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 Amyloid β-Peptide Promotes Permeability Transition Pore in Brain Mitochondria

2001 ◽  
Vol 21 (6) ◽  
pp. 789-800 ◽  
Author(s):  
Paula I. Moreira ◽  
Maria S. Santos ◽  
António Moreno ◽  
Catarina Oliveira
Keyword(s):  
Transmembrane Potential ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Brain Mitochondria ◽  
Amyloid Β Peptide ◽  
Mitochondrial Permeability ◽  
Pre Treatment

In this work the effect of the neurotoxic amino acid sequence, Aβ25–35, on brain mitochondrial permeability transition pore (PTP) was studied. For the purpose, the mitochondrial transmembrane potential (ΔΨm), mitochondrial respiration and the calcium fluxes were examined. It was observed that Aβ25–35, in the presence of Ca2+, decreased the ΔΨm, the capacity of brain mitochondria to accumulate calcium and led to a complete uncoupling of the respiration. However, the reverse sequence of the peptide Aβ25–35 (Aβ35–25) did not promote the PTP. The alterations promoted by Aβ35–25 and/or Ca2+ could be reversed when Ca2+ was removed by EGTA or when ADP plus oligomycin were present. The pre-treatment with CsA or ADP plus oligomycin prevented the ΔΨm drop and preserved the capacity of mitochondria to accumulate Ca2+. These results suggest that Aβ25–35 can promote the PTP induced by Ca2+.

Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle

2007 ◽  
Vol 292 (3) ◽  
pp. E748-E755 ◽  
Author(s):  
Peter J. Adhihetty ◽  
Vladimir Ljubicic ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Manganese Superoxide Dismutase ◽  
Mitochondrial Permeability Transition ◽  
Contractile Activity ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Production ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Chronic contractile activity of skeletal muscle induces an increase in mitochondria located in proximity to the sarcolemma [subsarcolemmal (SS)] and in mitochondria interspersed between the myofibrils [intermyofibrillar (IMF)]. These are energetically favorable metabolic adaptations, but because mitochondria are also involved in apoptosis, we investigated the effect of chronic contractile activity on mitochondrially mediated apoptotic signaling in muscle. We hypothesized that chronic contractile activity would provide protection against mitochondrially mediated apoptosis despite an elevation in the expression of proapoptotic proteins. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 h/day) rat muscle for 7 days. Chronic contractile activity did not alter the Bax/Bcl-2 ratio, an index of apoptotic susceptibility, and did not affect manganese superoxide dismutase levels. However, contractile activity increased antiapoptotic 70-kDa heat shock protein and apoptosis repressor with a caspase recruitment domain by 1.3- and 1.4-fold ( P < 0.05), respectively. Contractile activity elevated SS mitochondrial reactive oxygen species (ROS) production 1.4- and 1.9-fold ( P < 0.05) during states IV and III respiration, respectively, whereas IMF mitochondrial state IV ROS production was suppressed by 28% ( P < 0.05) and was unaffected during state III respiration. Following stimulation, exogenous ROS treatment produced less cytochrome c release (25–40%) from SS and IMF mitochondria, and also reduced apoptosis-inducing factor release (≈30%) from IMF mitochondria, despite higher inherent cytochrome c and apoptosis-inducing factor expression. Chronic contractile activity did not alter mitochondrial permeability transition pore (mtPTP) components in either subfraction. However, SS mitochondria exhibited a significant increase in the time to Vmax of mtPTP opening. Thus, chronic contractile activity induces predominantly antiapoptotic adaptations in both mitochondrial subfractions. Our data suggest the possibility that chronic contractile activity can exert a protective effect on mitochondrially mediated apoptosis in muscle.

scholarly journals Mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ROS and Ca2+

2010 ◽  
Vol 299 (2) ◽  
pp. C506-C515 ◽  
Author(s):  
Filip Sedlic ◽  
Ana Sepac ◽  
Danijel Pravdic ◽  
Amadou K. S. Camara ◽  
Martin Bienengraeber ◽  
...  
Keyword(s):  
Cell Survival ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Underlying Mechanism ◽  
Ros Production ◽  
Trypan Blue Exclusion ◽  
Mptp Opening ◽  
Mitochondrial Ros ◽  
Cardioprotective Effects

During reperfusion, the interplay between excess reactive oxygen species (ROS) production, mitochondrial Ca2+ overload, and mitochondrial permeability transition pore (mPTP) opening, as the crucial mechanism of cardiomyocyte injury, remains intriguing. Here, we investigated whether an induction of a partial decrease in mitochondrial membrane potential (ΔΨm) is an underlying mechanism of protection by anesthetic-induced preconditioning (APC) with isoflurane, specifically addressing the interplay between ROS, Ca2+, and mPTP opening. The magnitude of APC-induced decrease in ΔΨm was mimicked with the protonophore 2,4-dinitrophenol (DNP), and the addition of pyruvate was used to reverse APC- and DNP-induced decrease in ΔΨm. In cardiomyocytes, ΔΨm, ROS, mPTP opening, and cytosolic and mitochondrial Ca2+ were measured using confocal microscope, and cardiomyocyte survival was assessed by Trypan blue exclusion. In isolated cardiac mitochondria, antimycin A-induced ROS production and Ca2+ uptake were determined spectrofluorometrically. In cells exposed to oxidative stress, APC and DNP increased cell survival, delayed mPTP opening, and attenuated ROS production, which was reversed by mitochondrial repolarization with pyruvate. In isolated mitochondria, depolarization by APC and DNP attenuated ROS production, but not Ca2+ uptake. However, in stressed cardiomyocytes, a similar decrease in ΔΨm attenuated both cytosolic and mitochondrial Ca2+ accumulation. In conclusion, a partial decrease in ΔΨm underlies cardioprotective effects of APC by attenuating excess ROS production, resulting in a delay in mPTP opening and an increase in cell survival. Such decrease in ΔΨm primarily attenuates mitochondrial ROS production, with consequential decrease in mitochondrial Ca2+ uptake.

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 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.

scholarly journals Mitochondrial calcium signalling and neurodegenerative diseases

2018 ◽  
Vol 2 (4) ◽  
Author(s):  
Elena Britti ◽  
Fabien Delaspre ◽  
Jordi Tamarit ◽  
Joaquim Ros
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Friedreich Ataxia ◽  
Calcium Signalling ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytosolic Calcium ◽  
Mitochondrial Calcium ◽  
Atp Production ◽  
Calcium Buffering ◽  
Mitochondrial Calcium Uptake

Calcium is utilised by cells in signalling and in regulating ATP production; it also contributes to cell survival and, when concentrations are unbalanced, triggers pathways for cell death. Mitochondria contribute to calcium buffering, meaning that mitochondrial calcium uptake and release is intimately related to cytosolic calcium concentrations. This review focuses on the proteins contributing to mitochondrial calcium homoeostasis, the roles of the mitochondrial permeability transition pore (MPTP) and mitochondrial calcium-activated proteins, and their relevance in neurodegenerative pathologies. It also covers alterations to calcium homoeostasis in Friedreich ataxia (FA).

scholarly journals Mitochondria, Amyloid β, and Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Ryan D. Readnower ◽  
Andrew D. Sauerbeck ◽  
Patrick G. Sullivan
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Permeability Transition ◽  
Amyloid Β ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Enzymes ◽  
Cyclophilin D ◽  
Ample Evidence

Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβdeposition. In addition to increasing oxidative stress, Aβhas been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Aβinteraction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Aβhas also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that the mitochondrion plays a vital role in the pathophysiology observed in AD.

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.

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