Abnormal accumulation of brain iron has been detected in various neurodegenerative diseases, but the contribution of iron overload to pathology remains unclear. In a group of distinctive brain iron ...overload diseases known as 'neurodegeneration with brain iron accumulation' (NBIA) diseases, nine disease genes have been identified. Brain iron accumulation is observed in the globus pallidus and other brain regions in NBIA diseases, which are often associated with severe dystonia and gait abnormalities. Only two of these diseases, aceruloplasminaemia and neuroferritinopathy, are directly caused by abnormalities in iron metabolism, mainly in astrocytes and neurons, respectively. Understanding the early molecular pathophysiology of these diseases should aid insights into the role of iron and the design of specific therapeutic approaches.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Epilepsy: A Clinical Overview Milligan, Tracey A.
The American journal of medicine,
07/2021, Letnik:
134, Številka:
7
Journal Article
Recenzirano
The diagnosis and treatment of seizures and epilepsy is a common task of the physician. Approximately 1 in 10 people will have a seizure during their lifetime. Epilepsy is the tendency to have ...unprovoked seizures. Epilepsy is the fourth most common neurological disorder and affects 1 in 26 people in the United States and 65 million people worldwide. Evaluation of a patient presenting with a seizure involves excluding an underlying neurologic or medical condition, classifying the seizure type and determining if the patient has epilepsy. Proper treatment requires accurate diagnosis of the epilepsy type and syndrome and use of a medication that is effective and without adverse effects. Most patients can achieve complete seizure control with medication, but if medication is unsuccessful, surgical treatment can be an option. Special situations in the care of people with epilepsy include status epilepticus, women with epilepsy, the older adult, and safety issues.
Iron-sulphur (Fe-S) clusters are inorganic cofactors that are found in nearly all species and are composed of various combinations of iron and sulphur atoms. Fe-S clusters can accept or donate single ...electrons to carry out oxidation and reduction reactions and to facilitate electron transport. Many details of how these complex modular structures are assembled and ligated to cellular proteins in the mitochondrial, nuclear and cytosolic compartments of mammalian cells remain unclear. Recent evidence indicates that a Leu-Tyr-Arg (LYR) tripeptide motif found in some Fe-S recipient proteins may facilitate the direct and shielded transfer of Fe-S clusters from a scaffold to client proteins. Fe-S clusters are probably an unrecognized and elusive cofactor of many known proteins.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
In recent years, iron sulfur (Fe–S) proteins have been identified as key players in mammalian metabolism, ranging from long-known roles in the respiratory complexes and the citric acid cycle, to more ...recently recognized roles in RNA and DNA metabolism. Fe–S cofactors have often been missed because of their intrinsic lability and oxygen sensitivity. More Fe–S proteins have now been identified owing to detection of their direct interactions with components of the Fe–S biogenesis machinery, and through use of informatics to detect a motif that binds the co-chaperone responsible for transferring nascent Fe–S clusters to domains of recipient proteins. Dissection of the molecular steps involved in Fe–S transfer to Fe–S proteins has revealed that direct and shielded transfer occurs through highly conserved pathways that operate in parallel in the mitochondrial matrix and in the cytosolic/nuclear compartments of eukaryotic cells. Because Fe–S clusters have the unusual ability to accept or donate single electrons in chemical reactions, their presence renders complex chemical reactions possible. In addition, Fe–S clusters may function as sensors that interconnect activity of metabolic pathways with cellular redox status. Presence in pathways that control growth and division may enable cells to regulate their growth according to sufficiency of energy stores represented by redox capacity, and oxidation of such proteins could diminish anabolic activities to give cells an opportunity to restore energy supplies. This review will discuss mechanisms of Fe–S biogenesis and delivery, and methods that will likely reveal important roles of Fe–S proteins in proteins not yet recognized as Fe–S proteins.
Fe-S cofactors are composed of iron and inorganic sulfur in various stoichiometries. A complex assembly pathway conducts their initial synthesis and subsequent binding to recipient proteins. In this ...minireview, we discuss how discovery of the role of the mammalian cytosolic aconitase, known as iron regulatory protein 1 (IRP1), led to the characterization of the function of its Fe-S cluster in sensing and regulating cellular iron homeostasis. Moreover, we present an overview of recent studies that have provided insights into the mechanism of Fe-S cluster transfer to recipient Fe-S proteins.
Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize ...cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.
Calcium transport across plant membranes Demidchik, Vadim; Shabala, Sergey; Isayenkov, Stanislav ...
The New phytologist,
October 2018, Letnik:
220, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Calcium is an essential structural, metabolic and signalling element. The physiological functions of Ca2+ are enabled by its orchestrated transport across cell membranes, mediated by Ca2+-permeable ...ion channels,Ca2+-ATPases andCa2+/H+ exchangers. Bioinformatics analysis has not determined any Ca2+-selective filters in plant ion channels, but electrophysiological tests do reveal Ca2+ conductances in plant membranes. The biophysical characteristics of plant Ca2+ conductances have been studied in detail and were recently complemented by molecular genetic approaches. Plant Ca2+ 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 Ca2+-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-Ca2+ hub is discussed, linking Ca2+ transport to ROS generation. CNGC inactivation by cytosolic Ca2+, leading to the termination of Ca2+ signals, is now mechanistically explained. The structure–function relationships of Ca2+-ATPases and Ca2+/H+ exchangers, and their regulation and physiological roles are analysed.
Iron–sulfur (Fe–S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of ...cluster composition, oxidation states and protein environments, enables Fe–S clusters to participate in numerous biological processes. Fe–S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i.e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome.
Fe–S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein–protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe–S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe–S cluster biogenesis cause mitochondrial iron overload? How are specific Fe–S recipient proteins recognized in the process of Fe–S transfer?
This review focuses on the basic steps of Fe–S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe–S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.
•Fe-S assembly processes are highly conserved from bacteria to humans.•Defects in specific human biogenesis proteins cause rare diseases with variable phenotypes that are often tissue specific.•Transfer of Fe-S clusters downstream of the holo-ISCU-HSC20-HSPA9 transfer complex relies on selective pathways.•The co-chaperone (HSC20) of the Fe-S transfer complex binds to iterations of LYR motifs together with HSPA9 and holo-ISCU.•Binding of the Fe-S cluster transfer complex facilitates direct acquisition of Fe-S clusters by recipient proteins like SDHB.
Iron-sulfur (Fe-S) clusters are ubiquitous cofactors composed of iron and inorganic sulfur. They are required for the function of proteins involved in a wide range of activities, including electron ...transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. The proteins involved in the biogenesis of Fe-S clusters are evolutionarily conserved from bacteria to humans, and many insights into the process of Fe-S cluster biogenesis have come from studies of model organisms, including bacteria, fungi and plants. It is now clear that several rare and seemingly dissimilar human diseases are attributable to defects in the basic process of Fe-S cluster biogenesis. Although these diseases -which include Friedreich's ataxia (FRDA), ISCU myopathy, a rare form of sideroblastic anemia, an encephalomyopathy caused by dysfunction of respiratory chain complex I and multiple mitochondrial dysfunctions syndrome - affect different tissues, a feature common to many of them is that mitochondrial iron overload develops as a secondary consequence of a defect in Fe-S cluster biogenesis. This Commentary outlines the basic steps of Fe-S cluster biogenesis as they have been defined in model organisms. In addition, it draws attention to refinements of the process that might be specific to the subcellular compartmentalization of Fe-S cluster biogenesis proteins in some eukaryotes, including mammals. Finally, it outlines several important unresolved questions in the field that, once addressed, should offer important clues into how mitochondrial iron homeostasis is regulated, and how dysfunction in Fe-S cluster biogenesis can contribute to disease.
Iron–sulfur (Fe-S) clusters (ISCs) are ubiquitous cofactors essential to numerous fundamental cellular processes. Assembly of ISCs and their insertion into apoproteins involves the function of ...complex cellular machineries that operate in parallel in the mitochondrial and cytosolic/nuclear compartments of mammalian cells. The spectrum of diseases caused by inherited defects in genes that encode the Fe-S assembly proteins has recently expanded to include multiple rare human diseases, which manifest distinctive combinations and severities of global and tissue-specific impairments. In this review, we provide an overview of our understanding of ISC biogenesis in mammalian cells, discuss recent work that has shed light on the molecular interactions that govern ISC assembly, and focus on human diseases caused by failures of the biogenesis pathway.
Iron-sulfur (Fe-S) proteins have critical roles in essential metabolic pathways ranging from DNA and RNA metabolism to mitochondrial function, and regulation of cell growth and division.Mammalian cells likely contain many more Fe-S proteins than have been identified to date, due to loss of fragile iron–sulfur clusters (ISCs) during purification.Structural determinations of the architecture of the initial ISC biogenesis complex, comprising NFS1, ISD11, ACP, ISCU, and FXN, have shed light on the interactions that govern de novo ISC assembly.In mammalian cells, a full complement of initial ISC biogenesis factors localizes to the cytosol, where it initiates de novo ISC assembly.Further biochemical and clinical investigations of ISC-associated disorders and their phenotypes will elucidate the distinct pathways that assemble and deliver ISCs to the numerous enzymes that require them for function.
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