Abstract
Background: Molecular hydrogen (H2) is now recognized as a therapeutic gas for the treatment of numerous diseases including neurodegenerative diseases, metabolic disorders, and inflammatory diseases. Nonpolar, neutral H2 is assumed to have health benefits facilitated by its passive diffusion across the human body immediately after administration and is considered a safe therapeutic inert gas that does not interfere with physiological enzymatic reactions. The effects of H2 on mammalian cells are assumed to be based on non-enzymatic reactions with reactive oxygen species (ROS) exhibiting extremely high reactivity. However, many reports on therapeutic applications of H2 have the limitation to regard H2 only as a scavenger for the hydroxyl radical and peroxynitrite.
Methods: Apart from this proposed principle, a new possible mechanism of H2 activation and consumption in mammalian cells is considered in this review, which is specifically focused on the mitochondrial complex I that has a close evolutionary relationship with energy-converting, membrane-bound [NiFe]-hydrogenases (MBH). Notably, the possibility that H2 may function as both electron and proton donor in the ubiquinone-binding chamber of complex I is discussed.
Results: H2 is proposed to act as the rectifier of the mitochondrial electron flow in the disordered or pathological state when the accumulation of electrons leads to ROS production, specifically during the re-supply of O2 after hypoxia in the mitochondria.
Conclusion: Furthermore, H2 is proposed to convert the quinone intermediates to the fully reduced ubiquinol, thereby increasing the antioxidant capacity of the quinone pool as well as preventing the generation of ROS.
Keywords: Molecular hydrogen, semiquinone, hydrogenase, rectifier of electron flow, mitochondrial respiratory complex, electron and proton donor.
[1]
Vignais PM, Colbeau A. Molecular biology of microbial hydrogenases. Curr Issues Mol Biol 2004; 6(2): 159-88. [PMID: 15119826].
[2]
Schut GJ, Zadvornyy O, Wu CH, Peters JW, Boyd ES, Adams MW. The role of geochemistry and energetics in the evolution of modern respiratory complexes from a proton-reducing ancestor. Biochim Biophys Acta 2016; 1857(7): 958-70. [http://dx.doi.org/10.1016/j.bbabio.2016.01.010]. [PMID: 26808919].
[3]
Ichihara M, Sobue S, Ito M, Ito M, Hirayama M, Ohno K. Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles. Med Gas Res 2015; 5: 12. [http://dx.doi.org/10.1186/s13618-015-0035-1]. [PMID: 26483953].
[4]
Shirahata S, Kabayama S, Nakano M, et al. Electrolyzed-reduced water scavenges active oxygen species and protects DNA from oxidative damage. Biochem Biophys Res Commun 1997; 234(1): 269-74. [http://dx.doi.org/10.1006/bbrc.1997.6622]. [PMID: 9169001].
[5]
Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med 2007; 13(6): 688-94. [http://dx.doi.org/10.1038/nm1577]. [PMID: 17486089].
[6]
Ohta S. Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacol Ther 2014; 144(1): 1-11. [http://dx.doi.org/10.1016/j.pharmthera.2014.04.006]. [PMID: 24769081].
[7]
Yoritaka A, Ohtsuka C, Maeda T, et al. Randomized, double-blind, multicenter trial of hydrogen water for Parkinson’s disease. Mov Disord 2018; 33(9): 1505-7. [http://dx.doi.org/10.1002/mds.27472]. [PMID: 30207619].
[8]
Yoritaka A, Takanashi M, Hirayama M, Nakahara T, Ohta S, Hattori N. Pilot study of H2 therapy in Parkinson’s disease: a randomized double-blind placebo-controlled trial. Mov Disord 2013; 28(6): 836-9. [http://dx.doi.org/10.1002/mds.25375]. [PMID: 23400965].
[9]
Sakai T, Sato B, Hara K, et al. Consumption of water containing over 3.5 mg of dissolved hydrogen could improve vascular endothelial function. Vasc Health Risk Manag 2014; 10: 591-7. [PMID: 25378931].
[10]
Ishibashi T. Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases. Curr Pharm Des 2013; 19(35): 6375-81. [http://dx.doi.org/10.2174/13816128113199990507]. [PMID: 23859555].
[11]
Buxton GV, Greenstock CL, Helman WP, Ross AB. Critical review of rate constants for reactions of hydrated electrons, hydrogen atoms and hydroxyl radicals (･OH/･OH-) in aqueous solution. J Phys Chem Ref Data 1988; 17: 513-886. [http://dx.doi.org/10.1063/1.555805].
[12]
Filippin LI, Vercelino R, Marroni NP, Xavier RM. Redox signalling and the inflammatory response in rheumatoid arthritis. Clin Exp Immunol 2008; 152(3): 415-22. [http://dx.doi.org/10.1111/j.1365-2249.2008.03634.x]. [PMID: 18422737].
[13]
Jones KG, Cooper WJ, Mezykk SP. Bimolecular rate constant determination for the reaction of hydroxyl radicals with domoic and kainic acid in aqueous solution. Environ Sci Technol 2009; 43(17): 6764-8. [http://dx.doi.org/10.1021/es901128c]. [PMID: 19764247].
[14]
Kamimura N, Nishimaki K, Ohsawa I, Ohta S. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity (Silver Spring) 2011; 19(7): 1396-403. [http://dx.doi.org/10.1038/oby.2011.6]. [PMID: 21293445].
[15]
Ishibashi T, Sato B, Rikitake M, et al. Consumption of water containing a high concentration of molecular hydrogen reduces oxidative stress and disease activity in patients with rheumatoid arthritis: an open-label pilot study. Med Gas Res 2012; 2(1): 27. [http://dx.doi.org/10.1186/2045-9912-2-27]. [PMID: 23031079].
[16]
Feagin JE. The 6-kb element of Plasmodium falciparum encodes mitochondrial cytochrome genes. Mol Biochem Parasitol 1992; 52(1): 145-8. [http://dx.doi.org/10.1016/0166-6851(92)90046-M]. [PMID: 1320735].
[17]
Moser CC, Farid TA, Chobot SE, Dutton PL. Electron tunneling chains of mitochondria. Biochim Biophys Acta 2006; 1757(9-10): 1096-109. [http://dx.doi.org/10.1016/j.bbabio.2006.04.015]. [PMID: 16780790].
[18]
Murphy E, Steenbergen C. Preconditioning: the mitochondrial connection. Annu Rev Physiol 2007; 69: 51-67. [http://dx.doi.org/10.1146/annurev.physiol.69.031905.163645]. [PMID: 17007587].
[19]
Marreiros BC, Batista AP, Duarte AM, Pereira MM. A missing link between complex I and group 4 membrane-bound [NiFe] hydrogenases. Biochim Biophys Acta 2013; 1827(2): 198-209. [http://dx.doi.org/10.1016/j.bbabio.2012.09.012]. [PMID: 23000657].
[20]
Boveris A, Oshino N, Chance B. The cellular production of hydrogen peroxide. Biochem J 1972; 128(3): 617-30. [http://dx.doi.org/10.1042/bj1280617]. [PMID: 4404507].
[21]
Chen YR, Zweier JL. Cardiac mitochondria and reactive oxygen species generation. Circ Res 2014; 114(3): 524-37. [http://dx.doi.org/10.1161/CIRCRESAHA.114.300559]. [PMID: 24481843].
[22]
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 2010; 49(11): 1603-16. [http://dx.doi.org/10.1016/j.freeradbiomed.2010.09.006]. [PMID: 20840865].
[23]
Parey K, Brandt U, Xie H, et al. Cryo-EM structure of respiratory complex I at work. eLife 2018; 7: e39213.
[24]
Hirst J, Roessler MM. Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I. Biochim Biophys Acta 2016; 1857(7): 872-83. [http://dx.doi.org/10.1016/j.bbabio.2015.12.009]. [PMID: 26721206].
[25]
Ohnishi T, Ohnishi ST, Salerno JC. Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I). Biol Chem 2018; 399(11): 1249-64. [http://dx.doi.org/10.1515/hsz-2018-0164]. [PMID: 30243012].
[26]
Song Y, Buettner GR. Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide. Free Radic Biol Med 2010; 49(6): 919-62. [http://dx.doi.org/10.1016/j.freeradbiomed.2010.05.009]. [PMID: 20493944].
[27]
Dröse S, Brandt U. The mechanism of mitochondrial superoxide production by the cytochrome bc1 complex. J Biol Chem 2008; 283(31): 21649-54. [http://dx.doi.org/10.1074/jbc.M803236200]. [PMID: 18522938].
[28]
Sarewicz M, Borek A, Daldal F, Froncisz W, Osyczka A. Demonstration of short-lived complexes of cytochrome c with cytochrome bc1 by EPR spectroscopy: implications for the mechanism of interprotein electron transfer. J Biol Chem 2008; 283(36): 24826-36. [http://dx.doi.org/10.1074/jbc.M802174200]. [PMID: 18617515].
[29]
Mitchell P. Possible molecular mechanisms of the protonmotive function of cytochrome systems. J Theor Biol 1976; 62(2): 327-67. [http://dx.doi.org/10.1016/0022-5193(76)90124-7]. [PMID: 186667].
[30]
Ohnishi T, Ohnishi ST, Shinzawa-Itoh K, Yoshikawa S, Weber RT. EPR detection of two protein-associated ubiquinone components (SQ(Nf) and SQ(Ns)) in the membrane in situ and in proteoliposomes of isolated bovine heart complex I. Biochim Biophys Acta 2012; 1817(10): 1803-9. [http://dx.doi.org/10.1016/j.bbabio.2012.03.032]. [PMID: 22503829].
[31]
Breuer ME, Koopman WJ, Koene S, et al. The role of mitochondrial OXPHOS dysfunction in the development of neurologic diseases. Neurobiol Dis 2013; 51: 27-34. [http://dx.doi.org/10.1016/j.nbd.2012.03.007]. [PMID: 22426394].
[32]
Holper L, Ben-Shachar D, Mann JJ. Multivariate meta-analyses of mitochondrial complex I and IV in major depressive disorder, bipolar disorder, schizophrenia, Alzheimer disease, and Parkinson disease. Neuropsychopharmacology 2018; 2018: 1. [PMID: 29855563].
[33]
Letts JA, Sazanov LA. Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain. Nat Struct Mol Biol 2017; 24(10): 800-8. [http://dx.doi.org/10.1038/nsmb.3460]. [PMID: 28981073].
[34]
Brandt U. A two-state stabilization-change mechanism for proton-pumping complex I. Biochim Biophys Acta 2011; 1807(10): 1364-9. [http://dx.doi.org/10.1016/j.bbabio.2011.04.006]. [PMID: 21565159].
[35]
Ingledew WJ, Ohnishi T. An analysis of some thermodynamic properties of iron-sulphur centres in site I of mitochondria. Biochem J 1980; 186(1): 111-7. [http://dx.doi.org/10.1042/bj1860111]. [PMID: 6245637].
[36]
Baradaran R, Berrisford JM, Minhas GS, Sazanov LA. Crystal structure of the entire respiratory complex I. Nature 2013; 494(7438): 443-8. [http://dx.doi.org/10.1038/nature11871]. [PMID: 23417064].
[37]
Zickermann V, Wirth C, Nasiri H, et al. Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I. Science 2015; 347(6217): 44-9. [http://dx.doi.org/10.1126/science.1259859]. [PMID: 25554780].
[38]
Fiedorczuk K, Letts JA, Degliesposti G, Kaszuba K, Skehel M, Sazanov LA. Atomic structure of the entire mammalian mitochondrial complex I. Nature 2016; 538(7625): 406-10. [http://dx.doi.org/10.1038/nature19794]. [PMID: 27595392].
[39]
Blaza JN, Vinothkumar KR, Hirst J. Structure of the deactive state of mammalian respiratory complex I. Structure 2018; 26(2): 312-319.e3. [http://dx.doi.org/10.1016/j.str.2017.12.014]. [PMID: 29395787].
[40]
Zhu J, Vinothkumar KR, Hirst J. Structure of mammalian respiratory complex I. Nature 2016; 536(7616): 354-8. [http://dx.doi.org/10.1038/nature19095]. [PMID: 27509854].
[41]
Chouchani ET, Methner C, Nadtochiy SM, et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 2013; 19(6): 753-9. [http://dx.doi.org/10.1038/nm.3212]. [PMID: 23708290].
[42]
Yano T, Dunham WR, Ohnishi T. Characterization of the delta muH+-sensitive ubisemiquinone species (SQ(Nf)) and the interaction with cluster N2: new insight into the energy-coupled electron transfer in complex I. Biochemistry 2005; 44(5): 1744-54. [http://dx.doi.org/10.1021/bi048132i]. [PMID: 15683258].
[43]
Efremov RG, Sazanov LA. The coupling mechanism of respiratory complex I - a structural and evolutionary perspective. Biochim Biophys Acta 2012; 1817(10): 1785-95. [http://dx.doi.org/10.1016/j.bbabio.2012.02.015]. [PMID: 22386882].
[44]
Stephan DW, Erker G. Frustrated Lewis pairs: metal-free hydrogen activation and more. Angew Chem Int Ed Engl 2010; 49(1): 46-76. [http://dx.doi.org/10.1002/anie.200903708]. [PMID: 20025001].
[45]
Berrisford JM, Sazanov LA. Structural basis for the mechanism of respiratory complex I. J Biol Chem 2009; 284(43): 29773-83. [http://dx.doi.org/10.1074/jbc.M109.032144]. [PMID: 19635800].
[46]
Evans RM, Brooke EJ, Wehlin SA, et al. Mechanism of hydrogen activation by [NiFe] hydrogenases. Nat Chem Biol 2016; 12(1): 46-50. [http://dx.doi.org/10.1038/nchembio.1976]. [PMID: 26619250].
[47]
Welch GC, San Juan RR, Masuda JD, Stephan DW. Reversible, metal-free hydrogen activation. Science 2006; 314(5802): 1124-6. [http://dx.doi.org/10.1126/science.1134230]. [PMID: 17110572].
[48]
Medda R, Padiglia A, Pedersen JZ, Floris G. Evidence for alpha-proton abstraction and carbanion formation involving a functional histidine residue in lentil seedling amine oxidase. Biochem Biophys Res Commun 1993; 196(3): 1349-55. [http://dx.doi.org/10.1006/bbrc.1993.2401]. [PMID: 8250890].
[49]
Hernández-Ortega A, Lucas F, Ferreira P, Medina M, Guallar V, Martínez AT. Role of active site histidines in the two half-reactions of the aryl-alcohol oxidase catalytic cycle. Biochemistry 2012; 51(33): 6595-608. [http://dx.doi.org/10.1021/bi300505z]. [PMID: 22834786].
[50]
Carr SB, Evans RM, Brooke EJ, et al. Hydrogen activation by [NiFe]-hydrogenases. Biochem Soc Trans 2016; 44(3): 863-8. [http://dx.doi.org/10.1042/BST20160031]. [PMID: 27284053].
[51]
Sazanov LA, Hinchliffe P. Structure of the hydrophilic domain of respiratory complex I from Thermus thermophilus. Science 2006; 311(5766): 1430-6. [http://dx.doi.org/10.1126/science.1123809]. [PMID: 16469879].
[52]
Zwicker K, Galkin A, Dröse S, Grgic L, Kerscher S, Brandt U. The Redox-Bohr group associated with iron-sulfur cluster N2 of complex I. J Biol Chem 2006; 281(32): 23013-7. [http://dx.doi.org/10.1074/jbc.M603442200]. [PMID: 16760472].
[53]
Tocilescu MA, Zickermann V, Zwicker K, Brandt U. Quinone binding and reduction by respiratory complex I. Biochim Biophys Acta 2010; 1797(12): 1883-90. [http://dx.doi.org/10.1016/j.bbabio.2010.05.009]. [PMID: 20493164].
[54]
Kashani-Poor N, Zwicker K, Kerscher S, Brandt U. A central functional role for the 49-kDa subunit within the catalytic core of mitochondrial complex I. J Biol Chem 2001; 276(26): 24082-7. [http://dx.doi.org/10.1074/jbc.M102296200]. [PMID: 11342550].
[55]
Fiedorczuk K, Sazanov LA. Fiedorczuk., K, Sazanov LA. Mammalian mitochondrial complex I structure and disease-causing mutations. Trends Cell Biol 2018; 28(10): 835-67. [http://dx.doi.org/10.1016/j.tcb.2018.06.006]. [PMID: 30055843].
[56]
Stuehr DJ, Kwon NS, Nathan CF, Griffith OW, Feldman PL, Wiseman J. N omega-hydroxy-L-arginine is an intermediate in the biosynthesis of nitric oxide from L-arginine. J Biol Chem 1991; 266(10): 6259-63. [PMID: 1706713].
[57]
Mitchell P. The protonmotive Q cycle: a general formulation. FEBS Lett 1975; 59(2): 137-9. [http://dx.doi.org/10.1016/0014-5793(75)80359-0]. [PMID: 1227927].
[58]
Crofts AR, Holland JT, Victoria D, et al. The Q-cycle reviewed: How well does a monomeric mechanism of the bc(1) complex account for the function of a dimeric complex? Biochim Biophys Acta 2008; 1777(7-8): 1001-19. [http://dx.doi.org/10.1016/j.bbabio.2008.04.037]. [PMID: 18501698].
[59]
Wikström MK, Berden JA. Oxidoreduction of cytochrome b in the presence of antimycin. Biochim Biophys Acta 1972; 283(3): 403-20. [http://dx.doi.org/10.1016/0005-2728(72)90258-7]. [PMID: 4346389].
[60]
Lapointe J, Stepanyan Z, Bigras E, Hekimi S. Reversal of the mitochondrial phenotype and slow development of oxidative biomarkers of aging in long-lived Mclk1+/- mice. J Biol Chem 2009; 284(30): 20364-74. [http://dx.doi.org/10.1074/jbc.M109.006569]. [PMID: 19478076].
[61]
Wang Y, Hekimi S. Understanding Ubiquinone. Trends Cell Biol 2016; 26(5): 367-78. [http://dx.doi.org/10.1016/j.tcb.2015.12.007]. [PMID: 26827090].
[62]
Wang Y, Oxer D, Hekimi S. Mitochondrial function and lifespan of mice with controlled ubiquinone biosynthesis. Nat Commun 2015; 6: 6393. [http://dx.doi.org/10.1038/ncomms7393]. [PMID: 25744659].
[63]
Acín-Pérez R, Fernández-Silva P, Peleato ML, Pérez-Martos A, Enriquez JA. Respiratory active mitochondrial supercomplexes. Mol Cell 2008; 32(4): 529-39. [http://dx.doi.org/10.1016/j.molcel.2008.10.021]. [PMID: 19026783].
[64]
Genova ML, Lenaz G. Functional role of mitochondrial respiratory supercomplexes. Biochim Biophys Acta 2014; 1837(4): 427-43. [http://dx.doi.org/10.1016/j.bbabio.2013.11.002]. [PMID: 24246637].
[65]
Althoff T, Mills DJ, Popot JL, Kühlbrandt W. Arrangement of electron transport chain components in bovine mitochondrial supercomplex I1III2IV1. EMBO J 2011; 30(22): 4652-64. [http://dx.doi.org/10.1038/emboj.2011.324]. [PMID: 21909073].
[66]
Blaza JN, Serreli R, Jones AJ, Mohammed K, Hirst J. Kinetic evidence against partitioning of the ubiquinone pool and the catalytic relevance of respiratory-chain supercomplexes. Proc Natl Acad Sci USA 2014; 111(44): 15735-40. [http://dx.doi.org/10.1073/pnas.1413855111]. [PMID: 25331896].
[67]
Dröse S, Zwicker K, Brandt U. Full recovery of the NADH:ubiquinone activity of complex I (NADH:ubiquinone oxidoreductase) from Yarrowia lipolytica by the addition of phospholipids. Biochim Biophys Acta 2002; 1556(1): 65-72. [http://dx.doi.org/10.1016/S0005-2728(02)00307-9]. [PMID: 12351219].
[68]
Ono H, Nishijima Y, Adachi N, et al. A basic study on molecular hydrogen (H2) inhalation in acute cerebral ischemia patients for safety check with physiological parameters and measurement of blood H2 level. Med Gas Res 2012; 2(1): 21. [http://dx.doi.org/10.1186/2045-9912-2-21]. [PMID: 22916706].
[69]
Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S. Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol 2009; 64(4): 753-61. [http://dx.doi.org/10.1007/s00280-008-0924-2]. [PMID: 19148645].
[70]
Albracht SP. Nickel hydrogenases: in search of the active site. Biochim Biophys Acta 1994; 1188(3): 167-204. [http://dx.doi.org/10.1016/0005-2728(94)90036-1]. [PMID: 7803444].
[71]
Pershad HR, Duff JL, Heering HA, Duin EC, Albracht SP, Armstrong FA. Catalytic electron transport in Chromatium vinosum [NiFe]-hydrogenase: application of voltammetry in detecting redox-active centers and establishing that hydrogen oxidation is very fast even at potentials close to the reversible H+/H2 value. Biochemistry 1999; 38(28): 8992-9. [http://dx.doi.org/10.1021/bi990108v]. [PMID: 10413472].
Related Journals
Current Drug Safety
Current Medicinal Chemistry
Current Neuropharmacology
Current Pharmaceutical Analysis
Current Topics in Medicinal Chemistry
Current Vascular Pharmacology
Current Respiratory Medicine Reviews
Infectious Disorders - Drug Targets
Endocrine, Metabolic & Immune Disorders - Drug Targets
CNS & Neurological Disorders - Drug Targets
Related Books
New Findings from Natural Substances
Mitochondrial DNA and the Immuno-inflammatory Response: New Frontiers to Control Specific Microbial Diseases
Pharmaceutical Chemistry and Production: An Introductory Textbook
Evidence-Based Research in Ayurveda against COVID-19 in Compliance with Standardized Protocols and Practices
Frontiers in Clinical Drug Research – Anti Allergy Agents
Pharmaceuticals for Targeting Coronaviruses
Medical Applications of Beta-Glucan
Nanotechnology Driven Herbal Medicine for Burns: From Concept to Application
Postbiotics: Science, Technology and Applications
Frontiers in Inflammation
Article Metrics
42
5
1