 KO) mice and wild-type mice were subjected to chronic plus binge alcohol feeding. Both human AH and alcohol-fed mice had decreased hepatic DRP1 with increased accumulation of hepatic megamitochondria. Mechanistic studies revealed that alcohol feeding decreased DRP1 by impairing transcription factor EB-mediated induction of DNM1L . L-DRP1 KO mice had increased megamitochondria and decreased mitophagy with increased liver injury and inflammation, which were further exacerbated by alcohol feeding. Seahorse flux and unbiased metabolomics analysis showed alcohol intake increased mitochondria oxygen consumption and hepatic nicotinamide adenine dinucleotide (NAD + ), acylcarnitine, and ketone levels, which were attenuated in L-DRP1 KO mice, suggesting that loss of hepatic DRP1 leads to maladaptation to alcohol-induced metabolic stress. RNA-sequencing and real-time quantitative PCR analysis revealed increased gene expression of the cGAS-stimulator of interferon genes (STING)-interferon pathway in L-DRP1 KO mice regardless of alcohol feeding. Alcohol-fed L-DRP1 KO mice had increased cytosolic mtDNA and mitochondrial dysfunction leading to increased activation of cGAS-STING-interferon signaling pathways and liver injury. CONCLUSION: Alcohol consumption decreases hepatic DRP1 resulting in increased megamitochondria and mitochondrial maladaptation that promotes AH by mitochondria-mediated inflammation and cell injury.


Assuntos
Hepatite Alcoólica , Hepatopatias Alcoólicas , Camundongos , Humanos , Animais , Dilatação Mitocondrial , Hepatopatias Alcoólicas/metabolismo , Mitocôndrias/metabolismo , Etanol/toxicidade , Nucleotidiltransferases , Inflamação , Interferons , Dinâmica Mitocondrial
9.
Methods Mol Biol ; 2497: 129-140, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35771440

RESUMO

The loss of mitochondrial cristae integrity and mitochondrial swelling are hallmarks of multiple forms of necrotic cell death. One of the most well-studied and relevant inducers of mitochondrial swelling is matrix calcium (Ca2+). Respiring mitochondria will intake available Ca2+ into their matrix until a threshold is reached which triggers the opening of the mitochondrial permeability transition pore (MPTP). Upon opening of the pore, mitochondrial membrane potential dissipates and the mitochondria begin to swell, rendering them dysfunctional. The total amount of Ca2+ taken up by a mitochondrion prior to the engagement of the MPTP is referred to as mitochondrial Ca2+ retention capacity (CRC). The CRC/swelling assay is a useful tool for observing the dose-dependent event of mitochondrial dysfunction in real-time. In this technique, isolated mitochondria are treated with specific boluses of Ca2+ until they reach CRC and undergo swelling. A fluorometer is utilized to detect an increase in transmitted light passing through the sample as the mitochondria lose cristae density, and simultaneously measures calcium uptake by way of a Ca2+-specific membrane impermeable fluorescent dye. Here we provide a detailed protocol describing the mitochondrial CRC/swelling assay and we discuss how varying amounts of mitochondria and Ca2+ added to the system affect the dose-dependency of the assay. We also report how to validate the assay by using MPTP and calcium uptake inhibitors and troubleshooting common mistakes that occur with this approach.


Assuntos
Cálcio , Proteínas de Transporte da Membrana Mitocondrial , Cálcio/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Dilatação Mitocondrial , Permeabilidade
10.
Biosystems ; 217: 104679, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35413385

RESUMO

Theoretical biophysical model is reported for mitochondrial swelling (MS) dynamics in vivo. This newly developed model is based on the detailed biophysical model of MS dynamics in vitro, where mechanical properties of the inner mitochondrial membrane (IMM) were taken into account. The present model of MS dynamics in vivo is capable of analyzing MS dynamic transition from the reversible (physiological) to the irreversible (pathological) mode. This model was used to describe myocytes, assuming 1000 mitochondria distributed homogeneously over the sarcoplasm. Solute transport through the myocyte membrane was described by simplified phenomenological mechanisms of solute uptake and release. Biophysical processes occurring in mitochondria within cells were similar to those included in the earlier reported in vitro biophysical model of MS dynamics. Additionally, in vivo MS dynamics was simulated in different initial conditions, with results different from those of the in vitro model. Note that the presently reported model is the first attempt to develop a detailed biophysical model for the analysis of MS dynamics in vivo, capable of reproducing the transition between reversible and irreversible MS dynamics.


Assuntos
Mitocôndrias , Membranas Mitocondriais , Fenômenos Biofísicos , Mitocôndrias/fisiologia , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/fisiologia
11.
Prog Biophys Mol Biol ; 172: 15-23, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35447196

RESUMO

Existing theoretical approaches were considered that allow modelling of mitochondrial swelling (MS) dynamics. Simple phenomenological kinetic models were reviewed. Simple and extended biophysical and bioenergetic models that ignore mechanical properties of inner mitochondrial membrane (IMM), and similar models that include these mechanical properties were also reviewed. Limitations of these models we considered, as regards correct modelling of MS dynamics. It was found that simple phenomenological kinetic models have significant limitations, due to dependence of the kinetic parameter values estimated by fitting of the experimental data on the experimental conditions. Additionally, such simple models provide no understanding of the detailed mechanisms behind the MS dynamics, nor of the dynamics of various system parameters during MS. Thus, biophysical and bioenergetic models ignoring IMM mechanical properties can't be used to model the transition between reversible and irreversible MS. However, simple and extended biophysical models that include IMM mechanical properties allow modelling the transition to irreversible swelling. These latter models are still limited due to significantly simplified description of biochemistry, compared to those of bioenergetic models. Finally, a strategy of model development is proposed, towards correct interpretation of the mitochondrial life cycle, including the effects of MS dynamics.


Assuntos
Mitocôndrias , Membranas Mitocondriais , Metabolismo Energético , Cinética , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial
13.
Toxicol Mech Methods ; 32(2): 106-113, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34431445

RESUMO

Mitochondria have the main roles in myocardial tissue homeostasis, through providing ATP for the vital enzymes in intermediate metabolism, contractile apparatus and maintaining ion homeostasis. Mitochondria-related cardiotoxicity results from the exposure with illicit drugs have previously reported. These illicit drugs interference with processes of normal mitochondrial homeostasis and lead to mitochondrial dysfunction and mitochondrial-related oxidative stress. Cannabis consumption has been shown to cause ventricular tachycardia, to increase the risk of myocardial infarction (MI) and potentially sudden death. Here, we investigated this hypothesis that delta-9-tetrahydrocannabinol (Delta-9-THC) as a main cannabinoid found in cannabis could directly cause mitochondrial dysfunction. Cardiac mitochondria were isolated with mechanical lysis and differential centrifugation form rat heart. The isolated cardiac mitochondria were treated with different concentrations of THC (1, 5, 10, 50, 100 and 500 µM) for 1 hour at 37 °C. Then, succinate dehydrogenase (SDH) activity, mitochondrial swelling, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse and lipid peroxidation were measured in the treated and nontreated isolated cardiac mitochondria. Our observation showed that THC did not cause a deleterious alteration in mitochondrial functions, ROS production, MMP collapse, mitochondrial swelling, oxidative stress and lipid peroxidation in used concentrations (5-100 µM), even in several tests, toxicity showed a decreasing trend. Altogether, the results of the current study showed that THC is not directly toxic in isolated cardiac mitochondria, and even may be helpful in reducing mitochondrial toxicity.


Assuntos
Dronabinol , Mitocôndrias Cardíacas , Animais , Dronabinol/metabolismo , Dronabinol/toxicidade , Potencial da Membrana Mitocondrial , Mitocôndrias Cardíacas/metabolismo , Dilatação Mitocondrial , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo
14.
Biosystems ; 210: 104559, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34627969

RESUMO

An extended biophysical model was obtained by upgrading the previously reported one (Khmelinskii and Makarov, 2021). The upgraded model accommodates variations of solute transport rates through the inner mitochondrial membrane (IMM) within the mitochondrial population, described by a Gaussian distribution. However, the model may be used for any functional form of the distribution. The dynamics of system parameters as predicted by the current model differed from that predicted by the previous model in the same initial conditions (Khmelinskii and Makarov, 2021). The amount of change varied from one parameter to the other, remaining in the 1-38% range. The upgraded model fitted the available experimental data with a better accuracy (R = 0.993) compared to the previous model (R = 0.978) using the same experimental data (Khmelinskii and Makarov, 2021). The fitting procedure also estimated the Gaussian distribution parameters. The new model requires much larger computational resources, but given its higher accuracy, it may be used for better analysis of experimental data and for better prediction of MS dynamics in different initial conditions. Note that activities of individual mitochondria in mitochondrial populations should vary within biological tissues. Thus, the currently upgraded model is a better tool for biological and bio-medical applications. We believe that this model is much better adapted to the analysis of MS dynamics in vivo.


Assuntos
Fenômenos Biofísicos/fisiologia , Mitocôndrias/fisiologia , Dilatação Mitocondrial/fisiologia , Modelos Biológicos , Animais , Humanos , Membranas Mitocondriais/fisiologia
15.
Biophys Chem ; 278: 106668, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34418677

RESUMO

Mitochondrial activity as regards ATP production strongly depends on mitochondrial swelling (MS) mode. Therefore, this work analyzes reversible and irreversible MS using a detailed biophysical model. The reported model includes mechanical properties of the inner mitochondrial membrane (IMM). The model describes MS dynamics for spherically symmetric, axisymmetric ellipsoidal and general ellipsoidal mitochondria. Mechanical stretching properties of the IMM were described by a second-rank rigidity tensor. The tensor components were estimated by fitting to the earlier reported results of in vitro experiments. The IMM rigidity constant of ca. 0.008 dyn/nm was obtained for linear deformations. The model also included membrane bending effects, which were small compared to those of membrane stretching. The model was also tested by simulation of the earlier reported experimental data and of the system dynamics at different initial conditions, predicting the system behavior. The transition criteria from reversible to irreversible swelling were determined and tested. The presently developed model is applicable directly to the analysis of in vitro experimental data, while additional improvements are necessary before it could be used to describe mitochondrial swelling in vivo. The reported theoretical model also provides an idea of physically consistent mechanism for the permeability transport pore (PTP) opening, which depends on the IMM stretching stress. In the current study, this idea is discussed briefly, but a detailed theoretical analysis of these ideas will be performed later. The currently developed model provides new understanding of the detailed MS mechanism and of the conditions for the transition between reversible and irreversible MS modes. On the other hand, the current model provides useful mathematical tools, that may be successfully used in mitochondrial biophysics research, and also in other applications, predicting the behavior of mitochondria in different conditions of the surrounding media in vitro or cellular cyto(sarco)plasm in vivo. These mathematical tools are based on real biophysical processes occurring in mitochondria. Thus, we note a significant progress in the theoretical approach, which may be used in real biological systems, compared to the earlier reported models. Significance of this study derives from inclusion of IMM mechanical properties, which directly impact the reversible and irreversible mitochondrial swelling dynamics. Reversible swelling corresponds to reversible IMM deformations, while irreversible swelling corresponds to irreversible deformations, with eventual membrane disruption. The IMM mechanical properties are directly dependent on the membrane biochemical composition and structure. The IMM deformationas are induced by osmotic pressure created by the ionic/neutral solute imbalance between the mitochondrial matrix media and the bulk solution in vitro, or cyto(sarco)plasm in vivo. The novelty of the reported model is in the biophysical mechanism detailing ionic and neutral solute transport for a large number of solutes, which were not taken into account in the earlier reported biophysical models of MS. Therefore, the reported model allows understanding response of mitochondria to the changes of initial concentration(s) of any of the solute(s) included in the model. Note that the values of all of the model parameters and kinetic constants have been estimated and the resulting complete model may be used for quantitative analysis of mitochondrial swelling dynamics in conditions of real in vitro experiments.


Assuntos
Mitocôndrias , Membranas Mitocondriais , Fenômenos Biofísicos , Cálcio/metabolismo , Simulação por Computador , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/fisiologia
16.
J Pharmacol Sci ; 147(1): 156-167, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34294367

RESUMO

We investigated the effect of 3-methyladenine (3MA), a class III phosphatidylinositol 3-kinase (PI3K)-blocking autophagy inhibitor, on cancer cell death induced by simultaneous inhibition of glycolysis by 2-deoxyglucose (2DG) and mitochondrial respiration by rotenone. 2DG/rotenone reduced ATP levels and increased mitochondrial superoxide production, causing mitochondrial swelling and necrotic death in various cancer cell lines. 2DG/rotenone failed to increase proautophagic beclin-1 and autophagic flux in melanoma cells despite the activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin complex 1 (mTORC1). 3MA, but not autophagy inhibition with other PI3K and lysosomal inhibitors, attenuated 2DG/rotenone-induced mitochondrial damage, oxidative stress, ATP depletion, and cell death, while antioxidant treatment mimicked its protective action. The protection was not mediated by autophagy upregulation via class I PI3K/Akt inhibition, as it was preserved in cells with genetically inhibited autophagy. 3MA increased AMPK and mTORC1 activation in energy-stressed cells, but neither AMPK nor mTORC1 inhibition reduced its cytoprotective effect. 3MA reduced JNK activation, and JNK pharmacological/genetic suppression mimicked its mitochondria-preserving and cytoprotective activity. Therefore, 3MA prevents energy stress-triggered cancer cell death through autophagy-independent mechanisms possibly involving JNK suppression and decrease of oxidative stress. Our results warrant caution when using 3MA as an autophagy inhibitor.


Assuntos
Adenina/análogos & derivados , Autofagia/efeitos dos fármacos , Melanoma/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Adenina/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Desoxiglucose/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Melanoma/metabolismo , Melanoma Experimental , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Dilatação Mitocondrial , Necrose , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Rotenona/farmacologia
17.
Biosystems ; 208: 104488, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34274463

RESUMO

Presently a mechanism of permeability transition pore (PTP) opening was proposed and discussed. This mechanism is based on mechanical stretching of inner mitochondrial membrane (IMM) caused by mitochondrial swelling (MS). The latter is induced by osmotic pressure generated by solute imbalance between the matrix and the surrounding cyto(sarco)plasm. Modelled by the Monte-Carlo method, an IMM fragment of 350 simulated biological molecules exhibited formation of micro-domains containing two protein and seven phospholipid molecules. The energies (-0.191 eV per molecule) in these micro-domains were significantly larger than those (-0.375 eV per molecule) of other parts of the IMM fragment. Stretching forces applied to such domains expanded them much more than other parts of the IMM fragment. We identify these micro-domains as the PTPs. Both linear and nonlinear functions were used for the strain-stress relation of the IMM fragment, with nonlinear effects more important at large IMM stretching strains. Thus, two main factors are incorporated into the PTP opening mechanism: (1) presence of micro-domains in the IMM structure and (2) IMM stretching stress caused by MS. Taking into account both of these factors, the equation for the probability of PTP opening was deduced, with matrix Ca2+ and H+ ionic concentrations as its parameters. Note that the equation deduced was similar to an earlier reported empirical equation describing PTP opening dynamics. This correspondence provides support to the presently proposed mechanism. Thus, a new look at the PTP opening mechanism is provided, of interest to various research areas related to mitochondrial biophysics.


Assuntos
Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Membranas Mitocondriais/metabolismo , Dilatação Mitocondrial/fisiologia , Animais , Humanos , Método de Monte Carlo , Permeabilidade
18.
Cells ; 10(5)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067674

RESUMO

The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied either before ischemia or at the beginning of reperfusion, and this effect is associated with the mitochondrial permeability transition pore (MPTP). 8-Br (10 µM) was administered to Langendorff-perfused rat hearts for 5 min either before or at the end of 30 min regional ischaemia. Ca2+-induced mitochondria swelling (a measure of MPTP opening) and binding of hexokinase II (HKII) to mitochondria were assessed following the drug treatment at preischaemia. Haemodynamic function and ventricular arrhythmias were monitored during ischaemia and 2 h reperfusion. Infarct size was evaluated at the end of reperfusion. 8-Br administered before ischaemia attenuated ventricular arrhythmias, improved haemodynamic function, and reduced infarct size during ischaemia/reperfusion. Application of 8-Br at the end of ischaemia protected the heart during reperfusion. 8-Br promoted binding of HKII to the mitochondria and reduced Ca2+-induced mitochondria swelling. Thus, 8-Br protects the heart when administered before regional ischaemia or at the beginning of reperfusion. This effect is associated with inhibition of MPTP via binding of HKII to mitochondria, which may underlie the protective mechanism.


Assuntos
8-Bromo Monofosfato de Adenosina Cíclica/administração & dosagem , Fármacos Cardiovasculares/administração & dosagem , Mitocôndrias Cardíacas/efeitos dos fármacos , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , 8-Bromo Monofosfato de Adenosina Cíclica/análogos & derivados , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Hemodinâmica/efeitos dos fármacos , Hexoquinase/metabolismo , Preparação de Coração Isolado , Masculino , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Wistar , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos
19.
Toxicology ; 458: 152836, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34147545

RESUMO

China's clean energy and resources are mainly located in the west and north while electric load center is concentrated in the middle and east. Thus, these resources and energy need to be converted into electrical energy in situ and transported to electric load center through ultra-high voltage direct current (UHVDC) transmissions. China has built 25,000 km UHVDC transmission lines of 800 kV and 1100 kV, near which the impact of electric field on health has attracted public attention. Previous studies showed that time-varying electromagnetic field exposure could disturb testosterone secretion. To study the effect of non-time-varying electric field caused by direct current transmission lines on testosterone synthesis, male ICR mice were continually (24 h/d) exposed to static electric field of 56.3 ± 1.4 kV/m. Results showed that on the 3rd day of exposure and on the 7th day after ceasing the exposure of 28 d, serum testosterone level and testicular oxidative stress indicators didn't change significantly. On the 28th day of exposure, serum testosterone levels, testicular glutathione peroxidase (GSH-Px) activity, the mRNA and protein levels of testicular StAR, PBR, CYP11A1 decreased significantly, and testicular malondialdehyde (MDA) content increased significantly. Meanwhile, electron-dense edges and vacuolation appeared in lipid droplets of Leydig cells. The gap between inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) enlarged, which would cause the swelling of mitochondria, the rupture and deficiency of mitochondrial membranes. Analysis showed that testicular oxidative stress could induce the damage of mitochondrial structure in Leydig cells, which would decrease the rate of cholesterol transport from cytoplasm to mitochondria. Since cholesterol is the necessary precursor of testosterone synthesis, testosterone synthesis was inhibited. The decrease of the mRNA and protein expression levels of StAR and PBR in testes could diminish the cholesterol transported from OMM to IMM. The decrease of the mRNA and protein expression levels of CYP11A1 could reduce the pregnenolone required in testosterone synthesis and inhibit testosterone synthesis consequently.


Assuntos
Campos Eletromagnéticos , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/efeitos da radiação , Testosterona/biossíntese , Animais , Antioxidantes/metabolismo , Colesterol/metabolismo , Citoplasma/metabolismo , Citoplasma/efeitos da radiação , Glutationa Peroxidase/metabolismo , Células Intersticiais do Testículo/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos ICR , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/efeitos da radiação , Dilatação Mitocondrial/efeitos da radiação , Estresse Oxidativo/efeitos da radiação , Fosfoproteínas/metabolismo , Testosterona/sangue , Vacúolos/efeitos da radiação , Vacúolos/ultraestrutura
20.
Naunyn Schmiedebergs Arch Pharmacol ; 394(8): 1675-1684, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33937934

RESUMO

The generation of a reactive nitrenium ion by microsomal/mitochondrial cytochrome P450 (CYPs) from clozapine (CLZ) has been suggested as the main cause of cardiotoxicity by this drug. Previous studies indicated that thymoquinone (TQ) as an active constituent of Nigella sativa has pharmacological effects such as antioxidant, reactive oxygen species (ROS) scavenger, and inhibitory effect on CYPs enzymes. Therefore, we hypothesized that TQ with these pharmacological effects can reduce CLZ-induced toxicity in isolated cardiomyocytes and mitochondria. Rat left ventricular cardiomyocytes and mitochondria were isolated by collagenase perfusion and differential centrifugation respectively. Then, isolated cardiomyocytes and mitochondria were pretreated with different concentrations of TQ (1, 5, and 10 µmol/l) for 30 min and then followed by exposure to CLZ (50 µmol/l) for 6 h. After 6 h of incubation, using biochemical evaluations and flow cytometric analysis, the parameters of cellular toxicity including cytotoxicity, the level of oxidized/reduced glutathione (GSH/GSSG), malondialdehyde (MDA), reactive oxygen species (ROS) formation, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse, and mitochondrial toxicity including succinate dehydrogenase (SDH) activity and mitochondrial swelling were analyzed. We observed a significant toxicity in isolated cardiomyocytes and mitochondria after exposure with CLZ which was related to ROS formation, oxidative stress, GSH depletion, lysosomal and mitochondrial damages, and mitochondrial dysfunction and swelling, while TQ pretreatment reverted the above toxic effect of CLZ on isolated cardiomyocytes and mitochondria. Our results indicate that TQ prevents and reverses CLZ-induced cytotoxicity and mitochondrial damages in isolated cardiomyocytes and mitochondria, providing an experimental basis for clinical treatment on CLZ-induced cardiotoxicity.


Assuntos
Benzoquinonas/farmacologia , Cardiotoxicidade/prevenção & controle , Clozapina/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Animais , Antipsicóticos/toxicidade , Benzoquinonas/administração & dosagem , Cardiotoxicidade/etiologia , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
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