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Antioxidants & Redox Signaling Aug 2014Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of... (Review)
Review
SIGNIFICANCE
Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently.
RECENT ADVANCES
Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca2+ uniporter pore, mitochondrial permeability transition pore, and mitochondrial ATP-sensitive K+ channel. This new information enables us to form detailed molecular and functional characterizations of mitochondrial ion channels/transporters and their roles in mitochondrial redox signaling.
CRITICAL ISSUES
Redox-mediated post-translational modifications of mitochondrial ion channels/transporters and ETC serve as key mechanisms for the spatiotemporal control of mitochondrial ROS/RNS generation.
FUTURE DIRECTIONS
Identification of detailed molecular mechanisms for redox-mediated regulation of mitochondrial ion channels will enable us to find novel therapeutic targets for many diseases that are associated with cellular redox signaling and mitochondrial ion channels/transporters.
Topics: Animals; Calcium; Electron Transport Chain Complex Proteins; Humans; Ion Channels; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes; Mitochondrial Permeability Transition Pore; Oxidation-Reduction; Potassium Channels; Reactive Oxygen Species; Signal Transduction; Voltage-Dependent Anion Channels
PubMed: 24180309
DOI: 10.1089/ars.2013.5681 -
Molecules (Basel, Switzerland) Nov 2020Amphetamine derivatives have been used in a wide variety of pathologies because of their pharmacological properties as psychostimulants, entactogens, anorectics, and...
Amphetamine derivatives have been used in a wide variety of pathologies because of their pharmacological properties as psychostimulants, entactogens, anorectics, and antidepressants. However, adverse cardiovascular effects (sympathomimetics) and substance abuse problems (psychotropic and hallucinogenic effects) have limited their use. 4-Methylthioamphetamine (MTA) is an amphetamine derivative that has shown to inhibit monoamine uptake and monoamine oxidase. However, the pharmacological characterization (neurochemical, behavioral, and safety) of its derivatives 4-ethylthioamphetamine (ETA) and 4-methylthio-phenil-2-butanamine (MT-But) have not been studied. In the current experiments, we show that ETA and MT-But do not increase locomotor activity and conditioned place preference with respect to MTA. At the neurochemical level, ETA and MT-But do not increase in vivo DA release in striatum, but ETA and MT-But affect the nucleus accumbens bioaccumulation of DA and DOPAC. Regarding cardiovascular effects, the administration of MTA and ETA increased the mean arterial pressure and only ETA significantly increases the heart rate. Our results show that the pharmacological and safety profiles of MTA are modulated by changing the methyl-thio group or the methyl group of the aminoethyl chain.
Topics: 3,4-Dihydroxyphenylacetic Acid; Amphetamine; Amphetamines; Animals; Behavior, Animal; Body Temperature; Corpus Striatum; Dopamine; Ligands; Locomotion; Male; Molecular Docking Simulation; Nucleus Accumbens; Oxygen; Rats; Rats, Sprague-Dawley; Serotonin Plasma Membrane Transport Proteins
PubMed: 33203055
DOI: 10.3390/molecules25225310 -
Frontiers in Immunology 2023Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis... (Review)
Review
Nearly 50 ATP-binding cassette (ABC) transporters are encoded by mammalian genomes. These transporters are characterized by conserved nucleotide-binding and hydrolysis (i.e., ATPase) domains, and power directional transport of diverse substrate classes - ions, small molecule metabolites, xenobiotics, hydrophobic drugs, and even polypeptides - into or out of cells or subcellular organelles. Although immunological functions of ABC transporters are only beginning to be unraveled, emerging literature suggests these proteins have under-appreciated roles in the development and function of T lymphocytes, including many of the key effector, memory and regulatory subsets that arise during responses to infection, inflammation or cancers. One transporter in particular, MDR1 (Multidrug resistance-1; encoded by the locus in humans), has taken center stage as a novel player in immune regulation. Although MDR1 remains widely viewed as a simple drug efflux pump in tumor cells, recent evidence suggests that this transporter fills key endogenous roles in enforcing metabolic fitness of activated CD4 and CD8 T cells. Here, we summarize current understanding of the physiological functions of ABC transporters in immune regulation, with a focus on the anti-oxidant functions of MDR1 that may shape both the magnitude and repertoires of antigen-specific effector and memory T cell compartments. While much remains to be learned about the functions of ABC transporters in immunobiology, it is already clear that they represent fertile new ground, both for the definition of novel immunometabolic pathways, and for the discovery of new drug targets that could be leveraged to optimize immune responses to vaccines and cancer immunotherapies.
Topics: Animals; Humans; Membrane Transport Proteins; ATP-Binding Cassette Transporters; Drug Resistance; Neoplasms; Adenosine Triphosphate; Mammals
PubMed: 38022644
DOI: 10.3389/fimmu.2023.1286696 -
Journal of Molecular Medicine (Berlin,... Jan 2021Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are... (Review)
Review
Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as "solid-state" and "fluid-state" models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the "plasticity" model was proposed that partly reconciles both "solid-state" and "fluid-state" models. According to the "plasticity" model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.
Topics: Animals; Cell Respiration; Electron Transport Chain Complex Proteins; Humans; Mitochondria
PubMed: 33201259
DOI: 10.1007/s00109-020-02004-8 -
Development (Cambridge, England) Jan 2018Hemoglobin-expressing erythrocytes (red blood cells) act as fundamental metabolic regulators by providing oxygen to cells and tissues throughout the body. Whereas the... (Review)
Review
Hemoglobin-expressing erythrocytes (red blood cells) act as fundamental metabolic regulators by providing oxygen to cells and tissues throughout the body. Whereas the vital requirement for oxygen to support metabolically active cells and tissues is well established, almost nothing is known regarding how erythrocyte development and function impact regeneration. Furthermore, many questions remain unanswered relating to how insults to hematopoietic stem/progenitor cells and erythrocytes can trigger a massive regenerative process termed 'stress erythropoiesis' to produce billions of erythrocytes. Here, we review the cellular and molecular mechanisms governing erythrocyte development and regeneration, and discuss the potential links between these events and other regenerative processes.
Topics: Animals; Biological Transport, Active; Cell Differentiation; Erythrocytes; Erythropoiesis; Hematopoietic Stem Cells; Humans; Oxygen; Regeneration
PubMed: 29321181
DOI: 10.1242/dev.151423 -
Bioscience Reports Mar 2015Iron, an essential nutrient, is required for many diverse biological processes. The absence of a defined pathway to excrete excess iron makes it essential for the body... (Review)
Review
Iron, an essential nutrient, is required for many diverse biological processes. The absence of a defined pathway to excrete excess iron makes it essential for the body to regulate the amount of iron absorbed; a deficiency could lead to iron deficiency and an excess to iron overload and associated disorders such as anaemia and haemochromatosis respectively. This regulation is mediated by the iron-regulatory hormone hepcidin. Hepcidin binds to the only known iron export protein, ferroportin (FPN), inducing its internalization and degradation, thus limiting the amount of iron released into the blood. The major factors that are implicated in hepcidin regulation include iron stores, hypoxia, inflammation and erythropoiesis. The present review summarizes our present knowledge about the molecular mechanisms and signalling pathways contributing to hepcidin regulation by these factors.
Topics: Animals; Bone Morphogenetic Proteins; Cation Transport Proteins; Cell Hypoxia; Erythropoietin; Hemochromatosis; Hepcidins; Humans; Inflammation; Iron; Mice; Signal Transduction; Smad Proteins; Transferrin
PubMed: 26182354
DOI: 10.1042/BSR20150014 -
The New Phytologist Oct 2018Contents Summary 49 I. Introduction 49 II. Physiological and structural characteristics of plant Ca -permeable ion channels 50 III. Ca extrusion systems 61 IV.... (Review)
Review
Contents Summary 49 I. Introduction 49 II. Physiological and structural characteristics of plant Ca -permeable ion channels 50 III. Ca extrusion systems 61 IV. Concluding remarks 64 Acknowledgements 64 References 64 SUMMARY: Calcium is an essential structural, metabolic and signalling element. The physiological functions of Ca are enabled by its orchestrated transport across cell membranes, mediated by Ca -permeable ion channels, Ca -ATPases and Ca /H exchangers. Bioinformatics analysis has not determined any Ca -selective filters in plant ion channels, but electrophysiological tests do reveal Ca conductances in plant membranes. The biophysical characteristics of plant Ca conductances have been studied in detail and were recently complemented by molecular genetic approaches. Plant Ca conductances are mediated by several families of ion channels, including cyclic nucleotide-gated channels (CNGCs), ionotropic glutamate receptors, two-pore channel 1 (TPC1), annexins and several types of mechanosensitive channels. Key Ca -mediated reactions (e.g. sensing of temperature, gravity, touch and hormones, and cell elongation and guard cell closure) have now been associated with the activities of specific subunits from these families. Structural studies have demonstrated a unique selectivity filter in TPC1, which is passable for hydrated divalent cations. The hypothesis of a ROS-Ca hub is discussed, linking Ca transport to ROS generation. CNGC inactivation by cytosolic Ca , leading to the termination of Ca signals, is now mechanistically explained. The structure-function relationships of Ca -ATPases and Ca /H exchangers, and their regulation and physiological roles are analysed.
Topics: Calcium; Calcium Channels; Cell Membrane; Cell Membrane Permeability; Ion Transport
PubMed: 29916203
DOI: 10.1111/nph.15266 -
Nature Communications Jun 2023Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen...
Iron is essential to cells as a cofactor in enzymes of respiration and replication, however without correct storage, iron leads to the formation of dangerous oxygen radicals. In yeast and plants, iron is transported into a membrane-bound vacuole by the vacuolar iron transporter (VIT). This transporter is conserved in the apicomplexan family of obligate intracellular parasites, including in Toxoplasma gondii. Here, we assess the role of VIT and iron storage in T. gondii. By deleting VIT, we find a slight growth defect in vitro, and iron hypersensitivity, confirming its essential role in parasite iron detoxification, which can be rescued by scavenging of oxygen radicals. We show VIT expression is regulated by iron at transcript and protein levels, and by altering VIT localization. In the absence of VIT, T. gondii responds by altering expression of iron metabolism genes and by increasing antioxidant protein catalase activity. We also show that iron detoxification has an important role both in parasite survival within macrophages and in virulence in a mouse model. Together, by demonstrating a critical role for VIT during iron detoxification in T. gondii, we reveal the importance of iron storage in the parasite and provide the first insight into the machinery involved.
Topics: Animals; Mice; Toxoplasma; Vacuoles; Reactive Oxygen Species; Membrane Transport Proteins; Parasites; Protozoan Proteins
PubMed: 37339985
DOI: 10.1038/s41467-023-39436-y -
Antioxidants & Redox Signaling Feb 2015Oxygen plays a key role in cellular metabolism and function. Oxygen delivery to cells is crucial, and a lack of oxygen such as that which occurs during myocardial... (Review)
Review
SIGNIFICANCE
Oxygen plays a key role in cellular metabolism and function. Oxygen delivery to cells is crucial, and a lack of oxygen such as that which occurs during myocardial infarction can be lethal. Cells should, therefore, be able to respond to changes in oxygen tension.
RECENT ADVANCES
Since the first studies examining the acute cellular effect of hypoxia on activation of transmitter release from glomus or type I chemoreceptor cells, it is now known that virtually all cells are able to respond to changes in oxygen tension.
CRITICAL ISSUES
Despite advances made in characterizing hypoxic responses, the identity of the "oxygen sensor" remains debated. Recently, more evidence has evolved as to how cardiac myocytes sense acute changes in oxygen. This review will examine the available evidence in support of acute oxygen-sensing mechanisms providing a brief historical perspective and then more detailed insights into the heart and the role of cardiac ion channels in hypoxic responses.
FUTURE DIRECTIONS
A further understanding of these cellular processes should result in interventions that assist in preventing the deleterious effects of acute changes in oxygen tension such as alterations in contractile function and cardiac arrhythmia.
Topics: Animals; Cell Hypoxia; Hemeproteins; Humans; Ion Channels; Mitochondria; Myocardium; NADP; Oxygen; Reactive Oxygen Species
PubMed: 24684612
DOI: 10.1089/ars.2014.5880 -
Advances in Experimental Medicine and... 2017Electron paramagnetic resonance (EPR) spin-label oximetry allows the oxygen permeability coefficient to be evaluated across homogeneous lipid bilayer membranes and, in... (Review)
Review
Electron paramagnetic resonance (EPR) spin-label oximetry allows the oxygen permeability coefficient to be evaluated across homogeneous lipid bilayer membranes and, in some cases, across coexisting membrane domains without their physical separation. The most pronounced effect on oxygen permeability is observed for cholesterol, which additionally induces the formation of membrane domains. In intact biological membranes, integral proteins induce the formation of boundary and trapped lipid domains with a low oxygen permeability. The effective oxygen permeability coefficient across the intact biological membrane is affected not only by the oxygen permeability coefficients evaluated for each lipid domain but also by the surface area occupied by these domains in the membrane. All these factors observed in fiber cell plasma membranes of clear human eye lenses are reviewed here.
Topics: Biological Transport; Cell Membrane; Cell Membrane Permeability; Electron Spin Resonance Spectroscopy; Humans; Lens, Crystalline; Lipid Bilayers; Membrane Lipids; Optic Nerve; Oxygen; Permeability
PubMed: 28685424
DOI: 10.1007/978-3-319-55231-6_5