Key Points
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The endoplasmic reticulum (ER) forms tight membrane contact sites (MCSs) with several organelles in animal cells and yeast. The function of MCSs between the ER and mitochondria and endosomes are summarized in this Review.
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Electron microscopy studies reveal that although MCSs are less than 30 nm apart, the membranes do not fuse and each organelle maintains its identity. Ribosomes are excluded from the ER membrane at MCSs, and the distance between the ER and other membranes is close enough to suggest that the two organelles are tethered together by other proteins located on apposing membranes.
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Live-cell fluorescence microscopy reveals that ER-organelle MCSs can remain stable while both organelles traffic through the cell on the cytoskeleton. Recently identified factors have been shown to regulate organelle trafficking through MCS formation.
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ER–organelle MCSs regulate the lipid environment of the organelle membrane apposed to the ER. Lipid-synthesis proteins on the ER can modify lipids on the membrane of another organelle or on protein complexes. ER MCS may also transfer lipids between membranes.
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ER–organelle MCSs are sites of dynamic Ca2+ crosstalk. Organelles can sequester Ca2+ released from the ER, which can regulate processes in these organelles. Additionally, ER Ca2+ release may regulate protein complexes at ER MCS.
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Mitochondria and endosomes undergo fission and fusion to, respectively, maintain their integrity and properly sort signalling receptors in the cell. ER–organelle MCSs define the position of fission for both mitochondria and endosomes, and the ER could have a variety of roles at those specific MCSs that are destined for fission.
Abstract
The endoplasmic reticulum (ER) is the largest organelle in the cell, and its functions have been studied for decades. The past several years have provided novel insights into the existence of distinct domains between the ER and other organelles, known as membrane contact sites (MCSs). At these contact sites, organelle membranes are closely apposed and tethered, but do not fuse. Here, various protein complexes can work in concert to perform specialized functions such as binding, sensing and transferring molecules, as well as engaging in organelle biogenesis and dynamics. This Review describes the structure and functions of MCSs, primarily focusing on contacts of the ER with mitochondria and endosomes.
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References
Fawcett, D. W. The Cell (W. B. Saunders, 1981).
Ogata, T. & Yamasaki, Y. Ultra-high-resolution scanning electron microscopy of mitochondria and sarcoplasmic reticulum arrangement in human red, white, and intermediate muscle fibers. Anat. Rec. 248, 214–223 (1997).
Rolls, M. M., Hall, D. H., Victor, M., Stelzer, E. H. K. & Rapoport, T. A. Targeting of rough endoplasmic reticulum membrane proteins and ribosomes in invertebrate neurons. Mol. Biol. Cell 13, 1778–1791 (2002).
Shibata, Y., Voeltz, G. K. & Rapoport, T. A. Rough sheets and smooth tubules. Cell 126, 435–439 (2006).
Shibata, Y. et al. Mechanisms determining the morphology of the peripheral ER. Cell 143, 774–788 (2010).
West, M., Zurek, N., Hoenger, A. & Voeltz, G. K. A 3D analysis of yeast ER structure reveals how ER domains are organized by membrane curvature. J. Cell Biol. 193, 333–346 (2011).
Alpy, F. et al. STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER. J. Cell Sci. 126, 5500–5512 (2013). Measured ER–late endosome contact site distance using electron microscopy. Showed that the STARD3 and STARD3NL FFAT domain can interact with ER VAP proteins. Overexpression of STARD3 resulted in expansion of ER–endosome contact sites.
Csordás, G. et al. Structural and functional features and significance of the physical linkage between ER and mitochondria. J. Cell Biol. 174, 915–921 (2006).
Friedman, J. R. et al. ER tubules mark sites of mitochondrial division. Science 334, 358–362 (2011). Demonstrated that ER tubules mark the site of mitochondrial division and that ER contact occurs prior to recruitment of the mammalian division machinery DRP1.
Friedman, J. R., Dibenedetto, J. R., West, M., Rowland, A. A. & Voeltz, G. K. Endoplasmic reticulum–endosome contact increases as endosomes traffic and mature. Mol. Biol. Cell 24, 1030–1040 (2013).
Eden, E. R., White, I. J., Tsapara, A. & Futter, C. E. Membrane contacts between endosomes and ER provide sites for PTP1B–epidermal growth factor receptor interaction. Nat. Cell Biol. 12, 267–272 (2010).
Swayne, T. C. et al. Role for cER and Mmr1p in anchorage of mitochondria at sites of polarized surface growth in budding yeast. Curr. Biol. 21, 1994–1999 (2011).
Rowland, A. A., Chitwood, P. J., Phillips, M. J. & Voeltz, G. K. ER contact sites define the position and timing of endosome fission. Cell 159, 1027–1041 (2014). Demonstrated that ER tubules are recruited to pre-established endosome sorting domains that undergo fission to sort cargo, and that ER dynamics are required for endosome fission.
Kornmann, B. et al. An ER–mitochondria tethering complex revealed by a synthetic biology screen. Science 325, 477–481 (2009). Performed a yeast screen for mutants that could be rescued by an artificial ER–mitochondria tether. Identified a role for the ERMES complex in ER–mitochondria tethering in yeast.
Cosson, P., Marchetti, A., Ravazzola, M. & Orci, L. Mitofusin-2 independent juxtaposition of endoplasmic reticulum and mitochondria: an ultrastructural study. PLoS ONE 7, e46293 (2012).
Murley, A. et al. ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. eLife 2, e00422 (2013).
Zajac, A. L., Goldman, Y. E., Holzbaur, E. L. F. & Ostap, E. M. Local cytoskeletal and organelle interactions impact molecular-motor-driven early endosomal trafficking. Curr. Biol. 23, 1173–1180 (2013).
Woźniak, M. J. et al. Role of kinesin-1 and cytoplasmic dynein in endoplasmic reticulum movement in VERO cells. J. Cell Sci. 122, 1979–1989 (2009).
Hoepfner, S. et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–450 (2005).
Hurd, D. D. & Saxton, W. M. Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila. Genetics 144, 1075–1085 (1996).
Glater, E. E., Megeath, L. J., Stowers, R. S. & Schwarz, T. L. Axonal transport of mitochondria requires milton to recruit kinesin heavy chain and is light chain independent. J. Cell Biol. 173, 545–557 (2006).
Tanaka, Y. et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 93, 1147–1158 (1998).
Kornmann, B., Osman, C. & Walter, P. The conserved GTPase Gem1 regulates endoplasmic reticulum–mitochondria connections. Proc. Natl Acad. Sci. USA 108, 14151–14156 (2011).
Stowers, R. S., Megeath, L. J., Górska-Andrzejak, J., Meinertzhagen, I. A. & Schwarz, T. L. Axonal transport of mitochondria to synapses depends on Milton, a novel Drosophila protein. Neuron 36, 1063–1077 (2002).
Saotome, M. et al. Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc. Natl Acad. Sci. USA 105, 20728–20733 (2008).
Huotari, J. & Helenius, A. Endosome maturation. EMBO J. 30, 3481–3500 (2011).
Vihervaara, T. et al. Sterol binding by OSBP-related protein 1L regulates late endosome motility and function. Cell. Mol. Life Sci. 68, 537–551 (2011).
Rocha, N. et al. Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning. J. Cell Biol. 185, 1209–1225 (2009). Discovered that late-endosome-localized ORP1L interacts with ER membrane protein VAP when cholesterol levels are low in the late endosome membrane. ORP1L–VAP interaction inhibits dynein-directed positioning of late endosomes to the cell centre, resulting in late endosomes in the cell periphery.
Suchanek, M. et al. The mammalian oxysterol-binding protein-related proteins (ORPs) bind 25-hydroxycholesterol in an evolutionarily conserved pocket. Biochem. J. 405, 473–480 (2007).
Johansson, M. et al. Activation of endosomal dynein motors by stepwise assembly of Rab7–RILP–p150Glued, ORP1L, and the receptor βlll spectrin. J. Cell Biol. 176, 459–471 (2007).
Tsujishita, Y. & Hurley, J. H. Structure and lipid transport mechanism of a StAR-related domain. Nat. Struct. Biol. 7, 408–414 (2000).
Hölttä-Vuori, M. et al. MLN64 is involved in actin-mediated dynamics of late endocytic organelles. Mol. Biol. Cell 16, 3873–3886 (2005).
Chang, J., Lee, S. & Blackstone, C. Protrudin binds atlastins and endoplasmic reticulum-shaping proteins and regulates network formation. Proc. Natl Acad. Sci. USA 110, 14954–14959 (2013).
Raiborg, C. et al. Repeated ER–endosome contacts promote endosome translocation and neurite outgrowth. Nature 520, 234–238 (2015). Analysis of protrudin domains showed that protrudin interacts with the late endosome through PtdIns(3)P and RAB7, creating an ER–late endosome MCS. When the ER–late endosome MCS is formed, protrudin delivers kinesin-1 to FYCO1, which links the kinesin-1 to the late endosome RAB7. This promotes trafficking of late endosomes to the cell exterior.
Pankiv, S. et al. FYCO1 is a Rab7 effector that binds to LC3 and PI3P to mediate microtubule plus end-directed vesicle transport. J. Cell Biol. 188, 253–269 (2010).
Matsuzaki, F., Shirane, M., Matsumoto, M. & Nakayama, K. I. Protrudin serves as an adaptor molecule that connects KIF5 and its cargoes in vesicular transport during process formation. Mol. Biol. Cell 22, 4602–4620 (2011).
Vance, J. E., Aasman, E. J. & Szarka, R. Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites for synthesis to the cell surface. J. Biol. Chem. 266, 8241–8247 (1991).
Wirtz, K. W. & Zilversmit, D. B. Exchange of phospholipids between liver mitochondria and microsomes in vitro. J. Biol. Chem. 243, 3596–3602 (1968).
Lev, S. Non-vesicular lipid transport by lipid-transfer proteins and beyond. Nat. Rev. Mol. Cell. Biol. 11, 739–750 (2010).
Im, Y. J., Raychaudhuri, S., Prinz, W. A. & Hurley, J. H. Structural mechanism for sterol sensing and transport by OSBP-related proteins. Nature 437, 154–158 (2005).
Kopec, K. O., Alva, V. & Lupas, A. N. Bioinformatics of the TULIP domain superfamily. Biochem. Soc. Trans. 39, 1033–1038 (2011).
Dennis, E. A. & Kennedy, E. P. Intracellular sites of lipid synthesis and the biogenesis of mitochondria. J. Lipid Res. 13, 263–267 (1972).
Osman, C., Voelker, D. R. & Langer, T. Making heads or tails of phospholipids in mitochondria. J. Cell Biol. 192, 7–16 (2011).
Toulmay, A. & Prinz, W. A. A conserved membrane-binding domain targets proteins to organelle contact sites. J. Cell Sci. 125, 49–58 (2012).
Schauder, C. M. et al. Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer. Nature 510, 552–555 (2014).
Osman, C. et al. The genetic interactome of prohibitins: coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria. J. Cell Biol. 184, 583–596 (2009).
Tamura, Y. et al. Role for two conserved intermembrane space proteins, Ups1p and Ups2p, [corrected] in intra-mitochondrial phospholipid trafficking. J. Biol. Chem. 287, 15205–15218 (2012).
Tan, T., Ozbalci, C., Brügger, B., Rapaport, D. & Dimmer, K. S. Mcp1 and Mcp2, two novel proteins involved in mitochondrial lipid homeostasis. J. Cell Sci. 126, 3563–3574 (2013).
Nguyen, T. T. et al. Gem1 and ERMES do not directly affect phosphatidylserine transport from ER to mitochondria or mitochondrial inheritance. Traffic 13, 880–890 (2012).
Voss, C., Lahiri, S., Young, B. P., Loewen, C. J. & Prinz, W. A. ER-shaping proteins facilitate lipid exchange between the ER and mitochondria in S. cerevisiae. J. Cell Sci. 125, 4791–4799 (2012).
Elbaz-Alon, Y. et al. A dynamic interface between vacuoles and mitochondria in yeast. Dev. Cell 30, 95–102 (2014).
Hönscher, C. et al. Cellular metabolism regulates contact sites between vacuoles and mitochondria. Dev. Cell 30, 86–94 (2014).
Möbius, W. et al. Recycling compartments and the internal vesicles of multivesicular bodies harbor most of the cholesterol found in the endocytic pathway. Traffic 4, 222–231 (2003).
Neufeld, E. B. et al. Intracellular trafficking of cholesterol monitored with a cyclodextrin. J. Biol. Chem. 271, 21604–21613 (1996).
Liscum, L., Ruggiero, R. M. & Faust, J. R. The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts. J. Cell Biol. 108, 1625–1636 (1989).
Infante, R. E. et al. NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proc. Natl Acad. Sci. USA 105, 15287–15292 (2008).
Kwon, H. J. et al. Structure of N-terminal domain of NPC1 reveals distinct subdomains for binding and transfer of cholesterol. Cell 137, 1213–1224 (2009).
Du, X. et al. A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking. J. Cell Biol. 192, 121–135 (2011). Demonstrated that depletion of tail-anchored ER protein ORP5 resulted in cholesterol accumulation in the external membranes of late endosomes, leading to the model in which ORP5 accepts cholesterol from late endosome NPC1 and transfers it to the ER.
Van der Kant, R., Zondervan, I., Janssen, L. & Neefjes, J. Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1. J. Lipid Res. 54, 2153–2165 (2013).
Peretti, D., Dahan, N., Shimoni, E., Hirschberg, K. & Lev, S. Coordinated lipid transfer between the endoplasmic reticulum and the Golgi complex requires the VAP proteins and is essential for Golgi-mediated transport. Mol. Biol. Cell 19, 3871–3884 (2008).
Hanada, K. et al. Molecular machinery for non-vesicular trafficking of ceramide. Nature 426, 803–809 (2003).
D'Angelo, G. et al. Glycosphingolipid synthesis requires FAPP2 transfer of glucosylceramide. Nature 449, 62–67 (2007).
Litvak, V., Dahan, N., Ramachandran, S., Sabanay, H. & Lev, S. Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function. Nat. Cell Biol. 7, 225–234 (2005).
Mesmin, B. et al. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER–Golgi tether OSBP. Cell 155, 830–843 (2013). Demonstrated that OSBP binding to PtdIns(4)P localizes OSBP to the Golgi. OSBP moves sterol from the ER to the Golgi. OSBP moves PtdIns(4)P to the ER, where it is hydrolysed. Depletion of PtdIns(4)P from the Golgi membrane results in OSBP dissociation from the Golgi membrane.
Perry, R. J. & Ridgway, N. D. Oxysterol-binding protein and vesicle-associated membrane protein-associated protein are required for sterol-dependent activation of the ceramide transport protein. Mol. Biol. Cell 17, 2604–2616 (2006).
Loewen, C. J. R., Roy, A. & Levine, T. P. A conserved ER targeting motif in three families of lipid binding proteins and in Opi1p binds VAP. EMBO J. 22, 2025–2035 (2003).
Lev, S., Ben Halevy, D., Peretti, D. & Dahan, N. The VAP protein family: from cellular functions to motor neuron disease. Trends Cell Biol. 18, 282–290 (2008).
Amarilio, R., Ramachandran, S., Sabanay, H. & Lev, S. Differential regulation of endoplasmic reticulum structure through VAP–Nir protein interaction. J. Biol. Chem. 280, 5934–5944 (2005).
Foskett, J. K., White, C., Cheung, K. & Mak, D. D. Inositol trisphosphate receptor Ca2+ release channels. Physiol. Rev. 87, 593–658 (2007).
Tovey, S. C., Dedos, S. G., Taylor, E. J. A., Church, J. E. & Taylor, C. W. Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP. J. Cell Biol. 183, 297–311 (2008).
Taylor, C. W. & Tovey, S. C. IP3 receptors: toward understanding their activation. Cold Spring Harb. Perspect. Biol. 2, a004010 (2010).
Shuai, J. & Parker, I. Optical single-channel recording by imaging Ca2+ flux through individual ion channels: theoretical considerations and limits to resolution. Cell Calcium 37, 283–299 (2005).
Rizzuto, R. et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280, 1763–1766 (1998).
Morgan, A. J. et al. Bidirectional Ca2+ signaling occurs between the endoplasmic reticulum and acidic organelles. J. Cell Biol. 200, 789–805 (2013). Demonstrated that stimulated ER Ca2+ release can activate NAADP-regulated channels on the lysosome and result in Ca2+ release from lysosomes.
De Stefani, D., Raffaello, A., Teardo, E., Szabò, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).
Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).
Rizzuto, R., De Stefani, D., Raffaello, A. & Mammucari, C. Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell. Biol. 13, 566–578 (2012).
Scorrano, L. et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science 300, 135–139 (2003).
Zong, W.-X. et al. Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis. J. Cell Biol. 162, 59–69 (2003).
Rizzuto, R., Brini, M., Murgia, M. & Pozzan, T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science 262, 744–747 (1993).
Csordás, G. et al. Imaging interorganelle contacts and local calcium dynamics at the ER–mitochondrial interface. Mol. Cell 39, 121–132 (2010). Adjusted ER–mitochondria contact site distance using artificial tethers and showed that distance between ER and mitochondria affectsCa2+ transfer at the ER–mitochondria MCS.
De Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).
Filadi, R. et al. Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling. Proc. Natl Acad. Sci. USA 112, E2174–E2181 (2015).
Szabadkai, G. et al. Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J. Cell Biol. 175, 901–911 (2006).
Giorgi, C. et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330, 1247–1251 (2010).
Marchi, S. et al. Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuli. Biochem. Biophys. Res. Commun. 375, 501–505 (2008).
Marchi, S. et al. Selective modulation of subtype III IP3R by Akt regulates ER Ca2+ release and apoptosis. Cell Death Dis. 3, e304 (2012).
Gerasimenko, J. V., Tepikin, a V., Petersen, O. H. & Gerasimenko, O. V. Calcium uptake via endocytosis with rapid release from acidifying endosomes. Curr. Biol. 8, 1335–1338 (1998).
Pryor, P. R., Mullock, B. M., Bright, N. A., Gray, S. R. & Luzio, J. P. The role of intraorganellar Ca2+ in late endosome–lysosome heterotypic fusion and in the reformation of lysosomes from hybrid organelles. J. Cell Biol. 149, 1053–1062 (2000).
Morgan, A. J., Platt, F. M., Lloyd-Evans, E. & Galione, A. Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease. Biochem. J. 439, 349–374 (2011).
Albrecht, T., Zhao, Y., Nguyen, T. H., Campbell, R. E. & Johnson, J. D. Fluorescent biosensors illuminate calcium levels within defined beta-cell endosome subpopulations. Cell Calcium 57, 263–274 (2015).
Christensen, K. A., Myers, J. T. & Swanson, J. A. pH-dependent regulation of lysosomal calcium in macrophages. 115, 599–607 (2002).
Lloyd-Evans, E. et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14, 1247–1255 (2008).
Abe, K. & Puertollano, R. Role of TRP channels in the regulation of the endosomal pathway. Physiology 26, 14–22 (2011).
Lelouvier, B. & Puertollano, R. Mucolipin-3 regulates luminal calcium, acidification, and membrane fusion in the endosomal pathway. J. Biol. Chem. 286, 9826–9832 (2011).
Ruas, M. et al. Purified TPC isoforms form NAADP receptors with distinct roles for Ca2+ signaling and endolysosomal trafficking. Curr. Biol. 20, 703–709 (2010).
Kilpatrick, B. S., Eden, E. R., Schapira, A. H., Futter, C. E. & Patel, S. Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. J. Cell Sci. 126, 60–66 (2013).
López-Sanjurjo, C. I., Tovey, S. C., Prole, D. L. & Taylor, C. W. Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic reticulum. J. Cell Sci. 126, 289–300 (2013). Measured pH-adjusted Ca2+ levels in the lysosome and demonstrated that Ca2+ levels increase in the lysosome upon ER Ins(1,4,5)P 3 R stimulation, leading to the idea that lysosomes can sequester ER Ca2+.
Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).
Otsuga, D. et al. The dynamin-related GTPase, Dnm1p, controls mitochondrial morphology in yeast. J. Cell Biol. 143, 333–349 (1998).
Bleazard, W. et al. The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat. Cell Biol. 1, 298–304 (1999).
Smirnova, E., Griparic, L., Shurland, D. L. & van der Bliek, A. M. Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol. Biol. Cell 12, 2245–2256 (2001).
Mears, J. A. et al. Conformational changes in Dnm1 support a contractile mechanism for mitochondrial fission. Nat. Struct. Mol. Biol. 18, 20–26 (2011).
Ingerman, E. et al. Dnm1 forms spirals that are structurally tailored to fit mitochondria. J. Cell Biol. 170, 1021–1027 (2005).
Yoon, Y., Pitts, K. R. & McNiven, M. A. Mammalian dynamin-like protein DLP1 tubulates membranes. Mol. Biol. Cell 12, 2894–2905 (2001).
Legesse-Miller, A., Massol, R. H. & Kirchhausen, T. Constriction and Dnm1p recruitment are distinct processes in mitochondrial fission. Mol. Biol. Cell 14, 1953–1963 (2003).
Korobova, F., Ramabhadran, V. & Higgs, H. N. An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339, 464–467 (2013).
Korobova, F., Gauvin, T. J. & Higgs, H. N. A role for myosin II in mammalian mitochondrial fission. Curr. Biol. 24, 409–414 (2014).
Losón, O. C., Song, Z., Chen, H. & Chan, D. C. Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol. Biol. Cell 24, 659–667 (2013).
Tieu, Q. & Nunnari, J. Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division. J. Cell Biol. 151, 353–366 (2000).
Gandre-Babbe, S. & van der Bliek, A. M. The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol. Biol. Cell 19, 2402–2412 (2008).
Palmer, C. S. et al. MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep. 12, 565–573 (2011).
Mozdy, A. D., McCaffery, J. M. & Shaw, J. M. Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J. Cell Biol. 151, 367–380 (2000).
De Vos, K. J. et al. VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum. Mol. Genet. 21, 1299–1311 (2012).
Iwasawa, R., Mahul-Mellier, A.-L., Datler, C., Pazarentzos, E. & Grimm, S. Fis1 and Bap31 bridge the mitochondria–ER interface to establish a platform for apoptosis induction. EMBO J. 30, 556–568 (2011).
Palande, K. et al. Peroxiredoxin-controlled G-CSF signalling at the endoplasmic reticulum–early endosome interface. J. Cell Sci. 124, 3695–3705 (2011).
Xu, N. et al. The FATP1–DGAT2 complex facilitates lipid droplet expansion at the ER–lipid droplet interface. J. Cell Biol. 198, 895–911 (2012).
Knoblach, B. et al. An ER–peroxisome tether exerts peroxisome population control in yeast. EMBO J. 32, 2439–2453 (2013).
Acknowledgements
The authors thank Matt West, Jonathan Friedman, Jason Lee, Ashley Rowland and Patrick Chitwood for images used here, and Laura Westrate for comments on the manuscript. This work was supported by grants from the American Cancer Society and from the U.S. National Institutes of Health (NIH) (GM083977) to G.K.V.. M.J.P. was supported by a U.S. National Science Foundation (NSF) Graduate Research Fellowship (DGE 1144083) and by a pre-doctoral training grant from the NIH (T32 GM08759).
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Glossary
- Peripheral ER
-
The ER network that spans from the perinuclear region of the cell to the cell periphery.
- ER sliding
-
ER tubules attach to a motor protein on a stable microtubule. The motor protein then pulls the ER tubule along the microtubule.
- Early endosomes
-
Endosomes that have been recently internalized into cells and labelled with RAB5 GTPase, have a relatively low pH, and have not further internalized cargo, such as signalling receptors, from the plasma membrane into intraluminal vesicles.
- Late endosomes
-
Mature endosomes that have not yet fused with the lysosome. These endosomes are labelled with RAB7 GTPase, have a relatively high pH, and have abundant intraluminal vesicles internalized into the lumen for easier degradation of cargo when the late endosome fuses with the lysosome.
- Cortical ER
-
Peripheral ER that is found directly underneath and tethered to the plasma membrane.
- Microsomes
-
ER vesicles resulting from the breakage of the ER network as the ER is isolated from cells.
- Nucleoid
-
Mitochondrial DNA associated with proteins that compact into one region of the mitochondrion.
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Phillips, M., Voeltz, G. Structure and function of ER membrane contact sites with other organelles. Nat Rev Mol Cell Biol 17, 69–82 (2016). https://doi.org/10.1038/nrm.2015.8
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DOI: https://doi.org/10.1038/nrm.2015.8
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