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The Perfect Redox System

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The Perfect Redox System antioxidants Review The Pancreatic β-Cell: The Perfect Redox System Petr Ježek * , Blanka Holendová , Martin Jab ˚urek , Jan Tauber, Andrea Dlasková and Lydie Plecitá-Hlavatá Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, 14220 Prague, Czech Republic; [email protected] (B.H.); [email protected] (M.J.); [email protected] (J.T.); [email protected] (A.D.); [email protected] (L.P.-H.) * Correspondence: [email protected]; Tel.: +420-296442760 Abstract: Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H2O2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive + K channel (KATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block KATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed KATP ensemble is insufficient to reach the −50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca2+ channels. Open synergic NSCCs or Cl− channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca2+-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify 2+ 2+ integral Ca -influx (fortified by endoplasmic reticulum Ca ). ATP plus H2O2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or β Citation: Ježek, P.; Holendová, B.; FA -oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or Jab ˚urek, M.; Tauber, J.; Dlasková, A.; hypothetical SH relay via peroxiredoxin “redox kiss” to target proteins. Plecitá-Hlavatá, L. The Pancreatic β-Cell: The Perfect Redox System. Keywords: pancreatic β-cells; insulin secretion; redox signaling; NADPH oxidase 4; branched-chain + Antioxidants 2021, 10, 197. ketoacid oxidation; fatty-acid-stimulated insulin secretion; ATP-sensitive K channel; TRPM channels; https://doi.org/10.3390/ GLP-1; GPR40 antiox10020197 Academic Editor: Saverio Francesco Retta 1. Introduction Received: 29 December 2020 1.1. Emerging Concept of Redox Signaling Accepted: 25 January 2021 The emerging concept of redox signaling resulted from ceaseless efforts, and decades Published: 29 January 2021 of studies of the redox homeostasis of cells and cell organelles. Among organelles, the mi- tochondrion combines the key roles of the metabolic and redox hub. Prototypical redox Publisher’s Note: MDPI stays neutral signaling is involved in mechanisms of hypoxia-inducible factor (HIF) system-initiated with regard to jurisdictional claims in published maps and institutional affil- transcriptome reprogramming. Both cytosolic and mitochondrial redox signaling were α iations. implicated, e.g., in HIF-1 stabilization, either via the oxidation of iron II to iron III of the reaction center of prolyl hydroxylase domain enzymes (PHD/EglN) [1,2] and/or their sensitive cysteines [3]. Recently, we revealed another physiological redox signaling of enormous biomedical significance: NADPH oxidase 4- (NOX4-) initiated redox signaling (H2O2), which fun- Copyright: © 2021 by the authors. damentally determines the 1st phase of glucose-stimulated insulin secretion (GSIS) in Licensee MDPI, Basel, Switzerland. pancreatic β-cells, hypothetically by a cooperative closing of the ATP-sensitive K+ channel This article is an open access article distributed under the terms and (KATP) together with ATP elevation (Figure1A) [ 4]; or alternatively (Figure1B), we may conditions of the Creative Commons assume that the essentially synergic channels, such as transient receptor potential melastin Attribution (CC BY) license (https:// (TRPM) isoform 2, i.e., TRPM2, are also activated by H2O2 as reported [5], when the 100% creativecommons.org/licenses/by/ KATP ensemble is closed by the elevated ATP. 4.0/). Antioxidants 2021, 10, 197. https://doi.org/10.3390/antiox10020197 https://www.mdpi.com/journal/antioxidants Antioxidants 2021 10 Antioxidants 2021, , 10, 197, x FOR PEER REVIEW 22 of of 59 64 FigureFigure 1.1. A new paradigm in in the the mechanism mechanism of of glucose-stimulated glucose-stimulated insulin insulin secretion secretion (GSIS): (GSIS): Essen- Es- sentialtial requirement requirement of ofredox redox signaling. signaling. Upon Upon gluc glucoseose intake, intake, pentose pentose phosphate phosphate pathway pathway (PPP) (PPP) and redox shuttles supply cytosolic NADPH to increase NOX4 activity and thus elevate H2O2, which and redox shuttles supply cytosolic NADPH to increase NOX4 activity and thus elevate H2O2, substantiates redox signaling. The two possible hypotheses assume two distinct targets of H2O2: which substantiates redox signaling. The two possible hypotheses assume two distinct targets of either that (A) KATP is closed exclusively when both ATP plus H2O2 are elevated (as supported by H O : either that (A)K is closed exclusively when both ATP plus H O are elevated (as supported the2 patch-clamp2 data inATP Ref. [4]); or (B) that KATP is closed by ATP, wher2 2 eas the TRPM2 channel (or byother the nonspecific patch-clamp calcium data in channels Ref. [4]); (NSCCs)) or (B) that is K activatedATP is closed by H by2O ATP,2. In both whereas cases, the the TRPM2 depolarization channel (orshift other by NSCCs nonspecific is essentially calcium channelsrequired (NSCCs))for achieving is activated the −50 bymV H depolarization2O2. In both cases, threshold the depolar- for CaV izationactivation shift despite by NSCCs 100% is of essentially the KATP requiredensemble for being achieving closed. the Mechanism−50 mV depolarization(A) plus additional threshold H2O2 forstimulation CaV activation of TRPM2 despite is also 100% plausible. of the K ATP ensemble being closed. Mechanism (A) plus additional H2O2 stimulation of TRPM2 is also plausible. The inability of the closure of the entire KATP ensemble to reach the threshold depo- larizationThe inability of the plasma of the closure membrane of the for entire opening KATP voltage-gatedensemble to reach Ca2+ channels the threshold (CaV) depo- [6] is 2+ larizationdiscussed of in the this plasma review membrane as the key for elemen openingt for voltage-gated understanding Ca thechannels mechanism (Ca Vof)[ GSIS.6] is discussedThus synergy in this is required review as with the keythe other element cha fornnels. understanding Moreover, the the principle mechanism of a of “logical GSIS. Thussummation” synergy of is metabolic required withplus redox the other stimulation channels. will Moreover, be discussed the and principle the experimental of a “logi- calevidence summation” supporting of metabolic it. This plusprinciple redox seems stimulation to be universal will be discussed for any andmechanism the experimental of insulin evidencesecretion supporting dependent it.on This KATP principle and/or Ca seemsV. to be universal for any mechanism of insulin secretionFor dependentexample the on alternative, KATP and/or in this CaV case. mitochondrial redox signaling, is essentially requiredFor example for insulin the alternative,secretion stimulated in this case by mitochondrial metabolites of redox branched-chain signaling, is amino essentially acids required(BCAAs), for i.e., insulin BC keto secretion acids stimulated(BCKAs), incl by metabolitesuding 2-ketoisocaproate of branched-chain (KIC; aminotermed acids also (BCAAs),2-oxoisocaproate, i.e., BC ketoOIC; acids leucine (BCKAs), metabolite), including 2-ketoisovalerate 2-ketoisocaproate (KIV; (KIC; valine termed metabolite) also 2- oxoisocaproate,and 2-ketomethylvalerate OIC; leucine (KMV; metabolite), isoleucine 2-ketoisovalerate metabolite). Evidence (KIV; valine for metabolite)this mechanism and 2-ketomethylvaleratestems from the effects (KMV; of mitochondrial isoleucine metabolite). matrix-targeted Evidence antioxidant for this mechanismSkQ1, which stems does fromnot affect the effects GSIS ofin mitochondrial INS-1E cells, matrix-targetedbut completely antioxidantinhibits insulin SkQ1, secretion which does stimulated not affect by GSISBCKAs, in INS-1Ee.g., by cells,KIC [4]. but The completely interpretation inhibits of insulinthese results secretion is that stimulated the NOX4 by source BCKAs, of e.g., by KIC [4]. The interpretation of these results is that the NOX4 source of H O H2O2 cannot be easily inhibited by SkQ1 located within the inner phospholipid leaflet2 of2 cannotthe inner be mitochondrial easily inhibited membrane by SkQ1 located(IMM), whereas within the the inner redox phospholipid signaling originating leaflet of from the innerthe mitochondrion mitochondrial must membrane be blocked. (IMM), whereas the redox signaling originating from the mitochondrionPreviously, must also be coenzyme blocked. A-esters (CoA-esters) of fatty acids (FAs), malonyl-CoA and Previously,long-chain also acyl-CoA coenzyme were A-esters suggested (CoA-esters) to be coupling of fatty acids factors (FAs), for malonyl-CoA nutrient stimu- and long-chain acyl-CoA were suggested to be coupling factors for nutrient stimulus-insulin lus-insulin secretion coupling
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