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Membrane contact sites
BBA - Molecular Cell Research 1864 (2017) 1435–1438
Contents lists available at ScienceDirect
BBA - Molecular Cell Research journal homepage: www.elsevier.com/locate/bbamcr
Editorial
Membrane contact sites
MARK
Compartmentalization is the hallmark of eukaryotic cells. The importance of segregating the many metabolic activities into dedicated organelles has been recognized long ago. The term organelle was coined as an analogy to these miniature versions of body organs [1]. It was soon also recognized, that, akin to body organs, which are not positioned randomly in the body, organelles are distributed in a stereotypical manner in the cell. The nucleus is usually centrally located; beside it, very often lies the microtubule-organizing center, home of various other organelles such as the Golgi apparatus. The endoplasmic reticulum (ER) and the mitochondria often extend as large networks throughout the cell. With the advent of electron microscopy, a novel feature in cellular organization became evident. Organelles often like to associate with each other [2]. The ER membrane is often observed “touching” other membranes, such as the mitochondrial outer membrane or the plasma membrane. These contacts appear as regions where both membranes come to close proximity, and, though not fusing, remain associated at distances of tens of nanometers over extended surfaces. These membrane contact sites appear typically more frequently than expected by mere chance. These observations remained, however, phenomenological and no functional role could be assigned to these membrane contact sites for a very long time. The community therefore continued to see organelles as independent entities. At the same time, the discovery of intracellular trafficking clarified how proteins synthesized in the ER were routed to secretion via the Golgi apparatus, using small vesicles as vessels. This discovery killed two birds with one stone; since lipid molecules constitute the shell of vesicles, a necessary byproduct of protein trafficking is lipid trafficking, explaining how lipids, in majority synthesized in the ER, managed to reach distant cellular membranes, like plasma, Golgi or lysosomal membranes, despite their hydrophobic nature. The problem of lipid trafficking thus appeared solved for most organelles that are part of the endomembrane system. The story was quite different though for mitochondria. Mitochondria have two membranes, do not synthesize most of the lipids that constitute them, and even for those lipids that they synthesize, mitochondria heavily rely on lipid precursors synthesized elsewhere. Importantly, one crucial lipid biosynthesis pathway, the de novo synthesis of phosphatidylcholine (PC) – one of the most abundant phospholipids in eukaryotic membranes, goes from the ER to mitochondria and back [3]. A robust lipid exchange route between both organelles is therefore necessary. Yet, mitochondria are not part of the endomembrane system and do not exchange lipids with the ER via vesicular trafficking. 1. Connecting mitochondria to the endomembrane system ER-mitochondria contact sites became prime suspects in that exchange pathway, not thanks to microscopy, but to subcellular fractionation. The purification of mitochondria involves several steps of centrifugation. After cell lysis and removal of debris and nuclei, a series of velocity centrifugation steps sediment mitochondria, while leaving most other membranes in the supernatant. The “crude” mitochondrial fractions obtained this way are heavily contaminated with other membranes. A subsequent isodensity centrifugation step is necessary to obtain pure mitochondria. This step also allows collecting and characterizing the contaminating membranes [4]. These “mitochondria-associated membranes” look like ER membranes, but do not exactly behave as such. They are notably enriched in phosphatidylserine (PS) synthase activity. Since PS is the very lipid that needs to be shuttled to mitochondria in the de novo PC biosynthesis pathway, it was assumed that PS is synthesized in a subdomain of the ER attached to mitochondria to allow its rapid shuttling into this latter organelle [5]. These observations led to the first possible role of ER-mitochondria coupling; factors tethering the two compartments might facilitate lipid exchange between membranes. The idea of non-vesicular lipid trafficking between isolated membranes also affected our view of lipid exchange within the endomembrane system. After all, if vesicles clearly transport lipids, what is their actual contribution to total lipid exchange? Interestingly, a drug-mediated block of anterograde vesicular trafficking has no measurable effect on the delivery of PS, synthesized in the ER, to the cell surface [6], indicating that a significant fractions of lipids indeed reach the plasma membrane without help from the vesicular transport system. Recent years have seen the discovery of factors that are able to transfer lipids from one membrane to another. Many of these can be found at membrane contact sites, and while their actual contribution to total lipid transport is still to be defined, this shows that the original idea of nonvesicular lipid transport at contact sites was remarkably accurate [7]. 2. Microcompartmentalization of Ca2+ transfer – an example of contact site function Lipid exchange is not, by far, the sole function of inter-organelle contacts. Ion concentrations vary widely between different compartments, and contact between these compartments define privileged routes for ion exchange. A very important ion is Calcium (Ca2+). Ca2+, found in millimolar http://dx.doi.org/10.1016/j.bbamcr.2017.06.014
Available online 23 June 2017 0167-4889/ © 2017 Elsevier B.V. All rights reserved.
BBA - Molecular Cell Research 1864 (2017) 1435–1438
Editorial
concentrations in the extracellular medium, is maintained at nanomolar concentrations in the cytosol. The lumen of endomembrane organelles contains Ca2+ in the hundreds of micromolar range. Large burst of Ca2+ frequently inundate the cytosol consequent to the opening of Ca2+ channels in the plasma or ER membranes, leading to the activation of a myriad of signaling events. The role of membrane contact sites in Ca2+ signaling originally stems from the study of the paradoxical role of mitochondria in Ca2+ homeostasis. Purified mitochondria bathed in a Ca2+-containing solution import Ca2+ into their matrix, thanks to the electrophoretic force resulting from the electrochemical gradient across the inner mitochondrial membrane. Thus, energized mitochondria behave as efficient Ca2+ “sponges” [8]. Yet, mitochondria import Ca2+ only once it has reached a sufficient concentration. The machinery responsible for this import is a high-capacity, but low affinity Ca2+ uniporter, whose molecular identity has only been discovered recently [9,10]. The paradox is that the concentrations necessary to activate the uniporter are far above those you would normally find in the cytosol of a healthy cell. Thus, the activation of the mitochondrial Ca2+ uniporter was long considered as a last-resort buffering mechanism for cells in which the cytosol was poisoned by close-to-lethal concentrations of Ca2+ [11]. This view changed abruptly with a technical breakthrough in intracellular Ca2+ measurements. While Ca2+ concentrations were classically measured with Ca2+-sensitive chemical dyes, which permeated the cell but did not target defined compartments, the advent of genetically-encoded protein-based Ca2+ biosensors allowed to precisely target defined organelles by fusing targeting motifs. The jellyfish Aequorea Victoria is well-known for being the source of the green fluorescent protein (GFP) [12]. It is, however, less commonly appreciated that, since Aequorea Victoria lives far from a blue light source, it also produces a bioluminescent photoprotein, called aequorin [13]. This luciferase-like protein uses a cofactor called coelenterazine, and most importantly Ca2+, to emit blue photons, which in turn, excite GFP by resonance energy transfer. Aequorin fused to a mitochondrial matrix targeting sequence efficiently targets mitochondria in live cells, and, upon addition of coelenterazine in the culture medium, can serve as a mitochondrial Ca2+ monitoring device. Surprisingly, triggering ER-Ca2+ release with physiological stimuli leads to a transient elevation of mitochondrial Ca2+ [14]. Thus, the mitochondrial calcium uniporter can be triggered without cells sustaining a near-death experience, in conditions in which the general cytosolic Ca2+ concentration is theoretically not sufficient, based on the in vitro experiments. This paradox can be explained if cytosolic Ca2+ concentrations are not homogeneous throughout the cell. In particular, Ca2+ concentration is highest at the cytosolic face of ER-Ca2+ channels. If the ER-membrane is closely apposed on the mitochondrial membrane, the mitochondrial Ca2+ uniporter might experience a much higher Ca2+ concentration than the rest of the cytosol. Thus, organelle proximity might leverage heterogeneities in the cytosol to route Ca2+ fluxes in the desired direction. Membrane contact sites can also be more directly involved in Ca2+ signaling. This is particularly true for ER-plasma membrane contact sites, and the story starts again with a paradox. The ER needs to maintain a Ca2+ concentration that is five orders of magnitude higher than that of the cytosol. This is achieved via the Sarco/Endoplasmic Reticulum Ca2+ (SERCA) pumps, which pump cytosolic Ca2+ into the ER lumen. Yet, SERCA pumps compete for cytosolic Ca2+ with Plasma Membrane Ca2+ (PMCA) pumps, which pump it out of the cell. Thus, a coordination between ER and plasma membrane pumping activities is required in order to avoid total depletion of ER calcium. This coordination can be evidenced spectacularly when SERCA pumps are pharmacologically inhibited. Cells respond to the ensuing depletion of ER Ca2+ stores by widely opening plasma membrane Ca2+ channels, leading to a vast increase of cytosolic Ca2+ concentration [15]. This Store-Operated Ca2+ entry (SOCE) indicates that plasma-membrane Ca2+ channels are somehow made aware of the Ca2+ levels in the ER. How is this possible? Contrary to expectation, no second messenger travels from the ER to the plasma membrane. Instead, a Ca2+ sensor traversing the ER membrane senses ER Ca2+ depletion via its luminal domain, undergoes an allosteric transition that exposes its cytosolic domain, and is recruited to ER-plasma membrane contact sites [16,17]. The cytosolic domain of the sensor then interacts with and triggers the opening of plasma-membrane Ca2+ channels [18]. This direct communication between sensors and channels not only simplifies greatly the transduction pathway, it also comes with a great advantage; the source of Ca2+ being very close to where it is needed, Ca2+ can flow directly from the extracellular milieu to the ER lumen while minimally increasing its concentration in the cytosol [19]. Thus, membrane contact sites represent a solution that evolution has employed to fulfill the needs for metabolic coordination among its many constituting compartments. This newly discovered layer of complexity in the organization of the cell clearly indicates that organelles cannot be considered as isolated entities, but as part of a communication network. Recent years have seen an explosion of research in the field of membrane contact sites, with the discovery of several membrane tethers, lipid transporters and Ca2+ signaling factors. The field of membrane contact sites has really reached its molecular age, and we expect that factors involved in intracellular lipid and Ca2+ trafficking will continue to emerge, and new functions for membrane contact sites, beyond Ca2+ and lipid trafficking will come to light. It is therefore timely to assemble a special issue on membrane contact sites. Within this special issue we have tried to reflect the diversity of function, of structures, of model organisms, and of methods that constitute the field, but also to find the universal features that unite it. The different reviews cover a wide variety of membrane contact sites, and highlight recent findings of their relevance for organelle homeostasis and cellular physiology. Several proteins of membrane contact sites harbor tubular lipid binding protein (TULIP) domains with the now recognized ability to bind and transfer lipids [20–22]. Wong and Levine dissect the diverse functions of this seemingly heterogeneous group of proteins, with a particular focus on their evolutionary origin as a general fold in lipid binding at a central hydrophobic pocket within this domain. Interestingly, TULIP domains are not exclusively observed in intracellular proteins, but also found in extracellular proteins and have similarity to bacterial proteins. Within the cell, TULIP domains were identified in several proteins at ER-mitochondria and ER-plasma membrane contacts. Using a bioinformatics approach, the authors highlight the identity of previously unknown TULIPs in bacteria, thus providing an exciting evolutionary perspective on lipid transfer in general. A similar evolutionary perspective is sketched out by Jain and Holthuis, who describe the adaptation of lipid transfer proteins at the bacterial outer membrane to their role at intracellular organelle-organelle contact sites. They describe the need for lipid flow between membranes as a major logistical problem that is solved in eukaryotic cells by several lipid transfer proteins. The authors highlight the specific lipid requirements of diverse organelle membranes, the gradient of cholesterol and sphingolipids between ER and plasma membrane, and the solutions cells found via diversely regulated lipid transfer proteins. In particular the ER-Golgi interface and the role of the Golgi as a lipid and protein sorting platform is discussed in detail. The authors speculate that lipid sorting at the trans-Golgi might be a prerequisite of dedicated protein sorting, which changes the view of the trans-Golgi from a static compartment to an inducible transition zone of proteins and lipids. One of the central organelles of the cell that contacts virtually every other organelle is the ER. This does not come as a surprise, given that the ER is the major site of lipid biosynthesis. Yet it took a long time until its central role in lipid distribution across membrane contact sites was described at the molecular level [23]. Lipid biosynthesis is tightly coupled to their storage in lipid droplet (LDs) [24]. LDs form as a metabolic consequence of 1436
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Editorial
lipid surplus and to detoxify unesterified fatty acids in form of triacylglycerides (TGs). TGs are stored between the two leaflets of the ER and then concentrate into LDs that are either in contact with, or detached from the ER. In this issue, Barbosa and Siniossoglou dissect the proteins that form LDs, generate contacts to other organelles such as peroxisomes or mitochondria, or are required to mobilize lipids when required at certain organelles. This dual role of LDs in membrane biogenesis or energy production is tightly coupled to the metabolic status of the cell, which is discussed in detail. Mitochondria are at the heart of cell metabolism, and their function is closely linked to other organelles involved in lipid biosynthesis and turnover [25]. Moreover, mitochondria respond to changes in Ca2+, which is mainly stored in the ER, to alterations in metabolic needs or redox changes [26]. Like the ER, mitochondria form a filamentous network throughout the cell, and contact multiple organelles. With the identification of many lipid transfer proteins with overlapping activities at the same contact site, the dissection of the particular function of each membrane contact site of mitochondria with other organelles has become a major challenge. Eisenberg-Bord and Schuldiner now provide a detailed overview of all molecular players operating at the diverse mitochondrial contact sites, and highlight their particular role with respect to organelle needs and cellular physiology. Their analysis reveals a much better understanding of the molecular players, yet many questions on their precise contribution to mitochondrial function remain a challenge for future research. Contact sites do not only form between different organelles. They can also occur between two membranes of a single organelle. Mitochondria have two membranes, which are connected by a network of contacts. Martin van der Laan and colleagues (Wollweber et al.) place mitochondria and their membrane organization at the center of their review. The inner mitochondrial membrane forms tight contacts with the outer membrane, named inner boundary membrane, which is continuous with the extensive cristae. At cristae junctions, a multisubunit complex named MICOS, separates the inner boundary membrane from the extensive cristae. The authors were among the groups who identified MICOS as an organizational unit that determines cristae formation and the contact between the outer and inner membranes [27–29]. They now dissect the function of individual MICOS components and discuss their evolutionary origin and function in shaping membranes. Given that MICOS contacts also the translocases of the inner and outer membranes (TIM and TOM), and is positioned in proximity to ER-mitochondria contact sites, a model of an extensive contact network emerges, which is discussed by the authors. Communication between cells and their environment occurs via the plasma membrane and its multiple receptors. Its lipid homeostasis is critical for signaling, uptake of nutrients via transporters or cell-cell contacts. Four reviews focus on the plasma membrane and the contacts it forms with the ER. They discuss the proteins involved in membrane contact sites, the ultrastructure of these contacts, and their role in phagocytosis, where portions of the plasma membrane are endocytosed. Saheki and De Camilli focus their review on the central function of extended synaptotagmins (E-Syts), a group of proteins that is localized to the ER and makes Ca2+-dependent contacts with the plasma membrane. The heart of each protein is a central SMP lipid binding domain, which we already discussed in the context of TULIP domains. The authors reveal in their review how E-Syts use their C2-domains to respond to Ca2+ levels, and then transfer lipids between membranes, either to replenish missing phospholipids or to potentially channel the signaling byproduct diacylglycerol back to the ER. E-Syts are thus a prime example of membrane contact site proteins that dynamically respond to stimuli. Ca2+ regulation of contact sites between ER and plasma membrane is the focus of Jen Liou and colleagues. The authors discuss among others the role of store operated Ca2+ entry in muscle cells, the manipulation of the ER-PM contact site and the cellular consequences, its visualization via synthetic linker, and the overall function of this contact in all eukaryotic cells. Their analysis nicely complements the discussion on E-Syts and demonstrates how multiple proteins can regulate lipid homeostasis of the plasma membrane via various mechanisms. While many factors have been found to act at membrane contact sites, visualizing the precise make-up of these sites at the ultrastructural level remains a major challenge. The advent of novel detectors and tools in electron microscopy, including cryo-fixation methods, allows the tackling of this challenge, and has already revealed unexpected insights into the organization of contact sites in general, including their precise size and change during different metabolic stages [30–32]. A major advantage here is the possibility to observe membranes in their near-native environment. Collado and Fernándes-Busnadiego discuss the recent technical advances, and focus finally on their findings on E-Syts as a well-studied example, where this high-resolution technique has been extensively applied. Finally, Nunes-Hasler and Demaurex review the recent insights on membrane contact sites of plasma membrane derived phagosomes with the ER and other organelles. After scission from the PM, phagosomes can be considered an independent organelle with multiple contacts that either remain or remodel during the maturation of the phagosome. The authors focus in particular on the role of Ca2+ in ER-phagosome contacts and the involved proteins that mediate this contact and could be involved in lipid remodeling. As phagosomes generate peptides to be presented to MHC class I, ER contacts are important for peptide shuttling from the phagosome to the ER for cross-presentation, which is particularly important in immune cells. The authors discuss the different possible routes for peptide delivery, and describe how pathogens can use the same pathway to eventually transform phagosomes into a hybrid organelle with ER features. How and when membrane contact sites play a role in this transition will be an exciting question not only for our understanding of membrane identity, but also in the context of pathogenicity. The wide variety of membrane contact sites now identified in eukaryotic cells, their evolutionary importance as well as their function – as far as we understand them – have gained a lot of attention. We hope that this review series will be a stimulating read to the community. We would like to thank all authors (but also the helpful reviewers) for their contributions in making this issue possible. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
K. Möbius, Das Sterben der einzelligen und der vielzelligen Tiere Vergleichend betrachtet, Biol. Cent. 4 (1884) 389–392. J.D. Robertson, The molecular structure and contact relationships of cell membranes, Prog. Biophys. Mol. Biol. 10 (1960) 343–418. D. Voelker, Lipid synthesis and transport in mitochondrial biogenesis, Top. Curr. Genet. 8 (2004) 267–291. A.E. Rusiñol, Z. Cui, M.H. Chen, J.E. Vance, A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins, J. Biol. Chem. 269 (1994) 27494–27502. J. Vance, Phospholipid synthesis in a membrane fraction associated with mitochondria, J. Biol. Chem. 265 (1990) 7248–7256. J.E. Vance, E.J. Aasman, R. Szarka, Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites for synthesis to the cell surface, J. Biol. Chem. 266 (1991) 8241–8247. S. Lev, Non-vesicular lipid transport by lipid-transfer proteins and beyond, Nat. Rev. Mol. Cell Biol. 11 (2010) 739–750. E. Carafoli, A.L. Lehninger, A survey of the interaction of calcium ions with mitochondria from different tissues and species, Biochem. J. 122 (1971) 681–690. D. De Stefani, A. Raffaello, E. Teardo, I. Szabò, R. Rizzuto, A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter, Nature 476 (2011) 336–340. J.M. Baughman, F. Perocchi, H.S. Girgis, M. Plovanich, C.A. Belcher-Timme, Y. Sancak, X.R. Bao, L. Strittmatter, O. Goldberger, R.L. Bogorad, V. Koteliansky, V.K. Mootha, Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter, Nature 476 (2011) 341–345. E. Carafoli, The interplay of mitochondria with calcium: an historical appraisal, Cell Calcium 52 (2012) 1–8.
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[12] R.Y. Tsien, The green fluorescent protein, Annu. Rev. Biochem. 67 (1998) 509–544. [13] O. SHIMOMURA, F.H. JOHNSON, Y. SAIGA, Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea, J. Cell. Comp. Physiol. 59 (1962) 223–239. [14] 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 (1993) 744–747. [15] H. Takemura, A.R. Hughes, O. Thastrup, J.W. Putney, Activation of calcium entry by the tumor promoter thapsigargin in parotid acinar cells evidence that an intracellular calcium pool and not an inositol phosphate regulates calcium fluxes at the plasma membrane, J. Biol. Chem. 264 (1989) 12266–12271. [16] J. Liou, M.L. Kim, W. Do Heo, J.T. Jones, J.W. Myers, J.E. Ferrell, T. Meyer, STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx, Curr. Biol. 15 (2005) 1235–1241. [17] S.L. Zhang, Y. Yu, J. Roos, J.A. Kozak, T.J. Deerinck, M.H. Ellisman, K.A. Stauderman, M.D. Cahalan, STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane, Nature 437 (2005) 902–905. [18] S. Feske, Y. Gwack, M. Prakriya, S. Srikanth, S.-H. Puppel, B. Tanasa, P.G. Hogan, R.S. Lewis, M. Daly, A. Rao, A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function, Nature 441 (2006) 179–185. [19] H. Jousset, M. Frieden, N. Demaurex, STIM1 knockdown reveals that store-operated Ca2+ channels located close to sarco/endoplasmic Ca2+ ATPases (SERCA) pumps silently refill the endoplasmic reticulum, J. Biol. Chem. 282 (2007) 11456–11464. [20] A. Toulmay, W.A. Prinz, A conserved membrane-binding domain targets proteins to organelle contact sites, J. Cell Sci. 125 (2012) 49–58. [21] I. Lee, W. Hong, Diverse membrane-associated proteins contain a novel SMP domain, FASEB J. 20 (2006) 202–206. [22] K.O. Kopec, V. Alva, A.N. Lupas, Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochondria, Bioinformatics 26 (2010) 1927–1931. [23] J.C.M. Holthuis, A.K. Menon, Lipid landscapes and pipelines in membrane homeostasis, Nature 510 (2014) 48–57. [24] T.C. Walther, R.V. Farese, Lipid droplets and cellular lipid metabolism, Annu. Rev. Biochem. 81 (2012) 687–714. [25] C. Osman, D.R. Voelker, T. Langer, Making heads or tails of phospholipids in mitochondria, J. Cell Biol. 192 (2011) 7–16. [26] J. Nunnari, A. Suomalainen, Mitochondria: In sickness and in health, Cell 148 (2012) 1145–1159. [27] M. Harner, C. Körner, D. Walther, D. Mokranjac, J. Kaesmacher, U. Welsch, J. Griffith, M. Mann, F. Reggiori, W. Neupert, The mitochondrial contact site complex, a determinant of mitochondrial architecture, EMBO J. (2011) 1–15. [28] S. Hoppins, S.R. Collins, A. Cassidy-Stone, E. Hummel, R.M. DeVay, L.L. Lackner, B. Westermann, M. Schuldiner, J.S. Weissman, J. Nunnari, A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria, J. Cell Biol. (2011). [29] K. von der Malsburg, J.M. Müller, M. Bohnert, S. Oeljeklaus, P. Kwiatkowska, T. Becker, A. Loniewska-Lwowska, S. Wiese, S. Rao, D. Milenkovic, D.P. Hutu, R.M. Zerbes, A. SchulzeSpecking, H.E. Meyer, J.-C. Martinou, S. Rospert, P. Rehling, C. Meisinger, M. Veenhuis, B. Warscheid, et al., Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis, Dev. Cell 21 (2011) 694–707. [30] A.Y. Seo, P.-W. Lau, D. Feliciano, P. Sengupta, M.A. Le Gros, B. Cinquin, C.A. Larabell, J. Lippincott-Schwartz, AMPK and vacuole-associated Atg14p orchestrate μ-lipophagy for energy production and long-term survival under glucose starvation, elife 6 (2017). [31] C. Hönscher, M. Mari, K. Auffarth, M. Bohnert, J. Griffith, W. Geerts, M. van der Laan, M. Cabrera, F. Reggiori, C. Ungermann, Cellular metabolism regulates contact sites between vacuoles and mitochondria, Dev. Cell 30 (2014) 86–94. [32] T. Tsuji, M. Fujimoto, T. Tatematsu, J. Cheng, M. Orii, S. Takatori, T. Fujimoto, Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole, elife 6 (2017).
Benoît Kornmann is Assistant Professor of Organelle Biology at the Swiss Institute of Technology Zurich (ETH Zurich). Benoît Kornmann studied at the University of Geneva, Switzerland, and received his PhD in 2006 under the guidance of Dr. Ueli Schibler, working on mouse circadian clocks. In 2007, he moved to California for postdoctoral training in the laboratory of Dr. Peter Walter at UCSF. There, he got interested in the contact sites between the endoplasmic reticulum and the mitochondria, and discovered that the ER-Mitchondria Encounter Structure complex (ERMES) tethers the two organelles. In 2011, he was appointed as group leader at the Institute of Biochemistry of the Swiss Institute of Technology Zurich, and was soon after promoted to Assistant Professor of the Swiss National Science Foundation. His laboratory focuses on how mitochondria exchange metabolites and information with the rest of the cell.
Christian Ungermann is Professor of Biochemistry at the University of Osnabrück (Germany). He studied Biochemistry and Biophysics at the University of Tübingen, Germany, and at Oregon State University, U.S.A., and received his PhD in 1996 under the supervision of Walter Neupert from the University of Munich. Christian did his postdoctoral training from 1996-1999 with William Wickner at Dartmouth Medical School, where he focussed on the mechanisms of intracellular membrane fusion. From 1999-2006, Christian was at the Biochemistry Center Heidelberg (BZH) as a young investigator. Here, he began to dissect the machinery involved in endosome, autophagosome, and lysosome biogenesis and fusion. His group identified CORVET as a homologous tethering complex of the lysosomal HOPS, solved the overall structure of the HOPS complex, and characterized Rab7 and Rab5 GTPase regulators such as the Mon1Ccz1 GEF. Some of these proteins also participate in vacuole-mitochondrial contacts, which is a new additional focus of his lab. His lab is interested in the mechanisms, how the organelles form and function along the endolysosomal system.
Benoît Kornmann,, Christian Ungermann, Swiss Institute of Technology Zurich (ETH Zurich), Switzerland University of Osnabrück, Germany E-mail address: [email protected]
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Corresponding authors.
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Contents lists available at ScienceDirect
BBA - Molecular Cell Research journal homepage: www.elsevier.com/locate/bbamcr
Editorial
Membrane contact sites
MARK
Compartmentalization is the hallmark of eukaryotic cells. The importance of segregating the many metabolic activities into dedicated organelles has been recognized long ago. The term organelle was coined as an analogy to these miniature versions of body organs [1]. It was soon also recognized, that, akin to body organs, which are not positioned randomly in the body, organelles are distributed in a stereotypical manner in the cell. The nucleus is usually centrally located; beside it, very often lies the microtubule-organizing center, home of various other organelles such as the Golgi apparatus. The endoplasmic reticulum (ER) and the mitochondria often extend as large networks throughout the cell. With the advent of electron microscopy, a novel feature in cellular organization became evident. Organelles often like to associate with each other [2]. The ER membrane is often observed “touching” other membranes, such as the mitochondrial outer membrane or the plasma membrane. These contacts appear as regions where both membranes come to close proximity, and, though not fusing, remain associated at distances of tens of nanometers over extended surfaces. These membrane contact sites appear typically more frequently than expected by mere chance. These observations remained, however, phenomenological and no functional role could be assigned to these membrane contact sites for a very long time. The community therefore continued to see organelles as independent entities. At the same time, the discovery of intracellular trafficking clarified how proteins synthesized in the ER were routed to secretion via the Golgi apparatus, using small vesicles as vessels. This discovery killed two birds with one stone; since lipid molecules constitute the shell of vesicles, a necessary byproduct of protein trafficking is lipid trafficking, explaining how lipids, in majority synthesized in the ER, managed to reach distant cellular membranes, like plasma, Golgi or lysosomal membranes, despite their hydrophobic nature. The problem of lipid trafficking thus appeared solved for most organelles that are part of the endomembrane system. The story was quite different though for mitochondria. Mitochondria have two membranes, do not synthesize most of the lipids that constitute them, and even for those lipids that they synthesize, mitochondria heavily rely on lipid precursors synthesized elsewhere. Importantly, one crucial lipid biosynthesis pathway, the de novo synthesis of phosphatidylcholine (PC) – one of the most abundant phospholipids in eukaryotic membranes, goes from the ER to mitochondria and back [3]. A robust lipid exchange route between both organelles is therefore necessary. Yet, mitochondria are not part of the endomembrane system and do not exchange lipids with the ER via vesicular trafficking. 1. Connecting mitochondria to the endomembrane system ER-mitochondria contact sites became prime suspects in that exchange pathway, not thanks to microscopy, but to subcellular fractionation. The purification of mitochondria involves several steps of centrifugation. After cell lysis and removal of debris and nuclei, a series of velocity centrifugation steps sediment mitochondria, while leaving most other membranes in the supernatant. The “crude” mitochondrial fractions obtained this way are heavily contaminated with other membranes. A subsequent isodensity centrifugation step is necessary to obtain pure mitochondria. This step also allows collecting and characterizing the contaminating membranes [4]. These “mitochondria-associated membranes” look like ER membranes, but do not exactly behave as such. They are notably enriched in phosphatidylserine (PS) synthase activity. Since PS is the very lipid that needs to be shuttled to mitochondria in the de novo PC biosynthesis pathway, it was assumed that PS is synthesized in a subdomain of the ER attached to mitochondria to allow its rapid shuttling into this latter organelle [5]. These observations led to the first possible role of ER-mitochondria coupling; factors tethering the two compartments might facilitate lipid exchange between membranes. The idea of non-vesicular lipid trafficking between isolated membranes also affected our view of lipid exchange within the endomembrane system. After all, if vesicles clearly transport lipids, what is their actual contribution to total lipid exchange? Interestingly, a drug-mediated block of anterograde vesicular trafficking has no measurable effect on the delivery of PS, synthesized in the ER, to the cell surface [6], indicating that a significant fractions of lipids indeed reach the plasma membrane without help from the vesicular transport system. Recent years have seen the discovery of factors that are able to transfer lipids from one membrane to another. Many of these can be found at membrane contact sites, and while their actual contribution to total lipid transport is still to be defined, this shows that the original idea of nonvesicular lipid transport at contact sites was remarkably accurate [7]. 2. Microcompartmentalization of Ca2+ transfer – an example of contact site function Lipid exchange is not, by far, the sole function of inter-organelle contacts. Ion concentrations vary widely between different compartments, and contact between these compartments define privileged routes for ion exchange. A very important ion is Calcium (Ca2+). Ca2+, found in millimolar http://dx.doi.org/10.1016/j.bbamcr.2017.06.014
Available online 23 June 2017 0167-4889/ © 2017 Elsevier B.V. All rights reserved.
BBA - Molecular Cell Research 1864 (2017) 1435–1438
Editorial
concentrations in the extracellular medium, is maintained at nanomolar concentrations in the cytosol. The lumen of endomembrane organelles contains Ca2+ in the hundreds of micromolar range. Large burst of Ca2+ frequently inundate the cytosol consequent to the opening of Ca2+ channels in the plasma or ER membranes, leading to the activation of a myriad of signaling events. The role of membrane contact sites in Ca2+ signaling originally stems from the study of the paradoxical role of mitochondria in Ca2+ homeostasis. Purified mitochondria bathed in a Ca2+-containing solution import Ca2+ into their matrix, thanks to the electrophoretic force resulting from the electrochemical gradient across the inner mitochondrial membrane. Thus, energized mitochondria behave as efficient Ca2+ “sponges” [8]. Yet, mitochondria import Ca2+ only once it has reached a sufficient concentration. The machinery responsible for this import is a high-capacity, but low affinity Ca2+ uniporter, whose molecular identity has only been discovered recently [9,10]. The paradox is that the concentrations necessary to activate the uniporter are far above those you would normally find in the cytosol of a healthy cell. Thus, the activation of the mitochondrial Ca2+ uniporter was long considered as a last-resort buffering mechanism for cells in which the cytosol was poisoned by close-to-lethal concentrations of Ca2+ [11]. This view changed abruptly with a technical breakthrough in intracellular Ca2+ measurements. While Ca2+ concentrations were classically measured with Ca2+-sensitive chemical dyes, which permeated the cell but did not target defined compartments, the advent of genetically-encoded protein-based Ca2+ biosensors allowed to precisely target defined organelles by fusing targeting motifs. The jellyfish Aequorea Victoria is well-known for being the source of the green fluorescent protein (GFP) [12]. It is, however, less commonly appreciated that, since Aequorea Victoria lives far from a blue light source, it also produces a bioluminescent photoprotein, called aequorin [13]. This luciferase-like protein uses a cofactor called coelenterazine, and most importantly Ca2+, to emit blue photons, which in turn, excite GFP by resonance energy transfer. Aequorin fused to a mitochondrial matrix targeting sequence efficiently targets mitochondria in live cells, and, upon addition of coelenterazine in the culture medium, can serve as a mitochondrial Ca2+ monitoring device. Surprisingly, triggering ER-Ca2+ release with physiological stimuli leads to a transient elevation of mitochondrial Ca2+ [14]. Thus, the mitochondrial calcium uniporter can be triggered without cells sustaining a near-death experience, in conditions in which the general cytosolic Ca2+ concentration is theoretically not sufficient, based on the in vitro experiments. This paradox can be explained if cytosolic Ca2+ concentrations are not homogeneous throughout the cell. In particular, Ca2+ concentration is highest at the cytosolic face of ER-Ca2+ channels. If the ER-membrane is closely apposed on the mitochondrial membrane, the mitochondrial Ca2+ uniporter might experience a much higher Ca2+ concentration than the rest of the cytosol. Thus, organelle proximity might leverage heterogeneities in the cytosol to route Ca2+ fluxes in the desired direction. Membrane contact sites can also be more directly involved in Ca2+ signaling. This is particularly true for ER-plasma membrane contact sites, and the story starts again with a paradox. The ER needs to maintain a Ca2+ concentration that is five orders of magnitude higher than that of the cytosol. This is achieved via the Sarco/Endoplasmic Reticulum Ca2+ (SERCA) pumps, which pump cytosolic Ca2+ into the ER lumen. Yet, SERCA pumps compete for cytosolic Ca2+ with Plasma Membrane Ca2+ (PMCA) pumps, which pump it out of the cell. Thus, a coordination between ER and plasma membrane pumping activities is required in order to avoid total depletion of ER calcium. This coordination can be evidenced spectacularly when SERCA pumps are pharmacologically inhibited. Cells respond to the ensuing depletion of ER Ca2+ stores by widely opening plasma membrane Ca2+ channels, leading to a vast increase of cytosolic Ca2+ concentration [15]. This Store-Operated Ca2+ entry (SOCE) indicates that plasma-membrane Ca2+ channels are somehow made aware of the Ca2+ levels in the ER. How is this possible? Contrary to expectation, no second messenger travels from the ER to the plasma membrane. Instead, a Ca2+ sensor traversing the ER membrane senses ER Ca2+ depletion via its luminal domain, undergoes an allosteric transition that exposes its cytosolic domain, and is recruited to ER-plasma membrane contact sites [16,17]. The cytosolic domain of the sensor then interacts with and triggers the opening of plasma-membrane Ca2+ channels [18]. This direct communication between sensors and channels not only simplifies greatly the transduction pathway, it also comes with a great advantage; the source of Ca2+ being very close to where it is needed, Ca2+ can flow directly from the extracellular milieu to the ER lumen while minimally increasing its concentration in the cytosol [19]. Thus, membrane contact sites represent a solution that evolution has employed to fulfill the needs for metabolic coordination among its many constituting compartments. This newly discovered layer of complexity in the organization of the cell clearly indicates that organelles cannot be considered as isolated entities, but as part of a communication network. Recent years have seen an explosion of research in the field of membrane contact sites, with the discovery of several membrane tethers, lipid transporters and Ca2+ signaling factors. The field of membrane contact sites has really reached its molecular age, and we expect that factors involved in intracellular lipid and Ca2+ trafficking will continue to emerge, and new functions for membrane contact sites, beyond Ca2+ and lipid trafficking will come to light. It is therefore timely to assemble a special issue on membrane contact sites. Within this special issue we have tried to reflect the diversity of function, of structures, of model organisms, and of methods that constitute the field, but also to find the universal features that unite it. The different reviews cover a wide variety of membrane contact sites, and highlight recent findings of their relevance for organelle homeostasis and cellular physiology. Several proteins of membrane contact sites harbor tubular lipid binding protein (TULIP) domains with the now recognized ability to bind and transfer lipids [20–22]. Wong and Levine dissect the diverse functions of this seemingly heterogeneous group of proteins, with a particular focus on their evolutionary origin as a general fold in lipid binding at a central hydrophobic pocket within this domain. Interestingly, TULIP domains are not exclusively observed in intracellular proteins, but also found in extracellular proteins and have similarity to bacterial proteins. Within the cell, TULIP domains were identified in several proteins at ER-mitochondria and ER-plasma membrane contacts. Using a bioinformatics approach, the authors highlight the identity of previously unknown TULIPs in bacteria, thus providing an exciting evolutionary perspective on lipid transfer in general. A similar evolutionary perspective is sketched out by Jain and Holthuis, who describe the adaptation of lipid transfer proteins at the bacterial outer membrane to their role at intracellular organelle-organelle contact sites. They describe the need for lipid flow between membranes as a major logistical problem that is solved in eukaryotic cells by several lipid transfer proteins. The authors highlight the specific lipid requirements of diverse organelle membranes, the gradient of cholesterol and sphingolipids between ER and plasma membrane, and the solutions cells found via diversely regulated lipid transfer proteins. In particular the ER-Golgi interface and the role of the Golgi as a lipid and protein sorting platform is discussed in detail. The authors speculate that lipid sorting at the trans-Golgi might be a prerequisite of dedicated protein sorting, which changes the view of the trans-Golgi from a static compartment to an inducible transition zone of proteins and lipids. One of the central organelles of the cell that contacts virtually every other organelle is the ER. This does not come as a surprise, given that the ER is the major site of lipid biosynthesis. Yet it took a long time until its central role in lipid distribution across membrane contact sites was described at the molecular level [23]. Lipid biosynthesis is tightly coupled to their storage in lipid droplet (LDs) [24]. LDs form as a metabolic consequence of 1436
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lipid surplus and to detoxify unesterified fatty acids in form of triacylglycerides (TGs). TGs are stored between the two leaflets of the ER and then concentrate into LDs that are either in contact with, or detached from the ER. In this issue, Barbosa and Siniossoglou dissect the proteins that form LDs, generate contacts to other organelles such as peroxisomes or mitochondria, or are required to mobilize lipids when required at certain organelles. This dual role of LDs in membrane biogenesis or energy production is tightly coupled to the metabolic status of the cell, which is discussed in detail. Mitochondria are at the heart of cell metabolism, and their function is closely linked to other organelles involved in lipid biosynthesis and turnover [25]. Moreover, mitochondria respond to changes in Ca2+, which is mainly stored in the ER, to alterations in metabolic needs or redox changes [26]. Like the ER, mitochondria form a filamentous network throughout the cell, and contact multiple organelles. With the identification of many lipid transfer proteins with overlapping activities at the same contact site, the dissection of the particular function of each membrane contact site of mitochondria with other organelles has become a major challenge. Eisenberg-Bord and Schuldiner now provide a detailed overview of all molecular players operating at the diverse mitochondrial contact sites, and highlight their particular role with respect to organelle needs and cellular physiology. Their analysis reveals a much better understanding of the molecular players, yet many questions on their precise contribution to mitochondrial function remain a challenge for future research. Contact sites do not only form between different organelles. They can also occur between two membranes of a single organelle. Mitochondria have two membranes, which are connected by a network of contacts. Martin van der Laan and colleagues (Wollweber et al.) place mitochondria and their membrane organization at the center of their review. The inner mitochondrial membrane forms tight contacts with the outer membrane, named inner boundary membrane, which is continuous with the extensive cristae. At cristae junctions, a multisubunit complex named MICOS, separates the inner boundary membrane from the extensive cristae. The authors were among the groups who identified MICOS as an organizational unit that determines cristae formation and the contact between the outer and inner membranes [27–29]. They now dissect the function of individual MICOS components and discuss their evolutionary origin and function in shaping membranes. Given that MICOS contacts also the translocases of the inner and outer membranes (TIM and TOM), and is positioned in proximity to ER-mitochondria contact sites, a model of an extensive contact network emerges, which is discussed by the authors. Communication between cells and their environment occurs via the plasma membrane and its multiple receptors. Its lipid homeostasis is critical for signaling, uptake of nutrients via transporters or cell-cell contacts. Four reviews focus on the plasma membrane and the contacts it forms with the ER. They discuss the proteins involved in membrane contact sites, the ultrastructure of these contacts, and their role in phagocytosis, where portions of the plasma membrane are endocytosed. Saheki and De Camilli focus their review on the central function of extended synaptotagmins (E-Syts), a group of proteins that is localized to the ER and makes Ca2+-dependent contacts with the plasma membrane. The heart of each protein is a central SMP lipid binding domain, which we already discussed in the context of TULIP domains. The authors reveal in their review how E-Syts use their C2-domains to respond to Ca2+ levels, and then transfer lipids between membranes, either to replenish missing phospholipids or to potentially channel the signaling byproduct diacylglycerol back to the ER. E-Syts are thus a prime example of membrane contact site proteins that dynamically respond to stimuli. Ca2+ regulation of contact sites between ER and plasma membrane is the focus of Jen Liou and colleagues. The authors discuss among others the role of store operated Ca2+ entry in muscle cells, the manipulation of the ER-PM contact site and the cellular consequences, its visualization via synthetic linker, and the overall function of this contact in all eukaryotic cells. Their analysis nicely complements the discussion on E-Syts and demonstrates how multiple proteins can regulate lipid homeostasis of the plasma membrane via various mechanisms. While many factors have been found to act at membrane contact sites, visualizing the precise make-up of these sites at the ultrastructural level remains a major challenge. The advent of novel detectors and tools in electron microscopy, including cryo-fixation methods, allows the tackling of this challenge, and has already revealed unexpected insights into the organization of contact sites in general, including their precise size and change during different metabolic stages [30–32]. A major advantage here is the possibility to observe membranes in their near-native environment. Collado and Fernándes-Busnadiego discuss the recent technical advances, and focus finally on their findings on E-Syts as a well-studied example, where this high-resolution technique has been extensively applied. Finally, Nunes-Hasler and Demaurex review the recent insights on membrane contact sites of plasma membrane derived phagosomes with the ER and other organelles. After scission from the PM, phagosomes can be considered an independent organelle with multiple contacts that either remain or remodel during the maturation of the phagosome. The authors focus in particular on the role of Ca2+ in ER-phagosome contacts and the involved proteins that mediate this contact and could be involved in lipid remodeling. As phagosomes generate peptides to be presented to MHC class I, ER contacts are important for peptide shuttling from the phagosome to the ER for cross-presentation, which is particularly important in immune cells. The authors discuss the different possible routes for peptide delivery, and describe how pathogens can use the same pathway to eventually transform phagosomes into a hybrid organelle with ER features. How and when membrane contact sites play a role in this transition will be an exciting question not only for our understanding of membrane identity, but also in the context of pathogenicity. The wide variety of membrane contact sites now identified in eukaryotic cells, their evolutionary importance as well as their function – as far as we understand them – have gained a lot of attention. We hope that this review series will be a stimulating read to the community. We would like to thank all authors (but also the helpful reviewers) for their contributions in making this issue possible. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
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Benoît Kornmann is Assistant Professor of Organelle Biology at the Swiss Institute of Technology Zurich (ETH Zurich). Benoît Kornmann studied at the University of Geneva, Switzerland, and received his PhD in 2006 under the guidance of Dr. Ueli Schibler, working on mouse circadian clocks. In 2007, he moved to California for postdoctoral training in the laboratory of Dr. Peter Walter at UCSF. There, he got interested in the contact sites between the endoplasmic reticulum and the mitochondria, and discovered that the ER-Mitchondria Encounter Structure complex (ERMES) tethers the two organelles. In 2011, he was appointed as group leader at the Institute of Biochemistry of the Swiss Institute of Technology Zurich, and was soon after promoted to Assistant Professor of the Swiss National Science Foundation. His laboratory focuses on how mitochondria exchange metabolites and information with the rest of the cell.
Christian Ungermann is Professor of Biochemistry at the University of Osnabrück (Germany). He studied Biochemistry and Biophysics at the University of Tübingen, Germany, and at Oregon State University, U.S.A., and received his PhD in 1996 under the supervision of Walter Neupert from the University of Munich. Christian did his postdoctoral training from 1996-1999 with William Wickner at Dartmouth Medical School, where he focussed on the mechanisms of intracellular membrane fusion. From 1999-2006, Christian was at the Biochemistry Center Heidelberg (BZH) as a young investigator. Here, he began to dissect the machinery involved in endosome, autophagosome, and lysosome biogenesis and fusion. His group identified CORVET as a homologous tethering complex of the lysosomal HOPS, solved the overall structure of the HOPS complex, and characterized Rab7 and Rab5 GTPase regulators such as the Mon1Ccz1 GEF. Some of these proteins also participate in vacuole-mitochondrial contacts, which is a new additional focus of his lab. His lab is interested in the mechanisms, how the organelles form and function along the endolysosomal system.
Benoît Kornmann,, Christian Ungermann, Swiss Institute of Technology Zurich (ETH Zurich), Switzerland University of Osnabrück, Germany E-mail address: [email protected]
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Corresponding authors.
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