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Redox Homeostasis in Pancreatic Β-Cells: from Development to Failure

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Redox Homeostasis in Pancreatic Β-Cells: from Development to Failure antioxidants Review Redox Homeostasis in Pancreatic β-Cells: From Development to Failure Štˇepánka Benáková 1,2, Blanka Holendová 1 and Lydie Plecitá-Hlavatá 1,3,* 1 Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; [email protected] (Š.B.); [email protected] (B.H.) 2 First Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Prague, Czech Republic 3 Department of Mitochondrial Physiology, Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic * Correspondence: [email protected]; Tel.: +420-296-442-285 Abstract: Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxi- fying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thiore- doxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of Citation: Benáková, Š.; Holendová, B.; type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic Plecitá-Hlavatá, L. Redox Homeostasis feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplas- in Pancreatic β-Cells: From mic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded Development to Failure. Antioxidants protein response and insulin misfolding along with excessive hydrogen peroxide production. This 2021, 10, 526. https://doi.org/10.3390/ together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure antiox10040526 impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing Academic Editor: Mario Allegra insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation Received: 24 February 2021 prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and Accepted: 25 March 2021 eventually cell death. Published: 27 March 2021 Keywords: redox signaling; oxidative stress; redox homeostasis; pancreatic β-cells; de/differentiation; Publisher’s Note: MDPI stays neutral inflammation with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Redox Homeostasis in β-Cell Development and Maturation 1.1. Sources of Reactive Oxygen Species and Antioxidants in b-Cells Reactive oxygen species (ROS) are normally produced during the metabolism of β-cells Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. and play an important role in cellular signaling. For instance, mitochondrial ROS are oblig- This article is an open access article atory signals of glucose-induced insulin secretion (GSIS) [1,2]. However, excessive levels distributed under the terms and of ROS in both human and rodent β-cells cause oxidative stress, which is detrimental to conditions of the Creative Commons the cells. Several such conditions leading to excessive ROS generation in β-cells have been Attribution (CC BY) license (https:// proposed, such as hyperglycemia, hypoxia, hyperlipidemia and endoplasmic reticulum (ER) creativecommons.org/licenses/by/ stress [3]. Pancreatic β-cells both of rodents and humans are reportedly determined to be 4.0/). Antioxidants 2021, 10, 526. https://doi.org/10.3390/antiox10040526 https://www.mdpi.com/journal/antioxidants Antioxidants 2021, 10, 526 2 of 30 Antioxidants 2021, 10, 526 2 of 32 especiallydetermined vulnerable to be especially to oxidative vulnerable damage to oxidative [4] due to damage the low [4] expression due to the of low classical expression antioxi- dantof classical enzymes—catalases, antioxidant enzymes glutathione—catalases, peroxidases glutathione (GPX) peroxidases and superoxide (GPX) dismutases and superox- (SOD) whenide dismutases compared (SOD) to other when cell compa types [red5–7 ].to Theother main cell antioxidanttypes [5–7]. systemThe main in βantioxidant-cells consists sys- of peroxiredoxinstem in β-cells consists (PRX), thioredoxinsof peroxiredoxins (TRX) (PRX), and thioredoxin thioredoxins reductase (TRX) (TRXR).and thioredoxin Regeneration re- ofductase PRX thiol (TRXR). groups Regeneration is mediated of byPRX auxiliary thiol groups enzymes is mediate TRX andd by glutaredoxins auxiliary enzymes (GRX). TRX The recyclingand glutaredoxins of TRX is (GRX). mediated The byrecycling the activity of TRX of is TRXR, mediated which by reducesthe activity TRX of andTRXR, allows which the cyclereduces to continue.TRX and allows NADPH the serves cycle to as continue. an electron NADPH donor serves for the as reduction an electron ofTRXR donor [ for8]. GRXthe isreduction reduced of by TRXR glutathione, [8]. GRX which is reduced is then by regeneratedglutathione, which by glutathione is then regenerated reductase withby glu- the concurrenttathione reductase utilization with of the NADPH concurrent [8]. utilization This system of wasNADPH shown [8]. to This be system sufficient was to shown protect βto-cells be sufficient against short-runto protect oxidative β-cells against burst whileshort-run hypothetically oxidative burst also while providing hypothetically a signaling rolealso necessaryproviding fora signaling GSIS in bothrole rodentnecessary and for human GSIS cellsin both [9]. rodent Nevertheless, and human long-term cells [9] glu-. colipotoxicNevertheless, conditions, long-term often glucolipotoxic caused by conditions, overnutrition often leading caused to by an overnutrition increase in oxidativeleading stress,to an increase can cause in dysfunctionoxidative stress, of the canβ-cells cause and dysfunction contribute of to the type β 2-cells diabetes and (seecontributeSection to3 ). Thetyperedox 2 diabetes balance (see betweenSection 3). ROS The andredox the balance antioxidant between system ROS and is, therefore, the antiox crucialidant system for the properis, therefore physiological, crucial for function the proper of pancreatic physiologicalβ-cells, function and thusof pancreatic body glucose β-cells, homeostasis. and thus Becausebody glucose of the homeostasis. internal redox Because compartmentalization of the internal redox in β-cells, compartmentalization we have focused onin β the-cells, local sourceswe have of focused ROS and on the types local of sources antioxidant of ROS enzymes and types in individual of antioxidant cell partsenzymes (Figure in individ-1). ROS areual primarilycell parts produced(Figure 1 during). ROS mitochondrialare primarily oxidativeproduced phosphorylationduring mitochondrial but also oxidative originate fromphosphorylation other cell compartments but also originate and organelles, from other such cell ascompartments ER, peroxisomes and ororganelles cytoplasm, such [10 ,as11 ]. AtER, a peroxisomes “redox triangle” or cytoplasm called redoxosome, [10,11]. At which a “redox is formed triangle by” closelycalled redoxosome, attached membranes which is of theformed ER, mitochondriaby closely attached and peroxisomes, membranes redox-regulatoryof the ER, mitochondria enzymes and are peroxisomes, thought to assemble. redox- Theseregulatory sense enzymes ROS accumulations are thought andto assemble. redox imbalances, These sense and ROS its accumulations enzymes use ROS and to redox trans- mitimbalances intercompartmental, and its enzymes signals use ROS via chemical to transmit modifications intercompartmental of downstream signals via proteins chemical and lipidsmodifications [12]. Under of downstream physiological prote conditions,ins and ROS lipids production [12]. Under in individualphysiological compartments conditions, is wellROS controlledproduction by in specificindividual resident compartments antioxidant is well enzymes controlled with smallby specific differences resident between anti- rodentsoxidant andenzymes humans. with small differences between rodents and humans. FigureFigure 1.1. CompartmentalizationCompartmentalization of of redox redox regulating regulating proteins proteins in β in-cellsβ-cells involves involves mitochondria, mitochondria, cytosol, cytosol, endoplasmic endoplasmic retic- ulum (ER), peroxisomes and extracellular space. SOD—superoxide dismutase, GPX—glutathione peroxidase, PRX— reticulum (ER), peroxisomes and extracellular space. SOD—superoxide dismutase, GPX—glutathione peroxidase, PRX— peroxiredoxin, TRX—thioredoxin, GRX—glutaredoxin. peroxiredoxin, TRX—thioredoxin, GRX—glutaredoxin. 1.1.1. Mitochondria 1.1.1. Mitochondria Mitochondrial
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