Abstract
Growing evidence indicate that mitochondria play a functional role in arrhythmogenesis. We report here the molecular mechanisms underlying the action of these highly dynamic organelles in the regulation of cell metabolism, action potential and, overall, heart excitability. In particular, we examine the role of cardiac mitochondria in linking metabolism and cell excitability. The importance of the main mitochondrial channels is evaluated as well, including the recently identified calcium uniporter. Promises and pitfalls of potential therapeutic strategies targeting mitochondrial pathways are also assessed.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Santulli G, Iaccarino G, De Luca N, Trimarco B, Condorelli G. Atrial fibrillation and microRNAs. Front Physiol. 2014;5:15.
Mitchell P. Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature. 1961;191:144–8.
Ryu SY, Lee SH, Ho WK. Generation of metabolic oscillations by mitoKATP and ATP synthase during simulated ischemia in ventricular myocytes. J Mol Cell Cardiol. 2005;39:874–81.
Aon MA, Cortassa S, Marban E, O’Rourke B. Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J Biol Chem. 2003;278:44735–44.
O’Rourke B, Ramza BM, Marban E. Oscillations of membrane current and excitability driven by metabolic oscillations in heart cells. Science. 1994;265:962–6.
Terzic A, Jahangir A, Kurachi Y. Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and K+ channel-opening drugs. Am J Phys. 1995;269:C525–45.
Johnson MS, Moore RL, Brown DA. Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat. Am J Physiol Heart Circ Physiol. 2006;290:H2644–7.
Chicco AJ, Johnson MS, Armstrong CJ, Lynch JM, Gardner RT, Fasen GS, Gillenwater CP, Moore RL. Sex-specific and exercise-acquired cardioprotection is abolished by sarcolemmal KATP channel blockade in the rat heart. Am J Physiol Heart Circ Physiol. 2007;292:H2432–7.
Brown DA, Chicco AJ, Jew KN, Johnson MS, Lynch JM, Watson PA, Moore RL. Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat. J Physiol. 2005;569:913–24.
Akar FG, Aon MA, Tomaselli GF, O’Rourke B. The mitochondrial origin of postischemic arrhythmias. J Clin Invest. 2005;115:3527–35.
Wirth KJ, Rosenstein B, Uhde J, Englert HC, Busch AE, Scholkens BA. ATP-sensitive potassium channel blocker HMR 1883 reduces mortality and ischemia-associated electrocardiographic changes in pigs with coronary occlusion. J Pharmacol Exp Ther. 1999;291:474–81.
Vajda S, Baczko I, Lepran I. Selective cardiac plasma-membrane K(ATP) channel inhibition is defibrillatory and improves survival during acute myocardial ischemia and reperfusion. Eur J Pharmacol. 2007;577:115–23.
Fischbach PS, White A, Barrett TD, Lucchesi BR. Risk of ventricular proarrhythmia with selective opening of the myocardial sarcolemmal versus mitochondrial ATP-gated potassium channel. J Pharmacol Exp Ther. 2004;309:554–9.
Aronson D, Mittleman MA, Burger AJ. Effects of sulfonylurea hypoglycemic agents and adenosine triphosphate dependent potassium channel antagonists on ventricular arrhythmias in patients with decompensated heart failure. Pacing Clin Electrophysiol. 2003;26:1254–61.
del Valle HF, Lascano EC, Negroni JA, Crottogini AJ. Glibenclamide effects on reperfusion-induced malignant arrhythmias and left ventricular mechanical recovery from stunning in conscious sheep. Cardiovasc Res. 2001;50:474–85.
Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 2000;192:1001–14.
Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial ROS-induced ROS release: an update and review. Biochim Biophys Acta. 2006;1757:509–17.
Wang J, Wang H, Zhang Y, Gao H, Nattel S, Wang Z. Impairment of HERG K(+) channel function by tumor necrosis factor-alpha: role of reactive oxygen species as a mediator. J Biol Chem. 2004;279:13289–92.
Santulli G, Nakashima R, Yuan Q, Marks AR. Intracellular calcium release channels: an update. J Physiol. 2017 (in press). doi: 10.1113/JP272781.
Biary N, Xie C, Kauffman J, Akar FG. Biophysical properties and functional consequences of reactive oxygen species (ROS)-induced ROS release in intact myocardium. J Physiol. 2011;589:5167–79.
Garlid KD, Beavis AD, Ratkje SK. On the nature of ion leaks in energy-transducing membranes. Biochim Biophys Acta. 1989;976:109–20.
Brierley GP. Energy-linked alteration of the permeability of heart mitochondria to chloride and other anions. Biochemistry. 1970;9:697–707.
Beavis AD. Properties of the inner membrane anion channel in intact mitochondria. J Bioenerg Biomembr. 1992;24:77–90.
Garlid KD, Beavis AD. Evidence for the existence of an inner membrane anion channel in mitochondria. Biochim Biophys Acta. 1986;853:187–204.
Brown DA, Aon MA, Akar FG, Liu T, Sorarrain N, O’Rourke B. Effects of 4′-chlorodiazepam on cellular excitation-contraction coupling and ischaemia-reperfusion injury in rabbit heart. Cardiovasc Res. 2008;79:141–9.
Brown DA, Aon MA, Frasier CR, Sloan RC, Maloney AH, Anderson EJ, O'Rourke B. Cardiac arrhythmias induced by glutathione oxidation can be inhibited by preventing mitochondrial depolarization. J Mol Cell Cardiol. 2010;48:673–9.
McCully JD, Wakiyama H, Hsieh YJ, Jones M, Levitsky S. Differential contribution of necrosis and apoptosis in myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2004;286:H1923–35.
Romashko DN, Marban E, O’Rourke B. Subcellular metabolic transients and mitochondrial redox waves in heart cells. Proc Natl Acad Sci U S A. 1998;95:1618–23.
Sato T, Takizawa T, Saito T, Kobayashi S, Hara Y, Nakaya H. Amiodarone inhibits sarcolemmal but not mitochondrial KATP channels in guinea pig ventricular cells. J Pharmacol Exp Ther. 2003;307:955–60.
Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier JP, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008;359:473–81.
Aon MA, Cortassa S, O’Rourke B. The fundamental organization of cardiac mitochondria as a network of coupled oscillators. Biophys J. 2006;91:4317–27.
Akar FG. Mitochondrial targets for arrhythmia suppression: is there a role for pharmacological intervention? J Interv Card Electrophysiol. 2013;37:249–58.
Beavis AD. On the inhibition of the mitochondrial inner membrane anion uniporter by cationic amphiphiles and other drugs. J Biol Chem. 1989;264:1508–15.
Kinnally KW, Zorov DB, Antonenko YN, Snyder SH, McEnery MW, Tedeschi H. Mitochondrial benzodiazepine receptor linked to inner membrane ion channels by nanomolar actions of ligands. Proc Natl Acad Sci U S A. 1993;90:1374–8.
Sileikyte J, Petronilli V, Zulian A, Dabbeni-Sala F, Tognon G, Nikolov P, Bernardi P, Ricchelli F. Regulation of the inner membrane mitochondrial permeability transition by the outer membrane translocator protein (peripheral benzodiazepine receptor). J Biol Chem. 2011;286:1046–53.
McEnery MW, Snowman AM, Trifiletti RR, Snyder SH. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci U S A. 1992;89:3170–4.
Leducq N, Bono F, Sulpice T, Vin V, Janiak P, Fur GL, O’Connor SE, Herbert JM. Role of peripheral benzodiazepine receptors in mitochondrial, cellular, and cardiac damage induced by oxidative stress and ischemia-reperfusion. J Pharmacol Exp Ther. 2003;306:828–37.
Motloch LJ, Hu J, Akar FG. The mitochondrial translocator protein and arrhythmogenesis in ischemic heart disease. Oxidative Med Cell Longev. 2015;2015:234104.
Paucek P, Mironova G, Mahdi F, Beavis AD, Woldegiorgis G, Garlid KD. Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent K+ channel from rat liver and beef heart mitochondria. J Biol Chem. 1992;267:26062–9.
Rajesh KG, Sasaguri S, Suzuki R, Xing Y, Maeda H. Ischemic preconditioning prevents reperfusion heart injury in cardiac hypertrophy by activation of mitochondrial KATP channels. Int J Cardiol. 2004;96:41–9.
Headrick JP, Willems L, Ashton KJ, Holmgren K, Peart J, Matherne GP. Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression. J Physiol. 2003;549:823–33.
Fryer RM, Hsu AK, Nagase H, Gross GJ. Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels. J Pharmacol Exp Ther. 2000;294:451–7.
Schwartz LM, Welch TS, Crago MS. Cardioprotection by multiple preconditioning cycles does not require mitochondrial K(ATP) channels in pigs. Am J Physiol Heart Circ Physiol. 2002;283:H1538–44.
Belmonte S, Morad M. ‘Pressure-flow’-triggered intracellular Ca2+ transients in rat cardiac myocytes: possible mechanisms and role of mitochondria. J Physiol. 2008;586:1379–97.
Garcia-Rivas Gde J, Carvajal K, Correa F, Zazueta C. Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo. Br J Pharmacol. 2006;149:829–37.
Santulli G, Pagano G, Sardu C, Xie W, Reiken S, D’Ascia SL, Cannone M, Marziliano N, Trimarco B, Guise TA, Lacampagne A, Marks AR. Calcium release channel RyR2 regulates insulin release and glucose homeostasis. J Clin Invest. 2015;125:4316.
Xie W, Santulli G, Guo X, Gao M, Chen BX, Marks AR. Imaging atrial arrhythmic intracellular calcium in intact heart. J Mol Cell Cardiol. 2013;64:120–3.
Xie W, Santulli G, Reiken SR, Yuan Q, Osborne BW, Chen BX, Marks AR. Mitochondrial oxidative stress promotes atrial fibrillation. Sci Rep. 2015;5:11427.
Santulli G, D’Ascia SL, D’Ascia C. Development of atrial fibrillation in recipients of cardiac resynchronization therapy: the role of atrial reverse remodelling. Can J Cardiol. 2012;28:245 e17; author reply 245 e17–8.
D’Ascia SL, D’Ascia C, Marino V, Lombardi A, Santulli R, Chiariello M, Santulli G. Cardiac resynchronisation therapy response predicts occurrence of atrial fibrillation in non-ischaemic dilated cardiomyopathy. Int J Clin Pract. 2011;65:1149–55.
Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34:232–7.
Panth N, Paudel KR, Parajuli K. Reactive oxygen species: a key hallmark of cardiovascular disease. Adv Med. 2016;2016:9152732.
Leong HS, Brownsey RW, Kulpa JE, Allard MF. Glycolysis and pyruvate oxidation in cardiac hypertrophy – why so unbalanced? Comp Biochem Physiol A Mol Integr Physiol. 2003;135:499–513.
Laskowski KR, Russell 3rd RR. Uncoupling proteins in heart failure. Curr Heart Fail Rep. 2008;5:75–9.
Ozcan C, Palmeri M, Horvath TL, Russell KS, Russell 3rd RR. Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning. Am J Physiol Heart Circ Physiol. 2013;304:H1192–200.
Brennan JP, Southworth R, Medina RA, Davidson SM, Duchen MR, Shattock MJ. Mitochondrial uncoupling, with low concentration FCCP, induces ROS-dependent cardioprotection independent of KATP channel activation. Cardiovasc Res. 2006;72:313–21.
Jin H, Nass RD, Joudrey PJ, Lyon AR, Chemaly ER, Rapti K, Akar FG. Altered spatiotemporal dynamics of the mitochondrial membrane potential in the hypertrophied heart. Biophys J. 2010;98:2063–71.
Konya L, Kekesi V, Juhasz-Nagy S, Feher J. The effect of superoxide dismutase in the myocardium during reperfusion in the dog. Free Radic Biol Med. 1992;13:527–32.
Cho J, Won K, Wu D, Soong Y, Liu S, Szeto HH, Hong MK. Potent mitochondria-targeted peptides reduce myocardial infarction in rats. Coron Artery Dis. 2007;18:215–20.
Erdogan O. N-acetylcysteine for the prevention of postoperative atrial fibrillation: a prospective, randomized, placebo-controlled pilot study. Eur Heart J 2008;29:1591; author reply 1591.
Acknowledgements
Dr. Gaetano Santulli, MD, PhD is supported by the National Institutes of Health (NIH, Grant NIDDK107895).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Gambardella, J. et al. (2017). Functional Role of Mitochondria in Arrhythmogenesis. In: Santulli, G. (eds) Mitochondrial Dynamics in Cardiovascular Medicine. Advances in Experimental Medicine and Biology, vol 982. Springer, Cham. https://doi.org/10.1007/978-3-319-55330-6_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-55330-6_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-55329-0
Online ISBN: 978-3-319-55330-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)
Keywords
- Reactive Oxygen Species
- Reactive Oxygen Species Production
- Reactive Oxygen Species Level
- Metabolic Stress
- Mitochondrial Reactive Oxygen Species Production
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.