Modulation of calcium signalling by mitochondria

Biochimica et Biophysica Acta 1787 (2009) 1374–1382

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Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / b b a b i o

Review

Modulation of calcium signalling by mitochondria Ciara Walsh, Stephanie Barrow, Svetlana Voronina, Michael Chvanov, Ole H. Petersen, Alexei Tepikin ⁎ Department of Physiology, School of Biomedical Sciences, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK

a r t i c l e

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Article history: Received 1 November 2008 Received in revised form 12 January 2009 Accepted 13 January 2009 Available online 22 January 2009 Keywords: Calcium signalling ATP ROS IP3 receptor Ryanodine receptor Store-operated Ca2+ entry

a b s t r a c t In this review we will attempt to summarise the complex and sometimes contradictory effects that mitochondria have on different forms of calcium signalling. Mitochondria can influence Ca2+ signalling indirectly by changing the concentration of ATP, NAD(P)H, pyruvate and reactive oxygen species — which in turn modulate components of the Ca2+ signalling machinery i.e. buffering, release from internal stores, influx from the extracellular solution, uptake into cellular organelles and extrusion by plasma membrane Ca2+ pumps. Mitochondria can directly influence the calcium concentration in the cytosol of the cell by importing Ca2+ via the mitochondrial Ca2+ uniporter or transporting Ca2+ from the interior of the organelle into the cytosol by means of Na+/Ca2+ or H+/Ca2+ exchangers. Considerable progress in understanding the relationship between Ca2+ signalling cascades and mitochondrial physiology has been accumulated over the last few years due to the development of more advanced optical techniques and electrophysiological approaches. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Relationships between Ca2+ signalling and mitochondria are intimate and dynamic. Accumulation of Ca2+ by isolated mitochondria was discovered in the 1950s [110]. Approximately one decade later it was shown that efficient Ca2+ accumulation by mitochondria requires oxidative phosphorylation [29,126]. Vasington and Murphy stated in their pioneering study published in 1962 [126] that “rather large quantities of Ca++ may be actively bound by rat kidney mitochondria in a process that is directly dependent on respiration and that requires adenosine triphosphate, Mg++, and inorganic phosphate in the medium”. Another important development that happened in the sixties was the realisation that phosphate influx can accompany mitochondrial Ca2+ uptake and increase the ability of mitochondria to accumulate and retain Ca [65,104]. In the early seventies the role of the mitochondrial membrane potential as a driving force for mitochondrial Ca2+ influx was elucidated [105,108,109]. The seventies also brought us the understanding that Ca2+ efflux from mitochondria relies on Na+/Ca2+ or H+/Ca2+ antiporters [19,24,35]. The existence of these Ca2+ extrusion mechanisms allows mitochondria to operate as a

Abbreviations: [Ca2+], calcium concentration; ER, endoplasmic reticulum; SR, sarcoplasmic reticulum; [Ca2+]c, cytosolic Ca2+ concentration; [Ca2+]m, mitochondrial Ca2+ concentration; [Ca2+]er, Ca2+ concentration in endoplasmic reticulum; IP3R, IP3 receptor; RyR, ryanodine receptor, ROS, reactive oxygen species; SOCE, store-operated Ca2+ entry; ICRAC, calcium release-activated calcium current; ACh, acetylcholine; PMCA, plasma membrane Ca2+ ATPase; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+ ATPase; Olig, Oligomycin; IA, Iodoacetate; Tg, thapsigargin; STIM1, stromal interacting molecule one ⁎ Corresponding author. The Physiological Laboratory, The University of Liverpool, Crown Street, Liverpool L69 3BX, UK. Fax: +44 151 794 5327. E-mail address: [email protected] (A. Tepikin). 0005-2728/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbabio.2009.01.007

dynamic and reversible Ca storage compartment. Finally, during the seventies the ability of Ca2+ to stimulate dehydrogenases involved in the Krebs cycle was discovered (reviewed in [78]), linking mitochondrial Ca2+ transport with the regulation of cellular bioenergetics. A detailed account of the research field investigating Ca2+ transport systems in mitochondria is given by Carafoli [18]. The notion that the affinity of the mitochondrial Ca2+ uniporter was too low for this mechanism to participate in the Ca2+ transport process at physiological cytosolic Ca2+ concentrations [18] and perhaps the fact that the new generation of readily usable fluorescence calcium indicators (e.g. Quinn 2, Fura-2, Indo-1, Fluo3) [45,81,121] were initially designed to measure cytosolic rather than mitochondrial Ca2+ concentration resulted in some loss of interest in mitochondrial Ca2+ transport in the eighties. Interest was revived in the early 90 s because of the technical developments that allowed the monitoring of mitochondrial Ca2+ concentration and the realisation that the mitochondria can indeed respond to physiological changes in cytosolic [Ca2+] concentration [102]. Interest in mitochondrial Ca2+ was also boosted by the recognition that the ability of Ca2+ to regulate the dehydrogenases of the Krebs cycle can be studied in intact cells using the autofluorescence of NAD(P)H and FAD [31,48]. The current understanding is that Ca2+ enters mitochondria not only during pathological but also during physiological Ca2+ responses and that mitochondria do not just passively buffer excessive Ca2+ but utilise Ca2+ signals to regulate their essential function — oxidative phosphorylation [101]. Mitochondria can respond to both low and high changes in cytosolic Ca2+ concentration ([96] reviewed in [113,114]). The molecular identity of the mitochondrial Ca2+ uniporter is still unknown. A recent study from Graier's laboratory [120] suggested uncoupling proteins 2 and 3 as possible components of the uniporter,

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but this has been challenged by Brookes et al. [11]; for the response of Graier's laboratory see [119]. This important issue remains unresolved. Mitochondria can form close contacts with Ca2+ handling organelles. This was first shown for mitochondria and ER in the elegant study by Rizzuto et al. [100] and later confirmed in a number of publications (e.g. [25,26,33,39,43,58,116]). The tethers linking the ER and mitochondria have been visualised [25] and a recent study by de Brito and Scorrano suggests that Mitofusin 2 is an essential component of these structures [28]. Mitochondria can also form contacts with the Golgi apparatus [30] and the plasma membrane [37,58,74,93,125]. This close co-positioning allows mitochondria preferential access to high Ca2+ microdomains formed in the vicinity of Ca2+ channels [26,100,116]. Under these conditions the mitochondrial uniporter, which was characterised electrophysiologically as a highly Ca2+ selective channel [64], can rapidly import large amounts of Ca2+ into the lumen of the organelle. Conversely, because of their close proximity to the mitochondria, Ca2+ releasing and Ca2+ importing mechanisms of the ER are exposed to elevated concentrations of ATP, reactive oxygen species (ROS) and other metabolites generated by mitochondria and can be regulated by these substances. It is important to note that although the importance of Ca2+ microdomains was documented in a very considerable number of authoritative publications (see above) mitochondria adjacent to ER strands do not always gain a specific advantage in terms of Ca2+ uptake [22] and considerable restructuring of the mitochondrial network, accompanied by a decrease in the number of ER-mitochondria contacts, was shown to result in little or no change in the ability of these organelles to import Ca2+ during Ca2+ release from the ER [125]. The importance of ER-mitochondria connections and the role of Ca2+ microdomains would probably vary in different cell types and depend on the profile of specific Ca2+ signals (see also [113]). The relationships between mitochondria and the Ca2+ signalling cascade are dynamic because a) mitochondria are not stationary, they move through the cytosol of a cell and, remarkably, this movement is influenced by Ca2+ signals [12,138] and b) mitochondria adjust their properties and functions (e.g. mitochondrial membrane potential, intramitochondrial pH, the rate of the Krebs cycle, ATP production…) in accordance with Ca2+ responses [1,48,60,77,128,131,132]. These changes in mitochondrial properties can modify Ca2+ signals, providing complex feedback mechanisms influencing both the mitochondria and the Ca2+ signalling cascade. This review will consider the ability of mitochondria to regulate individual components of the Ca2+ signalling machinery as well as the overall effects of mitochondria on local and global calcium responses. 2. Mitochondria, ATP and the Ca2+ signalling toolbox Metabolites produced by mitochondria can have significant effects on calcium releasing mechanisms. Maeda et al. observed and characterised the binding of ATP and other adenine nucleotides to IP3 receptors [70]. Another biochemical study described how ATP potentiated the binding of IP3 to IP3 receptors (IP3R) [112]. Bezprozvanny and Ehrlich have shown in experiments on cerebellar ER vesicles incorporated into artificial lipid bi-layers that ATP alone was not able to open the IP3R channel but it strongly increased both the frequency and average duration of channel opening when added together with IP3 [9]. The authors also observed that an increase in ATP concentration to above physiological levels has a negative effect on the open probability of IP3-induced opening of IP3R [9]. These high concentrations are unlikely to reflect “cellular average” but could potentially occur in the area of ER-mitochondria junctions. In experiments on patch-clamped Xenopus oocyte nuclei (the nuclear envelope is an extension of the ER) Mak et al. observed that ATP activates the gating of the type1 IP3 receptor (IP3R1) by increasing the sensitivity of the Ca2+ activation sites of the receptor/channel to [Ca2+]c [72]. Under similar experimental conditions the ATP potentia-

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tion of the stimulating action of [Ca2+]c (b 1 μM) on IP3R3 was described by the same group [73]. The ATP dependency of Ca2+ release from the stores of permeabilized cells that preferentially express IP3R1 (A7r5 cell line) or IP3R3 (16HBE14o cell line) was investigated by Missiaen et al. using the radioactive isotope 45Ca2+. ATP potentiated Ca2+ release in both cell types but A7r5 cells were substantially more ATP sensitive than 16HBE14o cells (i.e. lower concentrations of ATP were able to potentiate the Ca2+ release in cells preferentially expressing IP3R1) [82]. A later study from the same group confirmed the higher affinity of ATP for IP3R1 than for IP3R3 [71]. Miyakawa et al. also observed a higher sensitivity of IP3R1 to ATP in comparison with other types of IP3Rs [83]. Calcium release via IP3R2 is also potentiated by ATP. A comparison of the effects of ATP on IP3-induced Ca2+ release in DT40 cells expressing IP3R3 or IP3R2 revealed that IP3R2 was more sensitive to ATP than IP3R3 [8]. Importantly the stimulating effect of ATP on Ca2+ release through IP3R2 was observed only for sub-maximal concentrations of IP3 [8]. The open probability of IP3R2 channels was drastically increased by changing ATP from 0 to 5 mM in the presence of 1 μM IP3, whilst it was only slightly modified for 10 μM IP3 [8]. This probably explains why the high sensitivity of IP3R2 to ATP was not detected in the earlier study by Miyakawa et al. [83]. There is a considerable volume of evidence in favour of the potentiating action of ATP on RyRs (reviewed in [80,141]). The potentiating effect of ATP on Ca2+-induced Ca2+ release from SR vesicles from canine cardiac SR and on the open probability of the large conductance SR Ca2+ channel (incorporated in lipid bilayer) were described by Rousseau et al. [107]. Planar bilayer recordings of channels isolated from rabbit skeletal muscles also revealed the potentiating action of ATP [111]. A comparison of the behaviour of ryanodine-sensitive channels present in cardiac and skeletal SR indicated that both channel types are activated by Ca2+ and ATP [106]. Cardiac ryanodine-sensitive channels were strongly potentiated by 1 mM ATP [98]. Ryanodine receptors purified from rabbit fasttwitch skeletal muscle were strongly activated by 1 mM ATP at suboptimal Ca2+ levels [52]. Ryanodine receptors from sheep cardiac muscle were potentiated by ATP [3,66]. It seems that all types of RyR can be potentiated by ATP although RyR type 3 isolated from bovine diaphragm SR seems to be less sensitive to ATP than other sub-types [57]. A recent study on RyR from brain ER reported that ATP increased the open probability of the channels, decreased the threshold Ca2+ concentration necessary for the activation of the channels, and shifted to the higher Ca2+ concentrations inhibitory effect of Ca2+ on the receptors [14]. Not only “activatable” Ca2+-releasing channels (RyR or IP3R) in ER are regulated by ATP. ATP levels also modulate the passive Ca2+ leak. A reduction in ATP concentration from 4 to 0.375 mM drastically suppressed the passive Ca2+ leak from the ER [50]. Importantly this leak was not mediated by RyR or IP3R [50]. A number of candidate channels which could be responsible for the passive Ca2+ leak from the ER were recently identified [15,36,68,88,123,124]. Characterising the ATP-dependency of these channels would be an interesting topic for future investigations. In addition to the inhibition of Ca2+ release from internal stores, depletion of ATP also inhibits Ca2+ entry. Particular attention in this respect was received by the store-operated Ca2+ entry (SOCE) — mechanism activated by the depletion of [Ca2+] in intracellular stores. In many cell types depleting ATP using a variety of metabolic inhibitors drastically reduces the influx of Ca2+ induced by store depletion (with IP3R agonists or the SERCA pump inhibitor, thapsigargin) [6,21,38,68,76], consistent with the requirement of ATP for the activation of SOCE. Montalvo et al. found that the ATP concentration produced by subplasmalemmal mitochondria provide Ca2+ buffering sufficient to noticeably suppress the inactivation of the calcium release-activated calcium current (ICRAC) [84]. A particularly high

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sensitivity of the SOCE pathway to ATP was identified in a study by Gamberucci et al.. This study reported that a 5% drop in ATP levels, which may occur under physiological conditions, can reduce SOC influx by 50% [38]. The correlation of SOCE and ATP levels in pancreatic acinar cells also suggested a steep dependency of SOCE on the ATP concentration [6]. Ca2+ extrusion from pancreatic acinar cells (similar to many other non-excitable cells) is largely mediated by plasma membrane calcium ATP-ases (PMCA) [6,7,87]. The ATP-dependency of the PMCA is complex [34,17]. Interestingly in pancreatic acinar cells the rate of Ca2+ extrusion by the PMCA and store-operated Ca2+ entry had a very similar ATP dependency (both processes were synchronously suppressed by ATP depletion) leading to the conclusion that both processes have a common master-regulator [6]. Mitochondria localized in the vicinity of the plasma membrane can rapidly accumulate large amounts of Ca [93,130]. A number of studies identified mitochondrial Ca2+ uptake as an important mechanism in the regulation and maintenance of SOCE [41,42,51,125]. It is possible and probable that both Ca2+ uptake by mitochondria and mitochondrial ATP production play important roles in the regulation of SOCE.

Part of the Ca accumulated by mitochondria located in the vicinity of SOC channels can be efficiently transferred to the ER [61]. The mitochondrial Ca2+ uptake in the vicinity of the SOC channels decreases the amplitude of local Ca2+ signals, reduces feedback inhibition of the channels by Ca2+, facilitates transfer of Ca2+ to the ER and therefore potentiates ER Ca2+ re-loading [41,51,61,125]. Recent studies have identified proteins which are required for SOCE — the plasma membrane SOC component, ORAI (CRACM), and the ER Ca2+ sensing protein, STIM [32,67,97,103,129]. Formation of STIM–ORAI complexes is considered essential for the induction of SOCE [67,135]. Surprisingly ATP depletion actually triggered the formation of STIM1–ORAI1 complexes in the sub-plasmalemmal region. However, SOCE remains inhibited under these conditions [21]. Considering that ATP depletion inhibits Ca2+ release via the IP3R and RyR as well as the passive Ca2+ leak and Ca2+ influx, one can argue that at least in some cell types the relationships between Ca2+ signalling and bioenergetics (Fig. 1) are organised according to a “No ATP–No signalling” principle thus avoiding or delaying Ca2+ toxicity and terminating Ca2+-dependent energy consuming processes when

Fig. 1. Illustration of “No ATP–No signalling” principle. (A) Oscillations of [Ca2+]c induced by ACh in pancreatic acinar cells. (B) Decrease of ATP concentration (trace linked by an arrow to the left axis) due to application of oligomycin (Olig) and iodoacetate (IA) results in inhibition of ACh-induced oscillations. Compare the pattern of Ca2+ signalling in A and B. C. In HeLa cells the depletion of internal stores with thapsigargin (Tg) results in activation of SOC channels. This is revealed by pulses of Ca-containing extracellular solution. The amplitude of [Ca2+]c changes is similar for the first and second pulse of Ca-containing extracellular solution. D. Inhibition of ATP production with Olig and IA results in suppression of SOC mediated Ca2+ entry (compare [Ca2+] changes before and after inhibition of ATP production on D and responses depicted on C and D). A and B were adopted with modifications from [6]. C and D were adopted with modifications from [21].

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ATP production is compromised. Pancreatic acinar cells and hepatocytes are examples of cells operating in accordance with this principle [6,8,21,63,92]. In both cell types hypoxia or chemical hypoxia rapidly abolished Ca2+ signalling induced by neurotransmitters or hormones [6,63,92]. In addition to the ATP dependency of Ca2+-releasing channels, a decrease of stimulated IP3 production, under conditions of chemical hypoxia, observed in the study of Kawanishi et al. [63] could be another contributor to the “No ATP–No signalling” principle. The decrease of IP3 production under conditions of ATP depletion is probably mediated by the decline of PIP2 — the lipid precursor of IP3 [21]. Changes of activity of phosphoinositide kinases due to changes in the availability of phospholipids could be another contributing factor to ATP-dependent modulation of Ca2+ regulating mechanisms. Whilst extreme depletion of ATP should abolish the activity of most kinases, more moderate decreases in ATP concentration (and consequently increases of ADP and AMP concentrations) are expected to potentiate the activity of 5′ AMP-activated protein kinase (AMPK) [49]; some of the changes in Ca2+ signalling occurring as a result of mitochondrial inhibition could be mediated by this kinase. This is potentially interesting and at present a poorly explored link between bioenergetics and Ca2+ signalling. Not only ATP but also some other metabolites that are dependent on mitochondrial activity are involved in the regulation of Ca2+ signalling. Zima et al. observed that an increase in NADH concentration decreased the open probability of the RyR. In intact cells mitochondria can influence the cytosolic NADH concentration and consequently should be able to regulate RyR activity via this mechanism [139]. Pyruvate was shown to inhibit RyRs and suppress the frequency of Ca2+ sparks [140]. Pyruvate was also shown to potentiate SOCE by reducing inactivation of calcium release-activated calcium (CRAC) channels [5]. Pyruvate is a product of glycolysis and is efficiently imported and utilised by mitochondria. The effects of pyruvate highlight another important and clearly underexplored link between Ca2+ signalling and bioenergetics.

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The consequences of the mitochondrial handling of elementary cytosolic Ca2+ responses were observed and characterised in an elegant study by Pacher et al. [91]. They found that cytosolic [Ca2+] sparks led to the formation of miniature mitochondrial [Ca2+] signals termed “Ca2+ marks”. These Ca2+ marks were approximately 500 ms in duration (much more prolonged than underlying sparks) with the recovery process dependent on the mitochondrial Na+/Ca2+ exchanger. The discovery of Ca2+ marks is very important because it directly confirms that mitochondrial calcium uptake is fast enough to respond to and influence fast elementary cytosolic [Ca2+] responses. In the second part of their paper the authors described how the inhibition of mitochondrial Ca2+ uptake resulted in an increased frequency of cytosolic [Ca2+] sparks [91]. This study was conducted on H9c2 cells (a cardiac cell line) and the results clearly concur with observations on smooth muscle cells, oocytes and hepatocytes. In all these cell types mitochondria seem to serve as quenchers of elementary Ca2+ signals (Fig. 2A). In cardiac myocytes inhibition of mitochondria also increased the frequency of sparks [10]. The effect of mitochondria on elementary calcium signals is tissue specific and it can be not only inhibitory but also stimulatory. Unlike visceral and vascular myocytes in oligodendrocytes, elementary calcium events (Ca2+ puffs) occur preferentially in the vicinity of energised mitochondria [46]. In this cell type mitochondria are also necessary to convert Ca2+ puffs into Ca2+ waves [46]. The formation of sparks and clustering of RyR (type 2) was observed in the vicinity of perinuclear mitochondria in ventricular myocytes [69]. A stimulatory effect of mitochondria on elementary calcium signals could be mediated by mitochondrialy produced ROS (Fig. 2B) Moderate mitochondrial depolarisation by diazoxide (a putative opener of the KATP channel) or low (nanomolar) concentrations of the protonophore

3. Mitochondria and the shape of Ca2+ responses 3.1. Mitochondria and elementary Ca2+ signals In smooth muscle cells the localization of sparks was compared to the localization of mitochondria. In visceral and vascular myocytes the sites that display the highest frequency of Ca2+ sparks (termed frequent discharge sites) were observed near nuclei. The mitochondria were found in the vicinity of a different compartment of the SR but importantly not in the vicinity of frequent discharge sites [44]. The large volume of the Xenopus oocyte and the orderly arrangement of organelles in this cell type allowed Marchant et al. to perform a detailed examination of the relationships between mitochondria and calcium puffs [75]. They reported a relatively high density of puff sites in the vicinity (b 600 nm) of mitochondria. This is higher than expected from the random distribution. This higher density could perhaps be explained by the later observation of slowing down (trapping) of mitochondrial movement in regions of elevated [Ca2+]c [138]. Importantly, the release sites in the vicinity of mitochondria exhibited lower Ca2+ puff activity than the sites further removed from these organelles [75]. Near-mitochondrial puffs were also unlikely to initiate Ca2+ waves. The inhibitory action of mitochondria on local Ca2+ release from nearby ER was documented in hepatocytes by Hajnoczky et al. [47]. They observed that ER regions surrounded by a high density of mitochondria had a lower sensitivity to IP3. The authors attributed this inhibitory action of mitochondria to the suppression (by mitochondrial Ca2+ uptake) of the local positive feedback of Ca2+ on IP3 receptors. Indeed inhibition of mitochondrial Ca2+ uptake potentiated Ca2+ release from the ER, induced by submaximal concentrations of IP3 [47].

Fig. 2. Two opposite effects of mitochondria on Ca2+ signals. (A) In some cell types mitochondrial Ca2+ uptake can suppress elementary Ca2+ signals (shown in green) and prevent the formation of Ca2+ waves. This is particularly important in situations when mitochondria are located in the vicinity of Ca2+-releasing channels. (B) In other cells ROS produced by mitochondria can potentiate and even trigger elementary Ca2+ signals.

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CCCP was shown to increase ROS production and increase the frequency of Ca2+ sparks by a ROS dependent mechanism [136]. Importantly this study also describes that strong mitochondrial depolarisation, induced by high (micromolar) concentrations of CCCP has the opposite effect on ROS production and inhibits Ca2+ sparks [136]. Regulation/initiation of elementary Ca2+ release events by mitochondria is detailed in a paper from Shirokova's group [54]. This study attributes the initiation of sparks in skinned skeletal muscle fibres (slow-twitch oxidative fibres, intermediate fibres and fasttwitch glycolytic fibres were analysed) to mitochondrial ROS production [54]. A ROS-induced increase of spark frequency in cardiac myocytes was described and discussed in a study by Davidson and Duchen [27]. Yan et al. demonstrated that stimulated ROS production induced transient increases (followed by delayed suppression) in spark frequency in cardiac myocytes, whilst scavenging background (unstimulated) ROS production reduced the frequency of Ca2+ sparks [137]. The two opposite effects of mitochondria on elementary Ca2+ responses are determined by two distinct functions of these organelles — fast mitochondrial Ca2+ uptake can suppress local/ elementary calcium responses whilst mitochondrial ROS production could be important in maintaining the release channels in an optimally oxidised state (Fig. 2). 3.2. Effects of mitochondria on global [Ca2+]c responses and global [Ca2+]c oscillations As a calcium buffering system mitochondria usually display rather fast calcium uptake followed by slow calcium extrusion. In DRG neurons the mitochondrial uptake, followed by slow release, results in the formation of an extended [Ca2+]c plateau. This mitochondriamediated [Ca2+]c plateau develops following a brief period of depolarisation and the opening of voltage gated Ca2+ channels. Interestingly, the plateau is manifested only following rather vigorous stimulation, whilst the shape of [Ca2+]c transients of sub-micromolar amplitude does not seem to depend on mitochondrial buffering [133,134]. A very elegant illustration of the role of mitochondria as a temporal calcium buffer comes from a recent work from Usachev's group [79]. This study reported the formation of remarkably prolonged (more than 10 min) [Ca2+]c plateau in sensory neurons following a brief stimulation with capsaicin. The plateau was completely abolished by a combination of oligomycin and antimycin. The plateau was also completely and reversibly abolished by inhibition of the mitochondrial Na+/Ca2+ exchanger with CGP37157. Finally, measurements of [Ca2+]m with mtPericam revealed the profile of the intramitochondrial calcium transient developed following a brief stimulation of the cell [79]. This profile is characterised by a fast rise and very slow recovery of [Ca2+]m, consistent with a mitochondrial contribution to the [Ca2+]c plateau. Shortening of the post-stimulation [Ca2+]c transient due to inhibition of the mitochondrial Na+/Ca2+ exchanger with CGP-37157 was also observed in another type of excitable cell — chromaffin cells [4]. The amount of calcium accumulated by mitochondria in this cell type was revealed by measurements of [Ca2+]c changes following administration of CCCP. The amount of calcium accumulated by mitochondria following even a relatively brief pulse of cell depolarisation was remarkably large and the authors reached the conclusion that “…whenever [Ca2+]c rose above ≈ 500 nM, [Ca2+]c clearance by mitochondria exceeded clearance by either Na+–Ca2+ exchange or the Ca2+ pumps of the plasma and reticular membranes” [4]. This is probably one of the most drastic examples of the influence of mitochondrial buffering on global [Ca2+]c signals. In other cell types the application of protonophores or inhibitors of the electron transport following a global cytosolic [Ca2+]c rise can also release substantial amounts of calcium, revealing mitochondrial accumulation, [20,59] but the effects on [Ca2+]c are

less prominent than in the case of chromaffin cells [4]. The reason for this record-breaking behaviour of the chromaffin cells is the remarkably efficient coupling of their mitochondria with voltage gated Ca2+ channels and with ryanodine receptors; millimolar [Ca2+] transients were recorded using targeted aequorin in the mitochondria of this cell type following cell depolarisation or caffeine application [86]. Also a substantial [Ca2+] increase was observed in mitochondria, located in the soma of sympathetic neurons, following Ca2+ influx via voltageoperated Ca2+ channels or caffeine-induced Ca2+ release from the ER [89]. The fact that mitochondria can take up a significant amount of calcium during the [Ca2+]c rise and release this calcium later, influencing the shape of both the rising and declining phases of [Ca2+]c transients, is now well established. Ca temporarily accumulated by mitochondria during Ca2+ release from the ER can be effectively utilised to reload the ER or even to prevent further ER Ca2+ loss [2]. The efficiency of ER reloading by mitochondria was shown to be non-uniform with “privileged” reloading in regions with enhanced co-localization of the two organelles [2]. Perhaps the most remarkable illustration of this phenomenon is [Ca2+]c oscillations in HeLa cells based on Ca2+ shuttling between the ER, mitochondria and cytosol. Ishii et al. [55] monitored [Ca2+]m and [Ca2+]c or [Ca2+]er using targeted fluorescent proteins and observed oscillatory changes in all three compartments. A phase shift between [Ca2+] in the three compartments was observed. Importantly Ca2+ release from mitochondria was necessary to trigger regenerative Ca2+ release from the ER, which in turn charged the mitochondria. Inhibition of mitochondrial uptake or inhibition of mitochondrial calcium extrusion via the Na+/Ca2+ exchanger did not abolish the first histamine-induced calcium transient but completely wiped out any [Ca2+]c oscillations [55]. Recent studies from Vay et al. indicated that the pharmacological activation of mitochondrial Ca2+ uptake had a biphasic effect on histamine-induced [Ca2+]c oscillations in HeLa cells. This biphasic effect was composed of an initial potentiation of the oscillations followed by a suppression [127]. The application of protonophores or inhibitors of the electron transport chain or inhibition of ATP synthase abolished repeated calcium signals and calcium oscillations in many cell types [6,23,63,92]. Particularly prominent is the inhibitory phenomenon in cells which rely on IP3 receptors to generate oscillatory [Ca2+]c patterns. The mechanism of this inhibition could involve suppression of Ca2+ release, diminishing Ca2+ influx and inhibition of IP3 production — all these mechanisms were discussed above. An interesting idea regarding the mitochondrial control of Ca2+ oscillations was recently presented in studies from Camello's laboratory [16]. This group suggested (and provided relevant experimental evidence) that the background level of mitochondriamediated release of ROS is necessary to keep Ca2+ releasing channels in the ER in an active oxidised configuration [16]. Inhibition of mitochondria-dependent ROS production (e.g. by depolarisation of mitochondria) or scavenging ROS, results in the suppression of [Ca2+]c oscillations. Finally the application of protonophores or electron transport chain inhibitors during oscillations can trigger substantial calcium release from mitochondria, further amplified by Ca2+-induced Ca2+ release and accompanied by an emptying of the ER calcium store (which could be difficult to reload considering the disrupted ATP production). Very considerable calcium elevations/transients were indeed observed as a result of the application of mitochondrial inhibitors to oscillating cells [115,118,122]. Ca2+ oscillations could therefore be disrupted by a significant loss of Ca2+ from the ER and difficulties with Ca2+ reloading because of a decline in ATP concentration. For calcium oscillations that primarily depend on RyR both mitochondrial Ca2+ buffering and ATP dependent modulation of the Ca2+ release from the store are also relevant. In dorsal root ganglion neurons Ca2+ oscillations induced by caffeine and elevated external K+ are abolished by ryanodine. Application of oligomycin or FCCP

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considerably decreased the frequency of these oscillations [56]. Importantly both these mitochondrial inhibitors failed to change the oscillation frequency under conditions in which cells were patched and the intra patch pipette solution (and therefore cytosol) was supplemented with 3 mM Mg ATP. This is a rather clear indication that changes in ATP and not other disturbances occurring due to the inhibition of mitochondria are responsible for slowing the frequency of oscillations. In addition to Ca2+ efflux from the mitochondria via the Na+/Ca2+ and the H+/Ca2+ exchanger, Ca2+ can exit this organelle passively via the Ca2+ uniporter under conditions where the electrochemical gradient for Ca2+ is reversed [85]. Interestingly this mechanism is sensitive to cytosolic Ca2+ and can mediate Ca2+-induced release of Ca2+ from mitochondria [85]. Ca2+ release from mitochondria via the Ca2+ uniporter is unlikely to contribute to physiological Ca2+ signalling in the cytosol or mitochondria but could be important under pathological conditions (e.g. during periods of hypoxia). Ca2+induced release of Ca2+ from mitochondria can also operate via the permeability transition pore [53], which could be important during programmed cell death and under pathological conditions related to cell damage caused by Ca2+ overload. 3.3. Mitochondrial firewalls Pancreatic acinar cells provide an interesting example of the ability of mitochondria to segregate the cytosol into Ca2+-signalling compartments (Fig. 3). In this cell type physiological agonists induce Ca2+ signals that are initiated in the apical part of the cell. Some of these Ca2+ signals spend their entire existence in the apical region — these are local apical Ca2+ transients [62,90,117]. These signals can form complex patterns of [Ca2+]c oscillations composed of relatively brief transients taken from the baseline. The neurotransmitter ACh or infusion of IP3 via a patch pipette are convenient ways to produce local apical [Ca2+]c oscillations. Experiments with non-metabolizable analogues of IP3 revealed that these [Ca2+]c oscillations do not require oscillations in IP3 concentration [94]. The duration of the local spikes can vary from less than a second to 15 s for oscillations induced by secretagogues [40,94], even longer local apical responses were produced by bile acids [132]. Tinel et al. observed a very high density of mitochondria around the apical/secretory granule region

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of the cell (mitochondrial belt). Importantly this study showed that inhibition of mitochondria by protonophores results in the loss of the ability of the cell to create local [Ca2+]c responses whilst global [Ca2+]c transients originating in the apical region were still possible [118]. These results were largely confirmed by D. Yule's laboratory [115] who also coined the term “mitochondrial firewall”. So why is it useful to form mitochondrial firewalls? One reason is perhaps to restrict Ca2+ signalling to the region of the cell where it is most needed. In the case of acinar cells this is to provide Ca2+ transients for Ca2+dependent exocytosis and Ca2+ dependent fluid secretion — both important cellular events initiated in the apical region (reviewed in [95]). The idea of the involvement of perigranular mitochondria in restricting Ca2+ signals to apical region received further support from direct measurements of [Ca2+]m in pancreatic acinar cells [93]. Furthermore, significant NAD(P)H changes were observed in pancreatic acinar cells following very brief (approximately 3 s) calcium transients indicating that perigranular mitochondria are certainly capable of sensing local apical [Ca2+]c responses [131]. In this cell type mitochondria envelop the Golgi apparatus from both lateral and basal sides whilst Ca2+ releasing IP3R are located on the apical side of the Golgi. This spatial positioning allows the formation of steep Ca2+ transients across the Golgi apparatus [30]. Another example of the firewall function of mitochondria is found in airway epithelia. In this cell model mitochondria efficiently divide the cell into apical and basolateral Ca2+ signalling compartments during stimulation with purinergic receptor agonists [99]. Mitochondria can also be responsible for introducing a delay in the propagation of Ca2+ signals into specific cellular compartments. In an elegant study Jason Bruce et al. [13] documented a delayed entry of [Ca2+] signals into the nucleoplasm of parotid acinar cells. The majority of mitochondria in this cell type are clustered around the nucleus. This delay in nuclear [Ca2+] responses was abolished by inhibitors of the mitochondrial uniporter [13]. Preferential [Ca2+] accumulation by perinulear mitochondria was also observed in pancreatic acinar cells when Ca2+ was “uncaged” in the nucleus by a spatially restricted pulse of UV light [93]. It is not clear at the moment how many cell types mastered the art of making large scale mitochondrial firewalls but this seems to be an interesting structural and functional building block that could be successfully utilised in other cell types and in other signalling cascades.

Fig. 3. Mitochondria and formation of local Ca2+ signals. Mitochondria prevent the escape of Ca2+ signals from the apical region of a pancreatic acinar cell. A. Local Ca2+ signals in a doublet of pancreatic acinar cells, stimulated by a brief pulse of ACh. Scale bar corresponds to 5 μm. B. Distribution of mitochondria in a doublet of pancreatic acinar cells. Scale bar corresponds to 4 μm. Different cells are shown in A and B. A was adopted with modifications from [40]. B was adopted with modifications from [132].

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4. Conclusions Mitochondria seem to be capable of regulating all components of the calcium signalling machinery including Ca2+ release via IP3R and RyR, Ca2+ influx via store-operated channels, Ca2+ uptake and Ca2+ extrusion. Ca2+ uptake into mitochondria is fast enough to suppress local calcium signals and prevent the formation of Ca2+ waves; on the other hand ATP and ROS produced by mitochondria could induce local calcium responses and are important for sustaining global Ca2+ signalling. Due to a relatively fast Ca2+ uptake and slower Ca2+ extrusion, mitochondria can blunt abrupt transients of cytosolic Ca2+ and create long term Ca2+ elevations. In collaboration with the ER, mitochondria can create “two-pool” type Ca2+ oscillations. The strategic positioning of large groups of mitochondria (e.g. under the plasma membrane, around the nucleus, on the boundary of secretory granule area…) can limit cytosolic calcium signalling to a specific region of the cytoplasm. Millions of years of the co-evolution of mitochondria and their host cells has resulted not only in a useful cooperation in energy production but also in the development of a collaborative approach to Ca2+ signalling. Acknowledgements We are grateful to Mark Houghton for his creative help with illustrations and to Alan Conant for useful discussion of the manuscript. References [1] M.F. Abad, B.G. Di, P.J. Magalhaes, L. Filippin, T. Pozzan, Mitochondrial pH monitored by a new engineered green fluorescent protein mutant, J. Biol. Chem. 279 (2004) 11521. [2] S. Arnaudeau, W.L. Kelley, J.V. Walsh Jr., N. Demaurex, Mitochondria recycle Ca(2+) to the endoplasmic reticulum and prevent the depletion of neighboring endoplasmic reticulum regions, J. Biol. Chem. 276 (2001) 29430. [3] R.H. Ashley, A.J. Williams, Divalent cation activation and inhibition of single calcium release channels from sheep cardiac sarcoplasmic reticulum, J. Gen. Physiol. 95 (1990) 981. [4] D.F. Babcock, J. Herrington, P.C. Goodwin, Y.B. Park, B. Hille, Mitochondrial participation in the intracellular Ca2+ network, J. Cell Biol. 136 (1997) 833. [5] D. Bakowski, A.B. Parekh, Regulation of store-operated calcium channels by the intermediary metabolite pyruvic acid, Curr. Biol. 17 (2007) 1076. [6] S.L. Barrow, S.G. Voronina, S. da, X.M.A. Chvanov, R.E. Longbottom, O.V. Gerasimenko, O.H. Petersen, G.A. Rutter, A.V. Tepikin, ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile, Pflugers Arch. 455 (2008) 1025. [7] P. Belan, O. Gerasimenko, O.H. Petersen, A.V. Tepikin, Distribution of Ca2+ extrusion sites on the mouse pancreatic acinar cell surface, Cell Calcium 22 (1997) 5. [8] M.J. Betzenhauser, L.E. Wagner, M. Iwai, T. Michikawa, K. Mikoshiba, D.I. Yule, ATP modulation of Ca2+ release by type-2 and type-3 inositol (1, 4, 5)triphosphate receptors. Differing ATP sensitivities and molecular determinants of action, J. Biol. Chem. 283 (2008) 21579. [9] I. Bezprozvanny, B.E. Ehrlich, ATP modulates the function of inositol 1,4,5trisphosphate-gated channels at two sites, Neuron 10 (1993) 1175. [10] D.N. Bowser, T. Minamikawa, P. Nagley, D.A. Williams, Role of mitochondria in calcium regulation of spontaneously contracting cardiac muscle cells, Biophys. J. 75 (1998) 2004. [11] P.S. Brookes, N. Parker, J.A. Buckingham, A. Vidal-Puig, A.P. Halestrap, T.E. Gunter, D.G. Nicholls, P. Bernardi, J.J. Lemasters, M.D. Brand, UCPs—unlikely calcium porters, Nat. Cell Biol. 10 (2008) 1235. [12] D. Brough, M.J. Schell, R.F. Irvine, Agonist-induced regulation of mitochondrial and endoplasmic reticulum motility, Biochem. J. 392 (2005) 291. [13] J.I. Bruce, D.R. Giovannucci, G. Blinder, T.J. Shuttleworth, D.I. Yule, Modulation of [Ca2+]i signaling dynamics and metabolism by perinuclear mitochondria in mouse parotid acinar cells, J. Biol. Chem. 279 (2004) 12909. [14] R. Bull, J.P. Finkelstein, A. Humeres, M.I. Behrens, C. Hidalgo, Effects of ATP, Mg2+, and redox agents on the Ca2+ dependence of RyR channels from rat brain cortex, Am. J. Physiol Cell Physiol 293 (2007) C162–C171. [15] C. Camello, R. Lomax, O.H. Petersen, A.V. Tepikin, Calcium leak from intracellular stores—the enigma of calcium signalling, Cell Calcium 32 (2002) 355. [16] C. Camello-Almaraz, P.J. Gomez-Pinilla, M.J. Pozo, P.J. Camello, Mitochondrial reactive oxygen species and Ca2+ signaling, Am. J. Physiol. Cell Physiol. 291 (2006) C1082–C1088. [17] E. Carafoli, The Ca2+ pump of the plasma membrane, J. Biol. Chem. 267 (1992) 2115. [18] E. Carafoli, Historical review: mitochondria and calcium: ups and downs of an unusual relationship, Trends Biochem. Sci. 28 (2003) 175.

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