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Exogenous Hydrogen Sulfide Plays an Important Role by Regulating International Journal of Molecular Sciences Review Exogenous Hydrogen Sulfide Plays an Important Role by Regulating Autophagy in Diabetic-Related Diseases Shuangyu Lv , Huiyang Liu and Honggang Wang * Henan International Joint Laboratory of Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng 475000, China; [email protected] (S.L.); [email protected] (H.L.) * Correspondence: [email protected] Abstract: Autophagy is a vital cell mechanism which plays an important role in many physiological processes including clearing long-lived, accumulated and misfolded proteins, removing damaged organelles and regulating growth and aging. Autophagy also participates in a variety of biological functions, such as development, cell differentiation, resistance to pathogens and nutritional hunger. Recently, autophagy has been reported to be involved in diabetes, but the mechanism is not fully understood. Hydrogen sulfide (H2S) is a colorless, water-soluble, flammable gas with the typical odor of rotten eggs, which has been known as a highly toxic gas for many years. However, it has been reported recently that H2S, together with nitric oxide and carbon monoxide, is an important gas signal transduction molecule. H2S has been reported to play a protective role in many diabetes- related diseases, but the mechanism is not fully clear. Recent studies indicate that H2S plays an important role by regulating autophagy in many diseases including cancer, tissue fibrosis diseases and glycometabolic diseases; however, the related mechanism has not been fully studied. In this review, we summarize recent research on the role of H2S in regulating autophagy in diabetic-related diseases to provide references for future related research. Citation: Lv, S.; Liu, H.; Wang, H. Exogenous Hydrogen Sulfide Plays Keywords: hydrogen sulfide; autophagy; diabetes; signaling pathway; oxidative stress an Important Role by Regulating Autophagy in Diabetic-Related Diseases. Int. J. Mol. Sci. 2021, 22, 6715. https://doi.org/10.3390/ 1. Introduction ijms22136715 Autophagy is a closely coordinated process that isolates proteins and damaged or aged organelles in double-membrane vesicles called autophagosomes, which eventually fuse Academic Editor: Deok-Ryong Kim with lysosomes, leading to the degradation of the isolated components [1]. According to the type of degraded cargo and the way of transporting cargo to lysosomes, autophagy can Received: 8 June 2021 be divided into three types: macroautophagy, microautophagy and chaperone-mediated Accepted: 21 June 2021 Published: 23 June 2021 autophagy. Macroautophagy, which is the most common autophagy, promotes autophago- some formation. The autophagosome is a cytosolic double-membranous vesicle which Publisher’s Note: MDPI stays neutral isolates part of the cytoplasm. Autophagosomes then fuse with lysosomes to form au- with regard to jurisdictional claims in tolysosomes in which the isolated cytoplasm is degraded or recycled [2,3]. Microautophagy published maps and institutional affil- refers to the direct invagination of a lysosomal membrane, which then encapsulates the iations. cell contents [4]. Chaperone-mediated autophagy is a type of selective autophagy, in which proteins in cells are transported to lysosomal chambers after binding with chaperones and then digested by lysosomal enzymes [5,6] (Figure1). Autophagy is the main cellular pathway regulating the degradation of long-lived proteins and the only known degra- dation pathway of cytoplasmic organelles. It has been reported that autophagy and the Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. ubiquitin–proteasome system (UPS) are two important quality control systems for degrad- This article is an open access article ing proteins and organelles in eukaryotic cells [7]. Autophagy includes several successive distributed under the terms and steps: induction, autophagosome formation, autophagosome fusion and degradation [8]. conditions of the Creative Commons Beclin1, LC3, P62 and other conserved proteins participate in the autophagy process and Attribution (CC BY) license (https:// are regarded as autophagy-related proteins [9]. Among them, LC3, a ubiquitin-like pro- creativecommons.org/licenses/by/ tein, promotes the formation of autophagosomes [8,10]. It regulates the elongation and 4.0/). closure of the autophagic membrane by binding with phosphatidylethanolamine [11]. Int. J. Mol. Sci. 2021, 22, 6715. https://doi.org/10.3390/ijms22136715 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 13 Int. J. Mol. Sci. 2021, 22, 6715 2 of 13 LC3, a ubiquitin-like protein, promotes the formation of autophagosomes [8,10]. It regu- lates the elongation and closure of the autophagic membrane by binding with phosphati- Autophagydylethanolamine is influenced [11]. Autophagy by many factorsis influenced including by many immune factors or inflammatory including immune stimulation, or in- endoplasmicflammatory stimulation, reticulum stress, endo Caplasmic2+ concentration, reticulum stress, nutritional Ca2+ concentration, deficiency and nutritional accumulation de- officiency damaged and cells accumulation or organelles of damaged [12,13]. Autophagy cells or organelles is usually [12,13]. maintained Autophagy at the basic is usually level undermaintained physiological at the basic conditions. level under In the physiological pathological conditions. state, upregulated In the pathological autophagy state, can clear up- theregulated abnormal autophagy proteins can in cellsclear to the help abnormal cell survival proteins [14]. in However, cells to help if autophagy cell survival remains [14]. atHowever, a high level, if autophagy autophagy remains will induce at a high cell level, death autophagy [15,16]. Autophagy will induce plays cell adeath vital [15,16]. role in manyAutophagy physiological plays a vital processes role in and many diseases, physiological including processes the immune and diseases, response, including starvation the adaptation,immune response, development, starvation quality adaptation, control of intracellulardevelopment, proteins quality and control organelles, of intracellular anti-aging mechanisms,proteins and tumororganelles, suppression anti-aging [13 ,mechanisms,17–19], cardiovascular tumor suppression disease [20 [13,17–19],], neurodegenerative cardiovas- diseasescular disease [21], [20], infection neurodegenerative and immunity diseases [17]. However, [21], infection the related and immunity mechanisms [17]. are How- not fullyever, understood.the related mechanisms are not fully understood. FigureFigure 1.1. TheThe generalgeneral processprocess ofof macroautophagy,macroautophagy, microautophagymicroautophagy andand chaperone-mediatedchaperone-mediated au-au- tophagy.tophagy. InIn the the process process of of macroautophagy, macroautophagy, the the content content is wrappedis wrapped by by a bilayer a bilayer membrane membrane structure struc- toture form to form an autophagosome an autophagosome and then and fuses then withfuses lysosomes with lysosomes for degradation. for degradation. Microautophagy Microautophagy refers refers to the process by which the lysosomal membranes directly invaginate and then encapsulate to the process by which the lysosomal membranes directly invaginate and then encapsulate the the cell contents. In the process of chaperone-mediated autophagy, the cytosolic proteins are trans- cell contents. In the process of chaperone-mediated autophagy, the cytosolic proteins are trans- ported to the lysosomal chamber after binding to molecular chaperones and then are digested by portedlysosomal to the enzymes. lysosomal chamber after binding to molecular chaperones and then are digested by lysosomal enzymes. Diabetes is an important metabolic disease. Its prevalence rate is significantly higher Diabetes is an important metabolic disease. Its prevalence rate is significantly higher than before. In the 1990s, the number of diabetic patients worldwide was 135 million, and than before. In the 1990s, the number of diabetic patients worldwide was 135 million, and it may rise to 300 million by 2025 [22]. Diabetes is classified as type 1 diabetes and type 2 it may rise to 300 million by 2025 [22]. Diabetes is classified as type 1 diabetes and type diabetes. Insulin-dependent diabetes mellitus (also known as type 1 diabetes) is sensitive 2 diabetes. Insulin-dependent diabetes mellitus (also known as type 1 diabetes) is sensitive to insulin therapy. The incidence of the disease is closely related to genetic factors. Most to insulin therapy. The incidence of the disease is closely related to genetic factors. Most patients belong to autoimmune diseases. Insulin antibodies are found in the serum of pa- patients belong to autoimmune diseases. Insulin antibodies are found in the serum of patients,tients, which which renders renders insulin insulin unable unable to to play play it itss normal normal biological activities. TheThe patient’spatient’s insulininsulin secretionsecretion graduallygradually decreasesdecreases untiluntil itit isis completelycompletely lostlost andand anan insulininsulin supplementsupplement is needed. Patients with typical clinical symptoms and a serious condition are prone to ketoacidosis, and even coma. Noninsulin-dependent diabetes mellitus (also known as type Int. J. Mol. Sci. 2021, 22, 6715 3 of 13 2 diabetes) is commonly seen in obese adults. These patients’ blood insulin level is not low, but insulin receptor deficiency leads to a poor
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