scholarly journals Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition

2021 ◽  
Vol 14 (10) ◽  
pp. 1045
Author(s):  
Ekaterina S. Kharechkina ◽  
Anna B. Nikiforova ◽  
Konstantin N. Belosludtsev ◽  
Tatyana I. Rokitskaya ◽  
Yuri N. Antonenko ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Permeability Transition ◽  
Kidney Diseases ◽  
Adenine Nucleotides ◽  
Permeability Transition ◽  
Protective Effects ◽  
Retention Capacity ◽  
Mptp Opening

Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨm was measured using tetraphenylphosphonium and the fluorescent dye rhodamine 123. The coupling of oxidative phosphorylation was estimated polarographically. The transport of ions and solutes across membranes was registered by potentiometric and spectral techniques. We found that PIO decreased ΔΨm in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca2+. The presence of the cytosolic fraction mitigated mitochondrial depolarization but made it sustained. Carboxyatractyloside diminished the PIO-dependent depolarization. PIO activated proton transport in deenergized mitochondria but not in artificial phospholipid vesicles. PIO had no effect on K+ and Ca2+ inward transport but drastically decreased the mitochondrial Ca2+-retention capacity and protective effects of adenine nucleotides against mPTP opening. Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO.

Ageing-induced decrease in cardiac mitochondrial function in healthy rats

2013 ◽  
Vol 91 (8) ◽  
pp. 593-600 ◽  
Author(s):  
Oana M. Duicu ◽  
Silvia N. Mirica ◽  
Dorina E. Gheorgheosu ◽  
Andreea I. Privistirescu ◽  
Ovidiu Fira-Mladinescu ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Complex I ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Heart Mitochondria ◽  
Ros Production ◽  
Sprague Dawley ◽  
Retention Capacity ◽  
Mptp Opening ◽  
Sprague Dawley Rats

It is widely recognized that mitochondrial dysfunction is a key component of the multifactorial process of ageing. The effects of age on individual components of mitochondrial function vary across species and strains. In this study we investigated the oxygen consumption, the mitochondrial membrane potential (Δψ), the sensitivity of mitochondrial permeability transition pore (mPTP) to calcium overload, and the production of reactive oxygen species (ROS) in heart mitochondria isolated from old compared with adult healthy Sprague–Dawley rats. Respirometry studies and Δψ measurements were performed with an Oxygraph-2k equipped with a tetraphenylphosphonium electrode. ROS production and calcium retention capacity were measured spectrofluorimetrically. Our results show an important decline for all bioenergetic parameters for both complex I and complex II supported-respiration, a decreased Δψ in mitochondria energized with complex I substrates, and an increased mitochondrial ROS production in the old compared with the adult group. Mitochondrial sensitivity to Ca2+-induced mPTP opening was also increased in the old compared with the adult animals. Moreover, the protective effect of cyclosporine A on mPTP opening was significantly reduced in the old group. We conclude that healthy ageing is associated with a decrease in heart mitochondria function in Sprague–Dawley rats.

Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice

2007 ◽  
Vol 293 (3) ◽  
pp. H1654-H1661 ◽  
Author(s):  
Ludovic Gomez ◽  
Hélène Thibault ◽  
Adbdallah Gharib ◽  
Jean-Maurice Dumont ◽  
Grégoire Vuagniaux ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
At Risk ◽  
Infarct Size ◽  
Functional Recovery ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Control Group ◽  
Retention Capacity ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Inhibition of mitochondrial permeability transition pore (mPTP) opening by cyclosporin A or ischemic postconditioning attenuates lethal reperfusion injury. Its impact on major post-myocardial infarction events, including worsening of left ventricular (LV) function and death, remains unknown. We sought to determine whether pharmacological or postconditioning-induced inhibition of mPTP opening might improve functional recovery and survival following myocardial infarction in mice. Anesthetized mice underwent 25 min of ischemia and 24 h ( protocol 1) or 30 days ( protocol 2) of reperfusion. At reperfusion, they received no intervention (control), postconditioning (3 cycles of 1 min ischemia-1 min reperfusion), or intravenous injection of the mPTP inhibitor Debio-025 (10 mg/kg). At 24 h of reperfusion, mitochondria were isolated from the region at risk for assessment of the Ca2+ retention capacity (CRC). Infarct size was measured by triphenyltetrazolium chloride staining. At 30 days of reperfusion, mortality and LV contractile function (echocardiography) were evaluated. Postconditioning and Debio-025 significantly improved Ca2+ retention capacity (132 ± 13 and 153 ± 31 vs. 53 ± 16 nmol Ca2+/mg protein in control) and reduced infarct size to 35 ± 4 and 32 ± 7% of area at risk vs. 61 ± 6% in control ( P < 0.05). At 30 days, ejection fraction averaged 74 ± 6 and 77 ± 6% in postconditioned and Debio-025 groups, respectively, vs. 62 ± 12% in the control group ( P < 0.05). At 30 days, survival was improved from 58% in the control group to 92 and 89% in postconditioned and Debio-025 groups, respectively. Inhibition of mitochondrial permeability transition at reperfusion improves functional recovery and mortality in mice.

Abstract 3563: Postconditioning Inhibits Mitochondrial Permeability Transition Pore Opening Independently of any Modification of the Oxidative Phosphorylation and of the Inner Membrane Potential at Reperfusion

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mélanie Paillard ◽  
Ludovic Gomez ◽  
Lionel Augeul ◽  
Joseph Loufouat ◽  
Michel Ovize
Keyword(s):  
Membrane Potential ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Area At Risk ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Myocardial Area

Mitochondrial permeability transition pore (mPTP) inhibition plays a crucial role in postconditioning (PostC). We sought to determine whether oxidative phosphorylation and mitochondrial membrane potential (ΔΨ m ), which both modulate mPTP opening, are involved in the inhibition of mPTP opening in the postconditioned heart. Anesthetized rabbits underwent 30 minutes of ischemia followed by 10 minutes of reperfusion. At the onset of reperfusion, they received either no intervention (Control, C), 4 cycles of 1 min ischemia followed by 1 min reperfusion (PostC), or an IV injection of 5mg/kg of the powerful inhibitor of mPTP opening, i.e. cyclosporine A (CsA). Sham rabbits underwent no ischemic insult throughout the 40 minute experiment. At the end of the 10 minute reperfusion period, the myocardial area at risk was excised, and mitochondria were isolated by differential centrifugations. Calcium retention capacity, an index of mPTP inhibition (CRC: nmol Ca 2+ /mg prot) and ΔΨ m (at state 4: % of FCCP-evoked maximum) were assessed by spectrofluorimetry in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria. Oxidative phosphorylation (at states 3 and 4: nmol O 2 /min/mg) was assessed using a Clark-type electrode (RCR: state 3 / state 4). As expected, PostC and CsA treatments improved CRC when compared to the C group. Control, PostC and CsA mitochondria exhibited a comparable significant dissipation of ΔΨ m , together with a comparable significant decrease of RCR in both SSM and IFM. In all three groups, this latter effect was related to a concomitant significant decrease in state 3 and to an increase in state 4 respiration. These data suggest that during the early minutes of reperfusion, postconditioning inhibits mPTP opening, independent of any specific modification of the oxidative phosphorylation or of ΔΨ m . Summarized data:

scholarly journals Morphine Postconditioning Protects Against Reperfusion Injury: the Role of Protein Kinase C-Epsilon, Extracellular Signal-Regulated Kinase 1/2 and Mitochondrial Permeability Transition Pores

2016 ◽  
Vol 39 (5) ◽  
pp. 1930-1940 ◽  
Author(s):  
Zuolei Chen ◽  
Donat R. Spahn ◽  
Xuewei Zhang ◽  
Yingzhi Liu ◽  
Haichen Chu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Protective Effects ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Extracellular Signal ◽  
Rat Hearts ◽  
Cyt C

Background/Aims: The purpose of this study was to investigate the implications of protein kinase C-epsilon (PKCε), Extracellular Signal-regulated Kinase 1/2 (ERK1/2) and mitochondrial permeability transition pore (mPTP) in myocardial protection induced by morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of eight groups. Hearts in time control (TC) group were constantly perfused for 105min. Hearts in ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. εV1-2 (an inhibitor of PKCε) and PD (an inhibitor of ERK1/2) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. I/R injury was assessed by functional parameters, creatine kinase-MB (CK-MB) release and infarct size (IS/AAR). Additional hearts were excised at 20 min following reperfusion to detect the membrane-specific translocation of PKCε, ERK1/2 phosphorylation, mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) release. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of εV1-2 or PD. Compared to TC group, the membrane translocation of PKCε, ERK1/2 phosphorylation, mPTP opening, and Cyt-c release were significantly increased in I/R hearts. MpostC further increased the membrane translocation of PKCε and ERK1/2 phosphorylation, and significantly inhibited mPTP opening and Cyt-c release. However, those protective effects induced by MpostC were abolished by εV1-2 or PD, which, used alone, showed no influence on reperfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against ischemia-reperfusion injury via activating PKCε-ERK1/2 pathway and inhibiting mPTP opening.

scholarly journals The Valosin-Containing Protein Protects the Heart Against Pathological Ca2+ Overload by Modulating Ca2+ Uptake Proteins

2019 ◽  
Vol 171 (2) ◽  
pp. 473-484 ◽  
Author(s):  
Shaunrick Stoll ◽  
Jing Xi ◽  
Ben Ma ◽  
Christiana Leimena ◽  
Erik J Behringer ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Mitochondrial Calcium ◽  
Mptp Opening ◽  
Mitochondrial Calcium Uptake

Abstract Stress-induced mitochondrial calcium (Ca2+) overload is a key cellular toxic effectors and a trigger of cardiomyocyte death during cardiac ischemic injury through the opening of mitochondrial permeability transition pore (mPTP). We previously found that the valosin-containing protein (VCP), an ATPase-associated protein, protects cardiomyocytes against stress-induced death and also inhibits mPTP opening in vitro. However, the underlying molecular mechanisms are not fully understood. Here, we tested our hypothesis that VCP acts as a novel regulator of mitochondrial Ca2+ uptake proteins and resists cardiac mitochondrial Ca2+ overload by modulating mitochondrial Ca2+ homeostasis. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the heart compared to the wild type (WT) mouse, we found that, under the pathological extra-mitochondrial Ca2+ overload, Ca2+ entry into cardiac mitochondria was reduced in VCP TG mice compared to their little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca2+ challenge. Mechanistically, overexpression of VCP in the heart resulted in post-translational protein degradation of the mitochondrial Ca2+ uptake protein 1, an activator of the mitochondria Ca2+ uniporter that is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca2+ homeostasis and unlock the potential mechanism by which VCP confers its cardioprotection.

scholarly journals RIPK3 Induces Cardiomyocyte Necroptosis via Inhibition of AMPK-Parkin-Mitophagy in Cardiac Remodelling after Myocardial Infarction

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Pingjun Zhu ◽  
Kun Wan ◽  
Ming Yin ◽  
Peng Hu ◽  
Yifan Que ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mitochondrial Permeability Transition ◽  
Critical Role ◽  
Permeability Transition ◽  
Cardiac Remodelling ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Genetic Ablation ◽  
Mptp Opening

Receptor-interacting protein 3- (RIPK3-) modulated necroptosis plays a critical role in cardiac remodelling after myocardial infarction (MI). However, the precise regulatory mechanism is not fully elucidated yet. In the present study, we showed that RIPK3 expression was upregulated in myocardial tissue after MI in a mouse model by coronary artery ligation, as well as in the cardiomyocytes following hypoxic injury in vitro. The increase of RIPK3 expression was found to be accompanied by severe cardiac remodelling, cardiac dysfunction, and higher mortality. Elevated RIPK3 expression subsequently abrogated the AMPK pathway that was accompanied by inhibition of Parkin-mediated mitophagy. Loss of mitophagy increased the opening of mitochondrial permeability transition pore (mPTP), which ultimately induced the cardiomyocyte necroptosis. In contrast, genetic ablation of Ripk3 induced the AMPK/Parkin-mitophagy pathway, favouring a prosurvival state that eventually inhibited mPTP opening and induced the necroptosis of cardiomyocytes in the post-MI cardiac remodelling. In conclusion, our results revealed a key mechanism by which necroptosis could be mediated by RIPK3 via the AMPK/Parkin-mitophagy/mPTP opening axis, which provides a potential therapeutic target in the management of heart failure after MI.

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.

Abstract 168: Resveratrol Translocates Gsk-3β To Mitochondria And Protects The Heart At Reperfusion By Targeting The Mitochondrial Permeability Transition Pore

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jinkun Xi ◽  
Huihua Wang ◽  
Guillaume Chanoit ◽  
Guang Cheng ◽  
Robert A Mueller ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Risk Zone ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

Although resveratrol has been demonstrated to be cardioprotective, the detailed cellular and molecular mechanisms that mediate the protection remain elusive. We aimed to determine if resveratrol protects the heart at reperfusion by modulating the mitochondrial permeability transition pore (mPTP) opening through glycogen synthase kinase 3β (GSK-3β). Resveratrol (10μM) given at reperfusion reduced infarct size (12.2 ± 2.5 % of risk zone vs. 37.9 ± 3.1 % of risk zone in control, n = 6) in isolated rat hearts subjected to 30 min regional ischemia followed by 2 h of reperfusion, an effect that was abrogated by the mPTP opener atractyloside (30.9 ± 8.1 % of risk zone), implying that resveratrol may protect the heart at reperfusion by modulating the mPTP opening. To define the signaling mechanism underlying the action of resveratrol, we determined GSK-3β activity by measuring its phosphorylation at Ser 9 . Resveratrol significantly enhanced GSK-3β phosphorylation upon reperfusion (225.2 ± 30.0 % of control at 5 min of reperfusion). Further experiments showed that resveratrol induces translocation of GSK-3β to mitochondria and translocated GSK-3β interacts with the mPTP component cyclophilin D but not VDAC (the voltage-dependent anion channel) or ANT (the adenine nucleotide translocator) in cardiac mitochondria. Taken together, these data suggest that resveratrol prevents myocardial reperfusion injury by targeting the mPTP opening via GSK-3β. Translocation of GSK-3β to mitochondria and its interaction with the mPTP component cyclophilin D may serve as an essential mechanism that mediates the protective effect of resveratrol on reperfusion injury.

Protectors of the mitochondrial permeability transition pore activated by iron and doxorubicin

2021 ◽  
Vol 21 ◽  
Author(s):  
Tatiana A. Fedotcheva ◽  
Nadezhda I. Fedotcheva
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Membrane Damage ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Selective Electrode ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mptp Opening ◽  
Dependent Cell

Aim: The study of action of iron, DOX, and their complex on the mitochondrial permeability transition pore (MPTP) opening and the detection of possible protectors of MPTP in the conditions close to mitochondria-dependent ferroptosis. Background: The toxicity of doxorubicin (DOX) is mainly associated with the free iron accumulation and mitochondrial dysfunction. DOX can provoke ferroptosis, iron-dependent cell death driven by the membrane damage. The mitochondrial permeability transition pore (MPTP) is considered as a common pathway leading to the development of apoptosis, necrosis, and, possibly, ferroptosis. The influence of DOX on the Ca2+ -induced opening of MPTP in the presence of iron has not yet been studied. Objective: The study was conducted on isolated liver and heart mitochondria. MPTP and succinate-ubiquinone oxidoreductase were studied as targets of DOX in mitochondria-dependent ferroptosis. Methods: The study was conducted on isolated mitochondria of the liver and heart. Changes of threshold calcium concentrations required for MPTP opening were measured by a Ca2+ selective electrode, mitochondrial membrane potential was registered by tetraphenylphosphonium (TPP+)-selective electrode, and mitochondrial swelling was recorded as a decrease in absorbance at 540 nm. The activity of succinate dehydrogenase (SDH) was determined by the reduction of the electron acceptor DCPIP. Conclusion: MPTP and the respiratory complex II are identified as the main targets of the iron-dependent action of DOX on the isolated mitochondria. All MPTP protectors tested abolished or weakened the effect of iron and a complex of iron with DOX on Ca2+ -induced MPTP opening, acting in different stages of MPTP activation. These data open new approaches to the modulation of the toxic influence of DOX on mitochondria with the aim to reduce their dysfunction

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