scholarly journals Melatonin as a Potential Multitherapeutic Agent

2021 ◽  
Vol 11 (4) ◽  
pp. 274
Author(s):  
Yulia Baburina ◽  
Alexey Lomovsky ◽  
Olga Krestinina
Keyword(s):  
Mitochondrial Dysfunction ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Chemotherapeutic Agents ◽  
The Body ◽  
Muscle Disorders ◽  
Beneficial Effects ◽  
Term Administration ◽  
Skeletal Muscle Disorders ◽  
Leukemia Data

Melatonin (N-acetyl-5-methoxytryptamine, MEL) is a hormone produced by the pineal gland that was discovered many years ago. The physiological roles of this hormone in the body are varied. The beneficial effects of MEL administration may be related to its influence on mitochondrial physiology. Mitochondrial dysfunction is considered an important factor in various physiological and pathological processes, such as the development of neurodegenerative and cardiovascular diseases, diabetes, various forms of liver disease, skeletal muscle disorders, and aging. Mitochondrial dysfunction induces an increase in the permeability of the inner membrane, which leads to the formation of a permeability transition pore (mPTP) in the mitochondria. The long-term administration of MEL has been shown to improve the functional state of mitochondria and inhibit the opening of the mPTP during aging. It is known that MEL is able to suppress the initiation, progression, angiogenesis, and metastasis of cancer as well as the sensitization of malignant cells to conventional chemotherapy and radiation therapy. This review summarizes the studies carried out by our group on the combined effect of MEL with chemotherapeutic agents (retinoic acid, cytarabine, and navitoclax) on the HL-60 cells used as a model of acute promyelocytic leukemia. Data on the effects of MEL on oxidative stress, aging, and heart failure are also reported.

scholarly journals Capsaicin Protects Cardiomyocytes against Anoxia/Reoxygenation Injury via Preventing Mitochondrial Dysfunction Mediated by SIRT1

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Huan He ◽  
Yue Zhou ◽  
Jiyi Huang ◽  
Zelong Wu ◽  
Zhangping Liao ◽  
...  
Keyword(s):  
Cell Viability ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Neonatal Rat ◽  
Protective Effects ◽  
Rat Cardiomyocytes ◽  
Beneficial Effects ◽  
Sirt1 Inhibitor

Capsaicin (Cap) has been reported to have beneficial effects on cardiovascular system, but the mechanisms underlying these effects are still poorly understood. Apoptosis has been shown to be involved in mitochondrial dysfunction, and upregulating expression of SIRT1 can inhibit the apoptosis of cardiomyocytes induced by anoxia/reoxygenation (A/R). Therefore, the aim of this study was to test whether the protective effects of Cap against the injury to the cardiomyocytes are mediated by SIRT1. The effects of Cap with or without coadministration of sirtinol, a SIRT1 inhibitor, on changes induced by A/R in the cell viability, activities of lactate dehydrogenase (LDH), creatine phosphokinase (CPK), levels of intracellular reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), related protein expression, mitochondrial permeability transition pore (mPTP) opening, and apoptosis rate in the primary neonatal rat cardiomyocytes were tested. Cap significantly increased the cell viability, upregulated expression of SIRT1 and Bcl-2, and decreased the LDH and CPK release, generation of ROS, loss of MMP, mPTP openness, activities of caspase-3, release of the cytochrome c, and apoptosis of the cardiomyocytes. Sirtinol significantly blocked the cardioprotective effects of Cap. The results suggest that the protective effects of Cap against A/R-induced injury to the cardiomyocytes are involved with SIRT1.

Abstract 3782: β2-Adrenergic Receptor Signaling Positively Modulates Pro-Survival Kinases and Ameliorates Mitochondrial Dysfunction during Doxorubicin Cardiotoxicity

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Giovanni Fajardo ◽  
Mingming Zhao ◽  
Gerald Berry ◽  
Daria Mochly-Rosen ◽  
Daniel Bernstein
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Surface Receptors ◽  
Β2 Adrenergic Receptor ◽  
Improvement In Survival ◽  
Complex I Activity

β2-adrenergic receptors (β2-ARs) modulate cardioprotection through crosstalk with multiple pathways. We have previously shown that β2-ARs are cardioprotective during acute exposure to Doxorubicin (DOX). DOX cardiotoxicity is mediated through a Ca 2+ -dependent opening of the mitochondrial permeability transition pore (MPT) and mitochondrial dysfunction, however the upstream signals linking cell surface receptors and the MPT are not clear. The purpose of this study was to assess crosstalk between β2-AR signaling and mitochondrial function in DOX toxicity. DOX 10 mg/kg was administered to β2−/− and WT mice. Whereas there was no mortality in WT, 85% of β2−/− mice died within 30 min (n=20). Pro- and anti-survival kinases were assessed by immunobloting. At baseline, β2−/− showed normal levels of ϵPKC, but a 16% increase in δPKC compared to WT (p<0.05). After DOX, β2−/− showed a 64% decrease in ϵPKC (p<0.01) and 22% increase in δPKC (p<0.01). The ϵPKC activator ΨϵRACK decreased mortality by 40% in β2−/− mice receiving DOX; there was no improvement in survival with the δPKC inhibitor δV1–1. After DOX, AKT activity was decreased by 76% (p<0.01) in β2−/− but not in WT. The α1-AR blocker prazosin, inhibiting signaling through Gαq, restored AKT activity and reduced DOX mortality by 47%. We next assessed the role of mitochondrial dysfunction in β2−/− mediated DOX toxicity. DOX treated β2−/− mice, but not WT, show marked vacuolization of mitochondrial cristae. Complex I activity decreased 31% in β2−/− mice with DOX; but not in WT. Baseline rate of Ca2+ release and peak [Ca2+]i ratio were increased 85% and 17% respectively in β2−/− myocytes compared to WT. Verapamil decreased mortality by 27% in DOX treated β2−/− mice. Cyclosporine, a blocker of both MPT and calcineurin, reduced DOX mortality to 50%. In contrast, FK506, a blocker of calcineurin but not the MPT, did not reduce DOX mortality. Cyclosporine prevented the decrease in AKT activity in β2−/− whereas FK506 did not. These findings suggest that β2-ARs modulate pro-survival kinases and attenuate mitochondrial dysfunction during DOX cardiotoxicity; absence of β2-ARs enhances DOX toxicity via negative regulation of survival kinases and enhancement of intracellular Ca2+, sensitizing mitochondria to opening of the MPT.

Calcium, ATP, and ROS: a mitochondrial love-hate triangle

2004 ◽  
Vol 287 (4) ◽  
pp. C817-C833 ◽  
Author(s):  
Paul S. Brookes ◽  
Yisang Yoon ◽  
James L. Robotham ◽  
M. W. Anders ◽  
Shey-Shing Sheu
Keyword(s):  
Mitochondrial Dysfunction ◽  
Molecular Mechanisms ◽  
Atp Synthesis ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Negative Effects ◽  
Cytochrome C Release ◽  
Cellular Energy ◽  
Atp Generation

The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels within the organelle to stimulate ATP synthesis. However, the dysregulation of mitochondrial Ca2+ homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca2+ overload can lead to enhanced generation of reactive oxygen species, triggering of the permeability transition pore, and cytochrome c release, leading to apoptosis. Despite progress regarding the independent roles of both Ca2+ and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca2+ can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca2+ and the signaling events that perturb this balance. Overall, a “two-hit” hypothesis is developed, in which Ca2+ plus another pathological stimulus can bring about mitochondrial dysfunction.

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.

scholarly journals Dexamethasone-Induced Mitochondrial Dysfunction and Insulin Resistance-Study in 3T3-L1 Adipocytes and Mitochondria Isolated from Mouse Liver

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1982 ◽  
Author(s):  
Guangxiang Luan ◽  
Gang Li ◽  
Xiao Ma ◽  
Youcai Jin ◽  
Na Hu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mouse Liver ◽  
Mitochondrial Permeability Transition ◽  
Atp Synthesis ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mtdna Copy Number ◽  
Mitochondrial Dynamic

Dexamethasone is a glucocorticoid analog, which is reported to induce insulin resistance and to exacerbate diabetic symptoms. In this study, we investigated the association between mitochondrial dysfunction and the pathophysiology of dexamethasone-induced insulin resistance. An insulin resistance model in 3T3-L1 adipocyte was established by 48-h treatment of 1 μM dexamethasone, followed with the detection of mitochondrial function. Results showed that dexamethasone impaired insulin-induced glucose uptake and caused mitochondrial dysfunction. Abnormality in mitochondrial function was supported by decreased intracellular ATP and mitochondrial membrane potential (MMP), increased intracellular and mitochondrial reactive oxygen species (ROS) and mtDNA damage. Mitochondrial dynamic changes and biogenesis were suggested by decreased Drp1, increased Mfn2, and decreased PGC-1, NRF1, and TFam, respectively. The mitochondrial DNA (mtDNA) copy number exhibited no change while the mitochondrial mass increased. In agreement, studies in isolated mitochondria from mouse liver also showed dexamethasone-induced reduction of mitochondrial respiratory function, as suggested by decreased mitochondrial respiration controlling rate (RCR), lower MMP, declined ATP synthesis, opening of the mitochondrial permeability transition pore (mPTP), damage of mtDNA, and the accumulation of ROS. In summary, our study suggests that mitochondrial dysfunction occurs along with dexamethasone-induced insulin resistance in 3T3 L1 adipocytes and might be a potential mechanism of dexamethasone-induced insulin resistance.

Mitochondrial Permeability Transition Pore Sealing Agents and Antioxidants Protect Oxidative Stress and Mitochondrial Dysfunction Induced by Naproxen, Diclofenac and Celecoxib

Drug Research ◽  
2019 ◽  
Vol 69 (11) ◽  
pp. 598-605 ◽  
Author(s):  
Ahmad Salimi ◽  
Mohammad Reza Neshat ◽  
Parvaneh Naserzadeh ◽  
Jalal Pourahmad
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Isolated Rat Heart ◽  
Atp Depletion ◽  
Mitochondrial Permeability ◽  
Pore Sealing ◽  
Increased Risk

AbstractNonsteroidal anti-inflammatory drugs (NSAIDs) like naproxen, diclofenac and celecoxib used to reduce pain. Many of these drugs have been associated with an increased risk of cardiovascular disease (CVD). The molecular mechanism(s) by which NSAIDs induce CVD up to now is unknown. We investigated the effects of naproxen, diclofenac and celecoxib with different structures and mechanism action on isolated rat heart mitochondria. All tested NSAIDs increased reactive oxygen species (ROS) formation, mitochondrial membrane collapse (MMP), mitochondrial swelling, lipid peroxidation, and glutathione and ATP depletion, which all of them play important roles in developing cardiotoxicity. We reported that mitochondrial permeability transition (MPT) pore sealing agents and antioxidants have the capacity to significantly prevent mitochondrial toxicity. Therefore, the inhibition of mitochondrial oxidative stress and mitochondrial dysfunction by MPT pore sealing agents and antioxidants can double confirm NSAID-induced cardiomyocytes toxicity is resulted from induction of apoptosis signaling trough ROS-mediated mitochondrial permeability transition.

scholarly journals Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 649
Author(s):  
Kun Jia ◽  
Heng Du
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Brain Aging ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Brain Disorders ◽  
Mitochondrial Permeability

Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction.

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