Gallic acid inhibits celecoxib-induced mitochondrial permeability transition and reduces its toxicity in isolated cardiomyocytes and mitochondria

2021 ◽  
pp. 096032712110532
Author(s):  
A Salimi ◽  
S Atashbar ◽  
M Shabani
Keyword(s):  
Lipid Peroxidation ◽  
Mitochondrial Dysfunction ◽  
Gallic Acid ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Mitochondrial Toxicity ◽  
Isolated Cardiomyocytes ◽  
Mitochondrial Permeability ◽  
Ros Formation

Background: Mitochondria are the main target organelles through which drugs and chemicals exert their toxic effect on cardiomyocytes. The mitochondria-related mechanisms of celecoxib-induced cardiotoxicity have been extensively studied. Accumulated evidence shows natural molecules targeting mitochondria have proven to be effective in preventing cardiotoxicity. Purpose: In the present study, we examined the ameliorative effect of gallic acid (GA) against celecoxib-induced cellular and mitochondrial toxicity in isolated cardiomyocytes and mitochondria. Research Design: The isolated cardiomyocytes and mitochondria were divided into various group, namely, control, celecoxib, celecoxib + GA (10, 50, and 100 µM). Several cellular and mitochondrial parameters such as cell viability, lipid peroxidation, succinate dehydrogenase (SDH) activity, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, and mitochondrial swelling were assessed in isolated cardiomyocytes and mitochondria. Results: Our results showed that administration of celecoxib (16 µg/ml) induced cytotoxicity and mitochondrial dysfunction at 6 h and 1 h, respectively, which is associated with lipid peroxidation intact cardiomyocytes, mitochondrial ROS formation, MMP collapse, and mitochondrial swelling. The cardiomyocytes and mitochondria treated with celecoxib + GA (10, 50, and 100 µM) significantly and dose-dependently restore the altered levels of cellular and mitochondrial parameters. Conclusions: We concluded that GA through antioxidant potential and inhibition of mitochondrial permeability transition (MPT) pore exerted ameliorative role in celecoxib-induced toxicity in isolated cardiomyocytes and mitochondria. The data of the current study suggested that GA supplementation may reduce celecoxib-induced cellular and mitochondrial toxicity during exposure and may provide a potential prophylactic and defensive candidate for coxibs-induced mitochondrial dysfunction, oxidative stress, and cardiotoxicity.

scholarly journals Antioxidant Potential and Inhibition of Mitochondrial Permeability Transition Pore by Myricetin Reduces Aluminium Phosphide-Induced Cytotoxicity and Mitochondrial Impairments

2021 ◽  
Vol 12 ◽  
Author(s):  
Ahmad Salimi ◽  
Zhaleh Jamali ◽  
Mohammad Shabani
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Caspase 3 ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Atp Depletion ◽  
Antioxidant Potential ◽  
Protective Agent ◽  
Isolated Cardiomyocytes ◽  
Mitochondrial Permeability

Oxidative stress and mitochondrial dysfunction are involved in the mechanisms of cardiac toxicity induced by aluminum phosphide (AlP). AlP-induced cardiotoxicity leads to cardiomyocyte death, cardiomyopathy, cardiac dysfunction, and eventually severe heart failure and death. Importantly, protecting cardiomyocytes from death resulting from AlP is vital for improving survival. It has been reported that flavonoids such as myricetin (Myr) act as modifiers of mitochondrial function and prevent mitochondrial damage resulting from many insults and subsequent cell dysfunction. In this study, the ameliorative effect of Myr, as an important antioxidant and mitochondrial protective agent, was investigated in cardiomyocytes and mitochondria isolated from rat heart against AlP-induced toxicity, oxidative stress, and mitochondrial dysfunction. Treatment of AlP (20 μg/ml) significantly increased cytotoxicity; reduced glutathione (GSH) depletion, cellular reactive oxygen species (ROS) formation, malondialdehyde (MDA) level, ATP depletion, caspase-3 activation, mitochondrial membrane potential (ΔΨm) collapse, and lysosomal dysfunction; and decreased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in intact cardiomyocytes. Also, treatment of AlP (20 μg/ml) significantly increased mitochondrial dysfunction and swelling in isolated mitochondria. Myr (80 µM) appeared to ameliorate AlP-induced cytotoxicity in isolated cardiomyocytes; significantly lessened the AlP-stimulated intracellular ROS and MDA production and depletion of GSH; and increased the activities of SOD, CAT, and GSH-Px. Furthermore, Myr (40 and 80 µM) lowered AlP-induced lysosomal/mitochondrial dysfunction, ATP depletion, and caspase-3 activation. In the light of these findings, we concluded that Myr through antioxidant potential and inhibition of mitochondrial permeability transition (MPT) pore exerted an ameliorative role in AlP-induced toxicity in isolated cardiomyocytes and mitochondria, and it would be valuable to examine its in vivo effects.

scholarly journals Mitochondrial toxicity induced by a thiourea gold(i) complex: mitochondrial permeability transition and respiratory deficit

2018 ◽  
Vol 7 (6) ◽  
pp. 1081-1090 ◽  
Author(s):  
Bingqiong Yu ◽  
Long Ma ◽  
Jiancheng Jin ◽  
Fenglei Jiang ◽  
Gangcheng Zhou ◽  
...  
Keyword(s):  
Antitumor Agents ◽  
Mitochondrial Permeability Transition ◽  
Biological Activities ◽  
Permeability Transition ◽  
Mitochondrial Toxicity ◽  
Mitochondrial Permeability

Gold(i) complexes have been widely used as antibacterial and antitumor agents for their excellent biological activities.

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 The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Costanza Savino ◽  
PierGiuseppe Pelicci ◽  
Marco Giorgio
Keyword(s):  
Oxidative Stress ◽  
Knockout Mice ◽  
Mitochondrial Permeability Transition ◽  
Neuronal Damage ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Cyclophilin D ◽  
Knock Out ◽  
Mitochondrial Permeability

Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT) and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D), a key regulatory component of the PT pore (PTP) that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE) experiments in p66Shc knockout mice (p66Shc−/−), knock out mice for cyclophilin-D (Cyc-D−/−), and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/−) mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

scholarly journals Tissue Specific Sensitivity of Mitochondrial Permeability Transition Pore to Ca2+ Ions

2009 ◽  
Vol 52 (2) ◽  
pp. 69-72 ◽  
Author(s):  
René Endlicher ◽  
Pavla Křiváková ◽  
Halka Lotková ◽  
Marie Milerová ◽  
Zdeněk Drahota ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Heart Mitochondria ◽  
Cell Protection ◽  
Tissue Specific ◽  
Mitochondrial Permeability

Ca2+-induced opening of the mitochondrial permeability transition pore (MPTP) is involved in induction of apoptotic and necrotic processes. We studied sensitivity of MPTP to calcium using the model of Ca2+-induced, cyclosporine A-sensitive mitochondrial swelling. Presented data indicate that the extent of mitochondrial swelling (dA520/4 min) induced by addition of 25 μM Ca2+ is seven-fold higher in liver than in heart mitochondria (0.564 ± 0.08/0.077± 0.01). The extent of swelling induced by 100 μM Ca2+ was in liver tree times higher than in heart mitochondria (0.508±0.05/ 0.173±0.02). Cyclosporine A sensitivity showed that opening of the MPTP is involved. We may thus conclude that especially at low Ca2+ concentration heart mitochondria are more resistant to damaging effect of Ca2+ than liver mitochondria. These finding thus support hypothesis that there exist tissue specific strategies of cell protection against induction of the apoptotic and necrotic processes.

scholarly journals The mitochondrial permeability transition phenomenon elucidated by cryo-EM reveals the genuine impact of calcium overload on mitochondrial structure and function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jasiel O. Strubbe-Rivera ◽  
Jason R. Schrad ◽  
Evgeny V. Pavlov ◽  
James F. Conway ◽  
Kristin N. Parent ◽  
...  
Keyword(s):  
Calcium Phosphate ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Structure And Function ◽  
Calcium Overload ◽  
Mitochondrial Permeability ◽  
Mitochondrial Structure ◽  
And Function ◽  
The Impact

AbstractMitochondria have a remarkable ability to uptake and store massive amounts of calcium. However, the consequences of massive calcium accumulation remain enigmatic. In the present study, we analyzed a series of time-course experiments to identify the sequence of events that occur in a population of guinea pig cardiac mitochondria exposed to excessive calcium overload that cause mitochondrial permeability transition (MPT). By analyzing coincident structural and functional data, we determined that excessive calcium overload is associated with large calcium phosphate granules and inner membrane fragmentation, which explains the extent of mitochondrial dysfunction. This data also reveals a novel mechanism for cyclosporin A, an inhibitor of MPT, in which it preserves cristae despite the presence of massive calcium phosphate granules in the matrix. Overall, these findings establish a mechanism of calcium-induced mitochondrial dysfunction and the impact of calcium regulation on mitochondrial structure and function.

Abstract 1783: Pro-Apoptotic Bnip3 Mediates Permeabilization of Mitochondria and Release of Cytocrome c via a Novel Mechanism

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Melissa N Quinsay ◽  
Shivaji Rikka ◽  
M Richard Sayen ◽  
Jeffery D Molkentin ◽  
Roberta A Gottlieb ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Dysfunction ◽  
Matrix Protein ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Heart Association ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Cyclophilin D ◽  
The Matrix

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. The pro-apoptotic Bcl-2 proteins mediate mitochondrial dysfunction independent of the mitochondrial permeability transition pore (mPTP). However, Bnip3 has been reported to mediate cell death via the mPTP. In this study, we investigated the mechanism(s) by which Bnip3 causes mitochondrial dysfunction. Using a mitochondrial swelling assay to assess pore opening, we found that addition of 200 microM Ca2+ to mitochondria isolated from rat hearts induced rapid swelling of mitochondria and release of cytochrome c (cyto c). Bnip3 also induced mitochondrial swelling and cyto c release, but always at a slower rate and to a greater degree, suggesting that Bnip3 mediates swelling via a different mechanism. Cyclosporin A (CsA), an inhibitor of mPTP opening, prevented Ca2+-induced swelling and cyto c release, but had no effect on Bnip3. Another BH3-only protein, tBid, caused release of cyto c but failed to induce swelling of mitochondria. Interestingly, Bnip3, but not Ca2+ and tBid, induced release of the matrix protein MnSOD. Cyclophilin D (cycD) is an essential component of the mPTP and heart mitochondria isolated from cycD−/− mice were resistant to Ca2+-, but not to Bnip3-induced swelling and cyto c release. Also, tBid caused cyto c release without mitochondrial swelling in the absence of cycD. To further explore the mPTP as a downstream effector of Bnip3-mediated cell death, we assessed cell death in mouse embryonic fibroblasts (MEFs) isolated from wild type (wt) and cycD−/− mice. Infection with an adenovirus expressing Bnip3 caused significant cell death in wt (52.8±1.8%) and cycD−/− (61.8±6.1%) MEFs as measured by LDH release. In addition, both Bnip3 and opening of the mPTP have been reported to initiate upregulation of autophagy. Monitoring of GFP-LC3 incorporation into autophagosomes by fluorescence microscopy revealed that Bnip3 infection induced autophagy in wt (86.5±6.6%) and cycD−/− (96.4±1.4%) MEFs (n=3, p<0.05). Thus, these studies suggest that Bnip3 mediates permeabilization of the inner and outer mitochondrial membranes via a novel mechanism that is different from other BH3-only proteins. This research has received full or partial funding support from the American Heart Association, AHA National Center.

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