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Palácio PB, de Freitas Soares GC, Facundo HT. A glibenclamide analog lacking the cyclohexylurea portion fails to block ischemic preconditioning-induced mitochondrial and cardiac protection against ischemia/reperfusion injury. Arch Biochem Biophys 2025; 769:110418. [PMID: 40209872 DOI: 10.1016/j.abb.2025.110418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 03/19/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
Despite significant research, there are no definitive therapies to prevent ischemia/reperfusion injury. During reperfusion, mitochondrial reactive oxygen species (ROS) cause cell damage. Ischemic preconditioning (IP), characterized by brief cycles of ischemia and reperfusion, activates mitochondrial ATP-sensitive potassium channels (mitoKATP) and provides cardioprotection. The aim of the present study is to investigate the impact of a truncated glibenclamide (lacking the cyclohexylurea portion - IMP-A) in ischemic preconditioning (IP)-mediated cardioprotection. Our study shows that IMP-A (2-5 μM) does not inhibit the protective effects of IP against ischemia/reperfusion damage in isolated rat hearts. In this context, IP hearts (with or without IMP-A) exhibited preserved cardiac function, as indicated by stable left ventricular developed pressure, maximal and minimal first derivatives, and rate-pressure product, along with a reduced infarct size following ischemia/reperfusion injury. Conversely, glibenclamide (2 μM - a well-characterized mitoKATP inhibitor) abolished the protective effects of IP against ischemia/reperfusion damage. Mitochondria isolated from reperfused IP hearts (treated or not with IMP-A) produced significantly lower levels of mitochondrial ROS and had lower susceptibility to Ca2+-induced swelling secondary to mitochondrial permeability transition pore (mPTP) opening. Additionally, IP hearts (treated or not with IMP-A) had preserved protein sulfhydryls. Glibenclamide elevated mitochondrial ROS production and negatively impacted mPTP and the sulfhydryl protection seen in IP hearts. Importantly, mitochondrial O2 consumption was preserved in IP hearts (treated or not with IMP-A), and this preservation was disrupted by glibenclamide but not by IMP-A. These findings suggest that the cyclohexylurea group of glibenclamide is essential for its ability to block IP-mediated cardioprotection, providing valuable insights for developing novel therapeutic strategies.
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Flori L, Spezzini J, Calderone V, Testai L. Role of mitochondrial potassium channels in ageing. Mitochondrion 2024; 76:101857. [PMID: 38403095 DOI: 10.1016/j.mito.2024.101857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 02/13/2024] [Accepted: 02/22/2024] [Indexed: 02/27/2024]
Abstract
Ageing is described as an inevitable decline in body functions over time and an increase in susceptibility to age-related diseases. Therefore, the increase of life expectancy is also viewed as a condition in which many elderly will develop age-related diseases and disabilities, such as cardiovascular, metabolic, neurological and oncological ones. Currently, several recognized cellular hallmarks of senescence are taken in consideration to evaluate the level of biological ageing and are the topic to plan preventive/curative anti-ageing interventions, including genomic instability, epigenetic alterations, and mitochondrial dysfunction. In this scenario, alterations in the function/expression of mitochondrial ion channels have been found in ageing and associated to an impairment of calcium cycling and a reduced mitochondrial membrane potential. Although several ion channels have been described at mitochondrial level, undoubtedly the mitochondrial potassium (mitoK) channels are the most investigated. Therefore, this review summarized the evidence that sheds to light a correlation between age-related diseases and alteration of mitoK channels, focusing the attention of the main age-related diseases, i.e. cardiovascular, neurological and oncological ones.
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Affiliation(s)
- Lorenzo Flori
- Department of Pharmacy, University of Pisa, Pisa, Italy
| | | | - Vincenzo Calderone
- Department of Pharmacy, University of Pisa, Pisa, Italy; Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, Pisa, Italy
| | - Lara Testai
- Department of Pharmacy, University of Pisa, Pisa, Italy; Interdepartmental Research Centre of Ageing Biology and Pathology, University of Pisa, Pisa, Italy.
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Krajewska M, Możajew M, Filipek S, Koprowski P. Interaction of ROMK2 channel with lipid kinases DGKE and AGK: Potential channel activation by localized anionic lipid synthesis. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159443. [PMID: 38056763 DOI: 10.1016/j.bbalip.2023.159443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/20/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
In this study, we utilized enzyme-catalyzed proximity labeling with the engineered promiscuous biotin ligase Turbo-ID to identify the proxisome of the ROMK2 channel. This channel resides in various cellular membrane compartments of the cell including the plasma membrane, endoplasmic reticulum and mitochondria. Within mitochondria, ROMK2 has been suggested as a pore-forming subunit of mitochondrial ATP-regulated potassium channel (mitoKATP). We found that ROMK2 proxisome in addition to previously known protein partners included two lipid kinases: acylglycerol kinase (AGK) and diacylglycerol kinase ε (DGKE), which are localized in mitochondria and the endoplasmic reticulum, respectively. Through co-immunoprecipitation, we confirmed that these two kinases are present in complexes with ROMK2 channels. Additionally, we found that the products of AGK and DGKE, lysophosphatidic acid (LPA) and phosphatidic acid (PA), stimulated the activity of ROMK2 channels in artificial lipid bilayers. Our molecular docking studies revealed the presence of acidic lipid binding sites in the ROMK2 channel, similar to those previously identified in Kir2 channels. Based on these findings, we propose a model wherein localized lipid synthesis, mediated by channel-bound lipid kinases, contributes to the regulation of ROMK2 activity within distinct intracellular compartments, such as mitochondria and the endoplasmic reticulum.
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Affiliation(s)
- Milena Krajewska
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, Warsaw, Poland
| | - Mariusz Możajew
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, Warsaw, Poland; Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland
| | - Sławomir Filipek
- Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland
| | - Piotr Koprowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, Warsaw, Poland.
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Owjfard M, Rahmani N, Mallahzadeh A, Bayat M, Borhani-Haghighi A, Karimi F, Namavar MR. Mechanism of action and neuroprotective role of nicorandil in ischemic stroke. Heliyon 2024; 10:e26640. [PMID: 38434007 PMCID: PMC10906150 DOI: 10.1016/j.heliyon.2024.e26640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 01/24/2024] [Accepted: 02/16/2024] [Indexed: 03/05/2024] Open
Abstract
Nicorandil is a dual mechanism anti-anginal agent that acts as a nitric oxide (NO) donor and a potassium (K+) channel opener. Recent studies have evaluated the effect of nicorandil on ischemic stroke. Neurons have a low tolerance to hypoxia and therefore the brain tissue is significantly vulnerable to ischemia. Current approved treatments for ischemic stroke are tissue plasminogen activators and clot retrieval methods. The narrow therapeutic time window and lack of efficacy in restoring the dying neurons urge researchers to develop an alternative approach. In the terminal stages of anoxia, K+ channels induce hyperpolarization in various types of neuronal cells, leading to decreased neuronal activity and the preservation of the brain's energy. Nicorandil can open these K+ channels and sustain the hyperpolarization phase, which may have a neuroprotective effect during hypoxia. Additionally, we review how nicorandil can improve overall stroke outcomes through its anti-inflammatory, anti-oxidative, and edema-reducing effects. One of the major components evaluated in stroke patients is blood pressure. Studies have demonstrated that the effect of nicorandil on blood pressure is related to both its K+ channel opening and NO donating mechanisms. Since both hypertension and hypotension need correction before stroke intervention, it's crucial to consider the role of nicorandil and its impact on blood pressure. Previously published studies indicate that the right dosage of nicorandil can improve cerebral blood flow without significant changes in hemodynamic profiles. In this review, we discuss how nicorandil may contribute to better stroke outcomes based on previously published literature and laboratory findings.
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Affiliation(s)
- Maryam Owjfard
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rahmani
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arashk Mallahzadeh
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahnaz Bayat
- Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | - Mohammad Reza Namavar
- Histomorphometry & Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Zhang L, Zhou X, Zhao J, Wang X. Research hotspots and frontiers of preconditioning in cerebral ischemia: A bibliometric analysis. Heliyon 2024; 10:e24757. [PMID: 38317957 PMCID: PMC10839892 DOI: 10.1016/j.heliyon.2024.e24757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 12/13/2023] [Accepted: 01/12/2024] [Indexed: 02/07/2024] Open
Abstract
Background Preconditioning is a promising strategy against ischemic brain injury, and numerous studies in vitro and in vivo have demonstrated its neuroprotective effects. However, at present there is no bibliometric analysis of preconditioning in cerebral ischemia. Therefore, a comprehensive overview of the current status, hot spots, and emerging trends in this research field is necessary. Materials and methods Studies on preconditioning in cerebral ischemia from January 1999-December 2022 were retrieved from the Web of Science Core Collection (WOSCC) database. CiteSpace was used for data mining and visual analysis. Results A total of 1738 papers on preconditioning in cerebral ischemia were included in the study. The annual publications showed an upwards and then downwards trend but currently remain high in terms of annual publications. The US was the leading country, followed by China, the most active country in recent years. Capital Medical University published the largest number of articles. Perez-Pinzon, Miguel A contributed the most publications, while KITAGAWA K was the most cited author. The focus of the study covered three areas: (1) relevant diseases and experimental models, (2) types of preconditioning and stimuli, and (3) mechanisms of ischemic tolerance. Remote ischemic preconditioning, preconditioning of mesenchymal stem cells (MSCs), and inflammation are the frontiers of research in this field. Conclusion Our study provides a visual and scientific overview of research on preconditioning in cerebral ischemia, providing valuable information and new directions for researchers.
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Affiliation(s)
- Long Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Department of Traditional Chinese Medicine, Zibo TCM-Integrated Hospital, Zibo ,255026, China
| | - Xue Zhou
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jing Zhao
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Xingchen Wang
- Division of Neurology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250001, China
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Sun MK, Alkon DL. Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences. J Alzheimers Dis 2024; 101:S263-S274. [PMID: 39422958 DOI: 10.3233/jad-240479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed.
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Palácio PB, de Freitas Soares GC, Lima GMB, Cunha PLO, Varela ALN, Facundo HT. Competitive interaction between ATP and GTP regulates mitochondrial ATP-sensitive potassium channels. Chem Biol Interact 2023:110560. [PMID: 37244398 DOI: 10.1016/j.cbi.2023.110560] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/28/2023] [Accepted: 05/22/2023] [Indexed: 05/29/2023]
Abstract
Mitochondrial ATP-sensitive K+ channels (mitoKATP) have been recently characterized structurally, and possess a protein through which K+ enters mitochondria (MitoKIR), and a regulatory subunit (mitoSUR). The mitoSUR regulatory subunit is an ATP-binding cassette (ABC) protein isoform 8 (ABCB8). Opening these channels is known to be cardioprotective, but the molecular and physiological mechanisms that activate them are not fully known. Here, to better understand the molecular and physiological mechanisms of activators (GTP) and inhibitors (ATP) on the activity of mitoKATP, we exposed isolated mitochondria to both nucleotides. We also used molecular docking directed to the nucleotide-binding domain of human ABCB8/mitoSUR to test a comparative model of ATP and GTP effects. As expected, we find that ATP dose-dependently inhibits mitoKATP activity (IC50 = 21.24 ± 1.4 mM). However, simultaneous exposure of mitochondria to GTP dose-dependently (EC50 = 13.19 ± 1.33 mM) reversed ATP inhibition. Pharmacological and computational studies suggest that GTP reverses ATP activity competitively. Docking directed to the site of crystallized ADP reveals that both nucleotides bind to mitoSUR with high affinity, with their phosphates directed to the Mg2+ ion and the walker A motif of the protein (SGGGKTT). These effects, when combined, result in GTP binding, ATP displacement, mitochondrial ATP-sensitive K+ transport, and lower formation of reactive oxygen species. Overall, our findings demonstrate the basis for ATP and GTP binding in mitoSUR using a combination of biochemical, pharmacological, and computational experiments. Future studies may reveal the extent to which the balance between ATP and GTP actions contributes toward cardioprotection against ischemic events.
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Abstract
Mitochondria are involved in multiple cellular tasks, such as ATP synthesis, metabolism, metabolite and ion transport, regulation of apoptosis, inflammation, signaling, and inheritance of mitochondrial DNA. The majority of the correct functioning of mitochondria is based on the large electrochemical proton gradient, whose component, the inner mitochondrial membrane potential, is strictly controlled by ion transport through mitochondrial membranes. Consequently, mitochondrial function is critically dependent on ion homeostasis, the disturbance of which leads to abnormal cell functions. Therefore, the discovery of mitochondrial ion channels influencing ion permeability through the membrane has defined a new dimension of the function of ion channels in different cell types, mainly linked to the important tasks that mitochondrial ion channels perform in cell life and death. This review summarizes studies on animal mitochondrial ion channels with special focus on their biophysical properties, molecular identity, and regulation. Additionally, the potential of mitochondrial ion channels as therapeutic targets for several diseases is briefly discussed.
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Affiliation(s)
- Ildiko Szabo
- Department of Biology, University of Padova, Italy;
| | - Adam Szewczyk
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland;
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Krajewska M, Szewczyk A, Kulawiak B, Koprowski P. Pharmacological Characterization of a Recombinant Mitochondrial ROMK2 Potassium Channel Expressed in Bacteria and Reconstituted in Planar Lipid Bilayers. MEMBRANES 2023; 13:360. [PMID: 36984747 PMCID: PMC10052516 DOI: 10.3390/membranes13030360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 06/18/2023]
Abstract
In the inner mitochondrial membrane, several potassium channels that play a role in cell life and death have been identified. One of these channels is the ATP-regulated potassium channel (mitoKATP). The ROMK2 potassium channel is a potential molecular component of the mitoKATP channel. The current study aimed to investigate the pharmacological modulation of the activity of the ROMK2 potassium channel expressed in Escherichia coli bacteria. ROMK2 was solubilized in polymer nanodiscs and incorporated in planar lipid bilayers. The impact of known mitoKATP channel modulators on the activity of the ROMK2 was characterized. We found that the ROMK2 channel was activated by the mitoKATP channel opener diazoxide and blocked by mitoKATP inhibitors such as ATP/Mg2+, 5-hydroxydecanoic acid, and antidiabetic sulfonylurea glibenclamide. These results indicate that the ROMK2 potassium protein may be a pore-forming subunit of mitoKATP and that the impact of channel modulators is not related to the presence of accessory proteins.
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Affiliation(s)
- Milena Krajewska
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland
- Interdisciplinary Laboratory of Molecular Biology and Biophysics, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland
| | - Bogusz Kulawiak
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland
| | - Piotr Koprowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland
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Bercea C, Limbu R, Behnam K, Ng KE, Aziz Q, Tinker A, Tamagnini F, Cottrell GS, McNeish AJ. Omega-3 polyunsaturated fatty acid-induced vasodilation in mouse aorta and mesenteric arteries is not mediated by ATP-sensitive potassium channels. Front Physiol 2022; 13:1033216. [PMID: 36589427 PMCID: PMC9797959 DOI: 10.3389/fphys.2022.1033216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
There is strong evidence that the omega-3 polyunsaturated fatty acids (n-3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have cardioprotective effects. n-3 PUFAs cause vasodilation in hypertensive patients, in part controlled by increased membrane conductance to potassium. As KATP channels play a major role in vascular tone regulation and are involved in hypertension, we aimed to verify whether n-3 PUFA-mediated vasodilation involved the opening of KATP channels. We used a murine model in which the KATP channel pore subunit, Kir6.1, is deleted in vascular smooth muscle. The vasomotor response of preconstricted arteries to physiologically relevant concentrations of DHA and EPA was measured using wire myography, using the channel blocker PNU-37883A. The effect of n-3 PUFAs on potassium currents in wild-type native smooth muscle cells was investigated using whole-cell patch clamping. DHA and EPA induced vasodilation in mouse aorta and mesenteric arteries; relaxations in the aorta were sensitive to KATP blockade with PNU-37883A. Endothelium removal didn't affect relaxation to EPA and caused a small but significant inhibition of relaxation to DHA. In the knock-out model, relaxations to DHA and EPA were unaffected by channel knockdown but were still inhibited by PNU-37883A, indicating that the action of PNU-37883A on relaxation may not reflect inhibition of KATP. In native aortic smooth muscle cells DHA failed to activate KATP currents. We conclude that DHA and EPA cause vasodilation in mouse aorta and mesenteric arteries. Relaxations in blocker-treated arteries from knock-out mice demonstrate that KATP channels are not involved in the n-3 PUFA-induced relaxation.
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Affiliation(s)
- Cristiana Bercea
- McNeish Laboratory, School of Chemistry, Food and Pharmacy, Department of Pharmacology, University of Reading, London, United Kingdom
- Tinker Laboratory, William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University, London, United Kingdom
| | - Roshan Limbu
- McNeish Laboratory, School of Chemistry, Food and Pharmacy, Department of Pharmacology, University of Reading, London, United Kingdom
| | - Kamila Behnam
- McNeish Laboratory, School of Chemistry, Food and Pharmacy, Department of Pharmacology, University of Reading, London, United Kingdom
| | - Keat-Eng Ng
- Tinker Laboratory, William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University, London, United Kingdom
| | - Qadeer Aziz
- Tinker Laboratory, William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University, London, United Kingdom
| | - Andrew Tinker
- Tinker Laboratory, William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University, London, United Kingdom
| | - Francesco Tamagnini
- McNeish Laboratory, School of Chemistry, Food and Pharmacy, Department of Pharmacology, University of Reading, London, United Kingdom
| | - Graeme S Cottrell
- McNeish Laboratory, School of Chemistry, Food and Pharmacy, Department of Pharmacology, University of Reading, London, United Kingdom
| | - Alister J McNeish
- McNeish Laboratory, School of Chemistry, Food and Pharmacy, Department of Pharmacology, University of Reading, London, United Kingdom
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Kampa RP, Sęk A, Bednarczyk P, Szewczyk A, Calderone V, Testai L. Flavonoids as new regulators of mitochondrial potassium channels: contribution to cardioprotection. J Pharm Pharmacol 2022; 75:466-481. [PMID: 36508341 DOI: 10.1093/jpp/rgac093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 11/18/2022] [Indexed: 12/14/2022]
Abstract
Abstract
Objectives
Acute myocardial ischemia is one of the major causes of illness in western society. Reduced coronary blood supply leads to cell death and loss of cardiomyocyte population, resulting in serious and often irreversible consequences on myocardial function. Mitochondrial potassium (mitoK) channels have been identified as fine regulators of mitochondrial function and, consequently, in the metabolism of the whole cell, and in the mechanisms underlying the cardioprotection. Interestingly, mitoK channels represent a novel putative target for treating cardiovascular diseases, particularly myocardial infarction, and their modulators represent an interesting tool for pharmacological intervention. In this review, we took up the challenge of selecting flavonoids that show cardioprotective properties through the activation of mitoK channels.
Key findings
A brief overview of the main information on mitoK channels and their participation in the induction of cytoprotective processes was provided. Then, naringenin, quercetin, morin, theaflavin, baicalein, epigallocatechin gallate, genistein, puerarin, luteolin and proanthocyanidins demonstrated to be effective modulators of mitoK channels activity, mediating many beneficial effects.
Summary
The pathophysiological role of mitoK channels has been investigated as well as the impact of flavonoids on this target with particular attention to their potential role in the prevention of cardiovascular disorders.
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Affiliation(s)
- Rafał P Kampa
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS , Warsaw , Poland
- Department of Pharmacy, University of Pisa , Italy
| | - Aleksandra Sęk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS , Warsaw , Poland
- Faculty of Chemistry, University of Warsaw , Warsaw , Poland
| | - Piotr Bednarczyk
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences, SGGW , Warsaw , Poland
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology PAS , Warsaw , Poland
| | | | - Lara Testai
- Department of Pharmacy, University of Pisa , Italy
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Zorov DB. A Window to the Potassium World. The Evidence of Potassium Energetics in the Mitochondria and Identity of the Mitochondrial ATP-Dependent K + Channel. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:683-688. [PMID: 36171650 DOI: 10.1134/s0006297922080016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 07/04/2022] [Accepted: 07/04/2022] [Indexed: 06/16/2023]
Abstract
The conclusions made in the three papers published in Function by Juhaszova et al. [Function, 3, 2022, zqab065, zqac001, zqac018], can be seen as a breakthrough in bioenergetics and mitochondrial medicine. For more than half a century, it has been believed that mitochondrial energetics is solely protonic and is based on the generation of electrochemical potential of hydrogen ions across the inner mitochondrial membrane upon oxidation of respiratory substrates, resulting in the generation of ATP via reverse transport of protons through the ATP synthase complex. Juhaszova et al. demonstrated that ATP synthase transfers not only protons, but also potassium ions, with the generation of ATP. This mechanism seems logical, given the fact that in eukaryotic cells, the concentration of potassium ions is several million times higher than the concentration of protons. The transport of K+ through the ATP synthase was enhanced by the activators of mitochondrial ATP-dependent K+ channel (mK/ATP), leading to the conclusion that ATP synthase is the material essence of mK/ATP. Beside ATP generation, the transport of osmotically active K+ to the mitochondrial matrix is accompanied by water entry to the matrix, leading to an increase in the matrix volume and activation of mitochondrial respiration with the corresponding increase in the ATP synthesis, which suggests an advantage of such transport for energy production. The driving force for K+ transport into the mitochondria is the membrane potential; an excess of K+ is exported from the matrix by the hypothetical K+/H+ exchangers. Inhibitory factor 1 (IF1) plays an important role in the activation of mK/ATP by increasing the chemo-mechanical efficiency of ATP synthase, which may be a positive factor in the protective anti-ischemic signaling.
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Affiliation(s)
- Dmitry B Zorov
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119992, Russia.
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13
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Lv J, Xiao X, Bi M, Tang T, Kong D, Diao M, Jiao Q, Chen X, Yan C, Du X, Jiang H. ATP-sensitive potassium channels: A double-edged sword in neurodegenerative diseases. Ageing Res Rev 2022; 80:101676. [PMID: 35724860 DOI: 10.1016/j.arr.2022.101676] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 04/15/2022] [Accepted: 06/14/2022] [Indexed: 11/25/2022]
Abstract
ATP-sensitive potassium channels (KATP channels), a group of vital channels that link the electrical activity of the cell membrane with cell metabolism, were discovered on the ventricular myocytes of guinea pigs by Noma using the patch-clamp technique in 1983. Subsequently, KATP channels have been found to be expressed in pancreatic β cells, cardiomyocytes, skeletal muscle cells, and nerve cells in the substantia nigra (SN), hippocampus, cortex, and basal ganglia. KATP channel openers (KCOs) diazoxide, nicorandil, minoxidil, and the KATP channel inhibitor glibenclamide have been shown to have anti-hypertensive, anti-myocardial ischemia, and insulin-releasing regulatory effects. Increasing evidence has suggested that KATP channels also play roles in Alzheimer's disease (AD), Parkinson's disease (PD), vascular dementia (VD), Huntington's disease (HD) and other neurodegenerative diseases. KCOs and KATP channel inhibitors protect neurons from injury by regulating neuronal excitability and neurotransmitter release, inhibiting abnormal protein aggregation and Ca2+ overload, reducing reactive oxygen species (ROS) production and microglia activation. However, KATP channels have dual effects in some cases. In this review, we focus on the roles of KATP channels and their related openers and inhibitors in neurodegenerative diseases. This will enable us to precisely take advantage of the KATP channels and provide new ideas for the treatment of neurodegenerative diseases.
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Affiliation(s)
- Jirong Lv
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Xue Xiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Mingxia Bi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Tingting Tang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Deao Kong
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Meining Diao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Chunling Yan
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China.
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14
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Le N, Sayers S, Mata-Pacheco V, Wagner EJ. The PACAP Paradox: Dynamic and Surprisingly Pleiotropic Actions in the Central Regulation of Energy Homeostasis. Front Endocrinol (Lausanne) 2022; 13:877647. [PMID: 35721722 PMCID: PMC9198406 DOI: 10.3389/fendo.2022.877647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/30/2022] [Indexed: 12/11/2022] Open
Abstract
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), a pleiotropic neuropeptide, is widely distributed throughout the body. The abundance of PACAP expression in the central and peripheral nervous systems, and years of accompanying experimental evidence, indicates that PACAP plays crucial roles in diverse biological processes ranging from autonomic regulation to neuroprotection. In addition, PACAP is also abundantly expressed in the hypothalamic areas like the ventromedial and arcuate nuclei (VMN and ARC, respectively), as well as other brain regions such as the nucleus accumbens (NAc), bed nucleus of stria terminalis (BNST), and ventral tegmental area (VTA) - suggesting that PACAP is capable of regulating energy homeostasis via both the homeostatic and hedonic energy balance circuitries. The evidence gathered over the years has increased our appreciation for its function in controlling energy balance. Therefore, this review aims to further probe how the pleiotropic actions of PACAP in regulating energy homeostasis is influenced by sex and dynamic changes in energy status. We start with a general overview of energy homeostasis, and then introduce the integral components of the homeostatic and hedonic energy balance circuitries. Next, we discuss sex differences inherent to the regulation of energy homeostasis via these two circuitries, as well as the activational effects of sex steroid hormones that bring about these intrinsic disparities between males and females. Finally, we explore the multifaceted role of PACAP in regulating homeostatic and hedonic feeding through its actions in regions like the NAc, BNST, and in particular the ARC, VMN and VTA that occur in sex- and energy status-dependent ways.
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Affiliation(s)
- Nikki Le
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
| | - Sarah Sayers
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
| | - Veronica Mata-Pacheco
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
| | - Edward J. Wagner
- Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, United States
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
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15
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Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y, Fishbein KW, de Cabo R, Montoliu L, Gabelli SB, Aon MA, Cortassa S, Sollott SJ. ATP Synthase K +- and H +-fluxes Drive ATP Synthesis and Enable Mitochondrial K +-"Uniporter" Function: II. Ion and ATP Synthase Flux Regulation. FUNCTION (OXFORD, ENGLAND) 2022; 3:zqac001. [PMID: 35187492 PMCID: PMC8850977 DOI: 10.1093/function/zqac001] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/12/2022] [Accepted: 01/18/2022] [Indexed: 01/07/2023]
Abstract
We demonstrated that ATP synthase serves the functions of a primary mitochondrial K+ "uniporter," i.e., the primary way for K+ to enter mitochondria. This K+ entry is proportional to ATP synthesis, regulating matrix volume and energy supply-vs-demand matching. We show that ATP synthase can be upregulated by endogenous survival-related proteins via IF1. We identified a conserved BH3-like domain of IF1 which overlaps its "minimal inhibitory domain" that binds to the β-subunit of F1. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF1 and exert effects, requiring this interaction, comparable to diazoxide to augment ATP synthase's H+ and K+ flux and ATP synthesis. Bcl-xL and Mcl-1, but not Bcl-2, serve as endogenous regulatory ligands of ATP synthase via interaction with IF1 at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial KATP-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF1-progenitors, we found that IF1 is likely an ancient (∼2 Gya) Bcl-family member that evolved from primordial bacteria resident in eukaryotes, corresponding to their putative emergence as symbiotic mitochondria, and functioning to prevent their parasitic ATP consumption inside the host cell.
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Affiliation(s)
| | | | | | | | | | - Kenneth W Fishbein
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Lluis Montoliu
- National Centre for Biotechnology (CNB-CSIC), Biomedical Research Networking Center on Rare Diseases (CIBERER-ISCIII), 28049 Madrid, Spain
| | - Sandra B Gabelli
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Miguel A Aon
- Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA
| | - Sonia Cortassa
- Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Baltimore, MD 21224, USA
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16
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Methods of Measuring Mitochondrial Potassium Channels: A Critical Assessment. Int J Mol Sci 2022; 23:ijms23031210. [PMID: 35163132 PMCID: PMC8835872 DOI: 10.3390/ijms23031210] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/22/2022] Open
Abstract
In this paper, the techniques used to study the function of mitochondrial potassium channels are critically reviewed. The majority of these techniques have been known for many years as a result of research on plasma membrane ion channels. Hence, in this review, we focus on the critical evaluation of techniques used in the studies of mitochondrial potassium channels, describing their advantages and limitations. Functional analysis of mitochondrial potassium channels in comparison to that of plasmalemmal channels presents additional experimental challenges. The reliability of functional studies of mitochondrial potassium channels is often affected by the need to isolate mitochondria and by functional properties of mitochondria such as respiration, metabolic activity, swelling capacity, or high electrical potential. Three types of techniques are critically evaluated: electrophysiological techniques, potassium flux measurements, and biochemical techniques related to potassium flux measurements. Finally, new possible approaches to the study of the function of mitochondrial potassium channels are presented. We hope that this review will assist researchers in selecting reliable methods for studying, e.g., the effects of drugs on mitochondrial potassium channel function. Additionally, this review should aid in the critical evaluation of the results reported in various articles on mitochondrial potassium channels.
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17
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Wrzosek A, Gałecka S, Żochowska M, Olszewska A, Kulawiak B. Alternative Targets for Modulators of Mitochondrial Potassium Channels. Molecules 2022; 27:299. [PMID: 35011530 PMCID: PMC8746388 DOI: 10.3390/molecules27010299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/30/2021] [Accepted: 12/31/2021] [Indexed: 12/17/2022] Open
Abstract
Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.
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Affiliation(s)
- Antoni Wrzosek
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland; (A.W.); (S.G.); (M.Ż.)
| | - Shur Gałecka
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland; (A.W.); (S.G.); (M.Ż.)
| | - Monika Żochowska
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland; (A.W.); (S.G.); (M.Ż.)
| | - Anna Olszewska
- Department of Histology, Medical University of Gdansk, 1a Debinki, 80-211 Gdansk, Poland;
| | - Bogusz Kulawiak
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland; (A.W.); (S.G.); (M.Ż.)
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18
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Wang M, Li D. Ginsenoside-Mc1 reduces cerebral ischemia-reperfusion injury in hyperlipidemia through mitochondrial improvement and attenuation of oxidative/endoplasmic reticulum stress. ARCH BIOL SCI 2022. [DOI: 10.2298/abs220212015w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2022] Open
Abstract
The neuroprotective effect of ginsenoside-Mc1 (GMc1) in hyperlipidemic rats in the setting of cerebral ischemiareperfusion injury (I/RI), as well as the role of mitochondrial ATP-sensitive potassium (mitoKATP) channels and oxidative/ endoplasmic reticulum (ER) stress, was investigated. Hyperlipidemia (8 weeks) was induced by a high-fat diet in Sprague Dawley rats. GMc1 (10 mg/kg, i.p.) was given to hyperlipidemic rats daily for one month before I/RI. Rat brains were subjected to 2 h of local ischemia followed by 24 h reperfusion. The cerebral infarcted injury was measured by triphenyltetrazolium chloride staining and the levels of oxidative stress indicators were detected by ELISA and spectrophotometry. A fluorometric technique was employed to evaluate mitochondrial function. Western blotting was used to detect changes in the expression of ER stress proteins. GMc1 reduced cerebral infarct volume in hyperlipidemic rats in comparison to untreated ones (P<0.01). GMc1 reduced cerebral infarct volume in hyperlipidemic rats as compared to untreated rats (P<0.01). GMc1 significantly decreased mitochondrial membrane depolarization, mitochondrial reactive oxygen species (mitoROS) and malondialdehyde levels (P<0.01), while increasing the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione-peroxidase (GPx) (P<0.001). GMc1 administration reduced the expression of ER stress markers, including phosphorylated (p)-endoplasmic reticulum kinase (PERK), p-eukaryotic translation initiation factor 2 subunit 1 (elF2?), and C/EBP homologous protein (CHOP). Inhibition of mitoKATP channels with hydroxydecanoate significantly eliminated the protective impacts of GMc1 in hyperlipidemic rats subjected to cerebral I/RI. The neuroprotective effect of GMc1 preconditioning was remarkably improved by increasing mitoKATP channel activity and decreasing oxidative and ER stress levels in hyperlipidemic rats, implying that this compound could be an appropriate candidate for reducing cerebral I/RI in comorbidities.
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Affiliation(s)
- Min Wang
- Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
| | - Danni Li
- Department of Neurology, Central Hospital Affiliated to Shandong First Medical University, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, China
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19
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Kv7.4 Channels Regulate Potassium Permeability in Neuronal Mitochondria. Biochem Pharmacol 2022; 197:114931. [DOI: 10.1016/j.bcp.2022.114931] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/14/2022] [Accepted: 01/18/2022] [Indexed: 01/08/2023]
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20
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Kulawiak B, Bednarczyk P, Szewczyk A. Multidimensional Regulation of Cardiac Mitochondrial Potassium Channels. Cells 2021; 10:1554. [PMID: 34205420 PMCID: PMC8235349 DOI: 10.3390/cells10061554] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 02/07/2023] Open
Abstract
Mitochondria play a fundamental role in the energetics of cardiac cells. Moreover, mitochondria are involved in cardiac ischemia/reperfusion injury by opening the mitochondrial permeability transition pore which is the major cause of cell death. The preservation of mitochondrial function is an essential component of the cardioprotective mechanism. The involvement of mitochondrial K+ transport in this complex phenomenon seems to be well established. Several mitochondrial K+ channels in the inner mitochondrial membrane, such as ATP-sensitive, voltage-regulated, calcium-activated and Na+-activated channels, have been discovered. This obliges us to ask the following question: why is the simple potassium ion influx process carried out by several different mitochondrial potassium channels? In this review, we summarize the current knowledge of both the properties of mitochondrial potassium channels in cardiac mitochondria and the current understanding of their multidimensional functional role. We also critically summarize the pharmacological modulation of these proteins within the context of cardiac ischemia/reperfusion injury and cardioprotection.
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Affiliation(s)
- Bogusz Kulawiak
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warsaw, Poland;
| | - Piotr Bednarczyk
- Department of Physics and Biophysics, Institute of Biology, Warsaw University of Life Sciences-SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland;
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteura 3, 02-093 Warsaw, Poland;
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21
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Mitochondrial K + Transport: Modulation and Functional Consequences. Molecules 2021; 26:molecules26102935. [PMID: 34069217 PMCID: PMC8156104 DOI: 10.3390/molecules26102935] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/07/2021] [Accepted: 05/11/2021] [Indexed: 01/28/2023] Open
Abstract
The existence of a K+ cycle in mitochondria has been predicted since the development of the chemiosmotic theory and has been shown to be crucial for several cellular phenomena, including regulation of mitochondrial volume and redox state. One of the pathways known to participate in K+ cycling is the ATP-sensitive K+ channel, MitoKATP. This channel was vastly studied for promoting protection against ischemia reperfusion when pharmacologically activated, although its molecular identity remained unknown for decades. The recent molecular characterization of MitoKATP has opened new possibilities for modulation of this channel as a mechanism to control cellular processes. Here, we discuss different strategies to control MitoKATP activity and consider how these could be used as tools to regulate metabolism and cellular events.
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22
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Noterman MF, Chaubey K, Lin-Rahardja K, Rajadhyaksha AM, Pieper AA, Taylor EB. Dual-process brain mitochondria isolation preserves function and clarifies protein composition. Proc Natl Acad Sci U S A 2021; 118:e2019046118. [PMID: 33836587 PMCID: PMC7980376 DOI: 10.1073/pnas.2019046118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The brain requires continuously high energy production to maintain ion gradients and normal function. Mitochondria critically undergird brain energetics, and mitochondrial abnormalities feature prominently in neuropsychiatric disease. However, many unique aspects of brain mitochondria composition and function are poorly understood. Developing improved neuroprotective therapeutics thus requires more comprehensively understanding brain mitochondria, including accurately delineating protein composition and channel-transporter functional networks. However, obtaining pure mitochondria from the brain is especially challenging due to its distinctive lipid and cell structure properties. As a result, conflicting reports on protein localization to brain mitochondria abound. Here we illustrate this problem with the neuropsychiatric disease-associated L-type calcium channel Cav1.2α1 subunit previously observed in crude mitochondria. We applied a dual-process approach to obtain functionally intact versus compositionally pure brain mitochondria. One branch utilizes discontinuous density gradient centrifugation to isolate semipure mitochondria suitable for functional assays but unsuitable for protein localization because of endoplasmic reticulum (ER) contamination. The other branch utilizes self-forming density gradient ultracentrifugation to remove ER and yield ultrapure mitochondria that are suitable for investigating protein localization but functionally compromised. Through this process, we evaluated brain mitochondria protein content and observed the absence of Cav1.2α1 and other previously reported mitochondrial proteins, including the NMDA receptor, ryanodine receptor 1, monocarboxylate transporter 1, excitatory amino acid transporter 1, and glyceraldehyde 3-phosphate dehydrogenase. Conversely, we confirmed mitochondrial localization of several plasma membrane proteins previously reported to also localize to mitochondria. We expect this dual-process isolation procedure will enhance understanding of brain mitochondria in both health and disease.
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Affiliation(s)
- Maria F Noterman
- Interdisciplinary Graduate Program in Neuroscience, University of Iowa, Iowa City, IA 52242
| | - Kalyani Chaubey
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106
| | - Kristi Lin-Rahardja
- Department of Systems Biology and Bioinformatics, Case Western Reserve University, Cleveland, OH 44106
| | - Anjali M Rajadhyaksha
- Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY 10065
- Pediatric Neurology, Pediatrics, Weill Cornell Medicine of Cornell University, New York, NY 10065
| | - Andrew A Pieper
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106;
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106
- Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY 10065
- Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106
- Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH 44106
| | - Eric B Taylor
- Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
- Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242
- Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242
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23
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Maqoud F, Scala R, Hoxha M, Zappacosta B, Tricarico D. ATP-sensitive potassium channel subunits in the neuroinflammation: novel drug targets in neurodegenerative disorders. CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS 2021; 21:130-149. [PMID: 33463481 DOI: 10.2174/1871527320666210119095626] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/07/2020] [Accepted: 08/28/2020] [Indexed: 11/22/2022]
Abstract
Arachidonic acids and its metabolites modulate plenty of ligand-gated, voltage-dependent ion channels, and metabolically regulated potassium channels including ATP-sensitive potassium channels (KATP). KATP channels are hetero-multimeric complexes of sulfonylureas receptors (SUR1, SUR2A or SUR2B) and the pore-forming subunits (Kir6.1 and Kir6.2) likewise expressed in the pre-post synapsis of neurons and inflammatory cells, thereby affecting their proliferation and activity. KATP channels are involved in amyloid-β (Aβ)-induced pathology, therefore emerging as therapeutic targets against Alzheimer's and related diseases. The modulation of these channels can represent an innovative strategy for the treatment of neurodegenerative disorders; nevertheless, the currently available drugs are not selective for brain KATP channels and show contrasting effects. This phenomenon can be a consequence of the multiple physiological roles of the different varieties of KATP channels. Openings of cardiac and muscular KATP channel subunits, is protective against caspase-dependent atrophy in these tissues and some neurodegenerative disorders, whereas in some neuroinflammatory diseases benefits can be obtained through the inhibition of neuronal KATP channel subunits. For example, glibenclamide exerts an anti-inflammatory effect in respiratory, digestive, urological, and central nervous system (CNS) diseases, as well as in ischemia-reperfusion injury associated with abnormal SUR1-Trpm4/TNF-α or SUR1-Trpm4/ Nos2/ROS signaling. Despite this strategy is promising, glibenclamide may have limited clinical efficacy due to its unselective blocking action of SUR2A/B subunits also expressed in cardiovascular apparatus with pro-arrhythmic effects and SUR1 expressed in pancreatic beta cells with hypoglycemic risk. Alternatively, neuronal selective dual modulators showing agonist/antagonist actions on KATP channels can be an option.
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Affiliation(s)
- Fatima Maqoud
- Department of Pharmacy-Pharmaceutical Science, University of Bari Aldo Moro, via Orabona 4, 70125-I. Italy
| | - Rosa Scala
- Department of Pharmacy-Pharmaceutical Science, University of Bari Aldo Moro, via Orabona 4, 70125-I. Italy
| | - Malvina Hoxha
- Department of Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, "Catholic University Our Lady of Good Counsel", Tirana. Albania
| | - Bruno Zappacosta
- Department of Chemical-Toxicological and Pharmacological Evaluation of Drugs, Faculty of Pharmacy, "Catholic University Our Lady of Good Counsel", Tirana. Albania
| | - Domenico Tricarico
- Department of Pharmacy-Pharmaceutical Science, University of Bari Aldo Moro, via Orabona 4, 70125-I. Italy
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24
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Barancik M, Kura B, LeBaron TW, Bolli R, Buday J, Slezak J. Molecular and Cellular Mechanisms Associated with Effects of Molecular Hydrogen in Cardiovascular and Central Nervous Systems. Antioxidants (Basel) 2020; 9:antiox9121281. [PMID: 33333951 PMCID: PMC7765453 DOI: 10.3390/antiox9121281] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/12/2020] [Accepted: 12/13/2020] [Indexed: 02/06/2023] Open
Abstract
The increased production of reactive oxygen species and oxidative stress are important factors contributing to the development of diseases of the cardiovascular and central nervous systems. Molecular hydrogen is recognized as an emerging therapeutic, and its positive effects in the treatment of pathologies have been documented in both experimental and clinical studies. The therapeutic potential of hydrogen is attributed to several major molecular mechanisms. This review focuses on the effects of hydrogen on the cardiovascular and central nervous systems, and summarizes current knowledge about its actions, including the regulation of redox and intracellular signaling, alterations in gene expressions, and modulation of cellular responses (e.g., autophagy, apoptosis, and tissue remodeling). We summarize the functions of hydrogen as a regulator of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated redox signaling and the association of hydrogen with mitochondria as an important target of its therapeutic action. The antioxidant functions of hydrogen are closely associated with protein kinase signaling pathways, and we discuss possible roles of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and Wnt/β-catenin pathways, which are mediated through glycogen synthase kinase 3β and its involvement in the regulation of cellular apoptosis. Additionally, current knowledge about the role of molecular hydrogen in the modulation of autophagy and matrix metalloproteinases-mediated tissue remodeling, which are other responses to cellular stress, is summarized in this review.
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Affiliation(s)
- Miroslav Barancik
- Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (M.B.); (B.K.); (T.W.L.)
| | - Branislav Kura
- Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (M.B.); (B.K.); (T.W.L.)
- Faculty of Medicine, Institute of Physiology, Comenius University in Bratislava, 84215 Bratislava, Slovakia
| | - Tyler W. LeBaron
- Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (M.B.); (B.K.); (T.W.L.)
- Molecular Hydrogen Institute, Enoch, UT 84721, USA
- Department of Kinesiology and Outdoor Recreation, Southern Utah University, Cedar City, UT 84720, USA
| | - Roberto Bolli
- Department of Medicine, Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA;
| | - Jozef Buday
- Department of Psychiatry, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, 12108 Prague, Czech Republic;
| | - Jan Slezak
- Centre of Experimental Medicine, Slovak Academy of Sciences, 84104 Bratislava, Slovakia; (M.B.); (B.K.); (T.W.L.)
- Correspondence: ; Tel.: +42-19-03-620-181
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25
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Lei F, Wang W, Fu Y, Wang J, Zheng Y. Mitochondrial KATP channels contribute to the protective effects of hydrogen sulfide against impairment of central chemoreception of rat offspring exposed to maternal cigarette smoke. PLoS One 2020; 15:e0237643. [PMID: 33064729 PMCID: PMC7567348 DOI: 10.1371/journal.pone.0237643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 07/30/2020] [Indexed: 02/05/2023] Open
Abstract
We previously reported that maternal cigarette smoke (CS) exposure resulted in impairment of central chemoreception and induced mitochondrial dysfunction in offspring parafacial respiratory group (pFRG), the kernel for mammalian central chemoreception. We also found that hydrogen sulfide (H2S) could attenuate maternal CS exposure-induced impairment of central chemoreception in the rat offspring in vivo. Mitochondrial ATP sensitive potassium (mitoKATP) channel has been reported to play a significant role in mitochondrial functions and protect against apoptosis in neurons. Thus, we hypothesize here that mitoKATP channel plays a role in the protective effects of H2S on neonatal central chemoreception in maternal CS-exposed rats. Our findings revealed that pretreatment with NaHS (donor of H2S, 22.4mM) reversed the central chemosensitivity decreased by maternal CS exposure, and also inhibited cell apoptosis in offspring pFRG, however, 5-HD (blocker of mitoKATP channels, 19mM) attenuated the protective effects of NaHS. In addition, NaHS declined pro-apoptotic proteins related to mitochondrial pathway apoptosis in CS rat offspring pFRG, such as Bax, Cytochrome C, caspase9 and caspase3. NaHS or 5-HD alone had no significant effect on above indexes. These results suggest that mitoKATP channels play an important role in the protective effect of H2S against impairment of central chemoreception via anti-apoptosis in pFRG of rat offspring exposed to maternal CS.
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Affiliation(s)
- Fang Lei
- West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Wen Wang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Yating Fu
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Ji Wang
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Yu Zheng
- Department of Physiology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, Sichuan, P.R. China
- * E-mail:
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26
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Signaling pathways targeting mitochondrial potassium channels. Int J Biochem Cell Biol 2020; 125:105792. [PMID: 32574707 DOI: 10.1016/j.biocel.2020.105792] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 12/11/2022]
Abstract
In this review, we describe key signaling pathways regulating potassium channels present in the inner mitochondrial membrane. The signaling cascades covered here include phosphorylation, redox reactions, modulation by calcium ions and nucleotides. The following types of potassium channels have been identified in the inner mitochondrial membrane of various tissues: ATP-sensitive, Ca2+-activated, voltage-gated and two-pore domain potassium channels. The direct roles of these channels involve regulation of mitochondrial respiration, membrane potential and synthesis of reactive oxygen species (ROS). Changes in channel activity lead to diverse pro-life and pro-death responses in different cell types. Hence, characterizing the signaling pathways regulating mitochondrial potassium channels will facilitate understanding the physiological role of these proteins. Additionally, we describe in this paper certain regulatory mechanisms, which are unique to mitochondrial potassium channels.
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Nikbakht F, Khanizadeh AM, Golab F, Baluchnejadmojarad T, Vazifehkhah S, Moeinsadat A. Mitochondrial ATP-sensitive potassium channel, MitoKATP, ameliorates mitochondrial dynamic disturbance induced by temporal lobe epilepsy. J Chem Neuroanat 2020; 113:101808. [PMID: 32497687 DOI: 10.1016/j.jchemneu.2020.101808] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 05/04/2020] [Accepted: 05/26/2020] [Indexed: 01/06/2023]
Abstract
Temporal lobe epilepsy leads to a disturbance in the function and dynamic of the mitochondria. The mitoKATP channel is an important factor in controlling mitochondrial function. In this study, the protective role of mitoKATP was studied in temporal lobe epilepsy through the regulation of mitochondrial dynamic proteins. After induction of epilepsy, 5-HD (the inhibitor of mitoKATP) was administered daily for either 24 or 72 h. The results revealed an imbalance in dynamic proteins after epilepsy, specifically in the first 72 h. The disturbance in the mitochondrial dynamic worsened after blocking mitoKATP. In conclusion, mitoKATP has an important role in balancing mitochondrial dynamic proteins in epilepsy.
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Affiliation(s)
- Farnaz Nikbakht
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine Iran University of Medical Sciences, Tehran, Iran
| | - Ali Mohammad Khanizadeh
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine Iran University of Medical Sciences, Tehran, Iran.
| | - Fereshteh Golab
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine Iran University of Medical Sciences, Tehran, Iran
| | - Tourandokht Baluchnejadmojarad
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine Iran University of Medical Sciences, Tehran, Iran
| | - Somayeh Vazifehkhah
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Moeinsadat
- Cellular and Molecular Research Center and Department of Physiology, School of Medicine Iran University of Medical Sciences, Tehran, Iran
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Diazoxide blocks or reduces microgliosis when applied prior or subsequent to motor neuron injury in mice. Brain Res 2020; 1741:146875. [PMID: 32389588 DOI: 10.1016/j.brainres.2020.146875] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 04/23/2020] [Accepted: 05/04/2020] [Indexed: 12/11/2022]
Abstract
Diazoxide (DZX), an anti-hypertonic and anti-hypoglycemic drug, was shown to have anti-inflammatory effects in several injured cell types outside the central nervous system. In the brain, the neuroprotective potential of DZX is well described, however, its anticipated anti-inflammatory effect after acute injury has not been systematically analyzed. To disclose the anti-inflammatory effect of DZX in the central nervous system, an injury was induced in the hypoglossal and facial nuclei and in the oculomotor nucleus by unilateral axonal transection and unilateral target deprivation (enucleation), respectively. On the fourth day after surgery, microglial analysis was performed on tissue in which microglia were DAB-labeled and motoneurons were labeled with immunofluorescence. DZX treatment was given either prophylactically, starting 7 days prior to the injury and continuing until the animals were sacrificed, or postoperatively only, with daily intraperitoneal injections (1.25 mg/kg; in 10 mg/ml dimethyl sulfoxide in distilled water). Prophylactically + postoperatively applied DZX completely eliminated the microglial reaction in each motor nuclei. If DZX was applied only postoperatively, some microglial activation could be detected, but its magnitude was still significantly smaller than the non-DZX-treated controls. The effect of DZX could also be demonstrated through an extended period, as tested in the hypoglossal nucleus on day 7 after the operation. Neuronal counts, determined at day 4 after the operation in the hypoglossal nucleus, demonstrated no loss of motor neurons, however, an increased Feret's diameter of mitochondria could be measured, suggesting increased oxidative stress in the injured cells. The increase of mitochondrial Feret's diameter could also be prevented with DZX treatment.
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Akopova O, Kolchinskaya L, Nosar V, Mankovska I, Sagach V. Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale. BMC Mol Cell Biol 2020; 21:31. [PMID: 32306897 PMCID: PMC7168813 DOI: 10.1186/s12860-020-00275-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 04/07/2020] [Indexed: 12/21/2022] Open
Abstract
Background Cytoprotection afforded by mitochondrial ATP-sensitive K+-channel (mKATP-channel) opener diazoxide (DZ) largely depends on the activation of potassium cycle with eventual modulation of mitochondrial functions and ROS production. However, generally these effects were studied in the presence of Mg∙ATP known to block K+ transport. Thus, the purpose of our work was the estimation of DZ effects on K+ transport, K+ cycle and ROS production in rat liver mitochondria in the absence of Mg∙ATP. Results Without Mg·ATP, full activation of native mKATP-channel, accompanied by the increase in ATP-insensitive K+ uptake, activation of K+-cycle and respiratory uncoupling, was reached at ≤0.5 μM of DZ,. Higher diazoxide concentrations augmented ATP-insensitive K+ uptake, but not mKATP-channel activity. mKATP-channel was blocked by Mg·ATP, reactivated by DZ, and repeatedly blocked by mKATP-channel blockers glibenclamide and 5-hydroxydecanoate, whereas ATP-insensitive potassium transport was blocked by Mg2+ and was not restored by DZ. High sensitivity of potassium transport to DZ in native mitochondria resulted in suppression of mitochondrial ROS production caused by the activation of K+-cycle on sub-micromolar scale. Based on the oxygen consumption study, the share of mKATP-channel in respiratory uncoupling by DZ was found. Conclusions The study of mKATP-channel activation by diazoxide in the absence of MgATP discloses novel, not described earlier, aspects of mKATP-channel interaction with this drug. High sensitivity of mKATP-channel to DZ results in the modulation of mitochondrial functions and ROS production by DZ on sub-micromolar concentration scale. Our experiments led us to the hypothesis that under the conditions marked by ATP deficiency affinity of mKATP-channel to DZ can increase, which might contribute to the high effectiveness of this drug in cardio- and neuroprotection.
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Affiliation(s)
- Olga Akopova
- Circulation department, Bogomoletz Institute of Physiology, NAS of Ukraine, Bogomoletz str. 4, Kiev, 01601, Ukraine.
| | - Liudmila Kolchinskaya
- Circulation department, Bogomoletz Institute of Physiology, NAS of Ukraine, Bogomoletz str. 4, Kiev, 01601, Ukraine
| | - Valentina Nosar
- Hypoxic States Research Department, Bogomoletz Institute of Physiology, NAS of Ukraine, Kiev, Ukraine
| | - Iryna Mankovska
- Hypoxic States Research Department, Bogomoletz Institute of Physiology, NAS of Ukraine, Kiev, Ukraine
| | - Vadim Sagach
- Circulation department, Bogomoletz Institute of Physiology, NAS of Ukraine, Bogomoletz str. 4, Kiev, 01601, Ukraine
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Papanicolaou KN, Ashok D, Liu T, Bauer TM, Sun J, Li Z, da Costa E, D'Orleans CC, Nathan S, Lefer DJ, Murphy E, Paolocci N, Foster DB, O'Rourke B. Global knockout of ROMK potassium channel worsens cardiac ischemia-reperfusion injury but cardiomyocyte-specific knockout does not: Implications for the identity of mitoKATP. J Mol Cell Cardiol 2020; 139:176-189. [PMID: 32004507 PMCID: PMC7849919 DOI: 10.1016/j.yjmcc.2020.01.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 01/16/2020] [Accepted: 01/23/2020] [Indexed: 01/29/2023]
Abstract
The renal-outer-medullary‑potassium (ROMK) channel, mutated in Bartter's syndrome, regulates ion exchange in kidney, but its extra-renal functions remain unknown. Additionally, ROMK was postulated to be the pore-forming subunit of the mitochondrial ATP-sensitive K+ channel (mitoKATP), a mediator of cardioprotection. Using global and cardiomyocyte-specific knockout mice (ROMK-GKO and ROMK-CKO respectively), we characterize the effects of ROMK knockout on mitochondrial ion handling, the response to pharmacological KATP channel modulators, and ischemia/reperfusion (I/R) injury. Mitochondria from ROMK-GKO hearts exhibited a lower threshold for Ca2+-triggered permeability transition pore (mPTP) opening but normal matrix volume changes during oxidative phosphorylation. Isolated perfused ROMK-GKO hearts exhibited impaired functional recovery and increased infarct size when I/R was preceded by an ischemic preconditioning (IPC) protocol. Because ROMK-GKO mice exhibited severe renal defects and cardiac remodeling, we further characterized ROMK-CKO hearts to avoid confounding systemic effects. Mitochondria from ROMK-CKO hearts had unchanged matrix volume responses during oxidative phosphorylation and still swelled upon addition of a mitoKATP opener, but exhibited a lower threshold for mPTP opening, similar to GKO mitochondria. Nevertheless, I/R induced damage was not exacerbated in ROMK-CKO hearts, either ex vivo or in vivo. Lastly, we examined the response of ROMK-CKO hearts to ex vivo I/R injury with or without IPC and found that IPC still protected these hearts, suggesting that cardiomyocyte ROMK does not participate significantly in the cardioprotective pathway elicited by IPC. Collectively, our findings from these novel strains of mice suggest that cardiomyocyte ROMK is not a central mediator of mitoKATP function, although it can affect mPTP activation threshold.
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Affiliation(s)
- Kyriakos N Papanicolaou
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Deepthi Ashok
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ting Liu
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tyler M Bauer
- Cardiovascular Branch, NHLBI, NIH, 10 Center Drive, Bethesda, MD, USA
| | - Junhui Sun
- Cardiovascular Branch, NHLBI, NIH, 10 Center Drive, Bethesda, MD, USA
| | - Zhen Li
- Cardiovascular Center of Excellence, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA, USA; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA, USA
| | - Eduardo da Costa
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Charles Crepy D'Orleans
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Sara Nathan
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David J Lefer
- Cardiovascular Center of Excellence, Louisiana State University (LSU) Health Sciences Center, New Orleans, LA, USA; Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA, USA
| | - Elizabeth Murphy
- Cardiovascular Branch, NHLBI, NIH, 10 Center Drive, Bethesda, MD, USA
| | - Nazareno Paolocci
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - D Brian Foster
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brian O'Rourke
- Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Woo SK, Tsymbalyuk N, Tsymbalyuk O, Ivanova S, Gerzanich V, Simard JM. SUR1-TRPM4 channels, not K ATP, mediate brain swelling following cerebral ischemia. Neurosci Lett 2019; 718:134729. [PMID: 31899311 DOI: 10.1016/j.neulet.2019.134729] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 12/30/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND Preclinical and emerging clinical data show that glibenclamide reduces space occupying edema and brain swelling following cerebral ischemia. Glibenclamide is a potent inhibitor of numerous sulfonylurea receptor (SUR)-regulated channels, including KATP (SUR1-KIR6.2, SUR2A-KIR6.2, SUR2B-KIR6.2, SUR2B-KIR6.1) and SUR1-TRPM4. Here, we used molecularly specific oligodeoxynucleotides (ODNs) to investigate the role of various SUR-regulated ion channel subunits in post-ischemic brain swelling. METHODS Focal cerebral ischemia was induced in adult male rats by permanent middle cerebral artery occlusion (pMCAo). We used this model to study the effects of antisense-ODNs (AS-ODNs) directed against Abcc8/SUR1, Trpm4/TRPM4, Kcnj8/KIR6.1 and Kcnj11/KIR6.2 on hemispheric swelling, with sense or scrambled ODNs used as controls. We used antibody-based Förster resonance energy transfer (immuno-FRET) and co-immunoprecipitation to study the co-assembly of SUR1-TRPM4 heteromers. RESULTS In the combined control groups administered sense or scrambled ODNs, pMCAo resulted in uniformly large infarct volumes (mean ± SD: 57.4 ± 8.8 %; n = 34) at 24 h after onset of ischemia, with no effect of AS-ODNs on infarct size. In controls, hemispheric swelling was 23.9 ± 4.1 % (n = 34), and swelling was linearly related to infarct volume (P < 0.02). In the groups administered anti-Abcc8/SUR1 or anti-Trpm4/TRPM4 AS-ODN, hemispheric swelling was significantly less, 11.6 ± 3.9 % and 12.8 ± 5.8 % respectively (P < 0.0001), and the relationship between infarct volume and swelling was reduced and not significant. AS-ODNs directed against Kcnj8/KIR6.1 and Kcnj11/KIR6.2 had no significant effect on hemispheric swelling (23.3 ± 5.4 % and 22.9 ± 5.8 % respectively). Post-ischemic tissues showed co-assembly of SUR1-TRPM4 heteromers. CONCLUSIONS Post-ischemic hemispheric swelling can be decoupled from infarct volume. SUR1-TRPM4 channels, not KATP, mediate post-ischemic brain swelling.
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Affiliation(s)
- Seung Kyoon Woo
- Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Natalia Tsymbalyuk
- Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Orest Tsymbalyuk
- Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Svetlana Ivanova
- Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Volodymyr Gerzanich
- Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - J Marc Simard
- Departments of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Departments of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, United States; Departments of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States.
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Single-Channel Properties of the ROMK-Pore-Forming Subunit of the Mitochondrial ATP-Sensitive Potassium Channel. Int J Mol Sci 2019; 20:ijms20215323. [PMID: 31731540 PMCID: PMC6862428 DOI: 10.3390/ijms20215323] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Revised: 10/21/2019] [Accepted: 10/23/2019] [Indexed: 12/11/2022] Open
Abstract
An increased flux of potassium ions into the mitochondrial matrix through the ATP-sensitive potassium channel (mitoKATP) has been shown to provide protection against ischemia-reperfusion injury. Recently, it was proposed that the mitochondrial-targeted isoform of the renal outer medullary potassium channel (ROMK) protein creates a pore-forming subunit of mitoKATP in heart mitochondria. Our research focuses on the properties of mitoKATP from heart-derived H9c2 cells. For the first time, we detected single-channel activity and describe the pharmacology of mitoKATP in the H9c2 heart-derived cells. The patch-clamping of mitoplasts from wild type (WT) and cells overexpressing ROMK2 revealed the existence of a potassium channel that exhibits the same basic properties previously attributed to mitoKATP. ROMK2 overexpression resulted in a significant increase of mitoKATP activity. The conductance of both channels in symmetric 150/150 mM KCl was around 97 ± 2 pS in WT cells and 94 ± 3 pS in cells overexpressing ROMK2. The channels were inhibited by 5-hydroxydecanoic acid (a mitoKATP inhibitor) and by Tertiapin Q (an inhibitor of both the ROMK-type channels and mitoKATP). Additionally, mitoKATP from cells overexpressing ROMK2 were inhibited by ATP/Mg2+ and activated by diazoxide. We used an assay based on proteinase K to examine the topology of the channel in the inner mitochondrial membrane and found that both termini of the protein localized to the mitochondrial matrix. We conclude that the observed activity of the channel formed by the ROMK protein corresponds to the electrophysiological and pharmacological properties of mitoKATP.
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33
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Kampa RP, Kicinska A, Jarmuszkiewicz W, Pasikowska-Piwko M, Dolegowska B, Debowska R, Szewczyk A, Bednarczyk P. Naringenin as an opener of mitochondrial potassium channels in dermal fibroblasts. Exp Dermatol 2019; 28:543-550. [PMID: 30776180 DOI: 10.1111/exd.13903] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 02/14/2019] [Indexed: 12/25/2022]
Abstract
Flavonoids belong to a large group of polyphenolic compounds that are widely present in plants. Certain flavonoids, including naringenin, have cytoprotective properties. Although the antioxidant effect has long been thought to be a crucial factor accounting for the cellular effects of flavonoids, mitochondrial channels have emerged recently as targets for cytoprotective strategies. In the present study, we characterized interactions between naringenin and the mitochondrial potassium (mitoBKC a and mitoKATP ) channels recently described in dermal fibroblasts. With the use of the patch-clamp technique and mitoplasts isolated from primary human dermal fibroblast cells, our study shows that naringenin in micromolar concentrations leads to an increase in mitoBKC a channel activity. The opening probability of the channel decreased from 0.97 in the control conditions (200 μmol/L Ca2+ ) to 0.06 at a low Ca2+ level (1 μmol/L) and increased to 0.85 after the application of 10 μmol/L naringenin. Additionally, the activity of the mitoKATP channel increased following the application of 10 μmol/L naringenin. To investigate the effects of naringenin on mitochondrial function, the oxygen consumption of dermal fibroblast cells was measured in potassium-containing media. The addition of naringenin significantly and dose-dependently increased the respiratory rate from 5.8 ± 0.2 to 14.0 ± 0.6 nmol O2 × min-1 × mg protein-1 . Additionally, a Raman spectroscopy analysis of skin penetration indicated that the naringenin was distributed in all skin layers, including the epidermis and dermis. In this study, we demonstrated that a flavonoid, naringenin, can activate two potassium channels present in the inner mitochondrial membrane of dermal fibroblasts.
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Affiliation(s)
- Rafal Pawel Kampa
- Department of Biophysics, Warsaw, University of Life Sciences - SGGW, Warsaw, Poland.,Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw, Poland
| | - Anna Kicinska
- Laboratory of Bioenergetics, Adam Mickiewicz University, Poznan, Poland
| | | | | | - Barbara Dolegowska
- Department of Laboratory Medicine, Pomeranian Medical University, Szczecin, Poland
| | - Renata Debowska
- Dr Irena Eris Cosmetic Laboratory, Center for Science and Research, Piaseczno, Poland
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Science, Warsaw, Poland
| | - Piotr Bednarczyk
- Department of Biophysics, Warsaw, University of Life Sciences - SGGW, Warsaw, Poland
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Joshi S, Jarajapu YPR. Mitochondrial depolarization stimulates vascular repair-relevant functions of CD34 + cells via reactive oxygen species-induced nitric oxide generation. Br J Pharmacol 2018; 176:4373-4387. [PMID: 30367728 DOI: 10.1111/bph.14529] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 08/23/2018] [Accepted: 09/19/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND AND PURPOSE CD34+ haematopoietic stem/progenitor cells have revascularization potential and are now being tested for the treatment of ischaemic vascular diseases in clinical trials. We tested the hypothesis that mitochondrial depolarization stimulates the reparative functions of CD34+ cells. EXPERIMENTAL APPROACH Peripheral blood was obtained from healthy individuals (n = 63), and mononuclear cells (MNCs) were separated. MNCs were enriched for lineage negative cells, followed by isolation of CD34+ cells. Vascular repair-relevant functions of CD34+ cells, proliferation and migration, were evaluated in the presence and absence of diazoxide. Mitochondrial membrane potential, ROS and NO levels were evaluated by flow cytometry by using JC-1, mitoSOX and DAF-FM respectively. KEY RESULTS Diazoxide stimulated the proliferation and migration of CD34+ cells that were comparable to the responses induced by stromal-derived factor-1α (SDF) or VEGF. Effects of diazoxide were blocked by either 5-hydroxydecanoate (5HD), a selective mitochondrial ATP-sensitive potassium channel (mitoKATP ) inhibitor, or by L-NAME. Diazoxide induced mitochondrial depolarization, and NO and cGMP generation that were 5HD-sensitive. The generation of NO and cGMP by diazoxide was blocked by an endothelial NOS (eNOS)-selective inhibitor, NIO, but not by a neuronal (n)NOS-selective inhibitor, Nω -propyl-L-arginine (NPA). A Ca2+ chelator, BAPTA, Akt inhibitor, triciribine, or PI3K inhibitor, LY294002, inhibited the NO release induced by diazoxide. Phosphorylation of eNOS at Ser1177 and dephosphorylation at Thr495 were increased. Diazoxide-induced ROS generation and phosphorylation of eNOS at Ser1177 were reduced by NPA. CONCLUSION AND IMPLICATIONS Diazoxide stimulates vascular repair-relevant functions of CD34+ cells via the mitoKATP -dependent release of NO and ROS. LINKED ARTICLES This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
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Affiliation(s)
- Shrinidh Joshi
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
| | - Yagna P R Jarajapu
- Department of Pharmaceutical Sciences, College of Health Professions, North Dakota State University, Fargo, ND, USA
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Arabian M, Aboutaleb N, Soleimani M, Ajami M, Habibey R, Pazoki-Toroudi H. Activation of mitochondrial KATP channels mediates neuroprotection induced by chronic morphine preconditioning in hippocampal CA-1 neurons following cerebral ischemia. Adv Med Sci 2018; 63:213-219. [PMID: 29223124 DOI: 10.1016/j.advms.2017.11.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 09/22/2017] [Accepted: 11/13/2017] [Indexed: 12/22/2022]
Abstract
PURPOSE Pharmacologic preconditioning, through activating several mechanisms and mediators, can increase the tolerance of different tissues against ischemia/reperfusion (I/R) injury. Recent studies have shown that morphine preconditioning has protective effects in different organs, especially in the heart. Nevertheless, its mechanisms are not well elucidated in the brain. The present study aimed to clarify whether the activation of mitochondrial KATP (mKATP) channels in chronic morphine (CM) preconditioning could decrease hippocampus damage following I/R injury. MATERIALS AND METHODS CM preconditioning was performed by the administration of additive doses of morphine for 5days before I/R injury induction. I/R injury was induced by the occlusion of bilateral common carotid arteries. The possible role of mKATP channels was evaluated by the injection of 5-hydroxydecanoate (5-HD) before I/R injury. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was performed to detect apoptosis in hippocampal neurons. The expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX) and levels of malondialdehyde (MDA) and catalase (CAT) enzymes were assessed. RESULTS CM attenuated apoptosis in the hippocampal CA1 neurons (P<0.001 vs I/R), and mKATP channel blocking with 5-HD significantly increased apoptosis (P<0.001 vs CM+I/R). CM increased CAT activity (P<0.05 vs I/R) and Bcl-2 protein expression (P<0.01 vs I/R), while it decreased MDA level (P<0.05 vs I/R) and BAX protein expression (P<0.05 vs I/R). Pretreatment with 5-HD abolished all the above-mentioned effects of CM. CONCLUSIONS These findings describe novel evidence whereby CM preconditioning in hippocampal CA1 neurons can improve oxidative stress and apoptosis through the activation of mKATP channels and eventually protect the hippocampal tissue against I/R injury.
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Affiliation(s)
- Maedeh Arabian
- Rajaie Cardiovascular, Medical, and Research Centre, Iran University of Medical Sciences, Tehran, Iran
| | - Nahid Aboutaleb
- Physiology Research Center, Physiology Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mansoureh Soleimani
- Department of Anatomy, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Marjan Ajami
- Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Rouhollah Habibey
- Department of Neuroscience and Brain Technologies-Istituto Italiano di Technologia, Via Morego, 30, 16163 Genova, Italy
| | - Hamidreza Pazoki-Toroudi
- Physiology Research Center, Physiology Department, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
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Ramratnam M, Kenny B, Kyle JW, Wiedmeyer B, Hacker TA, Barefield DY, McNally EM, Makielski JC. Transgenic overexpression of the SUR2A-55 splice variant in mouse heart reduces infract size and promotes protective mitochondrial function. Heliyon 2018; 4:e00677. [PMID: 29998196 PMCID: PMC6037880 DOI: 10.1016/j.heliyon.2018.e00677] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 06/28/2018] [Indexed: 01/21/2023] Open
Abstract
ATP-sensitive potassium channels found in both the sarcolemma (sarcKATP) and mitochondria (mitoKATP) of cardiomyocytes are important mediators of cardioprotection during ischemic heart disease. Sulfonylurea receptor isoforms (SUR2), encoded by Abcc9, an ATP-binding cassette family member, form regulatory subunits of the sarcKATP channel and are also thought to regulate mitoKATP channel activity. A short-form splice variant of SUR2 (SUR2A-55) was previously shown to target mitochondria and display diaxoxide and ATP insensitive KATP activity when co-expressed with the inward rectifier channels Kir6.2 and Kir6.1. We hypothesized that mice with cardiac specific overexpression of SUR2A-55 would mediate cardioprotection from ischemia by altering mitoKATP properties. Mice overexpressing SUR2A-55 (TGSUR2A-55) in cardiomyocytes were generated and showed no significant difference in echocardiographic measured chamber dimension, percent fractional shortening, heart to body weight ratio, or gross histologic features compared to normal mice at 11–14 weeks of age. TGSUR2A-55 had improved hemodynamic functional recovery and smaller infarct size after ischemia reperfusion injury compared to WT mice in an isolated hanging heart model. The mitochondrial membrane potential of TGSUR2A-55 mice was less sensitive to ATP, diazoxide, and Ca2+ loading. These data suggest that the SUR2A-55 splice variant favorably affects mitochondrial function leading to cardioprotection. These data support a role for the regulation of mitoKATP activity by SUR2A-55.
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Affiliation(s)
- Mohun Ramratnam
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States.,Cardiology Section, Medical Service, William. S. Middleton Memorial Veterans Hospital, Madison, WI, United States
| | - Barrett Kenny
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - John W Kyle
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Brandi Wiedmeyer
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Timothy A Hacker
- Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - David Y Barefield
- Center for Genetic Medicine, Northwestern University, Chicago, IL, United States
| | - Elizabeth M McNally
- Center for Genetic Medicine, Northwestern University, Chicago, IL, United States
| | - Jonathan C Makielski
- Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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Zhu F, Zhong X, Zhou Y, Hou Z, Hu H, Liang L, Chen J, Chen Q, Ji X, Shang D. Protective effects of nicorandil against cerebral injury in a swine cardiac arrest model. Exp Ther Med 2018; 16:37-44. [PMID: 29977355 PMCID: PMC6030868 DOI: 10.3892/etm.2018.6136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 10/25/2017] [Indexed: 01/28/2023] Open
Abstract
The present study investigated the effects of nicorandil on cerebral injury following cardiopulmonary resuscitation (CPR) in a swine model of cardiac arrest. CPR was performed on swine following 4 min induced ventricular fibrillation. Surviving animals were randomly divided into 3 groups: A nicorandil group (n=8), a control group (n=8) and a sham group (n=4). The sham group underwent the same surgical procedure to imitate cardiac arrest, but ventricular fibrillation was not induced. When the earliest observable return of spontaneous circulation (ROSC) was detected, the nicorandil and control groups received injections of nicorandil and saline, respectively. Swine serum was collected at baseline and 5 min, 0.5, 3 and 6 h following ROSC. Serum levels of neuron-specific enolase (NSE), S100β, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured using ELISA. Animals were euthanized and brain tissue samples were collected and assessed using light and electron microscopy 6 h following ROSC. The expression of aquaporin-4 (AQP-4) in the brain tissue was measured using western blotting. Malondialdehyde (MDA) and glutathione (GSH) levels in the brain tissue were determined using thiobarbituric acid and thiobenzoic acid colorimetric methods, respectively. Serum NSE and S100β were significantly higher in the nicorandil and control groups following CPR, compared with baseline (P<0.05). Additionally, NSE and S100β levels were significantly lower in the nicorandil group compared with the control (P<0.05). Pathological examinations and electron microscopy indicated that nicorandil reduced brain tissue damage. TNF-α and IL-6 levels were significantly decreased in the nicorandil group compared with the control group (P<0.05). Furthermore, AQP-4 expression in brain tissue 6 h following ROSC was significantly lower in the nicorandil group compared with the control group (P<0.05). MDA and GSH levels in swine brain tissue decreased and increased, respectively, in the nicorandil group compared with the control group (P<0.05). The results of the present study demonstrate that nicorandil exerts a protective effect against brain injury following cardiac arrest by reducing oxidative damage, inflammatory responses and brain edema post-ROSC.
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Affiliation(s)
- Fangfang Zhu
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xia Zhong
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Yi Zhou
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Zhiqiang Hou
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Haoran Hu
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Lining Liang
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Jibin Chen
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Qianqian Chen
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Xianfei Ji
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
| | - Deya Shang
- Emergency Department, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
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38
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Berry BJ, Trewin AJ, Amitrano AM, Kim M, Wojtovich AP. Use the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species. J Mol Biol 2018; 430:3873-3891. [PMID: 29626541 DOI: 10.1016/j.jmb.2018.03.025] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/21/2018] [Accepted: 03/26/2018] [Indexed: 02/06/2023]
Abstract
Mitochondrial respiration results in an electrochemical proton gradient, or protonmotive force (pmf), across the mitochondrial inner membrane. The pmf is a form of potential energy consisting of charge (∆ψm) and chemical (∆pH) components, that together drive ATP production. In a process called uncoupling, proton leak into the mitochondrial matrix independent of ATP production dissipates the pmf and energy is lost as heat. Other events can directly dissipate the pmf independent of ATP production as well, such as chemical exposure or mechanisms involving regulated mitochondrial membrane electrolyte transport. Uncoupling has defined roles in metabolic plasticity and can be linked through signal transduction to physiologic events. In the latter case, the pmf impacts mitochondrial reactive oxygen species (ROS) production. Although capable of molecular damage, ROS also have signaling properties that depend on the timing, location, and quantity of their production. In this review, we provide a general overview of mitochondrial ROS production, mechanisms of uncoupling, and how these work in tandem to affect physiology and pathologies, including obesity, cardiovascular disease, and immunity. Overall, we highlight that isolated bioenergetic models-mitochondria and cells-only partially recapitulate the complex link between the pmf and ROS signaling that occurs in vivo.
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Affiliation(s)
- Brandon J Berry
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Box 711/604, 575 Elmwood Ave., Rochester, NY 14642, USA.
| | - Adam J Trewin
- Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Box 711/604, 575 Elmwood Ave., Rochester, NY 14642, USA.
| | - Andrea M Amitrano
- Department of Pathology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA; Department of Microbiology and Immunology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA.
| | - Minsoo Kim
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Box 711/604, 575 Elmwood Ave., Rochester, NY 14642, USA; Department of Pathology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA; Department of Microbiology and Immunology, University of Rochester Medical Center, Box 609, 601 Elmwood Ave., Rochester, NY 14642, USA.
| | - Andrew P Wojtovich
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Box 711/604, 575 Elmwood Ave., Rochester, NY 14642, USA; Department of Anesthesiology and Perioperative Medicine, University of Rochester Medical Center, Box 711/604, 575 Elmwood Ave., Rochester, NY 14642, USA.
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Chen S, Lotz C, Roewer N, Broscheit JA. Comparison of volatile anesthetic-induced preconditioning in cardiac and cerebral system: molecular mechanisms and clinical aspects. Eur J Med Res 2018; 23:10. [PMID: 29458412 PMCID: PMC5819224 DOI: 10.1186/s40001-018-0308-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2016] [Accepted: 02/12/2018] [Indexed: 12/17/2022] Open
Abstract
Volatile anesthetic-induced preconditioning (APC) has shown to have cardiac and cerebral protective properties in both pre-clinical models and clinical trials. Interestingly, accumulating evidences demonstrate that, except from some specific characters, the underlying molecular mechanisms of APC-induced protective effects in myocytes and neurons are very similar; they share several major intracellular signaling pathways, including mediating mitochondrial function, release of inflammatory cytokines and cell apoptosis. Among all the experimental results, cortical spreading depolarization is a relative newly discovered cellular mechanism of APC, which, however, just exists in central nervous system. Applying volatile anesthetic preconditioning to clinical practice seems to be a promising cardio-and neuroprotective strategy. In this review, we also summarized and discussed the results of recent clinical research of APC. Despite all the positive experimental evidences, large-scale, long-term, more precisely controlled clinical trials focusing on the perioperative use of volatile anesthetics for organ protection are still needed.
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Affiliation(s)
- Shasha Chen
- Department of Anesthesiology and Critical Care, University of Wuerzburg, Oberduerrbacher Str.6, 97080, Wuerzburg, Germany.
| | - Christopher Lotz
- Department of Anesthesiology and Critical Care, University of Wuerzburg, Oberduerrbacher Str.6, 97080, Wuerzburg, Germany
| | - Norbert Roewer
- Department of Anesthesiology and Critical Care, University of Wuerzburg, Oberduerrbacher Str.6, 97080, Wuerzburg, Germany
| | - Jens-Albert Broscheit
- Department of Anesthesiology and Critical Care, University of Wuerzburg, Oberduerrbacher Str.6, 97080, Wuerzburg, Germany
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40
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Bednarczyk P, Kicinska A, Laskowski M, Kulawiak B, Kampa R, Walewska A, Krajewska M, Jarmuszkiewicz W, Szewczyk A. Evidence for a mitochondrial ATP-regulated potassium channel in human dermal fibroblasts. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2018; 1859:309-318. [PMID: 29458000 DOI: 10.1016/j.bbabio.2018.02.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 01/04/2018] [Accepted: 02/14/2018] [Indexed: 02/07/2023]
Abstract
Mitochondrial ATP-regulated potassium channels are present in the inner membrane of the mitochondria of various cells. In the present study, we show for the first time mitochondrial ATP-regulated potassium channels in human dermal fibroblast cells. Using the patch-clamp technique on the inner mitochondrial membrane of fibroblasts, we detected a potassium channel with a mean conductance equal to 100 pS in symmetric 150 mM KCl. The activity of this channel was inhibited by a complex of ATP/Mg2+ and activated by potassium channel openers such as diazoxide or BMS 191095. Channel activity was inhibited by antidiabetic sulfonylurea glibenclamide and 5-hydroxydecanoic acid. The influence of substances modulating ATP-regulated potassium channel activity on oxygen consumption and membrane potential of isolated fibroblast mitochondria was also studied. Additionally, the potassium channel opener diazoxide lowered the amount of superoxide formed in isolated fibroblast mitochondria. Using reverse transcriptase-PCR, we found an mRNA transcript for the KCNJ1(ROMK) channel. The presence of ROMK protein was observed in the inner mitochondrial membrane fraction. Moreover, colocalization of the ROMK protein and a mitochondrial marker in the mitochondria of fibroblast cells was shown by immunofluorescence. In summary, the ATP-regulated mitochondrial potassium channel in a dermal fibroblast cell line have been identified.
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Affiliation(s)
- Piotr Bednarczyk
- Department of Biophysics, Warsaw University of Life Sciences (SGGW), Warsaw, Poland.
| | - Anna Kicinska
- Department of Bioenergetics, Adam Mickiewicz University, Poznan, Poland
| | - Michal Laskowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Bogusz Kulawiak
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Rafal Kampa
- Department of Biophysics, Warsaw University of Life Sciences (SGGW), Warsaw, Poland; Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Agnieszka Walewska
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland
| | - Milena Krajewska
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland
| | | | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Warsaw, Poland
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41
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Deryagin OG, Gavrilova SA, Gainutdinov KL, Golubeva AV, Andrianov VV, Yafarova GG, Buravkov SV, Koshelev VB. Molecular Bases of Brain Preconditioning. Front Neurosci 2017; 11:427. [PMID: 28790886 PMCID: PMC5524930 DOI: 10.3389/fnins.2017.00427] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 07/11/2017] [Indexed: 12/20/2022] Open
Abstract
Preconditioning of the brain induces tolerance to the damaging effects of ischemia and prevents cell death in ischemic penumbra. The development of this phenomenon is mediated by mitochondrial adenosine triphosphate-sensitive potassium (KATP+) channels and nitric oxide signaling (NO). The aim of this study was to investigate the dynamics of molecular changes in mitochondria after ischemic preconditioning (IP) and the effect of pharmacological preconditioning (PhP) with the KATP+-channels opener diazoxide on NO levels after ischemic stroke in rats. Immunofluorescence-histochemistry and laser-confocal microscopy were applied to evaluate the cortical expression of electron transport chain enzymes, mitochondrial KATP+-channels, neuronal and inducible NO-synthases, as well as the dynamics of nitrosylation and nitration of proteins in rats during the early and delayed phases of IP. NO cerebral content was studied with electron paramagnetic resonance (EPR) spectroscopy using spin trapping. We found that 24 h after IP in rats, there is a two-fold decrease in expression of mitochondrial KATP+-channels (p = 0.012) in nervous tissue, a comparable increase in expression of cytochrome c oxidase (p = 0.008), and a decrease in intensity of protein S-nitrosylation and nitration (p = 0.0004 and p = 0.001, respectively). PhP led to a 56% reduction of free NO concentration 72 h after ischemic stroke simulation (p = 0.002). We attribute this result to the restructuring of tissue energy metabolism, namely the provision of increased catalytic sites to mitochondria and the increased elimination of NO, which prevents a decrease in cell sensitivity to oxygen during subsequent periods of severe ischemia.
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Affiliation(s)
- Oleg G Deryagin
- Department of Physiology and General Pathology, Medical Faculty, Lomonosov Moscow State UniversityMoscow, Russia
| | - Svetlana A Gavrilova
- Department of Physiology and General Pathology, Medical Faculty, Lomonosov Moscow State UniversityMoscow, Russia
| | - Khalil L Gainutdinov
- Laboratory of Neurorehabilitation of Motor Disorders, Institute of Fundamental Medicine and Biology, Kazan Federal UniversityKazan, Russia.,Laboratory of Spin Physics and Spin Chemistry, Zavoisky Physical-Technical Institute of the Russian Academy of SciencesKazan, Russia
| | - Anna V Golubeva
- Department of Physiology and General Pathology, Medical Faculty, Lomonosov Moscow State UniversityMoscow, Russia
| | - Vyatcheslav V Andrianov
- Laboratory of Neurorehabilitation of Motor Disorders, Institute of Fundamental Medicine and Biology, Kazan Federal UniversityKazan, Russia.,Laboratory of Spin Physics and Spin Chemistry, Zavoisky Physical-Technical Institute of the Russian Academy of SciencesKazan, Russia
| | - Guzel G Yafarova
- Laboratory of Neurorehabilitation of Motor Disorders, Institute of Fundamental Medicine and Biology, Kazan Federal UniversityKazan, Russia.,Laboratory of Spin Physics and Spin Chemistry, Zavoisky Physical-Technical Institute of the Russian Academy of SciencesKazan, Russia
| | - Sergey V Buravkov
- Research Laboratory of Cellular Structure and Tissue Imaging Analysis, Medical Faculty, Lomonosov Moscow State UniversityMoscow, Russia
| | - Vladimir B Koshelev
- Department of Physiology and General Pathology, Medical Faculty, Lomonosov Moscow State UniversityMoscow, Russia
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Abstract
BACKGROUND ATP-sensitive K+ (KATP) channels couple metabolic state to cellular excitability. Activation of neuronal and astrocytic mitochondrial KATP (mitoKATP) channels regulates a variety of neuronal functions. However, less is known about the impact of mitoKATP on tonic γ-aminobutyric acid (GABA) inhibition. Tonic GABA inhibition is mediated by the binding of ambient GABA on extrasynaptic GABA A-type receptors (GABAARs) and is involved in regulating neuronal excitability. METHODS We determined the impact of activation of KATP channels with diazoxide (DIZ) on tonic inhibition and recorded tonic current from rat cortical layer 5 pyramidal cells by patch-clamp recordings. RESULTS We found that neonatal tonic current increased with an increase in GABA concentration, which was partially mediated by the GABA A-type receptor (GABAAR) α5, and likely the δ subunits. Activation of KATP channels resulted in decreased tonic current in newborns, but there was increased tonic current during the second postnatal week. CONCLUSIONS These findings suggest that activation of KATP channels with DIZ regulates GABAergic transmission in neocortical pyramidal cells during development.
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The Slo(w) path to identifying the mitochondrial channels responsible for ischemic protection. Biochem J 2017; 474:2067-2094. [PMID: 28600454 DOI: 10.1042/bcj20160623] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 02/10/2017] [Accepted: 02/13/2017] [Indexed: 12/19/2022]
Abstract
Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition pore being the major causes of IR-induced cell death. Thus, mitochondria are an appropriate focus for strategies to protect against IR injury. Two widely studied paradigms of IR protection, particularly in the field of cardiac IR, are ischemic preconditioning (IPC) and volatile anesthetic preconditioning (APC). While the molecular mechanisms recruited by these protective paradigms are not fully elucidated, a commonality is the involvement of mitochondrial K+ channel opening. In the case of IPC, research has focused on a mitochondrial ATP-sensitive K+ channel (mitoKATP), but, despite recent progress, the molecular identity of this channel remains a subject of contention. In the case of APC, early research suggested the existence of a mitochondrial large-conductance K+ (BK, big conductance of potassium) channel encoded by the Kcnma1 gene, although more recent work has shown that the channel that underlies APC is in fact encoded by Kcnt2 In this review, we discuss both the pharmacologic and genetic evidence for the existence and identity of mitochondrial K+ channels, and the role of these channels both in IR protection and in regulating normal mitochondrial function.
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Yuan F, Fu H, Sun K, Wu S, Dong T. Effect of dexmedetomidine on cerebral ischemia-reperfusion rats by activating mitochondrial ATP-sensitive potassium channel. Metab Brain Dis 2017; 32:539-546. [PMID: 28035625 DOI: 10.1007/s11011-016-9945-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 12/26/2016] [Indexed: 12/24/2022]
Abstract
The aim of the study reported here was to evaluate whether the mitochondrial ATP-sensitive potassium (mitoKATP) channel could participate in the effect of dexmedetomidine on cerebral ischemia-reperfusion (I/R) rats. Forty rats were randomly assigned into 5 groups: sham operation (S) group; cerebral I/R group; dexmedetomidine (D) group; 5-hydroxydecanoate (5-HD) group; 5-HD + D group. The cerebral I/R were produced by 2 h right middle cerebral artery occlusion followed by 24 h reperfusion. Dexmedetomidine (50μg/kg) was injected intraperitoneally before ischemia and after the onset of reperfusion. 5-HD (30 mg/kg) was injected intraperitoneally at 1 h before ischemia. The neurological deficit score (NDS) and the levels of super oxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were evaluated. Compared to group S, NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly higher, and SOD levels were significantly lower in the other groups (P < 0.05). Compared to group I/R,NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly lower, and SOD level was significantly higher in group D (P < 0.05). Compared to group D, NDS and the levels of MDA, MPO, IL-6 and TNF-α were significantly higher, and SOD level was significantly lower in group5-HD + D (P < 0.05). The activation of the mitoKATP channel could contribute to the protective effect of dexmedetomidine on rats induced by focal cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Feng Yuan
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, No. 2 of Jingba road of Jinshui District, Zhengzhou, 450014, China
| | - Hongguang Fu
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, No. 2 of Jingba road of Jinshui District, Zhengzhou, 450014, China
| | - Kai Sun
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, No. 2 of Jingba road of Jinshui District, Zhengzhou, 450014, China
| | - Shubiao Wu
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, No. 2 of Jingba road of Jinshui District, Zhengzhou, 450014, China
| | - Tieli Dong
- Department of Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, No. 2 of Jingba road of Jinshui District, Zhengzhou, 450014, China.
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45
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Augustynek B, Kunz WS, Szewczyk A. Guide to the Pharmacology of Mitochondrial Potassium Channels. Handb Exp Pharmacol 2017; 240:103-127. [PMID: 27838853 DOI: 10.1007/164_2016_79] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
This chapter provides a critical overview of the available literature on the pharmacology of mitochondrial potassium channels. In the first part, the reader is introduced to the topic, and eight known protein contributors to the potassium permeability of the inner mitochondrial membrane are presented. The main part of this chapter describes the basic characteristics of each channel type mentioned in the introduction. However, the most important and valuable information included in this chapter concerns the pharmacology of mitochondrial potassium channels. Several available channel modulators are critically evaluated and rated by suitability for research use. The last figure of this chapter shows the results of this evaluation at a glance. Thus, this chapter can be very useful for beginners in this field. It is intended to be a time- and resource-saving guide for those searching for proper modulators of mitochondrial potassium channels.
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Affiliation(s)
- Bartłomiej Augustynek
- Laboratory of Intracellular Ion Channels, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093, Warsaw, Poland
| | - Wolfram S Kunz
- Department of Epileptology, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093, Warsaw, Poland.
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Zhang S, Guo Z, Yang S, Ma H, Fu C, Wang S, Zhang Y, Liu Y, Hu J. Chronic intermittent hybobaric hypoxia protects against cerebral ischemia via modulation of mitoK ATP. Neurosci Lett 2016; 635:8-16. [PMID: 27760384 DOI: 10.1016/j.neulet.2016.10.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Revised: 10/14/2016] [Accepted: 10/15/2016] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Providing adequate protection against cerebral ischemia remains an unrealized goal. The present study was aimed at testing whether chronic intermittent hypobaric hypoxia (CIHH) would have protective effects against cerebral ischemia and investigating the potential role of mitochondrial membrane ATP-sensitive potassium channel (mitoKATP) in this effect. METHODS Ischemia was induced in rats by occlusion of bilateral common carotid arteries for 8min on day 2 after bilateral vertebral arteries were permanently electrocauterized and CIHH was simulated in a hypoxic chamber. Learning and memory impairments were analyzed using the Morris water maze. The delay neuronal death (DND) in the hippocampus CA1 was observed by thionine staining. The expression of the two subunits of mitoKATP, SUR1 and Kir 6.2, and the concentration of cytochrome c (Cyt c) were observed by Western blotting. The mitochondrial membrane potential (Δym) was determined by flow cytometry. Morphological changes of the mitochondria were investigated by electron microscopy. The antagonist of mitoKATP, 5-hydroxydecanoate (5-HD), was used to demonstrate the involvement of mitoKATP. RESULTS CIHH pretreatment ameliorated the learning and memory impairments produced by ischemia, concomitant with reduced DND in the hippocampus CA1 area. Expression levels of SUR1 and Kir6.2 both increased for at least one week after CIHH pretreatment. Levels of the two subunits were higher in the CIHH pretreatment combined with ischemia group than the ischemia only group at 2 d and 7 d after ischemia. Furthermore, the concentration of Cyt c was decreased in mitochondria and increased in the cytoplasm after ischemia which was prevented by CIHH. The decrease of Δψm and the destruction of mitochondrial ultrastructure were both rescued by CIHH pretreatment. The above protective effects of CIHH were blocked by 5-HD intraperitoneal injection 30min before ischemia. CONCLUSION CIHH pretreatment can reduce cerebral ischemic injury, which is mediated by upregulating the expression and activity of mitoKATP.
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Affiliation(s)
- Shixiao Zhang
- Department of Nursing, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China.
| | - Zan Guo
- Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, 050000, China.
| | - Shijie Yang
- Department of Urology, Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, 050051, China.
| | - Huijuan Ma
- Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, 050000, China.
| | - Congrui Fu
- Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China.
| | - Sheng Wang
- Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, 050000, China.
| | - Yi Zhang
- Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, 050000, China.
| | - Yixian Liu
- Department of Physiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China; Hebei Collaborative Innovation Center for Cardio-cerebrovascular Disease, Shijiazhuang, 050000, China.
| | - Jie Hu
- Department of Nursing, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, China.
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Yang HQ, Subbotina E, Ramasamy R, Coetzee WA. Cardiovascular K ATP channels and advanced aging. PATHOBIOLOGY OF AGING & AGE RELATED DISEASES 2016; 6:32517. [PMID: 27733235 PMCID: PMC5061878 DOI: 10.3402/pba.v6.32517] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 09/12/2016] [Accepted: 09/14/2016] [Indexed: 12/20/2022]
Abstract
With advanced aging, there is a decline in innate cardiovascular function. This decline is not general in nature. Instead, specific changes occur that impact the basic cardiovascular function, which include alterations in biochemical pathways and ion channel function. This review focuses on a particular ion channel that couple the latter two processes, namely the KATP channel, which opening is promoted by alterations in intracellular energy metabolism. We show that the intrinsic properties of the KATP channel changes with advanced aging and argue that the channel can be further modulated by biochemical changes. The importance is widespread, given the ubiquitous nature of the KATP channel in the cardiovascular system where it can regulate processes as diverse as cardiac function, blood flow and protection mechanisms against superimposed stress, such as cardiac ischemia. We highlight questions that remain to be answered before the KATP channel can be considered as a viable target for therapeutic intervention.
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Affiliation(s)
- Hua-Qian Yang
- Department of Pediatrics, NYU School of Medicine, New York, NY, USA
| | | | - Ravichandran Ramasamy
- Department of Medicine, NYU School of Medicine, New York, NY, USA.,Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA
| | - William A Coetzee
- Department of Pediatrics, NYU School of Medicine, New York, NY, USA.,Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA.,Department of Physiology & Neuroscience, NYU School of Medicine, New York, NY, USA;
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48
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Onukwufor JO, Stevens D, Kamunde C. Bioenergetic and volume regulatory effects of mitoKATP channel modulators protect against hypoxia-reoxygenation-induced mitochondrial dysfunction. ACTA ACUST UNITED AC 2016; 219:2743-51. [PMID: 27358470 DOI: 10.1242/jeb.140186] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 06/26/2016] [Indexed: 12/19/2022]
Abstract
The mitochondrial ATP-sensitive K(+) (mitoKATP) channel plays a significant role in mitochondrial physiology and protects against ischemic reperfusion injury in mammals. Although fish frequently face oxygen fluctuations in their environment, the role of the mitoKATP channel in regulating the responses to oxygen stress is rarely investigated in this class of animals. To elucidate whether and how the mitoKATP channel protects against hypoxia-reoxygenation (H-R)-induced mitochondrial dysfunction in fish, we first determined the mitochondrial bioenergetic effects of two key modulators of the channel, diazoxide and 5-hydroxydecanoate (5-HD), using a wide range of doses. Subsequently, the effects of low and high doses of the modulators on mitochondrial bioenergetics and volume under normoxia and after H-R using buffers with and without magnesium and ATP (Mg-ATP) were tested. In the absence of Mg-ATP (mitoKATP channel open), both low and high doses of diazoxide improved mitochondrial coupling, but only the high dose of 5-HD reversed the post-H-R coupling-enhancing effect of diazoxide. In the presence of Mg-ATP (mitoKATP channel closed), diazoxide at the low dose improved coupling post-H-R, and this effect was abolished by 5-HD at the low dose. Interestingly, both low and high doses of diazoxide reversed H-R-induced swelling under mitoKATP channel open conditions, but this effect was not sensitive to 5-HD. Under mitoKATP channel closed conditions, diazoxide at the low dose protected the mitochondria from H-R-induced swelling and 5-HD at the low dose reversed this effect. In contrast, diazoxide at the high dose failed to reduce the swelling caused by H-R, and the addition of the high dose of 5-HD enhanced mitochondrial swelling. Overall, our study showed that in the presence of Mg-ATP, both opening of mitoKATP channels and bioenergetic effects of diazoxide were protective against H-R in fish mitochondria, while in the absence of Mg-ATP only the bioenergetic effect of diazoxide was protective.
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Affiliation(s)
- John O Onukwufor
- Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3
| | - Don Stevens
- Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3
| | - Collins Kamunde
- Department of Biomedical Sciences, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada C1A 4P3
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Goharbari MH, Shadboores A, Abdollahi M. Inhibitory Effects of Thyroid Hormones on Mitochondrial
Oxidative Stress: A Systematic Review. INT J PHARMACOL 2016. [DOI: 10.3923/ijp.2016.249.261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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50
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Laskowski M, Augustynek B, Kulawiak B, Koprowski P, Bednarczyk P, Jarmuszkiewicz W, Szewczyk A. What do we not know about mitochondrial potassium channels? BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2016; 1857:1247-1257. [PMID: 26951942 DOI: 10.1016/j.bbabio.2016.03.007] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 03/02/2016] [Accepted: 03/03/2016] [Indexed: 01/14/2023]
Abstract
In this review, we summarize our knowledge about mitochondrial potassium channels, with a special focus on unanswered questions in this field. The following potassium channels have been well described in the inner mitochondrial membrane: ATP-regulated potassium channel, Ca(2+)-activated potassium channel, the voltage-gated Kv1.3 potassium channel, and the two-pore domain TASK-3 potassium channel. The primary functional roles of these channels include regulation of mitochondrial respiration and the alteration of membrane potential. Additionally, they modulate the mitochondrial matrix volume and the synthesis of reactive oxygen species by mitochondria. Mitochondrial potassium channels are believed to contribute to cytoprotection and cell death. In this paper, we discuss fundamental issues concerning mitochondrial potassium channels: their molecular identity, channel pharmacology and functional properties. Attention will be given to the current problems present in our understanding of the nature of mitochondrial potassium channels. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
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Affiliation(s)
- Michał Laskowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Bartłomiej Augustynek
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Bogusz Kulawiak
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Piotr Koprowski
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland
| | - Piotr Bednarczyk
- Department of Biophysics, Warsaw University of Life Sciences - SGGW, 159 Nowoursynowska St., 02-776 Warsaw, Poland
| | - Wieslawa Jarmuszkiewicz
- Laboratory of Bioenergetics, Faculty of Biology, Adam Mickiewicz University, Umultowska 89, 61-614 Poznan, Poland
| | - Adam Szewczyk
- Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland.
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