Abstract
Mitochondria are dynamic organelles that perform a number of interconnected tasks that are elegantly intertwined with the regulation of cell functions. This includes the provision of ATP, reactive oxygen species (ROS), and building blocks for the biosynthesis of macromolecules while also serving as signaling platforms for the cell. Although the functions executed by mitochondria are complex, at its core these roles are, to a certain degree, fulfilled by electron transfer reactions and the establishment of a protonmotive force (PMF). Indeed, mitochondria are energy conserving organelles that extract electrons from nutrients to establish a PMF, which is then used to drive ATP and NADPH production, solute import, and many other functions including the propagation of cell signals. These same electrons extracted from nutrients are also used to produce ROS, pro-oxidants that can have potentially damaging effects at high levels, but also serve as secondary messengers at low amounts. Mitochondria are also enriched with antioxidant defenses, which are required to buffer cellular ROS. These same redox buffering networks also fulfill another important role; regulation of proteins through the reversible oxidation of cysteine switches. The modification of cysteine switches with the antioxidant glutathione, a process called protein S-glutathionylation, has been found to play an integral role in controlling various mitochondrial functions. In addition, recent findings have demonstrated that disrupting mitochondrial protein S-glutathionylation reactions can have some dire pathological consequences. Accordingly, this chapter focuses on the role of mitochondrial cysteine switches in the modulation of different physiological functions and how defects in these pathways contribute to the development of disease.
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Ambrus A, Nemeria NS, Torocsik B, Tretter L, Nilsson M, Jordan F, Adam-Vizi V (2015) Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components. Free Radic Biol Med 89:642–650
Andrienko TN, Pasdois P, Pereira GC, Ovens MJ, Halestrap AP (2017) The role of succinate and ROS in reperfusion injury – a critical appraisal. J Mol Cell Cardiol 110:1–14
Applegate MA, Humphries KM, Szweda LI (2008) Reversible inhibition of alpha-ketoglutarate dehydrogenase by hydrogen peroxide: glutathionylation and protection of lipoic acid. Biochemistry 47:473–478
Axelsson K, Mannervik B (1983) An essential role of cytosolic thioltransferase in protection of pyruvate kinase from rabbit liver against oxidative inactivation. FEBS Lett 152:114–118
Balijepalli S, Annepu J, Boyd MR, Ravindranath V (1999) Effect of thiol modification on brain mitochondrial complex I activity. Neurosci Lett 272:203–206
Beer SM, Taylor ER, Brown SE, Dahm CC, Costa NJ, Runswick MJ, Murphy MP (2004) Glutaredoxin 2 catalyzes the reversible oxidation and glutathionylation of mitochondrial membrane thiol proteins: implications for mitochondrial redox regulation and antioxidant DEFENSE. J Biol Chem 279:47939–47951
Berry BJ, Trewin AJ, Amitrano AM, Kim M, Wojtovich AP (2018) Use the protonmotive force: mitochondrial uncoupling and reactive oxygen species. J Mol Biol 430:3873–3891
Bleier L, Drose S (2013) Superoxide generation by complex III: from mechanistic rationales to functional consequences. Biochim Biophys Acta 1827:1320–1331
Bohovych I, Khalimonchuk O (2016) Sending out an SOS: mitochondria as a signaling hub. Front Cell Dev Biol 4:109
Brand MD (2016) Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med 100:14–31
Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435:297–312
Bunik VI, Brand MD (2018) Generation of superoxide and hydrogen peroxide by side reactions of mitochondrial 2-oxoacid dehydrogenase complexes in isolation and in cells. Biol Chem 399:407–420
Chalker J, Gardiner D, Kuksal N, Mailloux RJ (2018) Characterization of the impact of glutaredoxin-2 (GRX2) deficiency on superoxide/hydrogen peroxide release from cardiac and liver mitochondria. Redox Biol 15:216–227
Chandel NS (2015) Evolution of mitochondria as signaling organelles. Cell Metab 22:204–206
Chen YR, Chen CL, Pfeiffer DR, Zweier JL (2007) Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation. J Biol Chem 282:32640–32654
Chouchani ET, Kazak L, Jedrychowski MP, Lu GZ, Erickson BK, Szpyt J, Pierce KA, Laznik-Bogoslavski D, Vetrivelan R, Clish CB, Robinson AJ, Gygi SP, Spiegelman BM (2016) Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1. Nature 532:112–116
Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, Logan A, Nadtochiy SM, Ord ENJ, Smith AC, Eyassu F, Shirley R, Hu CH, Dare AJ, James AM, Rogatti S, Hartley RC, Eaton S, Costa ASH, Brookes PS, Davidson SM, Duchen MR, Saeb-Parsy K, Shattock MJ, Robinson AJ, Work LM, Frezza C, Krieg T, Murphy MP (2014) Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515:431–435
Crofts AR, Holland JT, Victoria D, Kolling DR, Dikanov SA, Gilbreth R, Lhee S, Kuras R, Kuras MG (2008) 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 1777:1001–1019
Drose S, Brandt U, Wittig I (2014) Mitochondrial respiratory chain complexes as sources and targets of thiol-based redox-regulation. Biochim Biophys Acta 1844:1344–1354
Fisher-Wellman KH, Gilliam LA, Lin CT, Cathey BL, Lark DS, Neufer PD (2013) Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload. Free Radic Biol Med 65:1201–1208
Fisher-Wellman KH, Lin CT, Ryan TE, Reese LR, Gilliam LA, Cathey BL, Lark DS, Smith CD, Muoio DM, Neufer PD (2015) Pyruvate dehydrogenase complex and nicotinamide nucleotide transhydrogenase constitute an energy-consuming redox circuit. Biochem J 467:271–280
Gallogly MM, Starke DW, Leonberg AK, Ospina SM, Mieyal JJ (2008) Kinetic and mechanistic characterization and versatile catalytic properties of mammalian glutaredoxin 2: implications for intracellular roles. Biochemistry 47:11144–11157
Giangregorio N, Palmieri F, Indiveri C (2013) Glutathione controls the redox state of the mitochondrial carnitine/acylcarnitine carrier Cys residues by glutathionylation. Biochim Biophys Acta 1830:5299–5304
Gill RM, O’Brien M, Young A, Gardiner D, Mailloux RJ (2018) Protein S-glutathionylation lowers superoxide/hydrogen peroxide release from skeletal muscle mitochondria through modification of complex I and inhibition of pyruvate uptake. PLoS One 13:e0192801
Goncalves RL, Bunik VI, Brand MD (2016) Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex. Free Radic Biol Med 91:247–255
Goncalves RL, Quinlan CL, Perevoshchikova IV, Hey-Mogensen M, Brand MD (2015) Sites of superoxide and hydrogen peroxide production by muscle mitochondria assessed ex vivo under conditions mimicking rest and exercise. J Biol Chem 290:209–227
Goncalves RL, Rothschild DE, Quinlan CL, Scott GK, Benz CC, Brand MD (2014) Sources of superoxide/H2O2 during mitochondrial proline oxidation. Redox Biol 2:901–909
Gorelenkova Miller O, Mieyal JJ (2018) Critical roles of glutaredoxin in brain cells-implications for Parkinson’s disease. Antioxid Redox Signal 30:1352–1368
Hail N Jr, Chen P, Kepa JJ, Bushman LR, Shearn C (2010) Dihydroorotate dehydrogenase is required for N-(4-hydroxyphenyl)retinamide-induced reactive oxygen species production and apoptosis. Free Radic Biol Med 49:109–116
Han D, Canali R, Garcia J, Aguilera R, Gallaher TK, Cadenas E (2005) Sites and mechanisms of aconitase inactivation by peroxynitrite: modulation by citrate and glutathione. Biochemistry 44:11986–11996
Hey-Mogensen M, Goncalves RL, Orr AL, Brand MD (2014) Production of superoxide/H2O2 by dihydroorotate dehydrogenase in rat skeletal muscle mitochondria. Free Radic Biol Med 72:149–155
Hortelano S, Dallaporta B, Zamzami N, Hirsch T, Susin SA, Marzo I, Bosca L, Kroemer G (1997) Nitric oxide induces apoptosis via triggering mitochondrial permeability transition. FEBS Lett 410:373–377
Hurd TR, Requejo R, Filipovska A, Brown S, Prime TA, Robinson AJ, Fearnley IM, Murphy MP (2008) Complex I within oxidatively stressed bovine heart mitochondria is glutathionylated on Cys-531 and Cys-704 of the 75-kDa subunit: potential role of CYS residues in decreasing oxidative damage. J Biol Chem 283:24801–24815
Imlay JA (2013) The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium. Nat Rev Microbiol 11:443–454
Jensen KS, Pedersen JT, Winther JR, Teilum K (2014) The pKa value and accessibility of cysteine residues are key determinants for protein substrate discrimination by glutaredoxin. Biochemistry 53:2533–2540
Jones DP, Sies H (2015) The redox code. Antioxid Redox Signal 23:734–746
Kanaan GN, Ichim B, Gharibeh L, Maharsy W, Patten DA, Xuan JY, Reunov A, Marshall P, Veinot J, Menzies K, Nemer M, HARPER ME (2018) Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies. Redox Biol 14:509–521
Kornberg H (2000) Krebs and his trinity of cycles. Nat Rev Mol Cell Biol 1:225–228
Kramer PA, Duan J, Gaffrey MJ, Shukla AK, Wang L, Bammler TK, Qian WJ, Marcinek DJ (2018) Fatiguing contractions increase protein S-glutathionylation occupancy in mouse skeletal muscle. Redox Biol 17:367–376
Kuksal N, Chalker J, Mailloux RJ (2017) Progress in understanding the molecular oxygen paradox – function of mitochondrial reactive oxygen species in cell signaling. Biol Chem 398:1209–1227
Kuksal N, Gardiner D, Qi D, Mailloux RJ (2018) Partial loss of complex I due to NDUFS4 deficiency augments myocardial reperfusion damage by increasing mitochondrial superoxide/hydrogen peroxide production. Biochem Biophys Res Commun 498:214–220
Lane N (2015) The vital question. W.W. Norton and Company, New York
Lundberg M, Johansson C, Chandra J, Enoksson M, Jacobsson G, Ljung J, Johansson M, Holmgren A (2001) Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms. J Biol Chem 276:26269–26275
Mailloux RJ (2015) Teaching the fundamentals of electron transfer reactions in mitochondria and the production and detection of reactive oxygen species. Redox Biol 4:381–398
Mailloux RJ (2018) Mitochondrial antioxidants and the maintenance of cellular hydrogen peroxide levels. Oxidative Med Cell Longev 2018:7857251
Mailloux RJ, Adjeitey CN, Xuan JY, Harper ME (2012a) Crucial yet divergent roles of mitochondrial redox state in skeletal muscle vs. brown adipose tissue energetics. FASEB J 26:363–375
Mailloux RJ, Craig Ayre D, Christian SL (2016a) Induction of mitochondrial reactive oxygen species production by GSH mediated S-glutathionylation of 2-oxoglutarate dehydrogenase. Redox Biol 8:285–297
Mailloux RJ, Fu A, Robson-Doucette C, Allister EM, Wheeler MB, Screaton R, Harper ME (2012b) Glutathionylation state of uncoupling protein-2 and the control of glucose-stimulated insulin secretion. J Biol Chem 287:39673–39685
Mailloux RJ, Gardiner D, O’Brien M (2016b) 2-Oxoglutarate dehydrogenase is a more significant source of O2(.-)/H2O2 than pyruvate dehydrogenase in cardiac and liver tissue. Free Radic Biol Med 97:501–512
Mailloux RJ, Harper ME (2011) Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med 51:1106–1115
Mailloux RJ, Harper ME (2012) Mitochondrial proticity and ROS signaling: lessons from the uncoupling proteins. Trends Endocrinol Metab 23:451–458
Mailloux RJ, McBride SL, Harper ME (2013a) Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem Sci 38:592–602
Mailloux RJ, Seifert EL, Bouillaud F, Aguer C, Collins S, Harper ME (2011) Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3. J Biol Chem 286:21865–21875
Mailloux RJ, Treberg JR (2016) Protein S-glutathionlyation links energy metabolism to redox signaling in mitochondria. Redox Biol 8:110–118
Mailloux RJ, Willmore WG (2014) S-glutathionylation reactions in mitochondrial function and disease. Front Cell Dev Biol 2:68
Mailloux RJ, Xuan JY, Beauchamp B, Jui L, Lou M, Harper ME (2013b) Glutaredoxin-2 is required to control proton leak through uncoupling protein-3. J Biol Chem 288:8365–8379
Mailloux RJ, Xuan JY, McBride S, Maharsy W, Thorn S, Holterman CE, Kennedy CR, Rippstein P, Dekemp R, Da Silva J, Nemer M, Lou M, Harper ME (2014) Glutaredoxin-2 is required to control oxidative phosphorylation in cardiac muscle by mediating deglutathionylation reactions. J Biol Chem 289:14812–14828
Mailloux RJ, Young A, Chalker J, Gardiner D, O’Brien M, Slade L, Brosnan JT (2016c) Choline and dimethylglycine produce superoxide/hydrogen peroxide from the electron transport chain in liver mitochondria. FEBS Lett 590:4318–4328
Massey V (1994) Activation of molecular oxygen by flavins and flavoproteins. J Biol Chem 269:22459–22462
McLain AL, Szweda PA, Szweda LI (2011) alpha-Ketoglutarate dehydrogenase: a mitochondrial redox sensor. Free Radic Res 45:29–36
Mieyal JJ, Gallogly MM, Qanungo S, Sabens EA, Shelton MD (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10:1941–1988
Mills EL, Pierce KA, Jedrychowski MP, Garrity R, Winther S, Vidoni S, Yoneshiro T, Spinelli JB, Lu GZ, Kazak L, Banks AS, Haigis MC, Kajimura S, Murphy MP, Gygi SP, Clish CB, Chouchani ET (2018) Accumulation of succinate controls activation of adipose tissue thermogenesis. Nature 560:102–106
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13
Murphy MP (2012) Mitochondrial thiols in antioxidant protection and redox signaling: distinct roles for glutathionylation and other thiol modifications. Antioxid Redox Signal 16:476–495
Nemeria NS, Ambrus A, Patel H, Gerfen G, Adam-Vizi V, Tretter L, Zhou J, Wang J, Jordan F (2014) Human 2-oxoglutarate dehydrogenase complex E1 component forms a thiamin-derived radical by aerobic oxidation of the enamine intermediate. J Biol Chem 289:29859–29873
Nicholls DG (2001) A history of UCP1. Biochem Soc Trans 29:751–755
Nicholls DG (2008) Forty years of Mitchell’s proton circuit: from little grey books to little grey cells. Biochim Biophys Acta 1777:550–556
O’Brien M, Chalker J, Slade L, Gardiner D, Mailloux RJ (2017) Protein S-glutathionylation alters superoxide/hydrogen peroxide emission from pyruvate dehydrogenase complex. Free Radic Biol Med 106:302–314
Paddenberg R, Goldenberg A, Faulhammer P, Braun-Dullaeus RC, Kummer W (2003) Mitochondrial complex II is essential for hypoxia-induced ROS generation and vasoconstriction in the pulmonary vasculature. Adv Exp Med Biol 536:163–169
Palmieri F, Monne M (2016) Discoveries, metabolic roles and diseases of mitochondrial carriers: a review. Biochim Biophys Acta 1863:2362–2378
Perevoshchikova IV, Quinlan CL, Orr AL, Gerencser AA, Brand MD (2013) Sites of superoxide and hydrogen peroxide production during fatty acid oxidation in rat skeletal muscle mitochondria. Free Radic Biol Med 61:298–309
Pfefferle A, Mailloux RJ, Adjeitey CN, Harper ME (2013) Glutathionylation of UCP2 sensitizes drug resistant leukemia cells to chemotherapeutics. Biochim Biophys Acta 1833:80–89
Queiroga CS, Almeida AS, Martel C, Brenner C, Alves PM, Vieira HL (2010) Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilization and apoptosis. J Biol Chem 285:17077–17088
Quinlan CL, Goncalves RL, Hey-Mogensen M, Yadava N, Bunik VI, Brand MD (2014) The 2-oxoacid dehydrogenase complexes in mitochondria can produce superoxide/hydrogen peroxide at much higher rates than complex I. J Biol Chem 289:8312–8325
Radi R, Turrens JF, Chang LY, Bush KM, Crapo JD, Freeman BA (1991) Detection of catalase in rat heart mitochondria. J Biol Chem 266:22028–22034
Redpath CJ, Bou Khalil M, Drozdzal G, Radisic M, McBride HM (2013) Mitochondrial hyperfusion during oxidative stress is coupled to a dysregulation in calcium handling within a C2C12 cell model. PLoS One 8:e69165
Ronchi JA, Francisco A, Passos LA, Figueira TR, Castilho RF (2016) The contribution of nicotinamide nucleotide transhydrogenase to peroxide detoxification is dependent on the respiratory state and counterbalanced by other sources of NADPH in liver mitochondria. J Biol Chem 291:20173–20187
Scialo F, Sriram A, Fernandez-Ayala D, Gubina N, Lohmus M, Nelson G, Logan A, Cooper HM, Navas P, Enriquez JA, Murphy MP, Sanz A (2016) Mitochondrial ROS produced via reverse electron transport extend animal lifespan. Cell Metab 23:725–734
Shabalina IG, Vrbacky M, Pecinova A, Kalinovich AV, Drahota Z, Houstek J, Mracek T, Cannon B, Nedergaard J (2014) ROS production in brown adipose tissue mitochondria: the question of UCP1-dependence. Biochim Biophys Acta 1837:2017–2030
Shelton MD, Chock PB, Mieyal JJ (2005) Glutaredoxin: role in reversible protein s-glutathionylation and regulation of redox signal transduction and protein translocation. Antioxid Redox Signal 7:348–366
Shutt T, Geoffrion M, Milne R, McBride HM (2012) The intracellular redox state is a core determinant of mitochondrial fusion. EMBO Rep 13:909–915
Sies H (2017) Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress. Redox Biol 11:613–619
Sies H, Berndt C, Jones DP (2017) Oxidative stress. Annu Rev Biochem 86:715–748
Slade L, Chalker J, Kuksal N, Young A, Gardiner D, Mailloux RJ (2017) Examination of the superoxide/hydrogen peroxide forming and quenching potential of mouse liver mitochondria. Biochim Biophys Acta 1861:1960–1969
Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS, Beal MF (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788
Sweetlove LJ, Beard KF, Nunes-Nesi A, Fernie AR, Ratcliffe RG (2010) Not just a circle: flux modes in the plant TCA cycle. Trends Plant Sci 15:462–470
Tait SW, Green DR (2012) Mitochondria and cell signalling. J Cell Sci 125:807–815
Taylor ER, Hurrell F, Shannon RJ, Lin TK, Hirst J, Murphy MP (2003) Reversible glutathionylation of complex I increases mitochondrial superoxide formation. J Biol Chem 278:19603–19610
Thaher O, Wolf C, Dey PN, Pouya A, Wullner V, Tenzer S, Methner A (2018) The thiol switch C684 in Mitofusin-2 mediates redox-induced alterations of mitochondrial shape and respiration. Neurochem Int 117:167–173
Tretter L, Adam-Vizi V (2004) Generation of reactive oxygen species in the reaction catalyzed by alpha-ketoglutarate dehydrogenase. J Neurosci 24:7771–7778
Tretter L, Takacs K, Hegedus V, Adam-Vizi V (2007) Characteristics of alpha-glycerophosphate-evoked H2O2 generation in brain mitochondria. J Neurochem 100:650–663
Walker JE (2013) The ATP synthase: the understood, the uncertain and the unknown. Biochem Soc Trans 41:1–16
Wang SB, Foster DB, Rucker J, O’Rourke B, Kass DA, van Eyk JE (2011) Redox regulation of mitochondrial ATP synthase: implications for cardiac resynchronization therapy. Circ Res 109:750–757
Yun J, Finkel T (2014) Mitohormesis. Cell Metab 19:757–766
Zhang J, Ye ZW, Singh S, Townsend DM, Tew KD (2018) An evolving understanding of the S-glutathionylation cycle in pathways of redox regulation. Free Radic Biol Med 120:204–216
Ziegler DM (1985) Role of reversible oxidation-reduction of enzyme thiols-disulfides in metabolic regulation. Annu Rev Biochem 54:305–329
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Mailloux, R.J. (2019). Cysteine Switches and the Regulation of Mitochondrial Bioenergetics and ROS Production. In: Urbani, A., Babu, M. (eds) Mitochondria in Health and in Sickness. Advances in Experimental Medicine and Biology, vol 1158. Springer, Singapore. https://doi.org/10.1007/978-981-13-8367-0_11
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