Cardiovascular Research Advance Access originally published online on November 13, 2007
Cardiovascular Research 2008 77(2):231-233; doi:10.1093/cvr/cvm070
Sarcoplasmic reticulum and mitochondria in cardiac pathophysiology
1 Servicio de Cardiología, Institut de Recerca, Hospital Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain
2 Insitute of Physiology, Justus Liebig University of Giessen, Giessen, Germany
3 Unit of Cardiac Physiology, University of Manchester, Manchester, UK
* Corresponding author. Tel: +34 93 489 4038; fax: +34 93 489 4032. E-mail address: dgdorado{at}ir.vhebron.net
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1. Introduction |
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Muscle cells, and in particular cardiomyocytes, consume a large amount of chemical energy to produce mechanical work. Myofilament contraction is regulated and synchronized within the cell by rapid, transient changes in the cytosolic Ca2+ concentration. Most of this calcium is released from the sarcoplasmic reticulum (SR), which has a large surface for Ca2+ transport, in close contact with the myofilaments. In between the myofilaments, cardiomyocytes are packed with mitochondria. These generate the energy needed for myofilament contraction, but serve also as an additional store for Ca2+. Thus, SR and mitochondria interact physiologically to control cellular Ca2+ homeostasis. It is partly through the Ca2+ loading of the mitochondria that their energy production is matched with the contractile energy demand.
Mitochondria are now recognized as an essential effector structure determining cell death and survival. This is not only because of their central role in cellular energy metabolism, but also as key players in survival and death signalling. Alterations in the function of the SR are now known to be of primary importance for the development of hypertrophy and heart failure and in the genesis of life-threatening arrhythmias. Therefore, interaction between SR and mitochondria not only determines cardiomyocyte function under physiological conditions, but also is relevant for the development of cardiomyocyte dysfunction or death under pathophysiological conditions. The present Spotlight Issue of Cardiovascular Research aims to update our understanding of these important and rapidly evolving aspects of cardiac physiology and pathophysiology through a series of invited reviews and original contributions.
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2. Recent advances in sarcoplasmic reticulum physiology |
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Top1. Introduction2. Recent advances in...3. The role of...4. Recent news on...5. Sarcoplasmic-reticulum...6. SummaryReferences |
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In this issue, Orchard and Brette review the structure and function of t-tubules, their contribution to Ca2+ transients in cooperation with the SR, and the pathophysiological importance of their remodelling in different conditions.1 The regulatory mechanisms governing ryanodine receptors and Ca2+ ATPase (SERCA) are also discussed. Ryanodine receptors are regulated by luminal Ca2+ and a protein complex in which triadin, calsequestrin, and junctin are involved. Genetic defects in these proteins result in arrhythmia and heart failure, as described in a review by Györke and Terentyev.2 Nitric oxide derived from nNOS and eNOS also appears to regulate ryanodine receptors, in part by direct nitrosylation according to the nitrosative vs. oxidative balance. This balance can be modulated by the translocation of nNOS from the SR to the sarcolemma in the failing heart, and Lim et al.3 describe how this could be a target for pharmacological interventions. On the other hand, Periasamy et al.4 review how changes in the expression and/or activity of SERCA, regulated by phospholamban and sarcolipin, constitute a major regulatory mechanism of intracellular Ca2+ homeostasis. Along these lines, an original article demonstrates the importance of the phospholamban phosphorylation state to β-adrenergic dysfunction that is observed in various cardiomyopathies.5 The functional interactions of SERCA with other proteins appear more and more complex; new studies continue to demonstrate the importance of auxiliary proteins that function to stabilize SERCA, as described for sarcalumenin in another original article.6 Finally, the recent evidence identifying a new pacemaker function of SR as an essential element in the initiation of the cardiac impulse, in close interaction with the classical surface-membrane voltage-gated ion channels, is reviewed in an article by Maltsev and Lakatta.7
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3. The role of the SR in arrhythmia, hypertrophy, and heart failure |
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Although the pacemaker function of the SR has been only recently recognized, its importance in the genesis of certain types of arrhythmias has been known for a long time. How the SR produces Ca2+ waves in the presence of Ca2+ overload, what determines that Ca2+ waves result in arrhythmias, and how potentially lethal, Ca2+ wave-dependent arrhythmias can be treated by interventions aimed at the SR are reviewed by Venetucci et al.8 A particularly serious type of Ca2+ wave-dependent arrhythmias are those associated with catecholaminergic polymorphic ventricular tachycardia, an inherited disease caused by mutations in the ryanodine receptor or calsequestrin. The molecular mechanisms of this disease and the novel molecular targets proposed for its treatment are the subject of another review article by Lui and Priori.9
Arrhythmogenesis is responsible for the death of many patients with heart failure. There is solid evidence of the important role of the SR in the pathophysiology of heart failure, but the molecular details of this role remain obscure. The review by George10 discusses the Ca2+ leak from the SR due to a defective ryanodine receptor as a cause of arrhythmias and its less-clear role in contractile failure. A proposed mechanism for contractile dysfunction in patients with heart failure is reduced SR Ca2+ release. Bito et al.11 explain the importance of crosstalk between sarcolemmal L-type Ca2+ channels and the SR to ensure adequate Ca2+ kinetics for every single beat, the beat-to-beat coordination and for a long-term contractile steady state, and the potential mechanisms by which this crosstalk may be altered. An original article describes how Ca2+ reuptake by the SR may lead to altered contractility in diabetic mice when hypertension and diabetes are also present (a situation reminiscent of the so-called ‘metabolic syndrome’).12 On the other hand, NADPH-derived ROS signalling induced by tachycardia and exercise appears to induce cardioprotection by modulating ryanodine receptors.13
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4. Recent news on mitochondria |
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Despite being the object of an intense research effort, many aspects of mitochondrial structure, function, and role in disease remain unknown. A recent finding was the presence in mitochondrial membranes of connexin43, the protein forming gap junction channels in the sarcolemma of cardiomyocytes. In this issue, the studies demonstrating this new localization, its role in preconditioning protection, and its potential physiological functions are reviewed by Ruiz-Meana et al.14
The role of mitochondria in death or survival in stressed cells is beginning to be better understood. This issue presents an overview by Gustafsson and Gottlieb15 of the role of mitochondria as central integrators of multiple stress signals, resulting in altered mitochondrial dynamics (mitochondrial fission and mitophagy) or mitochondrial permeabilization. An original article deals with altered mitochondrial kinetics in response to ceramide.16
The exact mechanisms by which mitochondria participate in preconditioning protection remain relatively obscure. Recent data suggest that cGMP signalling can play an important role in pre- and postconditioning. This issue includes a review by Costa et al.17 analysing evidence that protein kinase G brings the protective signal to the outer mitochondrial membrane, where it initiates a protein phosphorylation cascade that propagates across the intermembrane space. This mechanism involves protein kinase C activation and results finally in ROS signalling. The identification of the role of cGMP in cardioprotection is a long story that may have a happy ending. Initial reports demonstrating the protective effects of cGMP on reperfusion injury in isolated cardiomyocytes18,19 were followed by preclinical studies showing the cGMP-mediated cardioprotective effect of natriuretic peptides in large animals.20 A recent, double-blind, placebo-controlled study in more than 1200 patients has demonstrated that atrial natriuretic peptide reduced infarct size when applied at the time of reperfusion.21
Original articles in this issue describe other pathways of protection: those involving protein kinase A and mitochondrial Ca2+-activated K+ (mitoKCa) channels,22 reduction of complex I-dependent mitochondrial respiration,23 and the mitochondrial Na+/H+ exchanger NHE-1.24 Finally, an original paper demonstrates the importance of mitochondria in vascular biology: mitochondrial uncoupling protein 2 may be responsible for the ‘local fever’ observed in atherosclerotic plaques.25
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5. Sarcoplasmic-reticulum–mitochondrial interactions |
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Top1. Introduction2. Recent advances in...3. The role of...4. Recent news on...5. Sarcoplasmic-reticulum...6. SummaryReferences |
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Recent studies have demonstrated that mitochondria and SR are tightly connected in cardiac cells, and for certain processes form a functional unit.26 An original article illustrates a different type of relationship between SR and mitochondria based on ROS signalling and its effect on Ca2+ sparks.27 The contribution by Piper et al.28 summarizes evidence that interactions between SR and mitochondria are also crucial for the pathogenesis of reperfusion injury as Ca2+ loading and release by one of these organelles can influence the function of the other. This relationship is analysed in relation to the effector mechanisms of cardioprotective signalling.
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6. Summary |
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Top1. Introduction2. Recent advances in...3. The role of...4. Recent news on...5. Sarcoplasmic-reticulum...6. SummaryReferences |
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The review articles and original contributions clearly demonstrate the increasingly recognized importance of mitochondria and the SR in cardiac pathophysiology and the progressively heightened understanding of interactions between both organelles. We hope that this issue will serve to update the knowledge of cardiovascular scientists in this rapidly moving field, stimulating new research that will not only elucidate the many unanswered questions in the field but will also contribute to reducing the burden of cardiovascular disease.
Conflict of interest: none declared.
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Notes |
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The opinions expressed in this article are not necessarily those of the European Society of Cardiology
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References |
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Top1. Introduction2. Recent advances in...3. The role of...4. Recent news on...5. Sarcoplasmic-reticulum...6. SummaryReferences |
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- Orchard C, Brette F. t-tubules and sarcoplasmic reticulum function in cardiac ventricular myocytes. Cardiovasc Res (2008) 77:237–244.
[Abstract/Free Full Text] - Györke S, Terentyev D. Modulation of ryanodine receptor by luminal calcium and accessory proteins in health and cardiac disease. Cardiovasc Res (2008) 77:245–255.
[Abstract/Free Full Text] - Lim S, Venetucci L, Eisner DA, Casadei B. Does nitric oxide modulate cardiac ryanodine receptor function? Implications for excitation–contraction coupling. Cardiovasc Res (2008) 77:256–264.
[Abstract/Free Full Text] - Periasamy M, Bhupathy P, Babu GJ. Regulation of Sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology. Cardiovasc Res (2008) 77:265–273.
[Abstract/Free Full Text] - Kohr MJ, Wang H, Wheeler DG, Velayutham M, Zweier JL, Ziolo MT. Targeting of phospholamban by peroxynitrite decreases ß-adrenergic stimulation in cardiomyocytes. Cardiovasc Res (2008) 77:353–361.
[Abstract/Free Full Text] - Shimura M, Minamisawa S, Takeshima H, Jiao Q, Bai Y, Umemura S, et al. Sarcalumenin alleviates stress-induced cardiac dysfunction by improving Ca2+ handling of the sarcoplasmic reticulum. Cardiovasc Res (2008) 77:362–370.
[Abstract/Free Full Text] - Maltsev VA, Lakatta EG. Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function. Cardiovasc Res (2008) 77:274–284.
[Abstract/Free Full Text] - Venetucci LA, Trafford AW, O'Neill SC, Eisner DA. The sarcoplasmic reticulum and arrhythmogenic calcium release. Cardiovasc Res (2008) 77:285–292.
[Abstract/Free Full Text] - Liu N, Priori SG. Disruption of calcium homeostasis and arrhythmogenesis induced by mutations in the cardiac ryanodine receptor and calsequestrin. Cardiovasc Res (2008) 77:293–301.
[Abstract/Free Full Text] - George CH. Sarcoplasmic reticulum Ca2+ leak in heart failure: mere observation or functional relevance? Cardiovasc Res (2008) 77:302–314.
[Abstract/Free Full Text] - Bito V, Heinzel FR, Biesmans L, Antoons G, Sipido KR. Crosstalk between L-type Ca2+ channels and the sarcoplasmic reticulum – alterations during cardiac remodelling. Cardiovasc Res (2008) 77:315–324.
[Abstract/Free Full Text] - Van den Bergh A, Vanderper A, Vangheluwe P, Desjardins F, Nevelsteen I, Verreth W, et al. Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness. Cardiovasc Res (2008) 77:371–379.
[Abstract/Free Full Text] - Sánchez G, Escobar M, Pedrozo Z, Macho P, Domenech R, Härtel S, et al. Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection. Cardiovasc Res (2008) 77:380–386.
[Abstract/Free Full Text] - Ruiz-Meana M, Rodríguez-Sinovas A, Cabestrero A, Boengler K, Heusch G, Garcia-Dorado D. Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia—reperfusion injury. Cardiovasc Res (2008) 77:325–333.
[Abstract/Free Full Text] - Gustafsson AB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovasc Res (2008) 77:334–343.
[Abstract/Free Full Text] - Parra V, Eisner V, Chiong M, Criollo A, Moraga F, Garcia A, et al. Changes in mitochondrial dynamics during ceramide-induced cardiomyocyte early apoptosis. Cardiovasc Res (2008) 77:387–397.
[Abstract/Free Full Text] - Costa ADT, Pierre SV, Cohen MV, Downey JM, Garlid KD. cGMP signalling in pre- and post-conditioning: the role of mitochondria. Cardiovasc Res (2008) 77:344–352.
[Abstract/Free Full Text] - Hempel A, Friedrich M, Schlüter KD, Forssmann WG, Kuhn M, Piper HM. ANP protects against reoxygenation-induced hypercontracture in adult cardiomyocytes. Am J Physiol (1997) 273:H244–H249.[Web of Science][Medline]
- Schlüter KD, Jakob G, Ruiz-Meana M, Garcia-Dorado D, Piper HM. Protection of reoxygenated cardiomyocytes against osmotic fragility by nitric oxide donors. Am J Physiol (1996) 271:H428–H434.[Web of Science][Medline]
- Padilla F, Garcia-Dorado D, Agullo L, Barrabes JA, Inserte J, Escalona N, et al. Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs. Cardiovasc Res (2001) 51:592–600.
[Abstract/Free Full Text] - Kitakaze M, Asakura M, Kim J, Shintani Y, Asanuma H, Hamasaki T, et al. (J-WIND investigators). Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials. Lancet (2007) 370:1483–1493.[CrossRef][Web of Science][Medline]
- Nishida H, Sato T, Miyazaki M, Nakaya H. Infarct size limitation by adrenomedullin: Protein kinase A but not PI3-kinase is linked to mitochondrial KCa channels. Cardiovasc Res (2008) 77:398–405.
[Abstract/Free Full Text] - Aldakkak M, Stowe DF, Chen Q, Lesnefsky EJ, Camara AKS. Inhibited mitochondrial respiration by amobarbital during cardiac ischaemia improves redox state and reduces matrix Ca2+ overload and ROS release. Cardiovasc Res (2008) 77:406–415.
[Abstract/Free Full Text] - Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG, Karmazyn M. NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res (2008) 77:416–424.
[Abstract/Free Full Text] - Van De Parre TJL, Martinet W, Verheye S, Kockx MM, Van Langenhove G, Herman AG, et al. Mitochondrial uncoupling protein 2 mediates temperature heterogeneity in atherosclerotic plaques. Cardiovasc Res (2008) 77:425–431.
[Abstract/Free Full Text] - Rizzuto R, Pozzan T. Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev (2006) 86:369–408.
[Abstract/Free Full Text] - Yan Y, Liu J, Wei C, Li K, Xie W, Wang Y, et al. Bidirectional regulation of Ca2+ sparks by mitochondria-derived reactive oxygen species in cardiac myocytes. Cardiovasc Res (2008) 77:432–441.
[Abstract/Free Full Text] - Piper HM, Abdallah Y, Kasseckert S, Schlüter KD. Sarcoplasmic reticulum—mitochondrial interaction in the mechanism of acute reperfusion injury. Cardiovasc Res (2008) 77:234–236.
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