scholarly journals A spatiotemporal ventricular myocyte model incorporating mitochondrial calcium cycling

2019 ◽  
Author(s):  
Z. Song ◽  
L-H Xie ◽  
J. N. Weiss ◽  
Z. Qu
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Ventricular Myocytes ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ventricular Myocyte ◽  
Mitochondrial Depolarization ◽  
3 Dimensional ◽  
Spatially Distributed ◽  
Intracellular Ca ◽  
Stochastic Events

AbstractIntracellular calcium (Ca2+) cycling dynamics in cardiac myocytes are spatiotemporally generated by stochastic events arising from a spatially distributed network of coupled Ca2+ release units (CRUs) that interact with an intertwined mitochondrial network. In this study, we developed a spatiotemporal ventricular myocyte model that integrates mitochondria-related Ca2+ cycling components into our previously developed ventricular myocyte model consisting of a 3-dimensional CRU network. Mathematical formulations of mitochondrial membrane potential, mitochondrial Ca2+ cycling, mitochondrial permeability transition pore (MPTP) stochastic opening and closing, intracellular reactive oxygen species (ROS) signaling, and oxidized Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling were incorporated into the model. We then used the model to simulate the effects of mitochondrial depolarization on mitochondrial Ca2+ cycling, Ca2+ spark frequency and amplitude, which agree well with experimental data. We also simulated the effects of the strength of mitochondrial Ca2+ uniporters and their spatial localization on intracellular Ca2+ cycling properties, which substantially affected diastolic and systolic Ca2+ levels in the mitochondria but exhibited only a small effect on sarcoplasmic reticulum and cytosolic Ca2+ levels under normal conditions. We show that mitochondrial depolarization can cause Ca2+ waves and Ca2+ alternans, which agrees with previous experimental observations. We propose that this new spatiotemporal ventricular myocyte model, incorporating properties of mitochondrial Ca2+ cycling and ROS-dependent signaling, will be useful for investigating the effects of mitochondria on intracellular Ca2+ cycling and action potential dynamics in ventricular myocytes.

scholarly journals Role of Calcium and Mitochondria in MeHg-Mediated Cytotoxicity

2012 ◽  
Vol 2012 ◽  
pp. 1-15 ◽  
Author(s):  
Daniel Roos ◽  
Rodrigo Seeger ◽  
Robson Puntel ◽  
Nilda Vargas Barbosa
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Dysfunctions ◽  
Mptp Opening ◽  
Molecular Events ◽  
Chain Complexes ◽  
Transport Chain ◽  
Intracellular Ca

Methylmercury (MeHg) mediated cytotoxicity is associated with loss of intracellular calcium (Ca2+) homeostasis. The imbalance in Ca2+physiology is believed to be associated with dysregulation of Ca2+intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca2+overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca2+overload. Mitochondrial disturbances elicited by Ca2+may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP) opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction) that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed.

Ca2+ overload and mitochondrial permeability transition pore activation in living δ-sarcoglycan-deficient cardiomyocytes

2010 ◽  
Vol 299 (3) ◽  
pp. C706-C713 ◽  
Author(s):  
Bodvaël Fraysse ◽  
Sadia M. Nagi ◽  
Belinda Boher ◽  
Hélène Ragot ◽  
Jeanne Lainé ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ventricular Myocytes ◽  
Gene Mutations ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Glycoprotein Complex ◽  
Ventricular Cells

Muscular dystrophies are often associated with significant cardiac disease that can be the prominent feature associated with gene mutations in sarcoglycan. Cardiac cell death is a main feature of cardiomyopathy in sarcoglycan deficiency and may arise as a cardiomyocyte intrinsic process that remains unclear. Deficiency of δ-sarcoglycan (δ-SG) induces disruption of the dystrophin-associated glycoprotein complex, a known cause of membrane instability that may explain cardiomyocytes cytosolic Ca2+ increase. In this study we assessed the hypothesis that cytosolic Ca2+ increase triggers cardiomyocyte death through mitochondrial Ca2+ overload and dysfunction in the δ-SG-deficient CHF147 hamster. We showed that virtually all isolated CHF147 ventricular myocytes exhibited elevated cytosolic and mitochondrial Ca2+ levels by the use of the Fura-2 and Rhod-2 fluorescent probes. Observation of living cells with Mito-Tracker red lead to the conclusion that ∼15% of isolated CHF147 cardiomyocytes had disorganized mitochondria. Transmission electron microscope imaging showed mitochondrial swelling associated with crest and membrane disruption. Analysis of the mitochondrial permeability transition pore (MPTP) activity using calcein revealed that mitochondria of CHF147 ventricular cells were twofold leakier than wild types, whereas reactive oxygen species production was unchanged. Bax, Bcl-2, and LC3 expression analysis by Western blot indicated that the intrinsic apoptosis and the cell death associated to autophagy pathways were not significantly activated in CHF147 hearts. Our results lead to conclusion that cardiomyocytes death in δ-SG-deficient animals is an intrinsic phenomenon, likely related to Ca2+-induced necrosis. In this process Ca2+ overload-induced MPTP activation and mitochondrial disorganization may have an important role.

scholarly journals Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide

1995 ◽  
Vol 307 (1) ◽  
pp. 99-106 ◽  
Author(s):  
A L Nieminen ◽  
A K Saylor ◽  
S A Tesfai ◽  
B Herman ◽  
J J Lemasters
Keyword(s):  
Cell Death ◽  
Laser Scanning ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Fluorescence Probes ◽  
Mitochondrial Depolarization ◽  
Intact Cells ◽  
Mitochondrial Permeability

We have developed a novel method for monitoring the mitochondrial permeability transition in single intact hepatocytes during injury with t-butylhydroperoxide (t-BuOOH). Cultured hepatocytes were loaded with the fluorescence probes, calcein and tetramethylrhodamine methyl ester (TMRM). Depending on loading conditions, calcein labelled the cytosolic space exclusively and did not enter mitochondria or it stained both cytosol and mitochondria. TMRM labelled mitochondria as an indicator of mitochondrial polarization. Fluorescence of two probes was imaged simultaneously using laser-scanning confocal microscopy. During normal incubations, TMRM labelled mitochondria indefinitely (longer than 63 min), and calcein did not redistribute between cytosol and mitochondria. These findings indicate that the mitochondrial permeability transition pore (‘megachannel’) remained closed continuously. After addition of 100 microM t-BuOOH, mitochondria filled quickly with calcein, indicating the onset of mitochondrial permeability transition. This event was accompanied by mitochondrial depolarization, as shown by loss of TMRM. Subsequently, the concentration of ATP declined and cells lost viability. Trifluoperazine, a phospholipase inhibitor that inhibits the permeability transition in isolated mitochondria, prevented calcein redistribution into mitochondria, mitochondrial depolarization, ATP depletion and cell death. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, also rapidly depolarized mitochondria of intact hepatocytes but did not alone induce a permeability transition. Trifluoperazine did not prevent ATP depletion and cell death after the addition of CCCP. In conclusion, the permeability transition pore does not ‘flicker’ open during normal incubation of hepatocytes but remains continuously closed. Moreover, mitochondrial depolarization per se does not cause the permeability transition in intact cells. During oxidative stress, however, a permeability transition occurs quickly which leads to mitochondrial depolarization and cell death.

Interaction of neurons and astrocytes underlies the mechanism of Aβ-induced neurotoxicity

2014 ◽  
Vol 42 (5) ◽  
pp. 1286-1290 ◽  
Author(s):  
Plamena R. Angelova ◽  
Andrey Y. Abramov
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Calcium Signalling ◽  
Amyloid Β ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Signal ◽  
Amyloid Β Peptide ◽  
Ros Production ◽  
Mitochondrial Depolarization ◽  
Aβ Fibrils

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the aggregation of amyloid β-peptide (Aβ) into β-sheet-rich fibrils. Although plaques containing Aβ fibrils have been viewed as the conventional hallmark of AD, recent research implicates small oligomeric species formed during the aggregation of Aβ in the neuronal toxicity and cognitive deficits associated with AD. We have demonstrated that oligomers, but not monomers, of Aβ40 and Aβ42 were found to induce calcium signalling in astrocytes but not in neurons. This cell specificity was dependent on the higher cholesterol level in the membrane of astrocytes compared with neurons. The Aβ-induced calcium signal stimulated NADPH oxidase and induced increased reactive oxygen species (ROS) production. These events are detectable at physiologically relevant concentrations of Aβ. Excessive ROS production and Ca2+ overload induced mitochondrial depolarization through activation of the DNA repairing enzyme poly(ADP-ribose) polymerase-1 (PARP-1) and opening mitochondrial permeability transition pore (mPTP). Aβ significantly reduced the level of GSH in both astrocytes and neurons, an effect which is dependent on external calcium. Thus Aβ induces a [Ca2+]c signal in astrocytes which could regulate the GSH level in co-cultures that in the area of excessive ROS production could be a trigger for neurotoxicity. The pineal hormone melatonin, the glycoprotein clusterin and regulation of the membrane cholesterol can modify Aβ-induced calcium signals, ROS production and mitochondrial depolarization, which eventually lead to neuroprotection.

scholarly journals Different effects of palmitoyl-l-carnitine and palmitoyl-CoA on mitochondrial function in rat ventricular myocytes

2008 ◽  
Vol 295 (1) ◽  
pp. H105-H112 ◽  
Author(s):  
Hiromutsu Tominaga ◽  
Hideki Katoh ◽  
Keiichi Odagiri ◽  
Yasuyo Takeuchi ◽  
Hirotaka Kawashima ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Laser Scanning ◽  
Mitochondrial Permeability Transition ◽  
Ventricular Myocytes ◽  
Elevated Serum ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Generation ◽  
Rat Ventricular Myocytes ◽  
Long Chain

Although mitochondrial oxidative catabolism of fatty acid (FA) is a major energy source for the adult mammalian heart, cardiac lipotoxity resulting from elevated serum FA and enhanced FA use has been implicated in the pathogenesis of heart failure. To investigate the effects of intermediates of FA metabolism [palmitoyl-l-carnitine (Pal-car) and palmitoyl-CoA (Pal-CoA)] on mitochondrial function, we measured membrane potential (ΔΨm), opening of the mitochondrial permeability transition pore (mPTP), and the production of ROS in saponin-treated rat ventricular myocytes with a laser scanning confocal microscope. Our results revealed that 1) lower concentrations of Pal-car (1 and 5 μM) caused a slight hyperpolarization of ΔΨm [tetramethylrhodamine ethyl ester (TMRE) intensity increased to 115.5 ± 5.4% and 110.7 ± 1.6% of baseline, respectively, P < 0.05] but did not open the mPTP, 2) a higher concentration of Pal-car (10 μM) depolarized ΔΨm (TMRE intensity decreased to 61.9 ± 12.2% of baseline, P < 0.01) and opened the mPTP (calcein intensity decreased to 70.7 ± 2.8% of baseline, P < 0.01), 3) Pal-CoA depolarized ΔΨm without opening the mPTP, and 4) only the higher concentration of Pal-car (10 μM) increased ROS generation (2′,7′-dichlorofluorescein diacetate intensity increased to 3.4 ± 0.3-fold of baseline). We concluded that excessive exogenous intermediates of long-chain saturated FA may disturb mitochondrial function in different ways between Pal-car and Pal-CoA. The distinct mechanisms of the deteriorating effects of long-chain FA on mitochondrial function are important for our understanding of the development of cardiac diseases in systemic metabolic disorders.

scholarly journals Iron Overload, Oxidative Stress and Calcium Mishandling in Cardiomyocytes: Role of the Mitochondrial Permeability Transition Pore

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 758 ◽  
Author(s):  
Richard Gordan ◽  
Nadezhda Fefelova ◽  
Judith K. Gwathmey ◽  
Lai-Hua Xie
Keyword(s):  
Iron Overload ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ventricular Myocytes ◽  
Ex Vivo ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Production ◽  
Mitochondrial Permeability ◽  
Mitochondrial Ros

Iron (Fe) plays an essential role in many physiological processes. Hereditary hemochromatosis or frequent blood transfusions often cause iron overload (IO), which can lead to cardiomyopathy and arrhythmias; however, the underlying mechanism is not well defined. In the present study, we assess the hypothesis that IO promotes arrhythmias via reactive oxygen species (ROS) production, mitochondrial membrane potential (∆Ψm) depolarization, and disruption of cytosolic Ca dynamics. In ventricular myocytes isolated from wild type (WT) mice, both cytosolic and mitochondrial Fe levels were elevated following perfusion with the Fe3+/8-hydroxyquinoline (8-HQ) complex. IO promoted mitochondrial superoxide generation (measured using MitoSOX Red) and induced the depolarization of the ΔΨm (measured using tetramethylrhodamine methyl ester, TMRM) in a dose-dependent manner. IO significantly increased the rate of Ca wave (CaW) formation measured in isolated ventricular myocytes using Fluo-4. Furthermore, in ex-vivo Langendorff-perfused hearts, IO increased arrhythmia scores as evaluated by ECG recordings under programmed S1-S2 stimulation protocols. We also carried out similar experiments in cyclophilin D knockout (CypD KO) mice in which the mitochondrial permeability transition pore (mPTP) opening is impaired. While comparable cytosolic and mitochondrial Fe load, mitochondrial ROS production, and depolarization of the ∆Ψm were observed in ventricular myocytes isolated from both WT and CypD KO mice, the rate of CaW formation in isolated cells and the arrhythmia scores in ex-vivo hearts were significantly lower in CypD KO mice compared to those observed in WT mice under conditions of IO. The mPTP inhibitor cyclosporine A (CsA, 1 µM) also exhibited a protective effect. In conclusion, our results suggest that IO induces mitochondrial ROS generation and ∆Ψm depolarization, thus opening the mPTP, thereby promoting CaWs and cardiac arrhythmias. Conversely, the inhibition of mPTP ameliorates the proarrhythmic effects of IO.

Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes

2007 ◽  
Vol 293 (1) ◽  
pp. H307-H313 ◽  
Author(s):  
Sung Hyun Kang ◽  
Won Sun Park ◽  
Nari Kim ◽  
Jae Boum Youm ◽  
Mohamad Warda ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Mitochondrial Permeability Transition ◽  
Ventricular Myocytes ◽  
Control Level ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Selective Inhibition ◽  
Dependent Manner ◽  
Rat Ventricular Myocytes

We investigated the role of the mitochondrial ATP-sensitive K+ (KATP) channel, the mitochondrial big-conductance Ca2+-activated K+ (BKCa) channel, and the mitochondrial permeability transition pore (MPTP) in the ouabain-induced increase of mitochondrial Ca2+ in native rat ventricular myocytes by loading cells with rhod 2-AM. To overload mitochondrial Ca2+, we pretreated cells with ouabain before applying mitochondrial KATP or BKCa channel and/or MPTP opener. Ouabain (1 mM) increased the rhod 2-sensitive fluorescence intensity (160 ± 5.0% of control), which was dramatically decreased to the control level on application of diazoxide and NS-1619 in a dose-dependent manner (half-inhibition concentrations of 78.3 and 7.78 μM for diazoxide and NS-1619, respectively). This effect was reversed by selective inhibition of the mitochondrial KATP channel by 5-hydroxydecanoate, the mitochondrial BKCa channel by paxilline, and the MPTP by cyclosporin A. Although diazoxide did not efficiently reduce mitochondrial Ca2+ during prolonged exposure to ouabain, NS-1619 reduced mitochondrial Ca2+. These results suggest that although mitochondrial BKCa and KATP channels contribute to reduction of ouabain-induced mitochondrial Ca2+ overload, activation of the mitochondrial BKCa channel more efficiently reduces ouabain-induced mitochondrial Ca2+ overload in our experimental model.

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