scholarly journals Corrigendum: Schisandrin B Antagonizes Cardiotoxicity Induced by Pirarubicin by Inhibiting Mitochondrial Permeability Transition Pore (mPTP) Opening and Decreasing Cardiomyocyte Apoptosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongwei Shi ◽  
Heng Tang ◽  
Wen Ai ◽  
Qingfu Zeng ◽  
Hong Yang ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cardiomyocyte Apoptosis ◽  
Schisandrin B ◽  
Mitochondrial Permeability ◽  
Mptp Opening

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

Abstract 321: Obesity Causes Enhanced Sensitivity Of The Mitochondrial Permeability Transition Pore

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Judith Bernal-Ramírez ◽  
Adriana Riojas-Hernández ◽  
Flor E Morales-Marroquín ◽  
Elvía M Domínguez-Barragán ◽  
David Rodríguez-Mier ◽  
...  
Keyword(s):  
Cell Death ◽  
Cardiac Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
H2o2 Production ◽  
Mitochondrial Permeability ◽  
Removal Capacity ◽  
Mptp Opening

Several mechanisms have been implicated in heart failure (HF) development due to obesity, including altered Ca2+ homeostasis and mitochondrial increased reactive oxygen species (ROS). Besides their metabolic role, mitochondria are important cell death regulators, since their disruption induces apoptosis. The mitochondrial permeability transition pore (MPTP) formation is key in this process. Ca2+ and ROS are known inducers of MPTP, and mitochondria are the main ROS generators. However, it has not been demonstrated that MPTP formation is involved in cardiac cell death due to obesity. Therefore, the aim of this work was to determine whether Ca2+ alterations and/or MPTP opening underlie cardiac dysfunction. We used obese Zucker fa/fa rats (32 weeks old), displaying concentric hypertrophy and cardiac dysfunction. We measured: i) Systolic and diastolic Ca2+ signaling in isolated myocytes, in basal conditions and upon β-adrenergic stimulation (β-AS), and ii) in vitro mitochondrial function: respiration, ROS production and MPTP opening. We found that the main alteration in Ca2+ signaling in fa/fa myocytes was a decrease in SERCA Ca2+ removal capacity, since Ca2+ transient amplitude and spark frequency were unchanged. Furthermore, in fa/fa myocytes, β-AS response was preserved. On the other hand, fa/fa mitochondria respiration, in state 3 decreased, but was unchanged in state 4, when glutamate/malate were used as substrate, resulting in an small decrease in respiratory control. In addition, fa/fa mitochondria were more sensitive to MPTP opening, induced by Ca2+ and carboxyatractiloside (CAT). Moreover, fa/fa mitochondria showed increased H2O2 production, and in exposed thiol groups in the adenine nucleotide translocase, a regulatory MPTP component. Since Ca2+ signaling is relatively normal in fa/fa cells, it does not seem to be the main contributor to the cardiac contractile dysfunction. However, given that fa/fa mitochondria showed decrease respiratory performance, were more susceptible to MPTP opening, and showed enhanced H2O2 production. We conclude that fa/fa mitochondria were more vulnerable to enhanced oxidative stress, causing MPTP opening, which could be exacerbated by SERCA slower Ca2+ removal capacity, leading to myocyte apoptosis.

Silencing of cardiac mitochondrial NHE1 prevents mitochondrial permeability transition pore opening

2011 ◽  
Vol 300 (4) ◽  
pp. H1237-H1251 ◽  
Author(s):  
María C. Villa-Abrille ◽  
Eugenio Cingolani ◽  
Horacio E. Cingolani ◽  
Bernardo V. Alvarez
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Heart Mitochondria ◽  
Rat Cardiomyocytes ◽  
Mitochondrial Permeability ◽  
Mptp Opening

Inhibition of Na+/H+ exchanger 1 (NHE1) reduces cardiac ischemia-reperfusion (I/R) injury and also cardiac hypertrophy and failure. Although the mechanisms underlying these NHE1-mediated effects suggest delay of mitochondrial permeability transition pore (MPTP) opening, and reduction of mitochondrial-derived superoxide production, the possibility of NHE1 blockade targeting mitochondria has been incompletely explored. A short-hairpin RNA sequence mediating specific knock down of NHE1 expression was incorporated into a lentiviral vector (shRNA-NHE1) and transduced in the rat myocardium. NHE1 expression of mitochondrial lysates revealed that shRNA-NHE1 transductions reduced mitochondrial NHE1 (mNHE1) by ∼60%, supporting the expression of NHE1 in mitochondria membranes. Electron microscopy studies corroborate the presence of NHE1 in heart mitochondria. Immunostaining of rat cardiomyocytes also suggests colocalization of NHE1 with the mitochondrial marker cytochrome c oxidase. To examine the functional role of mNHE1, mitochondrial suspensions were exposed to increasing concentrations of CaCl2 to induce MPTP opening and consequently mitochondrial swelling. shRNA-NHE1 transduction reduced CaCl2-induced mitochondrial swelling by 64 ± 4%. Whereas the NHE1 inhibitor HOE-642 (10 μM) decreased mitochondrial Ca2+-induced swelling in rats transduced with nonsilencing RNAi (37 ± 6%), no additional HOE-642 effects were detected in mitochondria from rats transduced with shRNA-NHE1. We have characterized the expression and function of NHE1 in rat heart mitochondria. Because mitochondria from rats injected with shRNA-NHE1 present a high threshold for MPTP formation, the beneficial effects of NHE1 inhibition in I/R resulting from mitochondrial targeting should be considered.

scholarly journals SPG7 targets the m-AAA protease complex to process MCU for uniporter assembly, Ca2+ influx, and regulation of mitochondrial permeability transition pore opening

2019 ◽  
Vol 294 (28) ◽  
pp. 10807-10818 ◽  
Author(s):  
Stephen Hurst ◽  
Ariele Baggett ◽  
Gyorgy Csordas ◽  
Shey-Shing Sheu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cyclophilin D ◽  
Spastic Paraplegia ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Permeability Transition Pore Opening ◽  
Pore Opening

The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca2+-induced mPTP opening. However, this occurs independently of cyclophilin D (cyclosporine A insensitive) rather it is through decreased mitochondrial Ca2+ concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca2+ uniporter complexes. We found that SPG7 directs the m-AAA complex to favor association with the mitochondrial Ca2+ uniporter (MCU) and MCU processing regulates higher order MCU-complex formation. The results suggest that SPG7 does not constitute a core component of the mPTP but can modulate mPTP through regulation of the basal mitochondrial Ca2+ concentration.

Cardioprotection of the aged rat heart by GSK-3β inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation

2011 ◽  
Vol 300 (3) ◽  
pp. H922-H930 ◽  
Author(s):  
Jiang Zhu ◽  
Mario J. Rebecchi ◽  
Peter S. A. Glass ◽  
Peter R. Brink ◽  
Lixin Liu
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Male Rats ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Gsk 3Β

It is well established that inhibition of glycogen synthase kinase (GSK)-3β in the young adult myocardium protects against ischemia-reperfusion (I/R) injury through inhibition of mitochondrial permeability transition pore (mPTP) opening. Here, we investigated age-associated differences in the ability of GSK-3β inhibitor [SB-216763 (SB)] to protect the heart and to modulate mPTP opening during I/R injury. Fischer 344 male rats were assigned from their respective young or old age groups. Animals were subjected to 30 min ischemia following 120 min reperfusion to determine myocardial infarction (MI) size in vivo. Ischemic tissues were collected 10 min after reperfusion for nicotinamide adenine dinucleotide (NAD+) measurements and immunoblotting. In parallel experiments, ventricular myocytes isolated from young or old rats were exposed to oxidative stress through generation of reactive oxygen species (ROS), and mPTP opening times were measured by using confocal microscopy. Our results showed that SB decreased MI in young SB-treated rats compared with young untreated I/R animals, whereas SB failed to significantly affect MI in the old animals. SB also significantly increased GSK-3β phosphorylation in young rats, but phosphorylation levels were already highly elevated in old control groups. There were no significant differences observed between SB-treated and untreated old animals. NAD+levels were better maintained in young SB-treated animals compared with the young untreated group during I/R, but this relative improvement was not observed in old animals. SB also significantly prolonged the time to mPTP opening induced by ROS in young cardiomyocytes, but not in aged cardiomyocytes. These results demonstrate that this GSK-3β inhibitor fails to protect the aged myocardium in response to I/R injury or prevent mPTP opening following a rise in ROS and suggest that healthy aging alters mPTP regulation by GSK-3β.

Abstract P234: S-nitrosylation of Cyclophilin D Attenuates Mitochondrial Permeability Transition Pore Opening: A Critical Role for Cysteine 203 Residue

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Tiffany T Nguyen ◽  
Mark V Stevens ◽  
Mark J Kohr ◽  
Charles Steenbergen ◽  
Michael N Sack ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Protective Role ◽  
Nitric Oxide Donor ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Mptp Opening

S-nitrosylation (SNO), a reversible, redox-dependent post-translational modification, has emerged as an important mechanism for dynamic regulation of many proteins. Our previous studies have shown that protein S-nitrosylation (SNO) plays a protective role in myocardial ischemia/reperfusion (IR) injury. The primary mediator of cell death in I/R injury is activation of the mitochondrial permeability transition pore (mPTP). Using a proteomic approach, we have previously found that cyclophilin D (CypD), a critical mPTP regulator, can be SNO on cysteine 203 (C203). To investigate whether SNO of CypD might attenuate mPTP activation, we mutated cysteine 203 of CypD, to a serine residue (C203S) and determined its effects on mPTP opening by assessing H 2 O 2 -induced mPTP opening using the calcein AM-cobalt chloride quenching method. Treatment of CypD -/- mouse embryonic fibroblasts (MEFs) with H 2 O 2 resulted loss in an ≈50 % loss of mPTP opening as compared to WT MEFs (n=5, p<0.05), consistent with the protective role of CypD in mPTP activation. Addition of a nitric oxide donor, GSNO, to CypD -/- MEFs did not further reduce mPTP opening; however, WT MEFs treated GSNO attenuated mPTP opening by half. To elucidate the role of SNO of C203 on CypD, we infected CypD -/- MEFs with a C203S-CypD vector. C203S-CypD re-constituted MEFs were also resistant to mPTP opening in the presence or absence of GSNO. This suggests that C203 is required for mPTP activation. To determine whether in vivo expression of C203S-CypD would alter mPTP opening, we generated adenovirus vectors encoding WT CypD or mutated C203S-CypD and injected these viral particles into CypD -/- mice via tail-vein. Mitochondria isolated from livers of CypD -/- mice or mice expressing C203S-CypD were resistant to Ca 2+ -induced swelling as compared to WT CypD reconstituted mice. In summary, our results indicate that C203 of CypD is required for mPTP opening and for the first time shows that SNO of C203 on CypD acts to attenuate mPTP activation.

Abstract 342: Increased Mitochondrial Permeability Transition Pore Opening Dominates Ischemia-Reperfusion Injury in the Aged Female Rat Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Alexandra M Machikas ◽  
James C Hunter ◽  
Veronica Lopez ◽  
Donna H Korzick
Keyword(s):  
Cell Death ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Mptp Opening ◽  
Menopausal Women ◽  
Post Menopausal

Background: Cardiovascular disease remains the leading cause of death in older post-menopausal women. Ischemia/Reperfusion (I/R) injury triggers mitochondrial calcium (Ca 2+ ) overload inducing mitochondrial permeability transition pore (MPTP) opening, mitochondrial dysfunction, and cell death potentially by necrosis, apoptosis, and/or autophagy. Purpose: We sought to determine if age-associated estrogen deficiency increases mitochondrial Ca 2+ sensitivity, providing a possible mechanism for increased vulnerability to I/R injury in older women. Methods: Mitochondrial respiration (MR) was assessed in isolated mitochondria from ventricles of adult (6 mo; n=15) and aged (24 mo; n=18) ovary-intact or ovariectomized (OVX) female F344 rats. MR at complexes I and II was compared in the absence (State 2) and presence (State 3) of ADP to calculate respiratory control index (RCI; state3/state 2). Reduced RCI following Ca 2+ addition was used to assess Ca 2+ sensitivity, while mitochondrial Ca 2+ retention capacity was measured to quantify MPTP opening (CRC; n=4-5/group) prior to and following coronary artery ligation (55 min I and 6 hr R). Apoptosis was examined using DNA laddering and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Markers of autophagy were evaluated by western blotting and mitochondrial morphology through electron microscopy (EM). Results: Significant age-dependent decreases in RCI for complex I (12%) and complex II (8%) were observed in the absence of Ca 2+ , and correlated with increased necrosis in aged hearts revealed by triphenyltetrazolium chloride (TTC) staining (p < 0.05). Ca 2+ exposure decreased MR (18-30%; p < 0.05) in Complex I of aged and OVX mitochondria vs adults. Furthermore, CRC worsened with age requiring less Ca 2+ to open the MPTP. Reduced DNA laddering and TUNEL staining combined with increased beclin-1 and cathepsinD expression in aged vs. adult further support a dominant role for necrosis over apoptosis underlying cell death in aged females (n=4-5/group). EM revealed morphological alterations with age and OVX. Conclusion: Decreased MR and increased MPTP opening with aging are likely causal in necrotic cell death mechanisms associated with I/R injury observed in post-menopausal women.

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