Targeted Mito- and Cardioprotection by Malonate

HomeCirculation ResearchVol. 131, No. 6Targeted Mito- and Cardioprotection by Malonate Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTargeted Mito- and Cardioprotection by Malonate Rainer Schulz and Gerd Heusch Rainer SchulzRainer Schulz Correspondence to: Rainer Schulz, MD, Institute of Physiology, Justus-Liebig University, Aulweg 129, Giessen 35385, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3017-0476 Institute of Physiology, Justus-Liebig University, Giessen, Germany (R.S.). and Gerd HeuschGerd Heusch https://orcid.org/0000-0001-7078-4160 Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, Germany (G.H.). Originally published1 Sep 2022https://doi.org/10.1161/CIRCRESAHA.122.321582Circulation Research. 2022;131:542–544This article is a commentary on the followingIschemia-Selective Cardioprotection by Malonate for Ischemia/Reperfusion InjuryDespite all improvements in the implementation of thrombolysis and interventional reperfusion in the last decades, the mortality and morbidity, notably from heart failure, in patients with acute myocardial infarction are still substantial, and adjunct cardioprotection beyond that by rapid reperfusion is still an urgent medical need.Article, see p 528Following the identification of the ischemic conditioning paradigm, numerous mechanical and pharmacological interventions have been demonstrated to reduce infarct size in a variety of experimental models of myocardial ischemia/reperfusion in different species. In smaller proof-of-concept studies, several mechanical and pharmacological interventions also reduced infarct size in patients with reperfused acute myocardial infarction. However, in larger phase III clinical trials, the success of mechanical and pharmacological attempts to reduce mortality and hospitalization for heart failure has been largely disappointing.1 The lack of translation of successful cardioprotection to the clinical benefit of patients has been attributed to lack of robust preclinical studies, in particular to the neglect of age, comorbidities, and comedications, as well as to the study of patients with very good prognosis who do not need adjunct cardioprotection.2 However, there is also still a lack of a fundamental and comprehensive understanding of cardioprotective signaling and mechanisms.Clearly, mitochondria are most important elements of any cardioprotection. Physiologically, mitochondria provide energy for cellular function through their respiratory chain complexes which stepwise transfer electrons from the Krebs cycle substrates to oxygen and create a protein gradient across the inner membrane with consequent hyperpolarization which ultimately drives ATP formation. Mitochondria are also physiologically important in the control of subcellular calcium concentrations. In ischemia, the lack of oxygen inhibits the flow of electrons along the respiratory chain and ATP formation, causing dysfunction of the energy-dependent ionic pumps and contractile machinery and ultimately cell death. Aberrant electron flux also causes increased reactive oxygen species (ROS) formation.3 Cell death results from opening of the mitochondrial permeability transition pore (MPTP) which is mostly closed during physiological conditions but opens in response to increased inorganic phosphate, ROS, and calcium concentrations during ischemia, then permits a large cation flow into the mitochondrial matrix which induces massive mitochondrial matrix swelling, ultimately rupture of the outer mitochondrial membrane and release of cytochrome C into the cytosol. The opening of the MPTP is even accentuated during early reperfusion when the inhibitory action of acidosis on it is removed.4 Several mitochondrial ion channels, including MPTP, the mitochondrial calcium uniporter, the mitochondrial KATP channel, the big calcium-activated potassium channel, and connexin 43, are involved in the control of the potential of the inner mitochondrial membrane, matrix volume, respiratory chain function, calcium homeostasis, and ROS formation and have thus become targets for cardioprotective interventions.5 A mild inner membrane depolarization by opening of connexin 43, KATP, and big calcium-activated potassium channels, as well as transient MPTP opening, reduces infarct size in preclinical studies, whereas massive opening of the MPTP and the calcium uniporter particularly during reperfusion causes collapse of the membrane potential, mitochondrial calcium overload, massive ROS formation and ultimately mitochondrial rupture.It is here that the inhibition of the reverse electron transport from complex II to complex I during early reperfusion comes into play—this reverse transport, which is catalyzed by SDH (succinate dehydrogenase) and fueled from the succinate accumulation during ischemia, increases ROS formation and MPTP opening.6 Succinate is released from ischemic cells through the sarcolemmal membrane MCT1 (monocarboxylate transporter 1),7 and blockade of the MCT1 before ischemia indeed increases cell death.8 Conversely, pharmacological inhibition of SDH by malonate reduced infarct size in mouse hearts6 and in juvenile pigs in situ which received intracoronary malonate during reperfusion.9Whereas pharmacological mitoprotective strategies in patients with acute myocardial infarction have mostly targeted the MPTP and—despite some promising proof-of-concept studies in smaller patient cohorts—failed to provide clinical benefit, SDH inhibition by malonate has not been studied in humans yet. In these prior patient studies on mitoprotective strategies, it was not clear whether the target was not the appropriate one or the pharmacokinetics of the drug under study did not permit a sufficient drug concentration at the target.It is here where the study by Prag et al10 (current issue of Circulation Research) provides important novel information. Using isolated cultured noncardiac and cardioblast cells, isolated, saline-perfused mouse hearts, and in situ mouse hearts with coronary occlusion/reperfusion, the authors demonstrated that cellular malonate uptake is dependent on an acidic pH and occurs through the sarcolemmal MCT1 in exchange for lactate; mitochondrial malonate uptake occurs subsequently through the mitochondrial dicarboxylate carrier. Thus, the prerequisites for malonate uptake are prior ischemia which decreases pH and increases lactate concentration and subsequent reperfusion which facilitates malonate entry into cardiomyocytes in exchange for lactate through the MCT1. In fact, malonate only reduced infarct size in the isolated mouse heart when administered at reperfusion, whereas an acidic malonate formulation was required to affect infarct size with administration before ischemia (Figure). The requisite of ischemia/reperfusion to achieve a high malonate concentration in the cardiomyocyte which was then sufficient to attenuate lethal injury led the authors to propose an ischemia-selective cardioprotective action of malonate. Indeed, intracoronary malonate which reduced infarct size in juvenile pigs when administered intracoronarily at reperfusion only transiently reduced contractile function at baseline and did not decrease nonischemic contractile function11 supporting the notion of an ischemia-selectivity. Ischemia-selectivity of cardioprotective agents has been proposed before for the coronary vascular and myocardial effects of certain calcium antagonists,12 and it is certainly advantageous to avoid any negative impact on metabolism and function of nonischemic myocardium in the setting of regional myocardial ischemia/reperfusion.As always, some open questions, however, remain to be answered:Although sex can impact on ischemia/reperfusion injury and cardioprotection, only male mice were used. In organs, such as the liver, MCT1 expression is regulated by sex hormones and expression levels vary with the estrogen cycle.13 Whether or not the same holds true for the heart and MCT1 transport kinetics and subsequently the cardioprotective action of malonate are also seen in females remains unknown.Reduction in infarct size by malonate was additive to that obtained by cyclosporine. Although a dose-response curve for malonate was provided, only a single dose of cyclosporine was used, leaving the possibility that the reduction of infarct size by cyclosporine was submaximal. Interestingly, in juvenile pigs receiving intracoronary malonate before reperfusion, the reduction in infarct size was of a similar magnitude as that with remote ischemic precondition and not additive,9 and remote ischemic conditioning also impacts on MPTP.Comorbidities modulate cardioprotective interventions. The infarct size reduction by SDH inhibition using dimethyl malonate was reduced in prediabetic rat hearts14 and isolated human trabeculae from diabetic patients.15Thus, although the present data are quite promising, it remains to be seen whether or not the beneficial kinetics and effects of malonate are confirmed in more relevant preclinical and clinical settings, including models with comorbidities.16 Data in adult pigs with intravenous malonate administration are needed to see whether a sufficient concentration can be achieved either in ischemic myocardium at very low collateral blood flow or during early reperfusion and without systemic hemodynamic effects. Of course, ultimate proof for cardioprotection by malonate would have to come from studies in patients, initially with infarct size and eventually with clinical outcome as end points (Figure).Download figureDownload PowerPointFigure. Under physiological conditions, lactate and ketones are taken up into the cardiomyocyte through the sarcolemmal MCT1 (monocarboxylate transporter 1) to fuel the Krebs cycle; their uptake is increased during exercise and in heart failure. During ischemia, anaerobic glycolysis produces cytosolic lactate and protons (H+) which are released into the extracellular space through MCT1 to control intracellular pH. During ischemia, succinate accumulates in the mitochondria and can be transported into the extracellular space through MCT1. Upon reperfusion, the accumulated succinate is rapidly oxidized by the mitochondrial respiratory chain enzyme SDH (succinate dehydrogenase), driving reactive oxygen species (ROS) formation by reverse electron transport (RET) at mitochondrial complex I. Several mitochondrial ion channels, including the MCU (mitochondrial calcium [Ca2+] uniporter), the mitochondrial KATP channel, the big calcium-activated potassium channel (KCa), and Cx43 (connexin 43), impact on the opening probability of the MPTP (mitochondrial permeability transition pore). Swelling of the mitochondrial matrix and rupture of the mitochondrial membrane in response to sustained opening of MPTP causes release of cytochrome C. Ischemia/reperfusion injury can be attenuated not only by cyclosporine, which interacts with Cyp D (cyclophilin D) to inhibit MPTP opening, but also through malonate by inhibition of SDH. Malonate, however, uptake into the cardiomyocyte through MCT1 is greatly facilitated in the presence of low pH (ie, during ischemia or in an acidic formulation); malonate uptake into mitochondria is through the DIC (dicarboxylate carrier). FAD indicates flavine adenine dinucleotide; and FADH2, dihydroflavine adenine dinucleotide.Article InformationSources of FundingR. Schulz is supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [Project number 268555672—SFB 1213, Project B05]. G. Heusch is supported by CRC 1116 B8 of the Deutsche Forschungsgemeinschaft.Disclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 544.Correspondence to: Rainer Schulz, MD, Institute of Physiology, Justus-Liebig University, Aulweg 129, Giessen 35385, Germany. Email rainer.schulz@physiologie.med.uni-giessen.deReferences1. Heusch G. Myocardial ischaemia-reperfusion injury and cardioprotection in perspective.Nat Rev Cardiol. 2020; 17:773–789. doi: 10.1038/s41569-020-0403-yCrossrefMedlineGoogle Scholar2. Heusch G, Gersh BJ. 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Heusch G, Andreadou I, Bell R, Bertero E, Botker H, Davidson S, Downey J, Eaton P, Ferdinandy P, Gersh B, Giacca M, Hausenloy D, Ibanez B, Krieg T, Maack C, Schulz R, Sellke F, Shah A, Thiele H, Yellon D and Di Lisa F (2023) Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection, Redox Biology, 10.1016/j.redox.2023.102894, 67, (102894), Online publication date: 1-Nov-2023. Li W, Quan L, Peng K, Wang Y, Wang X, Chen Q, Cheng H and Ma Q (2023) Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts, Basic Research in Cardiology, 10.1007/s00395-023-01015-z, 118:1 Lieder H, Adam V, Skyschally A, Sturek M, Kleinbongard P and Heusch G (2023) Attenuation of ST-segment elevation by ischemic preconditioning: Reflection of cardioprotection in Göttingen but not in Ossabaw minipigs, International Journal of Cardiology, 10.1016/j.ijcard.2023.05.026, 386, (109-117), Online publication date: 1-Sep-2023. 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Schulz R and Schlüter K (2023) Importance of Mitochondria in Cardiac Pathologies: Focus on Uncoupling Proteins and Monoamine Oxidases, International Journal of Molecular Sciences, 10.3390/ijms24076459, 24:7, (6459) Ferdinandy P, Andreadou I, Baxter G, Bøtker H, Davidson S, Dobrev D, Gersh B, Heusch G, Lecour S, Ruiz-Meana M, Zuurbier C, Hausenloy D, Schulz R and Levy F (2022) Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning, Pharmacological Reviews, 10.1124/pharmrev.121.000348, 75:1, (159-216), Online publication date: 1-Jan-2023. Lieder H, Skyschally A, Sturek M, Heusch G and Kleinbongard P (2022) Remote ischemic conditioning in Ossabaw minipigs induces the release of humoral cardioprotective triggers, but the myocardium does not respond with reduced infarct size, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00580.2022, 323:6, (H1365-H1375), Online publication date: 1-Dec-2022. Kleinbongard P, Lieder H, Skyschally A, Alloosh M, Gödecke A, Rahmann S, Sturek M and Heusch G (2022) Non-responsiveness to cardioprotection by ischaemic preconditioning in Ossabaw minipigs with genetic predisposition to, but without the phenotype of the metabolic syndrome, Basic Research in Cardiology, 10.1007/s00395-022-00965-0, 117:1, Online publication date: 1-Dec-2022. Related articlesIschemia-Selective Cardioprotection by Malonate for Ischemia/Reperfusion InjuryHiran A. Prag, et al. Circulation Research. 2022;131:528-541 September 2, 2022Vol 131, Issue 6 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.122.321582PMID: 36048916 Originally publishedSeptember 1, 2022 KeywordsEditorialsheart failureischemiamitochondriamyocardial infarctionreperfusionPDF download Advertisement