Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death

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YCECA-1868; No. of Pages 12

Cell Calcium xxx (2017) xxx–xxx

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Review

Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death Tomas Gutiérrez, Thomas Simmen ∗ Faculty of Medicine and Dentistry, Department of Cell Biology, University of Alberta, Edmonton, T6G2H7, Canada,

a r t i c l e

i n f o

Article history: Received 7 April 2017 Received in revised form 24 May 2017 Accepted 24 May 2017 Available online xxx Keywords: ER chaperones Protein folding Apoptosis Mitochondria-associated membrane MAM Mitochondria-ER contacts

a b s t r a c t The folding of secretory proteins is a well-understood mechanism, based on decades of research on endoplasmic reticulum (ER) chaperones. These chaperones interact with newly imported polypeptides close to the ER translocon. Classic examples for these proteins include the immunoglobulin binding protein (BiP/GRP78), and the lectins calnexin and calreticulin. Although not considered chaperones per se, the ER oxidoreductases of the protein disulfide isomerase (PDI) family complete the folding job by catalyzing the formation of disulfide bonds through cysteine oxidation. Research from the past decade has demonstrated that ER chaperones are multifunctional proteins. The regulation of ER-mitochondria Ca2+ crosstalk is one of their additional functions, as shown for calnexin, BiP/GRP78 or the oxidoreductases Ero1␣ and TMX1. This function depends on interactions of this group of proteins with the ER Ca2+ handling machinery. This novel function makes perfect sense for two reasons: i. It allows ER chaperones to control mitochondrial apoptosis instantly without a lengthy bypass involving the upregulation of pro-apoptotic transcription factors via the unfolded protein response (UPR); and ii. It allows the ER protein folding machinery to fine-tune ATP import via controlling the speed of mitochondrial oxidative phosphorylation. Therefore, the role of ER chaperones in regulating ER-mitochondria Ca2+ flux identifies the progression of secretory protein folding as a central regulator of cell survival and death, at least in cell types that secrete large amount of proteins. In other cell types, ER protein folding might serve as a sentinel mechanism that monitors cellular well-being to control cell metabolism and apoptosis. The selenoprotein SEPN1 is a classic example for such a role. Through the control of ER-mitochondria Ca2+ -flux, ER chaperones and folding assistants guide cellular apoptosis and mitochondrial metabolism. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 ER-mitochondria contacts act as an intracellular Ca2+ signaling hub that determines mitochondria metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 ER oxidative protein folding 101 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Chaperones distribute throughout the entire ER, where they may have functions unrelated to folding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Examples of MAM chaperones and folding assistants that regulte ER-mitochondria Ca2+ flux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.1. SIGMAR1: a paradigm for chaperone-mediated regulation of MAM signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.2. BiP/Grp78 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.3. ERp44 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.4. Ero1␣ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.5. Calnexin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.6. TMX1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.7. SEPN1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.8. ERdj5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 5.9. Other chaperones and folding assistants mediating ER-mitochondria Ca2+ flux . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author. E-mail address: [email protected] (T. Simmen). http://dx.doi.org/10.1016/j.ceca.2017.05.015 0143-4160/© 2017 Elsevier Ltd. All rights reserved.

Please cite this article in press as: T. Gutiérrez, T. Simmen, Endoplasmic reticulum chaperones tweak the mitochondrial calcium rheostat to control metabolism and cell death, Cell Calcium (2017), http://dx.doi.org/10.1016/j.ceca.2017.05.015

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6.

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction The production of secretory proteins inside the endoplasmic reticulum (ER) requires the joint activity of the polypeptide import machinery, folding chaperones and oxidoreductases. The ensemble of these enzymes sequentially interacts with newly imported polypeptides that correspond to approximately one third of potential intracellular substrates [1]. Together, folding chaperones and oxidoreductive folding enzymes mediate the production of fully functional proteins and prepare them for an oxidizing extracellular environment that is very different from the reducing redox environment of the cytosol [2,3]. ER chaperones and folding assistants are typically very abundant in most cell types, reaching concentrations up to the millimolar range [4], due to the large load of polypeptides entering the ER to be subsequently exported [5]. However, most chaperones moonlight in other functions, some of which have been summarized in a recent review [6]. Most notably, ER protein folding has emerged as an important determinant of mitochondrial functions [7]. An important example of such proteins is calnexin, which determines the activity of ER Ca2+ import [8], but also the transfer of Ca2+ to mitochondria [9]. This novel role of ER chaperones and folding assistants depends on the interaction with Ca2+ handling proteins, a function that requires localization to the mitochondria-associated membrane (MAM), as shown in the calnexin paradigm [9]. Other ER chaperones and folding assistants perform similar, sometimes overlapping functions via the regulation of ER Ca2+ channels and pumps, as well as the storage of free Ca2+ within the ER lumen (Fig. 1) [7,10]. This review will focus on these secondary functions of ER chaperones and folding assistants in ER-mitochondria Ca2+ signaling to determine mitochondrial functions such as apoptosis and energy production. 2. ER-mitochondria contacts act as an intracellular Ca2+ signaling hub that determines mitochondria metabolism MAMs are a subdomain of the ER that mediate the interaction of the ER with mitochondria and accommodate the exchange of lipids and Ca2+ ions between the two organelles [11,12]. These contacts had originally been discovered in pioneering studies by Bernhard, Fawcett, Hay and others in the 1950s [13–16]. For decades dismissed as contaminations, it became clear at the beginning of the 1990s that physical ER-mitochondria contacts are required for lipid synthesis in yeast and human cells by the laboratories of Jean Vance [17,18] and Günther Daum [19,20]. Further breakthrough research determined that MAMs allow for the transfer of Ca2+ ions from the ER to mitochondria, in particular during apoptosis [21–24]. A burgeoning body of research on MAMs has led to a detailed understanding of the build and function of this intracellular signaling hub. The latest insight on this has been recently published in a beautiful review [25]. ER-mitochondria contacts form when ER membrane domains approach mitochondrial domains to less than 80 nm of distance if studded with ribosomes, or less than 30 nm if lacking ribosomes [26]. Under conditions of ER stress, MAMs become tighter [27]. The distance between the two organelles decreases by approximately 25%, while the length of a contact site that is normally 220 nm increases by approximately 60% [28]. Most notably, this increased coverage of mitochondria with ER membranes during ER stress significantly increases the availability of Ca2+ within mitochondria. As a consequence, ER stress will improve

the efficiency of mitochondrial dehydrogenases and, hence, ATP production [29]. Astonishingly, this function had been anticipated by Silvio and Anna Fiala in 1959, who observed that ER protein synthesis served as the switch that turns on mitochondrial activity in liver cells [30]. A question of ongoing research is how the MAM undergoes this plasticity and which proteins are connected to this function. Another role of the MAM is the promotion of apoptosis progression, as occurs upon very high levels of Ca2+ flux from the ER to mitochondria [31]. Such Ca2+ flux results in microdomains that are necessary for mitochondrial Ca2+ import by uniporters [23] to result in quasi-synaptic Ca2+ signal transmission between the ER and mitochondria [32]. Ca2+ overload within mitochondria is antagonized by the mitochondrial Na+ /Ca2+ exchanger (NCLX), which extrudes excess Ca2+ from the mitochondrial matrix [33]. ER-mitochondria tethering is currently best understood in yeast, where the ER-mitochondria encounter structure (ERMES) links the two organelles [34]. However, of the members of this protein complex, only two ERMES-regulatory proteins (Gem1p and Lam6p) are conserved in mammalian cells [35,36]. In that latter system, phosphoacidic cluster sorting protein 2 (PACS-2, [37]) and mitofusin-2 [38] have been identified as tethering determinants. More recently, tethering complexes mediated by the outer mitochondrial membrane proteins PTPIP51 and SYNJ2BP have been described. These interact with the ER-localized vesicle-associated membrane protein- associated protein B (VAPB) [39] or ribosome binding protein 1 (RRBP1) [40], respectively. Another protein implicated in ER-mitochondria tethering is FATE1, a bridging factor that establishes longer distance ER-mitochondria contacts [41]. Moreover, protein kinase RNA-like endoplasmic reticulum kinase (PERK), a sensor protein of the unfolded protein response (UPR) also localizes to the MAM and boosts ER-mitochondria tethering [42], allowing for normal apoptosis progression [43] while associated with mitofusin-2 [44]. We have recently reviewed this topic in the context of cancer (Herrera-Cruz et al., in press). Upon interference with ER-mitochondria tethering, ER stress results, highlighting the intimate relationship between ER oxidative folding and the ERmitochondria contacts [37,38]. 3. ER oxidative protein folding 101 To understand their roles in MAM signaling, we will next discuss the roles of ER chaperones and folding assistants in their classic realm, ER oxidative protein folding. When performing their folding activities, ER folding assistants localize to the proximity of ribosomes, where secretory proteins enter the ER upon their recognition of a signal peptide by the signal recognition particle (SRP) and their subsequent import into the ER through the translocon pore [45]. This complex assembly of proteins comes together upon binding of the signal sequence to the SRP, which precedes the association of the ribosome with the translocon [46]. On the ER luminal side, chaperones immediately recognize the polypeptide that is about to be inserted into the ER lumen (Table 1). The immunoglobulin binding protein (BiP/Grp78) is typically the first chaperone interacting with imported polypeptides [47]. As its name suggests, this chaperone had originally been identified as a major protein binding to nascent immunoglobulins [48]. When interacting with its client proteins, BiP/Grp78 interacts with disordered, hydrophobic patches [49]. Its chaperone activity

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Fig. 1. Multiple ER chaperones and folding assistants localize to the mitochondria-associated membrane (MAM). Their localization could occur during homeostatic conditions (left) or stressed situations (right), resulting in Ca2+ crosstalk (left) or a Ca2+ one way street (right). Under conditions, when localization to the MAM is observed, members of this group of proteins determine ER-mitochondria Ca2+ flux by interaction with Ca2+ handling proteins or by determining ER Ca2+ content. Here, they determine mitochondrial ATP output via activating dehydrogenases of the TCA cycle (left) or promote/inhibit mitochondrial permeability transition and the release of pro-apoptotic proteins (right). Thus, some ER chaperones and folding assistants act to preserve homeostatic conditions (BiP/GRP78, SIGMAR1, TMX1) or to restore them (ERdj5, SEPN1). Others fine-tune mitochondrial energy production and the responsiveness to stress (calnexin) and inhibit (ERp44) or accelerate cell death if found on MAMs (Ero1␣). On the mitochondrial side, NCLX and MCU are critical to complete the Ca2+ cycle.

Table 1 A summary of the roles of ER chaperones and folding assistants on the MAM for the regulation of mitochondrial functions. Chaperone

Main interactors

Function

References

SIGMAR1

IP3R, BiP/GRP78

[103,110]

BiP/Grp78

IP3R, Sec61␣, SIGMAR1

ERp44

IP3R, Ero1␣

Ero1␣

IP3R, ERp44

Calnexin

SERCA

TMX1

SERCA

SEPN1 ERdj5

SERCA SERCA

Interacts with BiP/Grp78 under resting conditions. Interacts with IP3R and promotes ER-mitochondria Ca2+ flux and mitochondrial metabolism. Activates and stabilizes IP3R tetramers. Promotes ER-mitochondria Ca2+ flux and mitochondrial metabolism under homeostatic conditions. The interaction with IP3R is lost during stress. Blocks Ca2+ leak through the translocon. This inhibition is lost during stress. Inhibits IP3R mediated Ca2+ release preventing apoptosis. Competes with BiP/Grp78 and Ero1␣ for IP3R binding. The interaction with IP3R increases during stress. Promotes IP3R mediated Ca2+ release and transfer to the mitochondria facilitating apoptosis. Interferes with the binding of ERp44 with IP3R. Activates SERCA and prevents Ca2+ flux to the mitochondria during homeostatic conditions. Allows the MAM to increase Ca2+ transfer to the mitochondria during stress. Inhibits SERCA and promotes Ca2+ flux to the mitochondria, preserving mitochondrial metabolism. Activates SERCA and prevents oxidative stress. Activates SERCA during stress, preserving ER Ca2+ content and preventing mitochondrial dysfunction.

and subsequent release from client proteins requires the cyclical binding of ADP and ATP [50]. Specifically, upon ATP hydrolysis, BiP/Grp78 interacts strongly with its substrates and only releases

[117,53]

[118]

[141,142] [8,9]

[95] [144] [172]

them slowly, following exchange of ADP for ATP mediated by the nucleotide exchange factors BAP/Sil1 and Grp170 [51]. In contrast, ER-localized J proteins (ERdj) act as its co-chaperones and acti-

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vate the ATPase activity of BiP/Grp78 [52]. Due to this immediate activity, BiP/GRP78 is also the one most clearly identified as binding to the translocon, where it also functions to close this channel for ion flux [53] or to control retro-translocation of misfolded proteins [54]. Consistent with the spatial proximity of BiP/Grp78 to the translocon, one of the ERdj proteins (ERdj3/Sec63) is actually part of the translocon itself [55]. ER protein folding is a multi-step process and BiP/Grp78 as well as the Hsp90 chaperone Grp94 [56] are only involved in the first ones. Following the interaction with these chaperones, client proteins which are glycosylated interact with a set of lectin chaperones. Diglucosylated substrates interact with malectin at an early step of their maturation [57,58], but also in particular with aberrantly folded substrates [59]. Consistent with an early interaction, malectin appears to localize close to the translocon and interacts with ribophorin [60]. The ER luminal, soluble lectin calreticulin was originally discovered as a major Ca2+ -binding protein of the sarcoplasmic reticulum [61]. This property already suggests that this chaperone may have functions that go beyond just protein folding, some of which are the topic of this review. Following the trimming of the sugar structure of newly synthesized proteins, calreticulin, like its membrane-inserted counterpart calnexin, can bind mono-glucosylated folding substrates with the Glc1 Man9 GlcNAc2 intermediate form [62]. During the time of binding, these folding substrates attempt to achieve their fully folded state [63]. Mechanisms facilitated by calreticulin and calnexin include the deceleration of the folding process [64], the prevention of aggregation [65], as well as the retention of folding intermediates within close proximity of the translocon [66]. Interestingly, the calnexin interaction appears to precede the calreticulin interaction, suggesting calnexin is closer associated with the translocon [67]. The enrichment motif required for this localization has been identified as the palmitoylation of two membrane-proximal cysteines in calnexin [68]. The time when calnexin and calreticulin associate with their substrates also coincides with the engagement of folding enzymes of the oxidoreductase group, particularly ERp57 [69,70]. These comprise proteins related to thioredoxin, including protein disulfide isomerase (PDI) [71]. These oxidoreductases bridge the functions of chaperones with the formation of disulfide bonds, since they recognize folding substrates by their exposure of hydrophobic patches, not unlike BiP/Grp78 [72]. The enzymatic activity of oxidized PDI and ERp57 promotes the formation of disulfide bonds when these oxidoreductases interact with reduced substrates [73]. Under conditions when such bonds have been formed improperly, resulting in misfolded proteins, oxidoreductases can also act as reductases. Potentially, such a function could be performed preferentially by some oxidoreductases rather than others [74]. An additional refinement could result from substrate specificities. For instance, the membrane-bound oxidoreductase TMX1 appears to specifically mediate the folding of membrane proteins [75]. Similar to lectin chaperones, ERp57 specifically oxidizes glycosylated substrates, when associated with calnexin and calreticulin [76]. To restore their role in oxidative protein folding, the ER is equipped with an additional set of redox enzymes that interact with proteins of the PDI family. These enzymes serve to control and restore oxidoreductive potential for PDI and related folding assistants [73]. The first described of these is Ero1, discovered in yeast, where it is necessary and sufficient for disulfide bond formation by Pdi1p [77]. Ero1 generates an electron flow from newly imported polypeptides onto oxygen that includes the re-oxidation of PDI and results in the formation of hydrogen peroxide, using flavin adenine dinucleotide (FAD) bound to Ero1 as an intermediary [78]. Human cells express two isoforms of Ero1, called Ero1␣ and Ero1␤, that have distinct tissue expression patterns, as well as distinct responsiveness to oxidative stress [79,80]. Within the human

ER, peroxiredoxin 4 (PRDX4) assists Ero1 by accepting electrons from reduced PDI and handing them over to hydrogen peroxide, thus allowing the generation of two disulfide bonds with an end product of one water molecule [81–83]. While the knockout of the two mammalian Ero1 isoforms has only a mild phenotype, knockdown of PRDX4 interferes more drastically with disulfide bond formation [83]. These findings suggest a central role for hydrogen peroxide in the production of ER disulfide bonds, either as a byproduct from the Ero1 enzymatic activities as well as other sources, or as a substrate for their formation using PRDX4 [84]. Two additional peroxidases, glutathione peroxidases 7 and 8 (Gpx7, Gpx8) are able to recharge PDI, but also interact with Ero1 [85]. A peculiar case of an ER oxidoreductase is quiescin sulfhydryl oxidase (QSOX), which is a membrane-bound, thioredoxin domain-containing protein that uses an FAD-binding domain to achieve disulfide bond formation without the assistance of another enzyme [86,87]. QSOX can undergo proteolytic cleavage at some point along the secretory pathway and is therefore able to catalyze disulfide bond formation outside the cellular environment [88].

4. Chaperones distribute throughout the entire ER, where they may have functions unrelated to folding Consistent with their classic roles as chaperones and folding assistants, we would expect to find ER folding enzymes to predominantly reside close to the translocon and certainly preferentially within the rough ER (rER). However, most chaperones and folding enzymes spread out through the entire ER [89]. Currently, it is unclear for most enzymes whether they fulfill folding functions throughout these extensive locations. Potentially, moieties far from translocons could serve as a reservoir that the ER can tap into upon ER stress. Alternatively, and in our opinion more likely, chaperones and folding assistants found in other locations throughout the ER could make use of their ability to detect misfolded proteins to potentially perform other tasks. Calreticulin and BiP/Grp78 are prominent examples of ER chaperones with multiple functions that could rely on moieties far from translocons [90,91]. Such secondary functions are summarized under the term “moonlighting”, the acquisition of modified or completely new functions by proteins [92,93]. In the case of the ER, such functions are poorly explored, one example being the cytosolic phosphofurin acidic cluster sorting protein 2 (PACS-2) that mediates localization of calnexin to specific domains of the ER [94]. Interestingly and not consistent with a unique function in protein folding, some ER chaperones and folding assistants are enriched in the proximity of mitochondria on MAMs, a localization that is relevant for the topic of this review. It is important to distinguish between “enrichment” and mere presence of ER chaperones and folding assistants on the MAMs [95]. For example, the chaperone calnexin is enriched on the MAMs under homeostatic conditions, but tends to be excluded from them, when cells undergo ER stress [96,97]. Other examples are PDI or calreticulin, which are abundant throughout the ER [98,99], or ERp44, which has a subpopulation found on the MAM [98]. Yet others are excluded from MAMs. An outstanding question is whether the MAM domains housing ER chaperones are of the rough or smooth type. Historically, the MAM had been described as part of the smooth ER (sER), under the control of cytosolic Ca2+ availability [100,101]. Given the role played by the MAM in lipid and Ca2+ flux, two functions historically ascribed to the sER, this apparently made sense. However, recent discoveries have demonstrated that the MAM consists of two populations, a sER and a rER version that exhibit distinct and characteristic proximity to mitochondria [25,102]. These findings raise the possibility in the context of this review that ER chaperones

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and folding assistants may localize to the proximity of mitochondria whether associated with the translocon or not. Our review will list what is known for MAM-localized ER chaperones and folding assistants and their role in mitochondrial Ca2+ flux determining ATP production and apoptosis. We will first focus on chaperones and folding assistants interacting with IP3 Rs and then on proteins of this group interacting with SERCA. 5. Examples of MAM chaperones and folding assistants that regulte ER-mitochondria Ca2+ flux 5.1. SIGMAR1: a paradigm for chaperone-mediated regulation of MAM signaling Following the discovery of MAM-localized chaperones and folding assistants, the question immediately arose, as to what function they may perform there. One set of clues was provided by the analysis of proteins they interact with on this location. For instance, BiP/Grp78 interacts here with the sigma-1 receptor (SIGMAR1) [103], a chaperone for inositol 1,4,5-trisphosphate receptors (IP3 Rs) [104]. This interaction serves in more than one way as a paradigm for potential MAM-associated ER chaperone functions and how these are achieved. SIGMAR1 localizes to ER lipid rafts enriched in cholesterol [105,106]. The SIGMAR1-BiP/Grp78 interaction decreases upon ER stress caused by Ca2+ depletion, and subsequently boosts Ca2+ flux from the ER to mitochondria through IP3 Rs, following the shift of SIGMAR1 from BiP/Grp78 to IP3 R3 [103]. While not resulting in differences in cytosolic Ca2+ availability, this ensuing Ca2+ flux has two important physiological functions at mitochondria: it activates the Krebs cycle through activation of five dehydrogenases, which require Ca2+ [29], but also promotes apoptosis through disruption of the mitochondrial membrane potential [107–109]. Using a splice variant that results in a truncated SIGMAR1 unable to interact with IP3 Rs, the significance of SIGMAR1 for this Ca2+ flux was elucidated: while the interacting variant augments ER-mitochondria Ca2+ flux and activates the Krebs cycle, concomitant with increased ATP production, the splice variant cannot promote mitochondrial ATP production, but rather exacerbates apoptotic signalling upon ER stress [110]. We use the SIGMAR1 example for a list of requirements that chaperones and folding assistants must fulfill to play a role in Ca2+ flux between the ER and mitochondria (completely or in part): i. Localization or enrichment on the MAM, potentially dependent on ER stress (i.e., enrichment on or depletion from the MAM upon ER stress); ii. Interaction with the ER Ca2+ handling machinery (e.g., IP3 Rs, or Ca2+ pumps of the sarco/endoplasmic reticulum Ca2+ ATPase/SERCA group). iii. Significance of the chaperone or folding assistant for apoptosis or mitochondrial metabolism. While most chaperones show at least a moiety on the MAM, some chaperones are enriched there under some conditions, including the transmembrane chaperones and folding assistants calnexin and TMX1 [96,97]. However, enrichment is not a condition to play a role in MAM Ca2+ signalling, as shown in the protein-specific chapters below and as exemplified by the oxidoreductase ERp44, which is typically present on the MAM in relatively small amounts [98]. 5.2. BiP/Grp78 The activity of the chaperone BiP/Grp78 is connected to cellular Ca2+ homeostasis in several ways and makes some of the most important links between ER protein folding and ER-mitochondria Ca2+ flux. BiP/Grp78 itself can bind Ca2+ , albeit at relatively low stoichiometry of 1–2 mol of calcium/mole of BiP/Grp78 [111]. As a consequence, BiP/Grp78 over-expression increases the Ca2+ -pool that is available for transfer to mitochondria. This effect could be

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particularly relevant during the induction of ER stress that results in significant increases of BiP/Grp78 [112–114]. However, while ER stress is known to result in increased ER-mitochondria Ca2+ -flux [115], the induction of BiP/Grp78 might initially mostly mitigate this flux, since it reduces ER stress via improved protein folding at the same time [116]. In addition to its role to determine ER Ca2+ storage capacity and its interaction with SIGMAR1 described above, BiP/Grp78 also directly regulates IP3 Rs. The interaction of this chaperone with the luminal domains of IP3 R1 promotes its tetrameric assembly and, hence, allows this channel to become active [117]. Specifically, BiP/Grp78 requires its ATPase activity to interact with the L3 V region, a luminal loop between the transmembrane regions 5 and 6 that provides a subtype specific regulation of the IP3 R activity [118]. As has been published for a variety of substrates, the interaction of BiP/Grp78 with the IP3 R1 is under the control of ER stress. Under homeostatic conditions, BiP/Grp78 binds to the IP3 R1 L3 V region, but during ER stress the interaction between BiP/Grp78 and IP3 R1 was lost [118]. The maintenance of the interaction and ER-mitochondria Ca2+ flux acts mostly as pro-survival, since reduced Ca2+ release via IP3 R1 when BiP/Grp78 is not bound to IP3 R1 increases cell death during ER stress. This suggests that the BiP/Grp78-regulated activities of IP3R1 might be particularly relevant for the maintenance of mitochondrial dehydrogenase activity and oxidative phosphorylation in some cell types under homeostatic conditions, including brain tissue of a Huntington’s disease model [119,120], but not so much for the stressed situation. Accordingly, IP3 R1-mediated Ca2+ -transfer to mitochondria acts primarily to protect from injury and apoptosis in a cardiomyocyte model [121]. However, in glial cells [122] and astrocytes, the expression of BiP/Grp78 decreases IP3R activity presumably, thus reducing mitochondrial Ca2+ import, and resulting in a preservation of mitochondrial functions upon glucose deprivation [123]. Another study showed that BiP/Grp78 knockout in Purkinje neurons also acted to decrease the viability of these cells [124]. The synthesis of these findings suggests that BiP/Grp78 may influence IP3 R functions and ER-mitochondria Ca2+ -flux in a cell type-specific manner. Potentially, these discrepant findings are connected to the role of BiP/Grp78 in protein folding at the translocon. Here, this chaperone has an additional function by preventing the intrinsic Ca2+ leakage function of this ER channel: while the translocon is Ca2+ -permeable in a Sec61␣-dependent manner [53,125–127], this leakage increased in cells with reduced levels of BiP/Grp78, but not of other ER chaperones or folding assistants [128,129]. In this function, BiP/Grp78 interacts with Sec61␣ on the ER-exposed loop 7 [129], and potentially requires the activity of BiP/Grp78 co-chaperones, since the knockdown of the ER luminal BiP/Grp78 co-chaperones ERj3 and ERj6 also promotes leak via the translocon [130]. As expected, stimulators of the BiP/GRP78 ATPase activity also influence ER Ca2+ homeostasis: The BiP/Grp78 nucleotide exchange factor Grp170/ORP150 is upregulated during hypoxia [131], increasing resistance to apoptosis from a variety of triggers in a Ca2+ -dependent manner [132]. This function is perhaps especially important for neuronal survival [133]. Under conditions of accumulated misfolded proteins, the translocon-mediated leak increases, suggesting that BiP/Grp78 exerts its inhibitory effect on Ca2+ leak only when it is not participating in protein folding. This Ca2+ release pathway is apparently significant also when comparing to IP3 -mediated Ca2+ -release, since the pharmacological inhibition of leak through the translocon using anisomycin protects against thapsigargin-induced apoptosis [53]. Together, BiP/Grp78 emerges as a complex regulator of ER Ca2+ content and ER-mitochondria Ca2+ flux that determines mitochondria metabolism and apoptosis. The functions of BiP/GRP78 appear

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to control the ER-mitochondria interaction mostly during homeostatic conditions and serve to control the ER folding environment. 5.3. ERp44 The thioredoxin family protein ERp44 is a soluble protein that cycles between the ER and the Golgi complex to retrieve ER proteins with exposed reduced cysteines [134,135]. A fraction of ERp44 localizes to the MAM [98], where it interacts with IP3 R1 and competes with BiP/Grp78 for the same binding site on the L3V region of IP3 R1 [118]. Cells over-expressing ERp44 show reduced IP3 R1 Ca2+ -release, while the opposite occurs in cells with reduced levels of ERp44, indicating that ERp44 inhibits IP3 R1 activity [118]. This inhibitory activity requires three cysteine residues within L3V, but no covalent interaction with reactive cysteines of the ERp44 thioredoxin domain. Rather, a central region of this protein comprising residues 236–285 is necessary and sufficient for binding. Within this sequence, cysteine 241 is one of two cysteines that upon mutation to serine results in constitutive binding to IP3 R1, albeit also in a loss of IP3 R1 inhibition, suggesting non-covalent interaction is required for ERp44 to act as an IP3 R1 inhibitor [136]. Consistent with this hypothesis, the interaction between IP3 R1 and ERp44 was increased with lower luminal ER Ca2+ levels and reducing conditions that result in free thiol groups found within L3V [118]. In contrast to BiP/GRP78, ERp44 therefore acts as a Ca2+ regulator during stress conditions. The regulation of IP3 R1 by ERp44 is important for apoptosis. In cells that express exclusively IP3 R1 (DT40-KMN60), the overexpression of ERp44 reduced apoptosis induced by the release of Ca2+ via the IP3 R [118]. Similarly, ERp44-/- cardiomyocytes are more susceptible to apoptosis than wild type cells [137], similar to HeLa cells transfected with ERp44 RNAi [138]. Taken together, these results suggest that BiP/Grp78 and ERp44 act in concert to regulate IP3 R1. In homeostatic conditions BiP/Grp78 binds to IP3 R1 promoting the release of Ca2+ , likely to maintain mitochondrial dehydrogenase activities. During ER stress, BiP/Grp78 separates from IP3 R1 probably to participate in protein folding or binding to ER stress sensors [139,140], allowing ERp44 to bind IP3 R1. Since Ca2+ retention upon ER stress is only an initial response that is followed by Ca2+ release, once the UPR has morphed into an apoptotic response, it is likely that this interaction between ERp44 and IP3 R1 is also only of a temporary nature. 5.4. Ero1˛ Human Ero1␣ is another regulator of IP3 Rs. Such a role is not unexpected, since a major fraction of Ero1␣ localizes to the MAM in cells that are normoxic and whose ER is oxidizing [98,141]. At this location, Ero1␣ protein levels modulate ER-mitochondria Ca2+ flux by promoting IP3 R oxidation and IP3 R-mediated Ca2+ efflux from the ER [141]. In addition, Ero1␣ interferes with the inhibitory binding of ERp44 with IP3 R1. In terms of the regulation of cell survival, this function results in the activation of IP3 R-mediated Ca2+ release during ER stress and accelerates apoptosis onset in macrophages [142]. This role of Ero1␣ in Ca2+ homeostasis is also observed in loss-of-function cardiomyocytes, which show a twofold lower amplitude in cytosolic Ca2+ -transients, as well as in loss-of-function Ero1␣ mice, which are protected from heart failure [143]. This function of Ero1␣ could be tied to the hyperoxidation of luminal cysteines within SERCA, which compromise the activity of this pump [144]. Given the transcriptional induction of Ero1␣ by the pro-apoptotic C/EBP-homologous protein (CHOP) [145], it appears this oxidoreductase is part of an important pathway that triggers cell death upon extended ER stress, also evidenced by the activation of the pathway during acute liver failure [146]. Despite this strong evidence for a pro-death role, high expression of Ero1␣

is a poor prognostic indicator in cancer patients, potentially due to the upregulation of a hypoxic response [147], again highlighting that the context of chaperone and folding assistant expression may decide on whether their folding or their Ca2+ -related activities dominate.

5.5. Calnexin The lectin chaperone calnexin is distinct from most other ER chaperones and folding assistants by the presence of transmembrane and cytosolic domains [148]. These domains function to target calnexin to specific membrane domains of the ER [89]. As part of this function, the calnexin cytosolic tail contains three phosphorylation sites that together mediate its interaction with ribosomes and likely the translocon [149,150]. While phosphorylation of the most C-terminal serine 563 by extracellular-signal regulated kinase-1 (ERK-1) appears most important for this function, the other two phosphorylation sites at serines 534 and 544 mediate interaction of calnexin with PACS-2 when dephosphorylated [97]. Research from our laboratory [96] and others [103,151,152] has shown that large quantities of calnexin reside on the MAM, where it may serve as a docking site for MAM proteins [152]. This localization is mediated in part by PACS-2 [97]. Another mechanism to target calnexin to the MAM involves the palmitoylation of two membrane-proximal cytosolic cysteine residues [96]. However, the localization of calnexin to the MAM is neither exclusive, nor stable: under conditions of ER stress, MAM-localized calnexin moves to the rER, where it joins previously rER-localized calnexin and participates in protein folding [9]. Interestingly, calnexin association with the translocon can also depend on palmitoylation [68]. While this localization at first glance appears at odds with the role of palmitoylation in calnexin MAM targeting, this may not be the case, as the MAM is known to comprise rER and sER sections [25,26]. Stress influences both phosphorylation and palmitoylation: while this condition promotes the loss of calnexin phosphorylation and, thus, results in the association calnexin with PACS-2, it also leads to a loss of palmitoylation, which redistributes calnexin to the mitochondria-distal rER [9,97]. Before this localization of calnexin to the MAM had been discovered, the Camacho lab had already described the interaction of calnexin with the SERCA Ca2+ pump, which results in an inhibition of ER Ca2+ signaling following the energization of mitochondria with pyruvate [8]. Extending these findings, two independent approaches show that calnexin knockout and knockdown cells have reduced ER Ca2+ uptake rates, suggesting calnexin acts to activate SERCA if localized to the proximity of mitochondria [9,153]. This different Ca2+ handling of calnexin knockout cells increases their ER-mitochondria Ca2+ -flux that cannot be further increased upon ER stress [9], and induces caspase activation in cardiomyocytes [153]. Moreover, while calnexin over-expression does not significantly alter apoptosis onset [154], reduced calnexin expression leads to increased susceptibility to ER stress inducers, such as tunicamycin or DTT [155]. Remarkably, however, calnexin knockout cells are resistant to thapsigargin-mediated apoptosis [156]. This behavior is in our opinion consistent with a decreased SERCA activity of calnexin knockout cells [9], since their decreased ER Ca2+ levels would then not allow thapsigargin to significantly raise cytosolic Ca2+ needed to trigger mitochondrial permeability transition [9]. Calnexin knockout animals do not show obvious changes in most tissues, but a dysmyelination in the brain and spinal cord, resulting in reduced motor nerve conduction [157] and ataxia [158]. It is currently unclear whether this phenotype is tied to calnexin’s role in ER protein folding or ER-mitochondria Ca2+ signaling. Overall, calnexin therefore uses its localization at the MAM to reduce ER-mitochondria Ca2+ flux under homeostatic conditions.

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In contrast, the removal of calnexin from the MAM during stress conditions increases ER-mitochondria Ca2+ flux.

5.6. TMX1 Like calnexin, TMX1 spans the ER membrane, is enriched on the MAM and exposes a large domain containing phosphorylation and palmitoylation motifs to the cytosol [96]. This thioredoxin-domain containing protein had originally been described as a reductase of the ER that can protect from Brefeldin A-induced apoptosis [159]. Subsequently, it was shown that TMX1 can assist with the refolding of scrambled RNAse and thus acts as an oxidase [160] that can retain misfolded MHC class I variants [161]. Any folding role of TMX1 appears to be focused on transmembrane ER substrates [75]. In addition to these classic functions in protein folding, TMX1 also interacts with SERCA2b under oxidizing conditions as a protein that can bind this Ca2+ pump alternatively to calnexin [95]. Upon binding of SERCA2b, TMX1 acts to decrease the activity of SERCA2b, and at the same time increases Ca2+ flux from the ER to mitochondria. Therefore, TMX1 opposes calnexin during homeostatic conditions. Cells that express lower levels of TMX1 have a reduced mitochondrial metabolism, and, in consequence, are protected from mitochondrial poisoning. In a cancer context, these functions are reflected in increased growth of tumor cells with low levels of TMX1 in a xenograft assay, consistent their resistance to mitochondrial poisoning with rotenone and antimycin [95]. Mice lacking TMX1 expression showed no obvious phenotype, but were more susceptible to liver injury upon lipopolysaccharide-triggered inflammation and oxidative stress with thioacetamide [162]. It is possible that these observations are tied to increased levels of ROS upon TMX1 interference observed both in the tumor and liver context.

5.7. SEPN1 Selenoprotein N1 (SEPN1) is a ubiquitous ER transmembrane glycoprotein with a luminal cysteine-selenocysteine active site motif [163], whose N-terminus is exposed to the cytoplasm [164]. SEPN1 physically interacts with SERCA2b and activates this Ca2+ pump, thus opposing the oxidizing function of TMX1, but paralleling the activity of calnexin [10]. In this model, SEPN1 reduces regulatory cysteines within the luminal portion of SERCA back to their active form. Thus, SEPN1 counteracts activities of Ero1␣, which can lead to excessive ROS production that result in the inactivation and hyperoxidation of SERCA [144]. The physiological readout of calnexin and SEPN1 is very different: While calnexin slows ER-mitochondria communication, SEPN1 accelerates cellular NADPH metabolism [144]. As a consequence, SEPN1 loss of function is at the basis of rigid spine muscular dystrophy (RSMD) and SEPN1related myopathy [165]. In these two diseases, increased oxidative stress and reduced [Ca2+ ] [166] within the ER lead to muscle defects and are associated with inactive SERCA. These findings could suggest that SEPN1 preferentially interacts with SERCA to resolve stress situations. Interestingly, in the context of this review, these defects are also associated with localized loss of mitochondria within muscle [167,168]. At this point, it is unclear, whether this pathological change stems from the increased oxidative stress and an induction of mitophagy. Together, the functions of calnexin, TMX1 and SEPN1 suggest that inactive SERCA leads to reduced Ca2+ content within the ER, which can abnormally increase the transfer of this ion to mitochondria, leading to unwanted loss of mitochondrial membrane potential, clearance of these dysfunctional mitochondria and potentially increased apoptosis susceptibility.

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5.8. ERdj5 The ER-resident, DNAJ-domain-containing protein ERdj5 is a hybrid folding assistant, based on its protein sequence encompassing a BiP/Grp78-binding DNAJ domain and four thioredoxin domains [169]. ERdj5 acts as a reductase within the ER to mediate dislocation of its substrates via the translocon to the cytosol-localized proteasome and thus promotes ER-associated degradation (ERAD) [170]. Depending on the substrate, ERdj5 can, however, also act to promote folding by reducing non-native disulfide bonds [171]. On SERCA2b, ERdj5 also acts as a reductase and reduces two luminal cysteines. These two modifications lead to the activation of SERCA2b, similar to what is known about SEPN1 [172]. ERdj5 therefore also opposes the function of TMX1, but should act in parallel to calnexin. This activating role of ERdj5 occurs particularly when the ER Ca2+ content is low, in other words, when the ER is stressed. This behavior is different from the interactions of TMX1 and calnexin that occur when the ER is oxidizing, but potentially analogous to the SEPN1-SERCA interaction. Although it is currently not known how ERdj5 influences ER-mitochondria Ca2+ -flux, C. elegans ERdj5 over-expression protects from mitochondrial dysfunction from the incubation with a variety of toxins, as measured by mitochondrial fragmentation assays [173]. However, when using ER stressors, ERdj5 was able to promote apoptosis [174], suggesting that similar to TMX1, the subcellular origin of the apoptosis trigger might determine whether ERdj5 predominantly protects mitochondria from excessive Ca2+ influx, or whether it abnormally alters the redox conditions of the ER folding environment and ROS abundance. 5.9. Other chaperones and folding assistants mediating ER-mitochondria Ca2+ flux In addition to the aforementioned chaperones and folding assistants that interact as a secondary function with ER Ca2+ -handling proteins, some lesser known connections between these protein groups exist. For instance, the PDI family member ERp16 is able to potently accelerate apoptosis induced by ER stress, but its only characterized function is the catalysis of disulfide isomerization within the ER [175]. A special case is the PDI family member P5 that has been suspected to localize in part to mitochondria, but could perhaps localize to the MAM [176]. It is currently not clear whether P5 can influence Ca2+ signaling from its location on the ER. Likewise, while Grp94 is known as a high affinity Ca2+ -binding protein [177] and its inhibition leads to Ca2+ -mediated apoptosis [178], no mechanistic role in ER-mitochondria Ca2+ flux is currently known for this chaperone. Another example is the lectin chaperone calreticulin, a known Ca2+ storage protein [179]. Upon its over-expression, the ER Ca2+ content increases, and consistent with the examples of calnexin, TMX1 and SEPN1 that also modulate ER Ca2+ content, this results in reduced Ca2+ -flux to mitochondria [180]. This effect is accompanied by reduced cytosolic Ca2+ -oscillations and binding of calreticulin to SERCA [181]. In consequence, such cells with high levels of calreticulin are more susceptible for apoptosis [154]. Similarly, ERp57 also interacts with SERCA and inhibits cytosolic Ca2+ waves [182]. Presumably, this is accompanied by the inactivation of SERCA. However, ERp57 also inhibits store-operated Ca2+ entry (SOCE) and, thus, could lower ER Ca2+ content by other means [183]. The synthesis of both functions results in a reduction of mitochondrial Ca2+ uptake in cells with low levels of ERp57 (that should have higher ER Ca2+ content), but also due to the reduction of mitochondrial Ca2+ uniporter (MCU) expression in these cells [184]. These findings raise another issue with studies on ER chaperones and folding assistants as regulators of ER-mitochondria Ca2+ flux: the final readout of their functions at mitochondria is determined by the whole

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gamut of SOCE, Ca2+ release and uptake at the ER, as well as mitochondrial Ca2+ uptake and release, even though the latter may only indirectly be influenced by ER proteins. Glutathione peroxidase 8 (GPX8) is one of the enzymes that controls ER ROS output by clearing ROS generated from Ero1␣’s enzymatic reactions [187]. GPX8 has recently been identified as MAM-enriched and acts to reduce ER Ca2+ levels and release, concomitant with a reduced activity of SERCA2b, but increases Ca2+ leakage from the ER [188]. It is not known at this point, whether these activities of GPX8 are somehow connected to Ero1␣· Moreover, in many cases, it is currently not known whether there exists an actual connection between ER folding assistants and chaperones and any Ca2+ -handling proteins at the MAM or Ca2+ flux between the ER and mitochondria or whether the role of these proteins is restricted to the maintenance of ER redox and folding conditions. Given that ER folding conditions affect ER-mitochondria apposition [27,28], as well as ROS output from this organelle [185] that may freely penetrate ER membranes [186], these are not trivial concerns.

6. Conclusion In the early stages of research into the flux of Ca2+ ions between the ER and mitochondria, discoveries about ER chaperones and folding assistants being enriched on the MAM appeared paradoxical, given their supposedly exclusive role in ER oxidative protein folding. In the meantime, such roles are well-accepted examples of protein moonlighting and MAM enrichment of ER chaperones and folding assistants appears to be the rule, rather than the exception. This important functional connection is based on the tight connections between ER protein folding and mitochondrial functions, as proposed by us a couple of years ago [7]. There are two important caveats to these generalized observations, however: i. While most members of this protein group are found on the MAM, not all ER chaperones and folding assistants are enriched on the MAM. Examples for proteins not enriched on the MAM are, in our hands, calreticulin, ERp44, ERp57 and PDI [96,98]. ii. MAM enrichment of chaperones may change during time. The classic example of this behavior is calnexin, which is found in larger amounts on the MAM in proliferating cells, but not is cells undergoing ER stress, where the MAM appears devoid of calnexin [9]. Other examples are ERdj5 and potentially SEPN1, which interact with the Ca2+ handling machinery under conditions of ER stress. iii. While it may be possible to clearly define a functional readout of ER chaperones and folding assistants for ER-mitochondria Ca2+ flux, the delineation of this readout for mitochondrial functions may be less clear. While sometimes, increased ER-mitochondria Ca2+ flux appears to exclusively promote pro-death functions of mitochondria, in other examples, it may mostly serve to promote mitochondrial metabolism. We suspect these differences arise from different contexts, such as different baseline levels of ROS, different amounts of ER stress, different needs of mitochondrial ATP and different susceptibility for mitochondrial permeability transition. Another complication could be that ER chaperones and folding assistants may influence more than one ER Ca2+ handling mechanism, for instance by determining SOCE, ER Ca2+ storage, ER Ca2+ pumping or Ca2+ release at the same time or depending on cellular homeostasis or potentially in a cell type-specific manner. We suspect that in some cases, such overlapping functions may preclude successful pharmacological targeting of ER chaperones and folding assistants, since such intervention could lead to unpredictable results. On the flip side, the exciting connections between SEPN1 and ER-mitochondria Ca2+ flux and muscular dystrophy/myopathy might just foreshadow other, yet unknown, disease-relevant con-

nections between ER protein folding and ER-mitochondria Ca2+ flux. Funding Research in the Simmen lab on the topic at hand was funded by NSERC grant RGPIN-2015-04105. Acknowledgment We thank Carolina Ortiz-Sandoval for proof-reading of this manuscript. References [1] M. Wang, R.J. Kaufman, Protein misfolding in the endoplasmic reticulum as a conduit to human disease, Nature 529 (7586) (2016) 326–335. [2] I. Braakman, D.N. Hebert, Protein folding in the endoplasmic reticulum, Cold Spring Harb. Perspect. Biol. 5 (5) (2013), p. a013201. [3] L. Ellgaard, N. McCaul, A. Chatsisvili, I. Braakman, Co- and post-Translational protein folding in the ER, Traffic 17 (6) (2016) 615–638. [4] S. Guth, C. Volzing, A. Muller, M. Jung, R. Zimmermann, Protein transport into canine pancreatic microsomes: a quantitative approach, Eur. J. Biochem. 271 (15) (2004) 3200–3207. [5] M.J. Gething, Role and regulation of the ER chaperone BiP, Semin. Cell Dev. Biol. 10 (5) (1999) 465–472. [6] L. Halperin, J. Jung, M. Michalak, The many functions of the endoplasmic reticulum chaperones and folding enzymes, IUBMB Life 66 (5) (2014) 318–326. [7] T. Simmen, E.M. Lynes, K. Gesson, G. Thomas, Oxidative protein folding in the endoplasmic reticulum: tight links to the mitochondria-associated membrane (MAM), Biochim. Biophys. Acta 1798 (8) (2010) 1465–1473. [8] H.L. Roderick, J.D. Lechleiter, P. Camacho, Cytosolic phosphorylation of calnexin controls intracellular Ca(2+) oscillations via an interaction with SERCA2b, J. Cell Biol. 149 (6) (2000) 1235–1248. [9] E.M. Lynes, A. Raturi, M. Shenkman, C. Ortiz Sandoval, M.C. Yap, J. Wu, A. Janowicz, N. Myhill, M.D. Benson, R.E. Campbell, L.G. Berthiaume, G.Z. Lederkremer, T. Simmen, Palmitoylation is the switch that assigns calnexin to quality control or ER Ca2+ signaling, J. Cell Sci. 126 (Pt 17) (2013) 3893–3903. [10] C. Appenzeller-Herzog, T. Simmen, ER-luminal thiol/selenol-mediated regulation of Ca2+ signalling, Biochem. Soc. Trans. 44 (2) (2016) 452–459. [11] J.E. Vance, MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond, Biochim. Biophys. Acta 1841 (4) (2014) 595–609. [12] A. Raturi, T. Simmen, Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM), Biochim. Biophys. Acta 1833 (1) (2013) 213–224. [13] W. Bernhard, F. Haguenau, A. Gautier, C. Oberling, Submicroscopical structure of cytoplasmic basophils in the liver: pancreas and salivary gland; study of ultrafine slices by electron microscope, Z Zellforsch Mikrosk Anat 37 (3) (1952) 281–300. [14] W. Bernhard, C. Rouiller, Close topographical relationship between mitochondria and ergastoplasm of liver cells in a definite phase of cellular activity, J. Biophys. Biochem. Cytol. 2 (Suppl. 4) (1956) 73–78. [15] D.W. Fawcett, Observations on the cytology and electron microscopy of hepatic cells, J Natl Cancer Inst 15 (Suppl. 5) (1955) 1475–1503. [16] E.D. Hay, The fine structure of blastema cells and differentiating cartilage cells in regenerating limbs of Amblystoma larvae, J. Biophys. Biochem. Cytol. 4 (5) (1958) 583–591. [17] J.E. Vance, Phospholipid synthesis in a membrane fraction associated with mitochondria, J. Biol. Chem. 265 (13) (1990) 7248–7256. [18] J.E. Vance, Newly made phosphatidylserine and phosphatidylethanolamine are preferentially translocated between rat liver mitochondria and endoplasmic reticulum, J. Biol. Chem. 266 (1) (1991) 89–97. [19] K. Kuchler, G. Daum, F. Paltauf, Subcellular and submitochondrial localization of phospholipid-synthesizing enzymes in Saccharomyces cerevisiae, J. Bacteriol. 165 (3) (1986) 901–910. [20] E. Gnamusch, C. Kalaus, C. Hrastnik, F. Paltauf, G. Daum, Transport of phospholipids between subcellular membranes of wild-type yeast cells and of the phosphatidylinositol transfer protein-deficient strain Saccharomyces cerevisiae sec 14, Biochim. Biophys. Acta 1111 (1) (1992) 120–126. [21] T.J. Biden, C.B. Wollheim, W. Schlegel, Inositol 1,4,5-trisphosphate and intracellular Ca2+ homeostasis in clonal pituitary cells (GH3). Translocation of Ca2+ into mitochondria from a functionally discrete portion of the nonmitochondrial store, J. Biol. Chem. 261 (16) (1986) 7223–7229. [22] G.L. Becker, G. Fiskum, A.L. Lehninger, Regulation of free Ca2+ by liver mitochondria and endoplasmic reticulum, J. Biol. Chem. 255 (19) (1980) 9009–9012. [23] R. Rizzuto, M. Brini, M. Murgia, T. Pozzan, Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria, Science 262 (5134) (1993) 744–747.

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