Biopolym. Cell. 2019; 35(1):3-15.
http://dx.doi.org/10.7124/bc.000998
Reviews
Hydrogen sulfide and mitochondria
1Gerush I.V., 1Ferenchuk Ye.O.
  1. Higher State Educational Establishment of Ukraine «Bukovinian State Medical University»
    2, Theatralna sq., Chernivtsi, Ukraine, 58002

Abstract

There are different opinions about the role of hydrogen sulfide (H2S) in catalytic and energy processes, but the biochemistry of all possible effects of H2S is not well studied yet. The enzymatic synthesis of H2S is catalyzed by cystathionine-γ-lyase, cystathionine-β-synthase, cysteine aminotransferase and in mitochondria by 3-mercaptopyruvate sulfurtransferase only. H2S may function as an energy substrate to sustain the ATP synthesis under stress conditions, but in high concentration H2S inhibits respiratory complex IV, blocking electron transport and proton pumping. The interaction between glucose in high concentrtaion, H2S, and the KATP channels may constitute a novel mechanism for the control of insulin secretion. The positive effect of H2S on the bioenergetic function of mitochondria may be used in therapy of many diseases.
Keywords: hydrogen sulfide, mitochondria, bioenergetics
Full text: (PDF, in English)

References

[1] Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012;92(2):791-896.
[2] Beauchamp RO Jr, Bus JS, Popp JA, Boreiko CJ, Andjelkovich DA. A critical review of the literature on hydrogen sulfide toxicity. Crit Rev Toxicol. 1984;13(1):25-97.
[3] Goubern M, Andriamihaja M, Nübel T, Blachier F, Bouillaud F. Sulfide, the first inorganic substrate for human cells. FASEB J. 2007;21(8):1699-706.
[4] Szabo C, Ransy C, Módis K, Andriamihaja M, Murghes B, Coletta C, Olah G, Yanagi K, Bouillaud F. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. Br J Pharmacol. 2014;171(8):2099-122.
[5] Kabil O, Banerjee R. Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal. 2014;20(5):770-82.
[6] Chen X, Jhee KH, Kruger WD. Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. J Biol Chem. 2004;279(50):52082-6.
[7] Singh S, Padovani D, Leslie RA, Chiku T, Banerjee R. Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. J Biol Chem. 2009;284(33):22457-66.
[8] Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R. H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem. 2009;284(17):11601-12.
[9] Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem. 2009;146(5):623-6. PubMed
[10] Meister A, Fraser PE, Tice SV. Enzymatic desulfuration of beta-mercaptopyruvate to pyruvate. J Biol Chem. 1954;206(2):561-75.
[11] Kabil O, Vitvitsky V, Xie P, Banerjee R. The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues. Antioxid Redox Signal. 2011;15(2):363-72.
[12] Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S, Snyder SH, Wang R. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science. 2008;322(5901):587-90.
[13] Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal. 2009;11(4):703-14.
[14] Wang P, Isaak CK, Siow YL, O K. Downregulation of cystathionine β-synthase and cystathionine γ-lyase expression stimulates inflammation in kidney ischemia-reperfusion injury. Physiol Rep. 2014;2(12). pii: e12251.
[15] Ida T, Sawa T, Ihara H, Tsuchiya Y, Watanabe Y, Kumagai Y, Suematsu M, Motohashi H, Fujii S, Matsunaga T, Yamamoto M, Ono K, Devarie-Baez NO, Xian M, Fukuto JM, Akaike T. Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling. Proc Natl Acad Sci U S A. 2014;111(21):7606-11. PubMed PMID: 24733942;
[16] Yadav PK, Martinov M, Vitvitsky V, Seravalli J, Wedmann R, Filipovic MR, Banerjee R. Biosynthesis and Reactivity of Cysteine Persulfides in Signaling. J Am Chem Soc. 2016;138(1):289-99.
[17] Melideo SL, Jackson MR, Jorns MS. Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog. Biochemistry. 2014;53(28):4739-53.
[18] Zheng L, White RH, Cash VL, Dean DR. Mechanism for the desulfurization of L-cysteine catalyzed by the nifS gene product. Biochemistry. 1994;33(15):4714-20.
[19] Yadav PK, Yamada K, Chiku T, Koutmos M, Banerjee R. Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase. J Biol Chem. 2013;288(27):20002-13.
[20] Furne J, Saeed A, Levitt MD. Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than presently accepted values. Am J Physiol Regul Integr Comp Physiol. 2008;295(5):R1479-85.
[21] Vitvitsky V, Kabil O, Banerjee R. High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. Antioxid Redox Signal. 2012;17(1):22-31.
[22] Theissen U, Hoffmeister M, Grieshaber M, Martin W. Single eubacterial origin of eukaryotic sulfide:quinone oxidoreductase, a mitochondrial enzyme conserved from the early evolution of eukaryotes during anoxic and sulfidic times. Mol Biol Evol. 2003;20(9):1564-74.
[23] Libiad M, Yadav PK, Vitvitsky V, Martinov M, Banerjee R. Organization of the human mitochondrial hydrogen sulfide oxidation pathway. J Biol Chem. 2014;289(45):30901-10. PubMed PMID: 25225291;
[24] Kabil O, Banerjee R. Characterization of patient mutations in human persulfide dioxygenase (ETHE1) involved in H2S catabolism. J Biol Chem. 2012;287(53):44561-7.
[25] Hildebrandt TM, Grieshaber MK. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J. 2008;275(13):3352-61.
[26] Bucci M, Papapetropoulos A, Vellecco V, Zhou Z, Pyriochou A, Roussos C, Roviezzo F, Brancaleone V, Cirino G. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler Thromb Vasc Biol. 2010;30(10):1998-2004.
[27] Módis K, Panopoulos P, Coletta C, Papapetropoulos A, Szabo C. Hydrogen sulfide-mediated stimulation of mitochondrial electron transport involves inhibition of the mitochondrial phosphodiesterase 2A, elevation of cAMP and activation of protein kinase A. Biochem Pharmacol. 2013;86(9):1311-9.
[28] Bartholomew TC, Powell GM, Dodgson KS, Curtis CG. Oxidation of sodium sulphide by rat liver, lungs and kidney. Biochem Pharmacol. 1980;29(18):2431-7.
[29] Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C, Levitt MD, Prelle A, Fagiolari G, Rimoldi M, Zeviani M. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med. 2009;15(2):200-5.
[30] Cooper CE, Brown GC. The inhibition of mitochondrial cytochrome oxidase by the gases carbon monoxide, nitric oxide, hydrogen cyanide and hydrogen sulfide: chemical mechanism and physiological significance. J Bioenerg Biomembr. 2008;40(5):533-9. PubMed
[31] Bouillaud F, Blachier F. Mitochondria and sulfide: a very old story of poisoning, feeding, and signaling? Antioxid Redox Signal. 2011;15(2):379-91.
[32] Linden DR, Sha L, Mazzone A, Stoltz GJ, Bernard CE, Furne JK, Levitt MD, Farrugia G, Szurszewski JH. Production of the gaseous signal molecule hydrogen sulfide in mouse tissues. J Neurochem. 2008;106(4):1577-85.
[33] Khan AA, Schuler MM, Prior MG, Yong S, Coppock RW, Florence LZ, Lillie LE. Effects of hydrogen sulfide exposure on lung mitochondrial respiratory chain enzymes in rats. Toxicol Appl Pharmacol. 1990;103(3):482-90.
[34] Fu M, Zhang W, Wu L, Yang G, Li H, Wang R. Hydrogen sulfide (H2S) metabolism in mitochondria and its regulatory role in energy production. Proc Natl Acad Sci U S A. 2012;109(8):2943-8.
[35] Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J. 2001;20(21):6008-16.
[36] Guo W, Kan JT, Cheng ZY, Chen JF, Shen YQ, Xu J, Wu D, Zhu YZ. Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction. Oxid Med Cell Longev. 2012;2012:878052.
[37] Teng H, Wu B, Zhao K, Yang G, Wu L, Wang R. Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease. Proc Natl Acad Sci U S A. 2013;110(31):12679-84.
[38] Módis K, Bos EM, Calzia E, van Goor H, Coletta C, Papapetropoulos A, Hellmich MR, Radermacher P, Bouillaud F, Szabo C. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part II. Pathophysiological and therapeutic aspects. Br J Pharmacol. 2014;171(8):2123-46.
[39] Módis K, Coletta C, Erdélyi K, Papapetropoulos A, Szabo C. Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. FASEB J. 2013;27(2):601-11.
[40] Módis K, Asimakopoulou A, Coletta C, Papapetropoulos A, Szabo C. Oxidative stress suppresses the cellular bioenergetic effect of the 3-mercaptopyruvate sulfurtransferase/hydrogen sulfide pathway. Biochem Biophys Res Commun. 2013;433(4):401-7. ttps:// PubMed PMID: 23537657.
[41] Kamoun P. Endogenous production of hydrogen sulfide in mammals. Amino Acids. 2004;26(3):243-54.
[42] Shibuya N, Koike S, Tanaka M, Ishigami-Yuasa M, Kimura Y, Ogasawara Y, Fukui K, Nagahara N, Kimura H. A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun. 2013;4:1366.
[43] James AM, Murphy MP. How mitochondrial damage affects cell function. J Biomed Sci. 2002;9(6 Pt 1):475-87.
[44] Duchen MR. Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med. 2004;25(4):365-451.
[45] Predmore BL, Lefer DJ, Gojon G. Hydrogen sulfide in biochemistry and medicine. Antioxid Redox Signal. 2012;17(1):119-40.
[46] Essick EE, Sam F. Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer. Oxid Med Cell Longev. 2010;3(3):168-77.
[47] Nicholson RA, Roth SH, Zhang A, Zheng J, Brookes J, Skrajny B, Bennington R. Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain. J Toxicol Environ Health A. 1998;54(6):491-507.
[48] Dorman DC, Moulin FJ, McManus BE, Mahle KC, James RA, Struve MF. Cytochrome oxidase inhibition induced by acute hydrogen sulfide inhalation: correlation with tissue sulfide concentrations in the rat brain, liver, lung, and nasal epithelium. Toxicol Sci. 2002;65(1):18-25.
[49] Powell MA, Somero GN. Hydrogen Sulfide Oxidation Is Coupled to Oxidative Phosphorylation in Mitochondria of Solemya reidi. Science. 1986;233(4763):563-6.
[50] Detmer SA, Chan DC. Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol. 2007;8(11):870-9.
[51] Kimura Y, Goto Y, Kimura H. Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal. 2010;12(1):1-13.
[52] Guan Q, Zhang Y, Yu C, Liu Y, Gao L, Zhao J. Hydrogen sulfide protects against high-glucose-induced apoptosis in endothelial cells. J Cardiovasc Pharmacol. 2012;59(2):188-93.
[53] Zhou X, Lu X. Hydrogen sulfide inhibits high-glucose-induced apoptosis in neonatal rat cardiomyocytes. Exp Biol Med (Maywood). 2013;238(4):370-4.
[54] Yuan Q, Hong S, Han S, Zeng L, Liu F, Ding G, Kang Y, Mao J, Cai M, Zhu Y, Wang QX. Preconditioning with physiological levels of ethanol protect kidney against ischemia/reperfusion injury by modulating oxidative stress. PLoS One. 2011;6(10):e25811.
[55] Xia M, Chen L, Muh RW, Li PL, Li N. Production and actions of hydrogen sulfide, a novel gaseous bioactive substance, in the kidneys. J Pharmacol Exp Ther. 2009;329(3):1056-62.
[56] Yanchuk PI, Slobodianyk LA. [The role of hydrogen sulfide in regulation of circulation blood liver]. Fiziol Zh. 2015;61(3):28-34.
[57] Zheng SF, Bao RK, Zhang QJ, Wang SC, Lin HJ. Endogenous Hydrogen Sulfide Promotes Apoptosis via Mitochondrial Pathways in the Livers of Broilers with Selenium Deficiency Exudative Diathesis Disease. Biol Trace Elem Res. 2018;186(1):249-257.
[58] Shimizu Y, Polavarapu R, Eskla KL, Nicholson CK, Koczor CA, Wang R, Lewis W, Shiva S, Lefer DJ, Calvert JW. Hydrogen sulfide regulates cardiac mitochondrial biogenesis via the activation of AMPK. J Mol Cell Cardiol. 2018;116:29-40. PubMed Central
[59] Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12(4):537-77.
[60] Yang W, Yang G, Jia X, Wu L, Wang R. Activation of KATP channels by H2S in rat insulin-secreting cells and the underlying mechanisms. J Physiol. 2005;569(Pt 2):519-31.
[61] Szabó C. Hydrogen sulphide and its therapeutic potential. Nat Rev Drug Discov. 2007;6(11):917-35.
[62] Mel'nyk AV, Pentiuk OO. [Activity of hydrogen sulfide production enzymes in kidneys of rats]. Ukr Biokhim Zh (1999). 2009;81(4):12-22. Ukrainian.
[63] Sagach VF, Shymanska TV, Goshovska YuV. Influence of stimulation and blockade of synthesis of endogenous hydrogen sulfide on the function of the heart under conditions of ischemia-reperfusion. Fiziol Zh. 2013; 59 (4): 8-15.
[64] Berezovsky VYa, Plotnikova LM. Hydrogen sulfide and its role in the regulation of vascular tone. J hydrology and rehabilitation. 2012; 10 (1): 4-10.
[65] Zaichko NV, Yoltukhivsky MM, Olkhovsky O. S., Palamarchuk VI. Age characteristics of the effect of propargylglycine and sodium hydrogen sulfide on the H2S exchange rate in myocardium of rats. Bull. Biology and Medicine. 2013; 4 (2): 105-10.
[66] Strutinskaya NA, Semenykhina OM, Chornaya SV. Hydrogen sulfide suppresses the calcium induced opening of the mitochondrial pores in the heart of adults and old rats. Phys Journ. 2011; 57 (6): 3-13.
[67] Dugbartey GJ. The smell of renal protection against chronic kidney disease: Hydrogen sulfide offers a potential stinky remedy. Pharmacol Rep. 2018;70(2):196-205.
[68] Wu W, Hou CL, Mu XP, Sun C, Zhu YC, Wang MJ, Lv QZ. H(2)S Donor NaHS Changes the Production of Endogenous H(2)S and NO in D-Galactose-Induced Accelerated Ageing. Oxid Med Cell Longev. 2017;2017:5707830.
[69] Zhou H, Ding L, Wu Z, Cao X, Zhang Q, Lin L, Bian JS. Hydrogen sulfide reduces RAGE toxicity through inhibition of its dimer formation. Free Radic Biol Med. 2017;104:262-271.
[70] Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058-70.
[71] Pangare M, Makino A. Mitochondrial function in vascular endothelial cell in diabetes. J Smooth Muscle Res. 2012;48(1):1-26.
[72] Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 2000;404(6779):787-90.
[73] Suzuki K, Olah G, Modis K, Coletta C, Kulp G, Gerö D, Szoleczky P, Chang T, Zhou Z, Wu L, Wang R, Papapetropoulos A, Szabo C. Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function. Proc Natl Acad Sci U S A. 2011;108(33):13829-34.
[74] Szabo C. Roles of hydrogen sulfide in the pathogenesis of diabetes mellitus and its complications. Antioxid Redox Signal. 2012;17(1):68-80.
[75] Gerush IV, Bevzo VV, Ferenchuk YeO. The effect of melatonin on lipid peroxide oxidation, oxidative modification of proteins and mitochondria swelling in the skeletal muscle tissue of rats under alloxan diabetes Ukr Biochem J. 2018; 90 (3):62-9.
[76] Yamamoto J, Sato W, Kosugi T, Yamamoto T, Kimura T, Taniguchi S, Taniguchi S, Kojima H, Maruyama S, Imai, E, Matsuo, S, Yuzawa, Y, Niki, I. Distribution of hydrogen sulfide (H2S)-producing enzymes and the roles of the H2S donor sodium hydrosulfide in diabetic nephropathy. Clin Exp Nephrol. 2013; 17(1): 32-40.
[77] Jain SK, Bull R, Rains JL, Bass PF, Levine SN, Reddy S, McVie R, Bocchini JA. Low levels of hydrogen sulfide in the blood of diabetes patients and streptozotocin-treated rats causes vascular inflammation? Antioxid Redox Signal. 2010;12(11):1333-7.
[78] Okamoto M, Yamaoka M, Takei M, Ando T, Taniguchi S, Ishii I, Tohya K, Ishizaki T, Niki I, Kimura T. Endogenous hydrogen sulfide protects pancreatic beta-cells from a high-fat diet-induced glucotoxicity and prevents the development of type 2 diabetes. Biochem Biophys Res Commun. 2013;442(3-4):227-33.
[79] Gadalla MM, Snyder SH. Hydrogen sulfide as a gasotransmitter. J Neurochem. 2010;113(1):14-26.
[80] Si YF, Wang J, Guan J, Zhou L, Sheng Y, Zhao J. Treatment with hydrogen sulfide alleviates streptozotocin-induced diabetic retinopathy in rats. Br J Pharmacol. 2013;169(3):619-31.
[81] Lee HJ, Mariappan MM, Feliers D, Cavaglieri RC, Sataranatarajan K, Abboud HE, Choudhury GG, Kasinath BS. Hydrogen sulfide inhibits high glucose-induced matrix protein synthesis by activating AMP-activated protein kinase in renal epithelial cells. J Biol Chem. 2012;287(7):4451-61.
[82] Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996;16(3):1066-71.
[83] Wang R. Hydrogen sulfide: the third gasotransmitter in biology and medicine. Antioxid Redox Signal. 2010;12(9):1061-4.
[84] Yuan P, Xue H, Zhou L, Qu L, Li C, Wang Z, Ni J, Yu C, Yao T, Huang Y, Wang R, Lu L. Rescue of mesangial cells from high glucose-induced over-proliferation and extracellular matrix secretion by hydrogen sulfide. Nephrol Dial Transplant. 2011;26(7):2119-26.