scholarly journals Melatonin in Mitochondrial Dysfunction and Related Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Venkatramanujam Srinivasan ◽  
D. Warren Spence ◽  
Seithikurippu R. Pandi-Perumal ◽  
Gregory M. Brown ◽  
Daniel P. Cardinali
Keyword(s):  
Septic Shock ◽  
Electron Transport ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Nitrosative Stress ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
No Production ◽  
Lethal Effects ◽  
Respiratory Complex

Mitochondrial dysfunction is considered one of the major causative factors in the aging process, ischemia/reperfusion (I/R), septic shock, and neurodegenerative disorders like Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Increased free radical generation, enhanced mitochondrial inducible nitric oxide (NO) synthase activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pore all have been suggested as factors responsible for impaired mitochondrial function. Melatonin, the major hormone of the pineal gland, also acts as an antioxidant and as a regulator of mitochondrial bioenergetic function. Both in vitro and in vivo, melatonin was effective for preventing oxidative stress/nitrosative stress-induced mitochondrial dysfunction seen in experimental models of PD, AD, and HD. In addition, melatonin is known to retard aging and to inhibit the lethal effects of septic shock or I/R lesions by maintaining respiratory complex activities, electron transport chain, and ATP production in mitochondria. Melatonin is selectively taken up by mitochondrial membranes, a function not shared by other antioxidants. Melatonin has thus emerged as a major potential therapeutic tool for treating neurodegenerative disorders such as PD or AD, and for preventing the lethal effects of septic shock or I/R.

scholarly journals Age-Dependent Myocardial Dysfunction in Critically Ill Patients: Role of Mitochondrial Dysfunction

2019 ◽  
Vol 20 (14) ◽  
pp. 3523 ◽  
Author(s):  
Andrew J. Lautz ◽  
Basilia Zingarelli
Keyword(s):  
Septic Shock ◽  
Cardiac Arrest ◽  
Mitochondrial Dysfunction ◽  
Nitrosative Stress ◽  
Mitochondrial Permeability Transition ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Systolic Dysfunction ◽  
Future Research ◽  
Age Dependent

Myocardial dysfunction is common in septic shock and post-cardiac arrest but manifests differently in pediatric and adult patients. By conventional echocardiographic parameters, biventricular systolic dysfunction is more prevalent in children with septic shock, though strain imaging reveals that myocardial injury may be more common in adults than previously thought. In contrast, diastolic dysfunction in general and post-arrest myocardial systolic dysfunction appear to be more widespread in the adult population. A growing body of evidence suggests that mitochondrial dysfunction mediates myocardial depression in critical illness; alterations in mitochondrial electron transport system function, bioenergetic production, oxidative and nitrosative stress, uncoupling, mitochondrial permeability transition, fusion, fission, biogenesis, and autophagy all may play key pathophysiologic roles. In this review we summarize the epidemiologic and clinical phenotypes of myocardial dysfunction in septic shock and post-cardiac arrest and the multifaceted manifestations of mitochondrial injury in these disease processes. Since neonatal and pediatric-specific data for mitochondrial dysfunction remain sparse, conclusive age-dependent differences are not clear; instead, we highlight what evidence exists and identify gaps in knowledge to guide future research. Finally, since focal ischemic injury (with or without reperfusion) leading to myocardial infarction is predominantly an atherosclerotic disease of the elderly, this review focuses specifically on septic shock and global ischemia-reperfusion injury occurring after resuscitation from cardiac arrest.

Abstract P281: Bcl-2 Limits Ischemia-Reperfusion Injury of the Naive Myocardium by Preserving Mitochondrial Integrity and Respiratory Complex Functionality and Is Modulated by PKCε

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
David A Liem ◽  
Jun Zhang ◽  
Christopher Lotz ◽  
Ding Wang ◽  
Peipei Ping
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Mass Spectrometry Analysis ◽  
Myocardial Infarct Size ◽  
Cardiac Mitochondria ◽  
Respiratory Complex ◽  
Mitochondrial Respiratory Complex ◽  
Increased Susceptibility ◽  
Mitochondrial Respiratory

Over-expression of Bcl-2 protects against myocardial ischemia/reperfusion (I/R) injury. Nevertheless, the participation of Bcl-2 in basal myocardium, and its subcellular targets under such conditions, remains elusive. Using a mouse line with an ablation of the Bcl-2 gene, we found that myocardial infarct size (IS) was exacerbated vs. wild type (WT) mice, demonstrating that Bcl-2 limit IS in basal I/R injury. The exacerbated IS in Bcl-2 KO was abolished by in vivo treatment with the selective Mitochondrial Permeability Transition (MPT) inhibitor cyclosporine A (10 mg/kg, iv) , while isolated cardiac mitochondria from Bcl-2 null mice exhibited increased matrix swelling in response to CaCl 2 , showing an increased susceptibility to MPT. However, recombinant Bcl-2 or PKCε were both sufficient to attenuate the increased susceptibility to MPT. Interestingly, spectrophotometric analysis of baseline activities of Mitochondrial Electron Transport Chain Complexes (ETC) I and V (but not of ETC II, III and IV), were increased in cardiac mitochondria from Bcl-2 null mice as compared to mitochondria from normal WT mice, demonstrating an altered mitochondrial respiratory complex functionality. In addition, immunoprecipitation with PKCε in AE-PKCε mouse hearts (i.e. mice with an increased activity of PKCε) followed by immunoblotting for Bcl-2, showed an 2-fold increased interaction between PKCε and Bcl-2. Similarly, immunoprecipitation with Phospho-Serine followed by immunoblotting for Bcl-2 indicated a 2-fold increased Serine residue phosphorylation of Bcl-2. Mass spectrometry analysis further showed that PKCε can phosporylate Bcl-2 at its Serine24 residue site in vitro, indicating that PKCε can directly interact and phosphorylate Bcl-2. These data suggest that Bcl-2 is pivotal in limiting IS in basal I/R injury by counteracting MPT and preserving mitochondrial respiratory complex functionality, and implicate a direct interaction and phosphorylation of Bcl-2 by PKCε in this process.

scholarly journals Mitochondrial Dysfunction and Permeability Transition in Neonatal Brain and Lung Injuries

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 569
Author(s):  
Vadim S. Ten ◽  
Anna A. Stepanova ◽  
Veniamin Ratner ◽  
Maria Neginskaya ◽  
Zoya Niatsetskaya ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
White Matter Injury ◽  
Proton Leak ◽  
Acute Ischemia ◽  
Supporting Evidence ◽  
Neonatal Brain ◽  
Lung Injuries

This review discusses the potential mechanistic role of abnormally elevated mitochondrial proton leak and mitochondrial bioenergetic dysfunction in the pathogenesis of neonatal brain and lung injuries associated with premature birth. Providing supporting evidence, we hypothesized that mitochondrial dysfunction contributes to postnatal alveolar developmental arrest in bronchopulmonary dysplasia (BPD) and cerebral myelination failure in diffuse white matter injury (WMI). This review also analyzes data on mitochondrial dysfunction triggered by activation of mitochondrial permeability transition pore(s) (mPTP) during the evolution of perinatal hypoxic-ischemic encephalopathy. While the still cryptic molecular identity of mPTP continues to be a subject for extensive basic science research efforts, the translational significance of mitochondrial proton leak received less scientific attention, especially in diseases of the developing organs. This review is focused on the potential mechanistic relevance of mPTP and mitochondrial dysfunction to neonatal diseases driven by developmental failure of organ maturation or by acute ischemia-reperfusion insult during development.

scholarly journals Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: implications for pharmacological cardioprotection

2018 ◽  
Vol 315 (5) ◽  
pp. H1341-H1352 ◽  
Author(s):  
Giuseppe Paradies ◽  
Valeria Paradies ◽  
Francesca Maria Ruggiero ◽  
Giuseppe Petrosillo
Keyword(s):  
Myocardial Ischemia ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Morphology ◽  
Myocardial Ischemia Reperfusion

Mitochondrial dysfunction plays a central role in myocardial ischemia-reperfusion (I/R) injury. Increased reactive oxygen species production, impaired electron transport chain activity, aberrant mitochondrial dynamics, Ca2+ overload, and opening of the mitochondrial permeability transition pore have been proposed as major contributory factors to mitochondrial dysfunction during myocardial I/R injury. Cardiolipin (CL), a mitochondria-specific phospholipid, plays a pivotal role in multiple mitochondrial bioenergetic processes, including respiration and energy conversion, in mitochondrial morphology and dynamics as well as in several steps of the apoptotic process. Changes in CL levels, species composition, and degree of oxidation may have deleterious consequences for mitochondrial function with important implications in a variety of pathophysiological conditions, including myocardial I/R injury. In this review, we focus on the role played by CL alterations in mitochondrial dysfunction in myocardial I/R injury. Pharmacological strategies to prevent myocardial injury during I/R targeting mitochondrial CL are also examined.

scholarly journals Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 176 ◽  
Author(s):  
George A. Porter ◽  
Gisela Beutner
Keyword(s):  
Electron Transport ◽  
Mitochondrial Function ◽  
Electron Transport Chain ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Cyclophilin D ◽  
Master Regulator ◽  
Transport Chain

Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but more recent evidence suggests that it may regulate electron transport chain activity. Given its identification as a peptidyl-prolyl, cis-trans isomerase (PPIase), CyPD, is thought to be involved in mitochondrial protein folding, but very few reports demonstrate the presence of this activity. By contrast, CyPD may also perform a scaffolding function, as it binds to a number of important proteins in the mitochondrial matrix and inner mitochondrial membrane. From a clinical perspective, inhibiting CyPD to inhibit PTP opening protects against ischemia–reperfusion injury, making modulation of CyPD activity a potentially important therapeutic goal, but the lack of knowledge about the mechanisms of CyPD’s actions remains problematic for such therapies. Thus, the important yet enigmatic nature of CyPD somehow makes it a master regulator, yet a troublemaker, for mitochondrial function.

Abstract 1904: Myocardial Postconditioning Against Ischemia and Reperfusion Injury by Near Infrared Electromagnetic Radiation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Phillip F Pratt ◽  
Martin Bienengraeber ◽  
Dorothee Weihrauch ◽  
Judy R Kersten ◽  
David C Warltier
Keyword(s):  
Infarct Size ◽  
Electromagnetic Radiation ◽  
Reperfusion Injury ◽  
Near Infrared ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
No Production ◽  
Ischemia And Reperfusion ◽  
Early Reperfusion

Near-infrared electromagnetic radiation (NIR) has been reported to stimulate biochemical processes within cells and tissue, but whether NIR is capable of acutely protecting myocardium against ischemia+reperfusion injury in vivo is unknown. We tested the hypothesis that NIR (670 nm, 30 nm bandwith, 50 mW/cm 2 ) exposure immediately before and during early reperfusion protects rabbit myocardium against infarction that is dependent upon reactive oxygen species (ROS), nitric oxide synthase (NOS), mitochondrial K ATP (mito K ATP ) channels and inhibition of mitochondrial permeability transition pore (mPTP) opening. Rabbits subjected to a 30 min left anterior descending coronary artery occlusion and reperfusion received no irradiation (control) or continuous NIR (beginning 3 min before and ending 7 min after reperfusion) in the presence or absence of ROS scavengers [N-acetylcysteine (NAC; 150 mg/kg), or tempol (30 mg/kg)], nonselective NOS inhibitor L-nitro-arginine methyl ester (L-NAME; 10 mg/kg), selective mitoK ATP channel antagonist 5-hydroxydecanoate (5-HD; 10 mg/kg) or mPTP opener atractyloside (5 mg/kg). Dihydroethidium and diaminofluroscein immunofluorescence were used to detect ROS and NO production, respectively, in additional rabbits with or without NIR exposure. NIR reduced infarct size (24±4% of the area at risk; triphenyltetrazolium chloride staining) compared with control (46±3%). NAC, tempol, L-NAME, 5-HD, and atractyloside alone did not affect infarct size, but these drugs abolished the cardioprotective effect of NIR. NIR increased ROS production independent of ischemia and reperfusion, and this effect was blocked by NAC. NIR also enhanced NO generation during early reperfusion. In addition, NIR increased ATP synthesis in isolated rabbit mitochondria. Thus, NIR postconditions myocardium against infarction concomitant with ROS and NO production. MitoK ATP channels and mPTP mediate cardioprotection by NIR.

scholarly journals Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene: A Focus on the Nervous System

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 546
Author(s):  
Hammad Ullah ◽  
Alessandro Di Minno ◽  
Cristina Santarcangelo ◽  
Haroon Khan ◽  
Maria Daglia
Keyword(s):  
Oxidative Stress ◽  
Electron Transport ◽  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorders ◽  
Cannabinoid Receptor ◽  
Neuronal Loss ◽  
Food Plants ◽  
Active Principle ◽  
Atp Production ◽  
Anticancer Properties

Mitochondrial dysfunction results in a series of defective cellular events, including decreased adenosine triphosphate (ATP) production, enhanced reactive oxygen species (ROS) output, and altered proteastasis and cellular quality control. An enhanced output of ROS may damage mitochondrial components, such as mitochondrial DNA and elements of the electron transport chain, resulting in the loss of proper electrochemical gradient across the mitochondrial inner membrane and an ensuing shutdown of mitochondrial energy production. Neurons have an increased demand for ATP and oxygen, and thus are more prone to damage induced by mitochondrial dysfunction. Mitochondrial dysfunction, damaged electron transport chains, altered membrane permeability and Ca2+ homeostasis, and impaired mitochondrial defense systems induced by oxidative stress, are pathological changes involved in neurodegenerative disorders. A growing body of evidence suggests that the use of antioxidants could stabilize mitochondria and thus may be suitable for preventing neuronal loss. Numerous natural products exhibit the potential to counter oxidative stress and mitochondrial dysfunction; however, science is still looking for a breakthrough in the treatment of neurodegenerative disorders. β-caryophyllene is a bicyclic sesquiterpene, and an active principle of essential oils derived from a large number of spices and food plants. As a selective cannabinoid receptor 2 (CB2) agonist, several studies have reported it as possessing numerous pharmacological activities such as antibacterial (e.g., Helicobacter pylori), antioxidant, anti-inflammatory, analgesic (e.g., neuropathic pain), anti-neurodegenerative and anticancer properties. The present review mainly focuses on the potential of β-caryophyllene in reducing oxidative stress and mitochondrial dysfunction, and its possible links with neuroprotection.

Melatonin As a Modulator of Degenerative and Regenerative Signaling Pathways in Injured Retinal Ganglion Cells

2019 ◽  
Vol 25 (28) ◽  
pp. 3057-3073 ◽  
Author(s):  
Kobra B. Juybari ◽  
Azam Hosseinzadeh ◽  
Habib Ghaznavi ◽  
Mahboobeh Kamali ◽  
Ahad Sedaghat ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Retinal Ganglion Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Ganglion Cells ◽  
Axon Growth ◽  
Nerve Fibers ◽  
Retinal Ganglion

Optic neuropathies refer to the dysfunction or degeneration of optic nerve fibers caused by any reasons including ischemia, inflammation, trauma, tumor, mitochondrial dysfunction, toxins, nutritional deficiency, inheritance, etc. Post-mitotic CNS neurons, including retinal ganglion cells (RGCs) intrinsically have a limited capacity for axon growth after either trauma or disease, leading to irreversible vision loss. In recent years, an increasing number of laboratory evidence has evaluated optic nerve injuries, focusing on molecular signaling pathways involved in RGC death. Trophic factor deprivation (TFD), inflammation, oxidative stress, mitochondrial dysfunction, glutamate-induced excitotoxicity, ischemia, hypoxia, etc. have been recognized as important molecular mechanisms leading to RGC apoptosis. Understanding these obstacles provides a better view to find out new strategies against retinal cell damage. Melatonin, as a wide-spectrum antioxidant and powerful freeradical scavenger, has the ability to protect RGCs or other cells against a variety of deleterious conditions such as oxidative/nitrosative stress, hypoxia/ischemia, inflammatory processes, and apoptosis. In this review, we primarily highlight the molecular regenerative and degenerative mechanisms involved in RGC survival/death and then summarize the possible protective effects of melatonin in the process of RGC death in some ocular diseases including optic neuropathies. Based on the information provided in this review, melatonin may act as a promising agent to reduce RGC death in various retinal pathologic conditions.

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