YJMCC-07767; No. of pages: 8; 4C: 2 Journal of Molecular and Cellular Cardiology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Molecular and Cellular Cardiology journal homepage: www.elsevier.com/locate/yjmcc

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Review article

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Mitochondrial reactive oxygen species production and elimination Alexander Nickel, Michael Kohlhaas, Christoph Maack Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Saar, Germany

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Article history: Received 6 January 2014 Received in revised form 24 February 2014 Accepted 14 March 2014 Available online xxxx

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Keywords: Mitochondria Reactive oxygen species Heart failure Excitation–contraction coupling Redox regulation

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Reactive oxygen species (ROS) play an important role in cardiovascular diseases, and one important source for ROS are mitochondria. Emission of ROS from mitochondria is the net result of ROS production at the electron transport chain (ETC) and their elimination by antioxidative enzymes. Both of these processes are highly dependent on the mitochondrial redox state, which is dynamically altered under different physiological and pathological conditions. The concept of “redox-optimized ROS balance” integrates these aspects and implies that oxidative stress occurs when the optimal equilibrium of an intermediate redox state is disturbed towards either strong oxidation or reduction. Furthermore, mitochondria integrate ROS signals from other cellular sources, presumably through a process termed “ROS-induced ROS release” that involves mitochondrial ion channels. Here, we attempt to integrate these recent advances in our understanding of the control of mitochondrial ROS emission and develop a concept how in heart failure, defects in ion handling can lead to mitochondrial oxidative stress. This article is part of a Special Issue entitled ‘Redox Signalling in Heart’. © 2014 Published by Elsevier Ltd.

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1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Regulation of mitochondrial ATP production by ADP and Ca2 + . . . . . . . . 3. Mitochondrial ROS production and elimination . . . . . . . . . . . . . . . 4. The concept of Redox-optimized ROS balance . . . . . . . . . . . . . . . . 5. How defects in EC coupling trigger mitochondrial ROS emission in heart failure 6. Mitochondrial ROS production in diabetic cardiomyopathy . . . . . . . . . . 7. Mitochondria as integrators of cellular oxidative stress . . . . . . . . . . . 8. Therapies directed at mitochondrial ROS production . . . . . . . . . . . . 9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Financial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Reactive oxygen species (ROS) are involved in a number of physio50 logical and pathological processes of the cardiovascular system [1]. 51 They originate from various sources, in particular from NADPH oxidases 52 Q10 (NOX2 and NOX4) [2], uncoupled nitric oxide synthases (NOSs) [3], 53 xanthine oxidase (XO) [4] and mitochondria [5], with the latter being 54 considered as the main source for cellular ROS by many [6–9], but not 55 all authors [10]. In this respect, the cell type may play an important 56 role. In the heart, causal roles for ROS production from different sources

E-mail address: [email protected] (C. Maack).

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have been observed in the development of cardiac hypertrophy and failure [11–15], while mitochondria seem to be the dominating source of ROS in ageing [16–18]. Recent evidence suggests that mitochondria play an integrative role in the control of intracellular ROS production, since ROS from NOX2 are amplified by mitochondria, and myocardial hypertrophy, fibrosis and dysfunction in response to canonical NOX2 activation could be prevented by scavenging mitochondrial, but not cytosolic ROS production [11,19,20]. Here, we review recent advances in the understanding of the regulation of mitochondrial ROS production in the heart, focussing on the concepts of “redox-optimized ROS balance” [21–23] and “ROS-induced ROS release” [24–26]. The concept of “redox-optimized ROS balance” integrates mitochondrial ROS production with ROS scavenging mechanisms during different metabolic states

http://dx.doi.org/10.1016/j.yjmcc.2014.03.011 0022-2828/© 2014 Published by Elsevier Ltd.

Please cite this article as: Nickel A, et al, Mitochondrial reactive oxygen species production and elimination, J Mol Cell Cardiol (2014), http:// dx.doi.org/10.1016/j.yjmcc.2014.03.011

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The processes of EC coupling consume large amounts of ATP that need to be replenished efficiently in mitochondria by oxidative phosphorylation [28,29]. In the mitochondrial matrix, the Krebs cycle produces NADH and FADH2 that donate electrons to the electron transport chain (ETC; Fig. 1A). By sequential redox reactions along the complexes I–IV of the ETC, protons are translocated across the inner mitochondrial membrane, producing a proton gradient (ΔpH) [30]. Together with the electrical gradient (ΔΨm ), ΔpH

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constitutes the proton motive force (ΔμH) which provides the driving force for ATP production at the F1/Fo-ATP synthase (complex V; Fig. 1A). This coupling of electron transfer along the ETC to ATP synthesis by ΔμH is the essence of the “chemiosmotic theory” formulated by Peter Mitchell in 1961 [31], for which he was awarded with the Nobel Prize in 1979. To adapt the rate of ATP production to the constantly varying ATP demands of a cell, oxidative phosphorylation is tightly regulated by various factors, but in particular, by Ca2+ and ADP. When workload in the heart increases, ADP stimulates ATP production at the F1/Fo-ATP synthase, dissipating ΔμH. To maintain ΔμH, NADH and FADH2 donate more electrons to the ETC, accelerating electron flux along the ETC and O2 consumption. During physiological changes in cardiac workload, β-adrenergic stimulation triggers an increase of the amplitude and

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of a cell, and in context with mitochondrial ion homeostasis provides a mechanism how defects in excitation–contraction (EC) coupling in 72 Q11 heart failure can account for oxidative stress [27].

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Fig. 1. Regulation of mitochondrial ATP and ROS production in cardiac myocytes. A, NADH and FADH2 feed electrons to the electron transport chain (ETC) through complexes I and II, respectively, where sequential redox reactions allow translocation of protons (H+) across the inner mitochondrial membrane (IMM) and flux of electrons towards complexes III and IV, where O2 is transformed to H2O. The primary sites of O2- formation are complex I and the Q-cycle of complex III. B, Integration of mitochondrial ROS production (cyan field) with ROS elimination (purple field) and the control through ion handling (green field) as well as ROS signalling from extramitochondrial sources (red field). For details, see text. In brief, the close association of mitochondria to the SR facilitates efficient mitochondrial Ca2+ uptake through “Ca2+ microdomains” (green field). In the matrix, Ca2+ is important to activate Krebs cycle dehydrogenases to facilitate the regeneration of NADH to match ATP supply and demand. At the same time, through its link to NADPH regeneration, the Krebs cycle controls the antioxidative capacity in a process termed “redox-optimized ROS balance” (purple field). Mitochondria can integrate extramitochondrial ROS signals through ROS-induced ROS release that is mediated by ion channels in the inner mitochondrial membrane (red field). Cellular ROS are involved in a number of signalling events of EC coupling, metabolism and cardiac remodelling. Abbreviations: Nnt, nicotinamide nucleotide transhydrogenase; Mn-SOD, Mn2+-dependent superoxide dismutase; PRX, peroxiredoxin; GPX, glutathione peroxidase; TRXr/o, reduced/oxidized thioredoxin; GSH/GSSG, reduced/oxidized glutathione; TR, thioredoxin reductase; GR, glutathione reductase; α-KG, α-ketoglutarate; MCU, mitochondrial Ca2+ uniporter; NCLX, mitochondrial Na+/Ca2+ (and Li+) exchanger; RyR, ryanodine receptor; SERCA, SR Ca2+ ATPase; Mfn, mitofusin; IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; NCX, NHE and NKA, sarcolemmal Na+/Ca2+ exchanger, Na+/H+ exchanger and Na+/K+-ATPase, respectively; SR, sarcoplasmic reticulum; OMM, outer mitochondrial membrane; NOS, nitric oxide synthase; XO, xanthine oxidase; NOX, NADPH oxidase; CaMKII, Ca2+/Calmodulin-dependent protein kinase II; -ox, oxidation; ΔΨm, mitochondrial membrane potential; ΔμH, proton motive force; ΔpH, proton gradient; MAP, mitogen-activated protein kinases; HDAC4, histon deacetylases 4.

Please cite this article as: Nickel A, et al, Mitochondrial reactive oxygen species production and elimination, J Mol Cell Cardiol (2014), http:// dx.doi.org/10.1016/j.yjmcc.2014.03.011

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frequency of cytosolic Ca2 + transients. This leads to increased mitochondrial Ca2 + uptake via the mitochondrial Ca2+ uniporter (MCU), 98 and in the matrix, Ca2+ activates rate-limiting dehydrogenases of the 99 Krebs cycle [32,33] (Fig. 1B). This accelerates regeneration of NADH 100 and FADH2 and thus, maintains their redox states so that the ETC is 101 not deprived of its substrates for ATP production. This illustrates that 102 ADP and Ca2+ control oxidative phosphorylation and the mitochondrial 103 redox state in a complimentary way to maintain stable ratios of ATP/ 104 ADP and NADH/NAD+ (Fig. 1B, cyan field). 105 Mitochondria take up Ca2+ via the MCU, a Ca2+ selective channel in 106 the inner mitochondrial membrane [34], whose molecular identity was 107 revealed only recently [35,36]. The MCU has a relatively low affinity for 108 Ca2+ (in the range of 10–30 μmol/L), and since cytosolic Ca2+ concen109 trations ([Ca2 +]c) in cardiac myocytes are usually lower than these 110 values, the amounts and kinetics of mitochondrial Ca2+ uptake have 111 been a long-held controversy (for more extensive recent reviews, see 112 [33,37]). Although the overall amounts of mitochondrial Ca2+ uptake 113 on a beat-to-beat basis are still not fully resolved yet [32,38,39], there 114 is general agreement that mitochondria can take up Ca2 + rapidly, 115 which – given the low Ca2+ affinity of the MCU – can be explained by 116 the existence of a mitochondrial Ca2 + microdomain (Fig. 1B, green 117 field) [33,37,40]. This microdomain is established by the close proximity 118 of mitochondria to the Ca2 + stores of the cell, i.e., the sarcoplasmic 119 reticulum (SR), and allows Ca2 + concentrations to rise to the upper 120 micromolar range at the surface of mitochondria for a brief period 121 after Ca2 + release from ryanodine receptors (RyRs) of the SR [33]. 122 The SR–mitochondrial Ca 2 + transmission is governed not only by 123 the highly organized spatial arrangements of cardiomyocytes per se, 124 but also by direct tethering of mitochondria to the SR by molecular 125 Q12 links [41]. We recently identified mitofusin-2 to be one of these tethers 126 that control SR–mitochondrial Ca2+ transmission and thus, the matching 127 process of energy supply-and-demand and mitochondrial redox state in 128 cardiac myocytes [42]. For more detailed information of the role of mito129 chondrial fission and fusion as well as SR–mitochondrial cross-talk, we 130 refer the reader to our recent reviews on this [33,43].

During respiration, superoxide (•O− 2 ) is produced at the ETC by incomplete reduction of O2 (Fig. 1B, cyan field). The classical concept of •O− 2 production at the ETC is that in the presence of substrates and the 135 absence of ADP (i.e., respiratory state 4), the ETC is highly reduced, 136 which increases the likelihood of electrons “slipping” from the ETC to − 137 O2, reducing O2 with one electron to •O− 2 [7–9]. The main sites of •O2 138 formation are the flavin mononucleotide (FMN) site of complex I and 139 the Q cycle of complex III [9,25,44,45]. When ADP accelerates electron 140 flux and O2 consumption (state 3), the ETC becomes more oxidized, 141 which decreases its redox potential and thus, •O− 2 formation [8]. These 142 theoretical formulations [8] are supported by experimental data on iso143 lated mitochondria [46–48] and computational modelling [23], in which 144 mitochondrial ROS production at the ETC is a function of ΔΨm and/or the 145 redox state of NADH/NAD+ [8,47,48]. This concept is also the basis for 146 the idea that uncoupling mitochondrial respiration and thus, ΔΨm 147 (for instance, by uncoupling proteins) generally lowers oxidative stress 148 [49]. These concepts, however, to some degree neglect that the anti149 oxidative capacity of the mitochondrial matrix also depends on the 150 mitochondrial redox state (Fig. 1B, purple field). As explained in the 151 following passages, the relation between the metabolic state of a 152 cell and ROS emission from mitochondria (as a net result of ROS pro153 duction and elimination) is more complex (i.e., U-shaped; [21,22]) 154 than the mere assumption that mitochondrial ROS production corre155 lates with the NADH/NAD+ redox state and ΔΨm [47,48]. 2+ 156 •O− -dependent superox2 is efficiently dismutated to H2O2 by Mn 157 ide dismutase (Mn-SOD). H2O2 is transformed to water (H2O) by gluta158 thione peroxidase (GPX) and peroxiredoxin (PRX), which in turn are 159 Q13 regenerated by glutathione (GSH) and thioredoxin (TRX) [50,51]. The

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Conflicting data exist on the regulation of mitochondrial ROS production and emission not only during different metabolic situations, but also when comparing ROS measurements in isolated mitochondria and isolated cardiomyocytes [21]. For instance, while many studies on isolated mitochondria suggest that uncoupling respiration lowers ROS production [47,48], experiments on isolated cardiac myocytes revealed increased H2O2 emission during mitochondrial uncoupling [27] and dissipation of ΔΨm [25]. How can this seeming paradox be resolved? Key to this issue is to integrate ROS production and elimination through the tight balance between NADH and NADPH in the mitochondrial matrix via the Nnt, but also IDPm and malic enzyme (Fig. 1B, purple field). When respiration is accelerated by ADP, NADH and the ETC become more oxidized, which lowers •O− 2 production at the ETC [8,23]. On the other hand, oxidation of NADH limits the regeneration of NADPH, which dissipates the antioxidative capacity of H2O2-eliminating systems (i. e., GPX and PRX). Since the heart is an organ with high ATP demand and production, it is never in respiratory state 4 (no ATP demand), but rather in state 3 (high ATP demand) to different degrees. Aon et al. [21] proposed that “mitochondria have been evolutionarily optimized to maximize energy output while keeping ROS overflow to a minimum by operating in an intermediate redox state”. This implies that the optimal condition for cardiac mitochondria is when extreme oxidation and/or reduction of the mitochondrial redox state are avoided, since in the case of pronounced oxidation, depletion of the antioxidative capacity results in excessive H2O2 overflow despite decreased •O− 2 production at the ETC, while under highly reduced conditions, high •O− 2 production at the ETC overwhelms the antioxidative capacity (despite abundant levels of NADPH) [21,23]. This concept of redox-optimized ROS balance (Fig. 1B, purple field) was established on the basis of experimental findings in isolated mitochondria and isolated cardiomyocytes [21,22,27] and could recently be recapitulated by computational modelling [23]. Since Krebs cycle activity is central to the NAD(P)H/NAD(P)+ redox state, mitochondrial Ca2 + uptake during β-adrenergic stimulation plays an important role not only to match energy supply-and-demand in the heart, but also to dynamically regenerate the antioxidative capacity of the mitochondrial matrix to limit H2O2 emission from mitochondria [27,33] (Fig. 1B).

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redox states of GSH and TRX are reduced by NADPH, which is produced by three enzymes that derive their substrates from the Krebs cycle: NADP+-dependent isocitrate dehydrogenase (IDPm), malic enzyme and the nicotinamide nucleotide transhydrogenase (Nnt) [51] (Fig. 1B, purple field). Thus, the Krebs cycle is central not only to provide electron carriers for ATP production at the ETC (NADH and FADH2), but also to regenerate the antioxidative capacity of the mitochondrial matrix (through NADPH) [27].

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5. How defects in EC coupling trigger mitochondrial ROS emission in 207 heart failure 208 A central deficit in heart failure is the perturbation of EC coupling in cardiac myocytes [52–54]. In particular, reduced Ca2 + load of the SR related to decreased SR Ca2 + ATPase activity and increased Ca2 + leak from RyRs lowers the amplitude and velocity of cytosolic Ca2 + transients. Furthermore, [Na+]i is elevated [55,56] as a result of increased late Na+ current (INa,L), decreased Na+/K+-ATPase (NKA) and/or increased Na+/H+ exchanger (NHE) activity [57] (Fig. 1B, green field). Elevated [Na +] i increases trans-sarcolemmal Ca 2 + influx via the reverse mode of the sarcolemmal Na+/Ca2 + exchanger (NCX) during the early phase of the action potential and reduces NCX-mediated Ca2 + extrusion thereafter [58,59]. Although this improves SR Ca2 + load and cardiac contractility [59,60], elevated [Na + ] i reduces steady-state mitochondrial Ca2 + accumulation through activation

Please cite this article as: Nickel A, et al, Mitochondrial reactive oxygen species production and elimination, J Mol Cell Cardiol (2014), http:// dx.doi.org/10.1016/j.yjmcc.2014.03.011

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heart failure have heart failure with preserved ejection fraction (HFpEF) [91], which is characterized by diastolic dysfunction despite maintained systolic function [92]. Besides arterial hypertension and LV hypertrophy, diabetes and obesity are independent risk factors to develop clinically relevant diastolic dysfunction [93]. Oxidative stress is thought to play an important role in the development of HFpEF [94], but also of diabetic cardiomyopathy [95,96]. In human atrial myocardium of patients with diabetes, the capacity of mitochondria to oxidize fatty acids and glucose-based substrates was diminished, mitochondrial glutathione pools depleted and H2O2 emission increased [97]. Also in mouse models of Type 2 diabetes and obesity (db/db mice and cardiac insulin receptor knock-out mice, respectively), mitochondrial ROS production was increased, while oxidative phosphorylation capacity and contractile function were impaired [98,99]. A typical feature of the diabetic heart is that its substrate utilization is shifted even further towards fatty acid oxidation through signalling of peroxisome proliferator-activated receptor α (PPARα) [95]. Accordingly, when respiring fatty acids, respiration was uncoupled presumably by ROS-induced activation of UCPs, which would provide an explanation for mechanical inefficiency and contractile dysfunction in these models of diabetic cardiomyopathy [98,99]. In fact, isolated mitochondria produce more ROS when using palmitoyl carnitine as a substrate than with complex I and II-dependent substrates [100]. Furthermore, increased expression of UCP2 in cardiac myocytes lowered ΔΨm and mitochondrial Ca2 + uptake, which led to deterioration of EC coupling by slowing cytosolic Ca2 + decay kinetics [101]. Based on these findings, one could speculate that ROS-induced activation of UCP2 may play a central role in mediating mechanical inefficiency and diastolic dysfunction in diabetic cardiomyopathy [95]. 7. Mitochondria as integrators of cellular oxidative stress

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of the mitochondrial Na+/Ca2+ exchanger (NCLX), the dominant Ca2+ extrusion mechanism in mitochondria [32,61,62] (Fig. 1B, green field). Furthermore, increased contribution of reverse-mode NCX to the cytosolic Ca2+ transient in failing myocytes [58,59] has a negative impact on mitochondrial Ca2+ uptake, since the rather slow kinetics of NCXdriven Ca2+ influx are less efficient in triggering mitochondrial Ca2+ uptake than a comparable increase in Ca2+ after a coordinated SR Ca2+ release [63], due to the privileged Ca2 + communication between the SR and mitochondria [33,43]. Collectively, these defects in cytosolic Ca2+ and Na+ handling that occur in failing cardiac myocytes hamper mitochondrial Ca2+ uptake [27,32,64]. On the one hand, this has a negative impact on the regeneration of NADH [27,32,64], which is required for ATP production at the ETC, and thus may contribute to the energetic deficit observed in failing hearts [65,66]. On the other hand, since the antioxidative capacity in mitochondria is regenerated by NADPH through Krebs cycle products (NADH, isocitrate and malate; Fig. 1B, purple field), reduced mitochondrial Ca2+ uptake triggers increased H2O2 emission and thus, oxidative stress [27,67]. Taken together, these data indicate that the changes of EC coupling that occur in heart failure, and in particular decreased SR Ca2+ load and elevation of [Na+]i, can contribute to oxidative stress by potentiating mitochondrial ROS emission [61]. Also other sites of mitochondrial ROS production under pathological situations have been identified. Among these are NOX4 [68], uncoupled neuronal NO synthase [69], monoamine oxidase and p66Shc [70,71]. Since the mechanisms of impaired antioxidative capacity through alterations of EC coupling in failing myocytes would apply largely independent of the source of ROS in mitochondria (ETC and/or other sources), these mechanisms are not mutually exclusive but rather synergistic in increasing oxidative stress in heart failure. Vice versa, increased ROS production in cardiac myocytes interferes with EC coupling on multiple levels, involving modifications of Ca2 + and Na+ handling — as well as sarcomeric proteins [72,73]. These modification are mediated by oxidative post-translational modifications of ion channels and sarcomeric proteins directly [72–74] as well as by redox-dependent activation of protein kinases, such as protein kinase A [75], protein kinase C [76] and Ca2+/Calmodulin-dependent protein kinase II (CaMKII) [77], which in their own right affect Ca2+ and Na+ handling proteins through phosphorylation. CaMKII is upregulated and activated in human failing hearts [78], increases the leak of RyRs [79] and phosphorylates voltage-gate Na+-channels [80–82], increasing late INa and [Na+]i in cardiac myocytes [80]. In fact, genetic deletion of CaMKIIδ prevented ROS-induced activation of late INa and subsequent [Na+]i accumulation [83]. However, CaMKIIδ-mediated activation of late INa alone cannot entirely account for the observed [Na+]i accumulation, which is further potentiated by ROS-induced inhibition of the NKA [83,84], the primary Na+-extrusion mechanism. [Na+]i accumulation, in turn, activates reverse-mode NCX during the action potential [58,59,83], increasing cytosolic Ca2 + concentrations. Interestingly, in a recent study, overexpression of the α2 isoform of the NKA, which is more efficient in removing Na+ from the cytosol than the α1 isoform, protected from pressure-induced hypertrophy and dysfunction [85], supporting the concept that cytosolic Na + and Ca 2 + overload may aggravate the progression of cardiac dysfunction. Furthermore, ROS inhibit SR Ca2 +-ATPase [86,87], increase the opening probability of RyRs [88] and activate reverse-mode NCX [89], reconciling typical features of remodelled EC coupling in heart failure. Together, these data indicate that in heart failure, ROS deteriorate EC coupling and initiate a vicious cycle of CaMKII activation, [Na +] i accumulation and further ROS emission from mitochondria [27,77,80,83] (Fig. 1B), perpetuating contractile and metabolic dysfunction, oxidative stress and arrhythmias during the progression of heart failure [90].

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The prevalence of heart failure, but also of comorbidities increases 285 Q16 with age. About half of the patients presenting with symptoms of

Early work from Zorov et al. [24] and Aon et al. [25] developed the concept of “ROS-induced ROS release”, in which extramitochondrial ROS can trigger irreversible or reversible dissipations of ΔΨm that are mediated by ROS-induced activation of ion channels in the inner mitochondrial membrane. While Zorov et al. [24] identified the cyclosporine A-sensitive permeability transition pore (PTP) as the mediator of mostly irreversible dissipations, Aon et al. [25] found the 4′-chlorodiazepamsensitive (and cyclosporine A-insensitive) inner membrane anion channel (IMAC) as the ion channel that opens transiently in response to an elevation of extramitochondrial •O− 2 (Fig. 1B, red field). In myocardial ischemia/reperfusion, after reaching a critical threshold of intracellular ROS, IMAC-mediated ROS-induced ROS release can trigger cardiac arrhythmias through “metabolic sinks”, characterized by spatiotemporal heterogeneity of ΔΨm that may create a substrate for electrical re-entry cycles at the whole organ level [102,103]. In this scenario, ROS-induced opening of the IMAC dissipates ΔΨ m , releases •O− 2 and consumes NADH and NADPH. The consequent burst-like •O− 2 release from one mitochondrion can activate IMACs of neighbouring mitochondria, which leads to spatially and temporally synchronized oscillations of ΔΨm [25,104] (Fig. 1B, red field). While ΔΨm is dissipated, ATP production ceases, and elevated ADP opens sarcolemmal K ATP channels, hyperpolarizing the cellular membrane potential and making a cell unexcitable [25,104,105]. Regeneration is achieved when the ROS released from mitochondria are eliminated by intracellular antioxidative systems (SOD, catalase), facilitating the closing of IMACs and allowing mitochondria to regenerate NADH, NADPH, the antioxidative capacity and ΔΨm. When these systems are, however, exploited, irreversible ΔΨ m dissipation can induce necrotic cell death, then also involving the activation of the PTP [102], the classical inducer of necrotic cell death [106]. Ischemic preconditioning is a phenomenon in which brief episodes of ischemia and reperfusion protect the myocardium from injury induced by a prolonged phase of ischemia (with reperfusion) [107]. Transient mitochondrial ROS release triggers preconditioning during

Please cite this article as: Nickel A, et al, Mitochondrial reactive oxygen species production and elimination, J Mol Cell Cardiol (2014), http:// dx.doi.org/10.1016/j.yjmcc.2014.03.011

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glycolysis and fatty acid oxidation that in their own right may mediate maladaptive (and/or adaptive) signalling and may potentially be more important than the mere effects on mitochondrial ATP production [29, 127–129]. Taken together, mitochondrial ROS play a central role in the development of cardiac hypertrophy and failure by interfering with EC coupling to induce contractile dysfunction and arrhythmias [130], but also with metabolic, nuclear and apoptotic signalling pathways that trigger maladaptive cardiac remodelling [11,15,77,124,131], sustaining the progression of the disease.

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In clinical trials, antioxidative strategies were so far inefficient [132]. However, since these antioxidant therapies were not directed to specific ROS sources, and some cellular ROS sources (for instance, NOX4) may play rather protective roles [1,133], more recent pharmacological approaches are aimed at targeting mitochondria specifically [134]. The most promising and best-characterized strategies in this respect are antioxidants coupled to the lipophilic triphenylphosphonium cation (TPP+), such as MitoSNO [135], MitoQ [136] and related compounds [137,138], and the family of Szeto–Schiller peptides [139]. The pharmacology of mitochondria-targeted drugs has been reviewed in more detail recently [137–139]. The basic principle of MitoSNO and MitoQ is to couple a pharmacon to the lipophilic cation TPP+ that allows i) the passage of the drug across cellular and mitochondrial membranes through its lipophilicity and ii) the accumulation in negatively charged mitochondria through its positive charge according to the Nernst potential. Mitoquinone (MitoQ) is a ubiquinone derivative covalently coupled to TPP + [140]. MitoQ accumulates at the matrix side of the inner mitochondrial membrane many 100-fold and becomes reduced by electrons from the ETC, which provides a constant regenerative capacity in energized mitochondria [138, 140]. The resulting ubiquinol derivative is an effective antioxidant and prevents lipid peroxidation, protecting mitochondria from oxidative damage [138,140]. In animal models, MitoQ ameliorated I/R-induced LV dysfunction and cell death [136], reduced hypertension and LV hypertrophy [141], and protected from endotoxin[142] and cocaine-induced cardiotoxicity [143]. First clinical phase II trials in patients with Parkinson disease and hepatitis C indicated safety, but the drug has not been tested in cardiovascular diseases in humans yet [144]. MitoSNO is an S-nitrosothiol covalently linked to (TPP+) that allows mitochondrial generation of NO• and S-nitrosated proteins [145]. NO• is known to inhibit respiration by competing with O2 at cytochrome c oxidase (complex IV) of the ETC [146], which especially at low O2 concentrations can slow respiration and thus, prevent anoxia [145]. Furthermore, S-nitrosation of thiols in complex I by MitoSNO additionally inhibits electron flux through the ETC [145]. Since complex I is the main source of •O− 2 production during the reperfusion of ischemic myocardium, MitoSNO can ameliorate ROS production in this scenario by preventing the entry of electrons into the ETC, reducing cellular oxidative damage and infarct size in vivo [135,145]. Also in heart failure, a functional block of respiration at complex I was observed to account for increased •O− 2 production [5]. MitoSNO, however, has not been tested in a clinical setting yet. The family of Szeto–Schiller peptides (SS) was discovered by serendipity and consists of synthetic tetrapeptides with alternating aromatic–cationic motifs that allow their passage across membranes and achieve an ~ 5000-fold accumulation in the inner mitochondrial membrane [139,147]. SS-31 (D-Arg-2′6′-dimethylTyr-Lys-Phe-NH2) is the best characterized and most efficient compound from this family [148]. In contrast to TPP+-coupled compounds, however, mitochondrial uptake of SS-31 seems to be less dependent on ΔΨm [148], which may be of advantage in situations in which mitochondria are rather depolarized, such as during ischemia/reperfusion.

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these phases of ischemia/reperfusion [108,109] by signalling pathways that involve mitogen-activated protein (MAP) kinases and mito352 chondrial KATP channels, converging on the inhibition of PTP opening 353 [110–113]. Similarly, also ischemic postconditioning, and remote354 and pharmacological preconditioning all converge on mitochondria 355 and the PTP [114]. Meanwhile, various clinical trials have validated 356 the efficiency of different conditioning strategies in humans in vivo 357 [114–118]. In in vitro experiments, acute application of angiotensin 358 II, a canonical activator of NOX2, induced preconditioning in hearts 359 via ROS-dependent activation of mitochondrial KATP channels with 360 a subsequent amplification of ROS production by mitochondria [26, 361 119]. These data indicate that besides inducing arrhythmias and/or 362 cell death [102], ROS-induced ROS release could also play an impor363 tant role for myocardial protection through the activation of MAP 364 kinases and mitochondrial K ATP channels during preconditioning 365 [1,26,119] (Fig. 1B, red field). 366 Although this short term NOX2-induced mitochondrial ROS release 367 with subsequent MAP kinase activation is beneficial in ischemia/ 368 reperfusion, longer-term activation of this mechanism may be harmful 369 by inducing maladaptive remodelling. Dai et al. [19] confirmed the ob370 servation that angiotensin II increased mitochondrial ROS production 371 in neonatal cardiac myocytes. This ROS production was inhibited by a 372 mitochondria-targeted peptide, SS-31, but not by the non-targeted 373 antioxidant N-acetyl cysteine (NAC) [19]. In vivo, four weeks of angio374 tensin II infusion or cardiomyocyte-specific overexpression of Gαq led 375 to cardiac hypertrophy, fibrosis and diastolic dysfunction. These effects 376 were prevented by mitochondria-specific overexpression of catalase 377 and SS-31, but neither by NAC nor catalase overexpressed in peroxi378 somes [11,19]. Interestingly, in cardiac myocytes, the NOX2-induced 379 mitochondrial ROS production partly dissipated ΔΨm and was also ab380 rogated by inhibiting the IMAC or the PTP, supporting the concept that 381 ROS-induced ROS release is mediated by mitochondrial ion channels 382 [24,25] and that mitochondria may integrate and amplify cytosolic 383 ROS from other non-mitochondrial sources [20] (Fig. 1B, red field), 384 potentially also in chronic conditions like cardiac hypertrophy and 385 heart failure. In fact, we observed that in human failing myocardium, 386 Rac1-dependent NOX2 activity and oxidative stress are increased 387 [120] and mitochondrial KATP channels are endogenously activated, 388 exerting protection against ROS-induced contractile dysfunction [121] 389 and potentially reflecting a response to upstream signalling cascades 390 and/or ROS-induced ROS release between NOX2 and mitochondria. In 391 agreement with this paradox of protective preconditioning and mal392 adaptive remodelling being mediated by similar signalling cascades, in393 farct size was reduced in dogs with pacing-induced heart failure [122]. 394 More recent work from the Rabinovitch group revealed that besides 395 angiotensin II- and Gαq-induced cardiac hypertrophy, fibrosis and 396 dysfunction [11,19], also the development of heart failure in response 397 to trans-aortic constriction (TAC) was ameliorated by mitochondrial 398 overexpression of catalase [15], supporting that mitochondrial ROS 399 production plays a causal role in the development of heart failure in re400 Q19 sponse to different stresses. Likewise, overexpression of PRX-3 in mito401 chondria ameliorated LV remodelling after myocardial infarction in 402 mice [123]. During heart failure, the abundance of proteins involved in 403 fatty acid metabolism is decreased while that of proteins involved in 404 glycolysis, apoptosis, the unfolded protein response (UPR) and proteol405 ysis is increased [15]. This proteomic remodelling was largely prevented 406 by reducing mitochondrial ROS production by either mitochondrial 407 overexpression of catalase [15] or treatment with the mitochondria408 targeted peptide SS-31 [124]. Whether the metabolic switch from 409 fatty acid utilization to glucose utilization is an adaptive or maladaptive 410 response, and whether this has consequences for mitochondrial ATP 411 production or even cardiac remodelling is currently incompletely re412 solved and was recently reviewed in more detail by us [29] and others 413 [125,126]. This way or the other, several lines of evidence suggest that 414 the alterations in glucose- and fatty acid metabolism that occur in 415 heart failure lead to an accumulation of intermediary metabolites of

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[3] Dixon LJ, Morgan DR, Hughes SM, McGrath LT, El-Sherbeeny NA, Plumb RD, et al. Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure. Circulation 2003;107:1725–8. [4] Ekelund UE, Harrison RW, Shokek O, Thakkar RN, Tunin RS, Senzaki H, et al. Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. Circ Res 1999;85:437–45. [5] Ide T, Tsutsui H, Kinugawa S, Utsumi H, Kang D, Hattori N, et al. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 1999;85:357–63. [6] Adam-Vizi V. Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal 2005;7:1140–9. [7] Turrens JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335–44. [8] Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell 2005; 120:483–95. [9] Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009;417:1–13. [10] Brown GC, Borutaite V. There is no evidence that mitochondria are the main source of reactive oxygen species in mammalian cells. Mitochondrion 2012;12:1–4. [11] Dai DF, Johnson SC, Villarin JJ, Chin MT, Nieves-Cintron M, Chen T, et al. Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure. Circ Res 2011;108:837–46. [12] Moens AL, Takimoto E, Tocchetti CG, Chakir K, Bedja D, Cormaci G, et al. Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy. Circulation 2008;117:2626–36. [13] Takimoto E, Champion HC, Li M, Ren S, Rodriguez ER, Tavazzi B, et al. Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 2005;115:1221–31. [14] Bendall JK, Cave AC, Heymes C, Gall N, Shah AM. Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 2002;105:293–6. [15] Dai DF, Hsieh EJ, Liu Y, Chen T, Beyer RP, Chin MT, et al. Mitochondrial proteome remodelling in pressure overload-induced heart failure: the role of mitochondrial oxidative stress. Cardiovasc Res 2012;93:79–88. [16] Dai DF, Chen T, Wanagat J, Laflamme M, Marcinek DJ, Emond MJ, et al. Agedependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell 2010;9:536–44. [17] Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005;308:1909–11. [18] Dai DF, Rabinovitch PS, Ungvari Z. Mitochondria and cardiovascular aging. Circ Res 2012;110:1109–24. [19] Dai DF, Chen T, Szeto H, Nieves-Cintron M, Kutyavin V, Santana LF, et al. Mitochondrial targeted antioxidant Peptide ameliorates hypertensive cardiomyopathy. J Am Coll Cardiol 2011;58:73–82. [20] Maack C, Böhm M. Targeting mitochondrial oxidative stress in heart failure: throttling the afterburner. J Am Coll Cardiol 2011;58:83–6. [21] Aon MA, Cortassa S, O'Rourke B. Redox-optimized ROS balance: a unifying hypothesis. Biochim Biophys Acta 2010;1797:865–77. [22] Cortassa S, O'Rourke B, Aon MA. Redox-Optimized ROS Balance and the relationship between mitochondrial respiration and ROS. Biochim Biophys Acta 1837;2013:287–95. [23] Gauthier LD, Greenstein JL, Cortassa S, O'Rourke B, Winslow RL. A computational model of reactive oxygen species and redox balance in cardiac mitochondria. Biophys J 2013;105:1045–56. [24] Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. 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Furthermore, in contrast to TPP+-coupled agents [149], SS-31 does not interfere with respiration [139], which may be of advantage in dis481 eases in which an energetic deficit is believed to contribute (at least to 482 some extent) to malfunction, such as heart failure [29,65]. Initial studies 483 reported that SS-31 reduced mitochondrial ROS production and 484 protected mitochondria from ROS-induced damage, preventing apopto485 tic cell death [148]. SS-31 directly interacts with cardiolipin [150], a 486 phospholipid that is specifically expressed in the inner mitochondrial 487 membrane (IMM) and plays a key role in cristae formation and thereby, 488 the organization and efficient interaction of the respiratory complexes 489 with each other in so-called “supercomplexes” [139]. It may be specu490 lated that this interaction with cardiolipin prevents the release of SS491 31 from mitochondria upon mitochondrial depolarization. In heart 492 failure, cardiolipin biosynthesis and remodelling enzymes are altered, 493 affecting the lipid profile of the IMM [151]. ROS induce peroxidation of 494 cardiolipin, which impairs the interaction of the complexes of the ETC 495 and thus, provokes more aberrant deviation of electrons to O2 to form 496 •O− 2 . Specifically, the function of cytochrome c is critically controlled 497 by cardiolipin. When cardiolipin is reduced, cytochrome c functions as 498 an electron carrier, whereas when cardiolipin is oxidized, cytochrome 499 c behaves as a peroxidase, augmenting oxidative stress [139]. SS-31 500 stabilizes cardiolipin in its reduced form by direct interaction and 501 thus, prevents its peroxidation, maintaining ETC function, and ATP pro502 duction and preventing ROS production [139]. 503 SS-31 has been tested in various pathological situations, in particular 504 in neurodegenerative and cardiovascular diseases [139,147]. Various 505 animal models demonstrated beneficial effects of SS-31 in ischemia/ 506 reperfusion [152,153] but also hypertensive heart disease [19] and 507 Q22 heart failure [124,139]. Based on these positive preclinical data, SS508 31 has been introduced into clinical testing in various indications, 509 most importantly, in a phase II trial in patients with myocardial in510 farction [154]. An oral formulation of SS-31 has also been developed 511 and is planned to be tested in phase II trials in patients with heart 512 failure with either reduced or preserved ejection fraction [139]. 9. Conclusions

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Mitochondria are an important source for ROS in cardiovascular diseases, and the understanding of the regulation of mitochondrial function and ROS emission is critical to develop novel therapeutic strategies. 517 The concepts that the antioxidative capacity is dynamically regulated in 518 working cardiac myocytes and that mitochondria play an integrative 519 role in orchestrating cellular ROS signals have advanced our under520 standing of how mitochondrial ROS production is regulated in the 521 normal and failing heart and have facilitated the development of more 522 specific, targeted therapies that may hopefully provide additional bene523 fits in the treatment of patients with cardiovascular diseases beyond the 524 Q23 blockade of neurohormonal activation.

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Financial support

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C. M. is supported by the Deutsche Forschungsgemeinschaft (Heisenberg Programm, SFB 894 and KFO 196).

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C. M. received speaker honoraria from Berlin Chemie and serves as a scientific advisor to Stealth Peptides.

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