Mol. Cells

The Interface Between ER and Mitochondria: Molecular Compositions and Functions

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Mitochondria and endoplasmic reticulum (ER) are essential organelles in eukaryotic cells, which play key roles in various biological pathways. Mitochondria are responsible for ATP production, maintenance of Ca2+ homeostasis and regulation of apoptosis, while ER is involved in protein folding, lipid metabolism as well as Ca2+ homeostasis. These organelles have their own functions, but they also communicate via mitochondrial-associated ER membrane (MAM) to provide another level of regulations in energy production, lipid process, Ca2+ buffering, and apoptosis. Hence, defects in MAM alter cell survival and death. Here, we review components forming the molecular junctions of MAM and how MAM regulates cellular functions. Furthermore, we discuss the effects of impaired ER-mitochondrial communication in various neurodegenerative diseases.

Keywords: ER-mitochondria tethering, mitochondrial-associated ER membrane (MAM), neurodegenerative disease


The interface between ER and mitochondria is called mitochondrial-associated ER membrane (MAM) (Fig. 1 and Table 1). Numerous studies found different molecules in MAM and have attempted to investigate biological roles of MAM, but it still is not yet fully understood. In yeast cells, a structure of protein complexes that connects ER and mitochondria called the ER-mitochondria encounter structure (ERMES), has been reported to contain Mdm12, Mdm34, Mdm10 and Mmm1 proteins (Kornmann et al., 2009). Mdm12 is a linker protein connecting ER membrane protein Mmm1 to mitochondrial outer membrane proteins, Mdm34 or Mdm10. This physical tethering establishes ERMES, which then allow efficient lipid transport by soluble lipid-carrier proteins such as CERT and OSBP (D’Angelo et al., 2008). Mutant proteins disrupting ERMES cause defects in phospholipid exchange between ER and mitochondria, resulting in impaired cellular growth or organelle recycling (Kornmann et al., 2009).

Figure F1
Composition of ER-mitochondria interfaceYeast-specific ERMES is composed by a multiprotein complex including ER protein Mmm1, cytosolic protein Mdm12, as well as mitochondrial protein Mdm34 and Mdm10. In mammalian cells, the ...
Table 1

Mammalian cells have more complicated protein complexes in the ER-mitochondria interface. Proteins in MAM either play a direct role in physical connection between ER and mitochondria or modulates the tethering complexes in MAM. MFN1 and 2 (MFN1/2), a mitochondrial fusion GTPase, localized to the outer membrane of mitochondria is found in the MAM complex. MFN1/2 plays a role in mitochondrial fusion together with OPA1, another mitochondrial fusion GTPase, located on the inner membrane of mitochondria (Cipolat et al., 2004). During mitochondrial fusion process, mitochondrial MFN1/2 assembles homo- or heterodimer complexes with MFN2 presented in ER membrane (de Brito and Scorrano, 2008; Detmer and Chan, 2007). Fis1 and BAP31 interaction is also found in MAM (Iwasawa et al., 2011). Fis1 located on the mitochondrial outer membrane recruits dynamin related protein 1 (DRP1) to mitochondrial fission sites (Stojanovski et al., 2004). BAP31 is a chaperone located on the ER membrane, which regulates degradation of misfolded protein and apoptotic pathway (Nguyen et al., 2000; Wakana et al., 2008). When Fis1 binds to BAP31 in MAM, apoptotic signals is conveyed to ER, initiating apoptotic pathway (Iwasawa et al., 2011). Another interaction at the interface of ER and mitochondria occurs between PTPIP51 and VAPB (De Vos et al., 2012). While PTPIP51 is a mitochondrial outer membrane protein that modulates cellular development and tumorigenesis (Yu et al., 2008); VAPB is an ER membrane protein involved in vesicle trafficking and unfolded protein response (Kanekura et al., 2006; Nishimura et al., 2004). However, VABP and PTPIP51 complex in MAM acts on different pathways such as Ca2+ regulation and autophagy (De Vos et al., 2012; Gomez-Suaga et al., 2017). PTPIP51 also connects to other mitochondrial proteins, ORP5 and ORP8 found in MAM. It is reported that mutations in the orp genes induce defective mitochondrial morphology and impaired respiratory chain system (Galmes et al., 2016), however, roles of PTPIP51-ORP in MAM are not clear. Another important molecular complex in MAM is IP3R-Grp75-VDAC interaction. IP3R is an inositol triphosphate-dependent calcium channel located on ER membrane, controlling Ca2+ efflux from ER to cytosol. IP3R plays a role in cellular differentiation, survival, and apoptosis (Joseph and Hajnoczky, 2007; Mikoshiba, 2007). VDAC is a mitochondrial outer membrane protein, which regulates Ca2+ influx to mitochondria together with mitochondrial calcium uniporter (MCU) (Hoppe, 2010). VDAC also modulates ATP release to cytosol and controls an apoptotic pathway (Colombini, 2012; Rostovtseva et al., 2005). Interestingly, IP3R and VDAC in MAM does not directly interact but require a linker protein, cytoplasmic Grp75 (Szabadkai et al., 2006). Grp75 is known as a chaperone protein and mostly located in the mitochondrial matrix, but a low level of Grp75 is found in the cytoplasm plasm and nucleus (Wadhwa et al., 2002). Cytoplasmic Grp75 linking IP3R and VDAC enables close juxtaposition between ER and mitochondria to regulate Ca2+ transfer from ER to mitochondria (Szabadkai et al., 2006). Several studies report this Ca2+ delivery to mitochondria requires MCU, and this complex is called IP3R-Grp75-VDAC-MCU calcium regulation axis (Rizzuto et al., 2009; Xu et al., 2018). Since Ca2+ is a key regulator involved in various biological functions, modulation of the IP3R-Grp75-VDAC-MCU complex likely plays important roles in diverse cellular functions.

Several proteins are reported to mediate ER-mitochondria communications by interacting with the ER-mitochondria tethering protein complexes. Phosphofurin acidic cluster sorting 2 protein (PACS-2) is a multifunctional cytoplasmic protein, which controls ER quality and induces apoptosis (Myhill et al., 2008; Simmen et al., 2005). Whether PACS-2 directly attaches to MAM is not clear, however, depletion of PACS-2 causes reduction of ER-mitochondria contact and generation of mitochondrial fragmentation (Simmen et al., 2005), suggesting that PACS-2 modulates ER-mitochondria contacts. Sigma non-opioid intracellular receptor 1 (SigR1) and Tespa1 associate with the IP3R-Grp75-VDAC-MCU calcium axis in MAM. Overexpression of SigR1 increases Ca2+ flux from the ER by interacting with Ankyrin and ER chaperone protein, BiP (Su et al., 2016; Wu and Bowen, 2008). Tespa1 binds to both IP3R and Grp75, and Tespa1 knockdown decreases the levels of mitochondrial and cytoplasmic Ca2+ (Matsuzaki et al., 2013), however its mechanism is not known. FUN14 domain containing 1 (FUNDC1) is another protein that modulates MAM dynamics. FUNDC1 interacts with Calnexin, a ER chaperone protein, and this binding competes with FUNDC1’s binding to Drp1 during early hypoxia. In later hypoxia condition FUNDC1 dissociates from Calnexin and instead interacts with Drp1, which then induces mitochondrial fission and mitophagy (Wu et al., 2016). Presenilin (PS) is a multifunctional protein involved in amyloid beta (Aβ) production pathway, and it is known that PS mutants cause familial Alzheimer’s disease (AD) (De Strooper, 2007). Interestingly, PS affects Ca2+ dynamics in MAM by interacting with MFN2. Thus, mutations in the ps2 gene interferes with Ca2+ delivery to mitochondria (Filadi et al., 2016; Zampese et al., 2011).

Physical interactions linking ER and mitochondria play roles not only in Ca2+ homeostasis and apoptosis, but in lipid transferring between the two organelles. Lipid synthesis is performed mostly in the ER but still requires cooperation of enzymes on the mitochondrial membrane, because ER and mitochondria have distinct lipid processing enzymes. For example, newly synthesized phosphatidylserine (PS) in ER is transferred to the mitochondrial inner membrane, where it converts to phosphatidylethanolamine (PE) by PS decarboxylase (PSD). PE then transports back to the ER membrane through MAM contact (Vance, 2014). While various studies have discovered molecules involved in the MAM structure and functions, a comprehensive understanding of the complex MAM system is still lacking.


ER is the major site of Ca2+ storage within a cell, and IP3R on ER is highly accumulated in MAM (Marchi and Pinton, 2014; Patergnani et al., 2011). Numerous forms of interactions between Ca2+ channels and regulators are found in MAM, which regulate Ca2+-dependent cellular functions as well as maintain Ca2+ homeostasis. Furthermore, elevated Ca2+ level in MAM activates Ca2+ influx to mitochondria through the IP3R-Grp75-VDAC-MCU complex. When the linker protein Grp75 is reduced, mitochondrial Ca2+ level is decreased, suggesting that Grp75 connects ER and mitochondria indirectly by interacting with both IP3R and VDAC. The resulting apposition of ER and mitochondria facilitates Ca2+ transfer from ER to mitochondria. Indeed, Grp75 knockdown prevents cell death due to excess Ca2+ in mitochondria (Honrath et al., 2017).

Proteins associated with the IP3R-Grp75-VDAC-MCU complex can modulate Ca2+ transfer between ER and mitochondria. SigR1 interacts with BiP in normal condition. However, when ER is under stress or when ER Ca2+ is depleted, SigR1 switches its interacting partner from BiP to IP3R. This process protects IP3R from degradation, resulting in restoration of Ca2+ transfer from the ER to mitochondria (Hayashi and Su, 2007). Tespa-1 binds to both Grp75 and IP3R in T-cells. Knockout of Tespa-1 impairs Ca2+ flux to both cytosol and mitochondria, which causes decreased Ca2+ signaling and ERK activation (Liang et al., 2017; Matsuzaki et al., 2012), suggesting that the Tespa-1-Grp75-IP3R complex regulates Ca2+ efflux from ER to cytosol or mitochondria. Other physical tethering complexes in MAM that facilitate efficient Ca2+ transfer between ER and mitochondria are the VAPB-PTPIP51 complex and the MFN complex. For example, genetic modification of the vapb gene disturbs Ca2+ transfer from from ER to mitochondrial in neuronal cells (De Vos et al., 2012). Mitochondria without MFN2 also decrease Ca2+ uptake upon IP3R activation (de Brito and Scorrano, 2008).

Since energy production and cell death can be triggered by different levels of Ca2+, MAM plays a key role in delicate refinement of Ca2+ level in mitochondria. Upregulation of mitochondrial Ca2+ in physiological condition activates mitochondrial enzymes, which facilitates TCA cycle and oxidative phosphorylation. Activities of α-ketoglutarate dehydrogenase, isocitrate dehydrogenase and pyruvate dehydrogenase are Ca2+- dependent enzymes (McCormack and Denton, 1993). ATP synthase is also Ca2+-dependent enzyme (Das and Harris, 1990). Thus, increased Ca2+ level in mitochondria enhances electron activity, resulting in elevated generation of ATP (Hansford and Zorov, 1998). In contrast, prolonged or excessive mitochondrial Ca2+ level activates apoptotic pathway. Increased Ca2+ flux from ER to mitochondria initiates oligomerization of Bcl-2-associated X protein (BAX), which translocates to mitochondrial membrane and increases permeability of mitochondrial membrane (Rostovtseva et al., 2005). Furthermore, mitochondrial permeability transition pore (PTP) is induced by high level of Ca2+ (Haworth and Hunter, 1979). PTP also increases mitochondrial membrane permeability, leading to apoptosis by releasing cytochrome c, apoptosis-inducing factor (AIF), and Smac/DIABLO (Petronilli et al., 2001). Cytochrome c and AIF initiates apoptosis through caspase cascade pathway, but Smac/DIABLO triggers cell death independently from the caspase cascade (Kroemer et al., 2007). Furthermore, MAM proteins such as PACS-2, Bid, Fis1, and Bap31 are involved in apoptosis. PACS-2 initiates apoptosis by recruiting Bid into mitochondrial membrane upon activation of cell death signals. To activate Bid, Fis1 cleaves Bap31 into p20Bap31, proapoptotic molecule, followed by p20Bap31 converting procaspase-8 to caspase-8 (Iwasawa et al., 2011). Caspase-8 then activates Bid, allowing releasing cytochrome c from mitochondria, which then forms apoptosome with caspase-3, 7 and 9 (Simmen et al., 2005).


Impaired ER-mitochondrial communications may lead to metabolic diseases, cancers, and neurodegenerative diseases. Numerous studies have observed structural or functional changes in MAM in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). AD is a neurodegenerative disease characterized by progressive loss of cognitive functions. AD patient brains contain accumulation of amyloid plaque composed of primarily of Aβ and neurofibrillary tangles containing mostly hyperphosphorylated Tau. PS is a subunit protein of γ-secretase, involved in the processing of amyloid precursor protein (APP). Several mutations in ps1, ps2 or app genes are observed in early onset familiar AD, and the mutated proteins cause mis-processing of APP, leading to Aβ plaque formation (O’Brien and Wong, 2011). It is interesting to note that PS and APP are highly localized in MAM, and γ-secretase activity is increased in the MAM fraction (Area-Gomez et al., 2009). Furthermore, PS and APP mutant display enhanced ER-mitochondria contact, thereby accelerating Ca2+ and phospholipids/cholesteryl esters transfer from the ER to mitochondria (Area-Gomez et al., 2012; Cheung et al., 2008). Other MAM proteins such as PS synthase, PACS-2, and SigR1 are also highly upregulated in AD patients and animal AD models (Hedskog et al., 2013; Stone and Vance, 2000). These findings suggest that MAM may play a key role in generating AD pathogenesis. It is plausible that increased mitochondrial Ca2+ may cause cell death in AD neurons, however exact functions of MAM in generating AD pathology remains unclear.

PD is a neurodegenerative disease that causes tremor and a progressive loss of movement, which are associated with degeneration of dopaminergic neurons in substantia nigra in the brain. Dopaminergic neurons in PD contain Lewy bodies, composed of mostly aggregation of α-synuclein (α-syn) (Maries et al., 2003). The α-syn protein is also enriched in MAM (Guardia-Laguarta et al., 2014). Mutations are found in the α-syn genes among familial PD patients, and these mutant α-syn decrease ER-mitochondria communication and induce mitochondrial fragmentation (Cali et al., 2012). Mutations found in parkin, dj-1, and pink1 genes are also related to PD. Neuronal excitotoxicity increases Parkin, which translocates to MAM (Van Laar et al., 2015), where Parkin can ubiquitinate MFN2 and disrupt ER-mitochondria tethering (McLelland et al., 2018). Furthermore, under the stress conditions, PINK1 recruits Parkin to the outer mitochondria membrane, which activates mitophagy (Matsuda et al., 2010). Another example is DJ-1 that is highly concentrated in MAM. Overexpression of DJ-1 increases ER-mitochondria tethering (Ottolini et al., 2013). Interestingly, these three PD related proteins, Parkin, Pink, and DJ-1, can interact with Grp75 (Davison et al., 2009). Together, these results suggest that ER-mitochondria tethering can play key roles in generating PD pathology. However, how and why these mutant proteins underlying PD pathology show opposite effects on the strength of the ER-mitochondria communication is not clear. Additional studies are required to provide a comprehensive view of how ER-mitochondria tethering affects PD.

ALS is a neurodegenerative disease caused by loss of motor neurons, resulting in gradual deterioration of muscles. Although SOD1 and other candidate genes are reported to associate with familial ALS, the exact cause of ALS is still not clear. However, a mutation in sigr1 is discovered in a juvenile form of ALS (Al-Saif et al., 2011). Moreover, SigR1 knockout mouse exhibits ALS phenotypes such as muscle weakness and motor neuron loss. Loss of SigR1 reduces ER-mitochondria tethering, which disrupts Ca2+ homeostasis in mitochondria and alters mitochondrial dynamics (Bernard-Marissal et al., 2015). Another MAM protein, VAPB is also mutated in familiar ALS (Nishimura et al., 2004). A mutant VAPB increases its affinity to PTPIP51 and strengthens VAPB-PTPIP51 tethering, which alters Ca2+ shuttling between ER and mitochondria (De Vos et al., 2012). Mutations in the tdp-43 genes are also found in familial ALS, and mutated TDP-43s have higher affinity for FUS (Stoica et al., 2014). Interestingly, TDP-43 and FUS interaction activates GSK3β, which disrupts VAPB-PTPIP51 and weakens ER-mitochondria tethering. Altogether, these results indicate that miscommunications between ER-mitochondria regardless of weakened or enhanced ER-mitochondria tethering plays a key role in various neurodegenerative diseases. It is tempting to speculate that strong ER-mitochondria tethering generates excessive Ca2+ influx into mitochondria, thereby activating apoptotic pathways. On the other hand, weak tethering fails to deliver the optimum amount of Ca2+ required to activate mitochondrial enzymes for ATP production. Thus, both strong or weak ER-tethering consequently affect cell survival, which is manifested in neuronal cell death in the disease. However, whether dysfunctional MAM is a cause or consequence of these neurodegenerative diseases remains to be elucidated.


In this review, we discuss the molecular compositions and functions of ER-mitochondria interface. It is now clear that various molecules in the ER-mitochondria tethering complex are important for Ca2+ or lipid homeostasis, and for cell survival and apoptotic regulation. Moreover, several proteins disrupting MAM structure or functions have been identified in neurodegenerative diseases such as AD, PD, and ALS. While numerous molecules have been found in MAM, new molecules that affect MAM are still being identified. This implies that new MAM functions are waiting to be discovered in different cellular environments, cell types, and disease conditions. Furthermore, the underlying mechanism of how MAM is associated with neurological disorders is not fully understood. Thus, future studies will require considerable efforts to precisely delineate the structure and function of MAM. A better understanding of MAM may contribute to new strategies to treat and prevent neurodegenerative diseases in the future.

Article information

Mol. Cells.Dec 31, 2018; 41(12): 1000-1007.
Published online 2018-12-12. doi:  10.14348/molcells.2018.0438
1Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea
2National Creative Research Initiative Center for Proteostasis, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea
Received November 29, 2018; Accepted December 9, 2018.
Articles from Mol. Cells are provided here courtesy of Mol. Cells


  • Al-Saif, A., Al-Mohanna, F., and Bohlega, S. (2011). A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 70, 913-919.
  • Area-Gomez, E., de Groof, A.J., Boldogh, I., Bird, T.D., Gibson, G.E., Koehler, C.M., Yu, W.H., Duff, K.E., Yaffe, M.P., and Pon, L.A. (2009). Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol. 175, 1810-1816.
  • Area-Gomez, E., Del Carmen Lara Castillo, M., Tambini, M.D., Guardia-Laguarta, C., de Groof, A.J., Madra, M., Ikenouchi, J., Umeda, M., Bird, T.D., and Sturley, S.L. (2012). Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J. 31, 4106-4123.
  • Bernard-Marissal, N., Medard, J.J., Azzedine, H., and Chrast, R. (2015). Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain. 138, 875-890.
  • Bernhard, W., and Rouiller, C. (1956). Close topographical relationship between mitochondria and ergastoplasm of liver cells in a definite phase of cellular activity. J Biophys Biochem Cytol. 2, 73-78.
  • Cali, T., Ottolini, D., Negro, A., and Brini, M. (2012). alpha-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J Biol Chem. 287, 17914-17929.
  • Cheung, K.H., Shineman, D., Muller, M., Cardenas, C., Mei, L., Yang, J., Tomita, T., Iwatsubo, T., Lee, V.M., and Foskett, J.K. (2008). Mechanism of Ca2+ disruption in Alzheimer’s disease by presenilin regulation of InsP3 receptor channel gating. Neuron. 58, 871-883.
  • Chung, J., Torta, F., Masai, K., Lucast, L., Czapla, H., Tanner, L.B., Narayanaswamy, P., Wenk, M.R., Nakatsu, F., and De Camilli, P. (2015). PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER–plasma membrane contacts. Science. 349, 428-432.
  • Cipolat, S., Martins de Brito, O., Dal Zilio, B., and Scorrano, L. (2004). OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci USA. 101, 15927-15932.
  • Colombini, M. (2012). VDAC structure, selectivity, and dynamics. Biochim Biophys Acta. 1818, 1457-1465.
  • Copeland, D.E., and Dalton, A.J. (1959). An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost. J Biophys Biochem Cytol. 5, 393-396.
  • Csordas, G., Varnai, P., Golenar, T., Roy, S., Purkins, G., Schneider, T.G., Balla, T., and Hajnoczky, G. (2010). Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell. 39, 121-132.
  • D’Angelo, G., Vicinanza, M., and De Matteis, M.A. (2008). Lipid-transfer proteins in biosynthetic pathways. Curr Opin Cell Biol. 20, 360-370.
  • Das, A.M., and Harris, D.A. (1990). Control of mitochondrial ATP synthase in heart cells: inactive to active transitions caused by beating or positive inotropic agents. Cardiovasc Res. 24, 411-417.
  • Davison, E.J., Pennington, K., Hung, C-C, Peng, J., Rafiq, R., Ostareck-Lederer, A., Ostareck, D.H., Ardley, H.C., Banks, R.E., and Robinson, P.A. (2009). Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function. PROTEOMICS. 9, 4284-4297.
  • de Brito, O.M., and Scorrano, L. (2008). Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature. 456, 605-610.
  • de Brito, O.M., and Scorrano, L. (2010). An intimate liaison: spatial organization of the endoplasmic reticulum-mitochondria relationship. EMBO J. 29, 2715-2723.
  • De Strooper, B. (2007). Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 8, 141-146.
  • De Vos, K.J., Morotz, G.M., Stoica, R., Tudor, E.L., Lau, K.F., Ackerley, S., Warley, A., Shaw, C.E., and Miller, C.C. (2012). VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet. 21, 1299-1311.
  • Detmer, S.A., and Chan, D.C. (2007). Functions and dysfunctions of mitochondrial dynamics. Nat Rev Mol Cell Biol. 8, 870-879.
  • Eisenberg-Bord, M., Shai, N., Schuldiner, M., and Bohnert, M. (2016). A tether is a tether is a tether: tethering at membrane contact sites. Dev Cell. 39, 395-409.
  • Filadi, R., Greotti, E., Turacchio, G., Luini, A., Pozzan, T., and Pizzo, P. (2016). Presenilin 2 modulates endoplasmic reticulum-mitochodria coupling by tuning the antagonistic effect of mitofusin 2. Cell Rep. 15, 2226-2238.
  • Galmes, R., Houcine, A., van Vliet, A.R., Agostinis, P., Jackson, C.L., and Giordano, F. (2016). ORP5/ORP8 localize to endoplasmic reticulum-mitochondria contacts and are involved in mitochondrial function. EMBO Rep. 17, 800-810.
  • Gomez-Suaga, P., Paillusson, S., Stoica, R., Noble, W., Hanger, D.P., and Miller, C.C.J. (2017). The ER-mitochondria tethering complex VAPB-PTPIP51 regulates autophagy. Curr Biol. 27, 371-385.
  • Guardia-Laguarta, C., Area-Gomez, E., Rub, C., Liu, Y., Magrane, J., Becker, D., Voos, W., Schon, E.A., and Przedborski, S. (2014). alpha-Synuclein is localized to mitochondria-associated ER membranes. J Neurosci. 34, 249-259.
  • Hansford, R.G., and Zorov, D. (1998). Role of mitochondrial calcium transport in the control of substrate oxidation. Mol Cell Biochem. 184, 359-369.
  • Harmon, M., Larkman, P., Hardingham, G., Jackson, M., and Skehel, P. (2017). A Bi-fluorescence complementation system to detect associations between the Endoplasmic reticulum and mitochondria. Sci Rep. 7, 17467.
  • Haworth, R.A., and Hunter, D.R. (1979). The Ca2+-induced membrane transition in mitochondria: II. Nature of the Ca2+ trigger site. Arch Biochem Biophys. 195, 460-467.
  • Hayashi, T., Rizzuto, R., Hajnoczky, G., and Su, T.P. (2009). MAM: more than just a housekeeper. Trends Cell Biol. 19, 81-88.
  • Hayashi, T., and Su, T.P. (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 131, 596-610.
  • Hedskog, L., Pinho, C.M., Filadi, R., Ronnback, A., Hertwig, L., Wiehager, B., Larssen, P., Gellhaar, S., Sandebring, A., and Westerlund, M. (2013). Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci USA. 110, 7916-7921.
  • Honrath, B., Metz, I., Bendridi, N., Rieusset, J., Culmsee, C., and Dolga, A.M. (2017). Glucose-regulated protein 75 determines ER-mitochondrial coupling and sensitivity to oxidative stress in neuronal cells. Cell Death Discov. 3, 17076.
  • Hoppe, U.C. (2010). Mitochondrial calcium channels. FEBS Lett. 584, 1975-1981.
  • Iwasawa, R., Mahul-Mellier, A.L., Datler, C., Pazarentzos, E., and Grimm, S. (2011). Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J. 30, 556-568.
  • Joseph, S.K., and Hajnoczky, G. (2007). IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond. Apoptosis. 12, 951-968.
  • Kanekura, K., Nishimoto, I., Aiso, S., and Matsuoka, M. (2006). Characterization of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated membrane protein-associated protein B (VAPB/ALS8). J Biol Chem. 281, 30223-30233.
  • Kornmann, B., Currie, E., Collins, S.R., Schuldiner, M., Nunnari, J., Weissman, J.S., and Walter, P. (2009). An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science. 325, 477-481.
  • Kroemer, G., Galluzzi, L., and Brenner, C. (2007). Mitochondrial membrane permeabilization in cell death. Physiol Rev. 87, 99-163.
  • Liang, J., Lyu, J., Zhao, M., Li, D., Zheng, M., Fang, Y., Zhao, F., Lou, J., Guo, C., and Wang, L. (2017). Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. Nat Commun. 8, 15732.
  • Liou, J., Fivaz, M., Inoue, T., and Meyer, T. (2007). Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc Natl Acad Sci USA. 104, 9301-9306.
  • Marchi, S., and Pinton, P. (2014). The mitochondrial calcium uniporter complex: molecular components, structure and physiopathological implications. J Physiol. 592, 829-839.
  • Maries, E., Dass, B., Collier, T.J., Kordower, J.H., and Steece-Collier, K. (2003). The role of alpha-synuclein in Parkinson’s disease: insights from animal models. Nat Rev Neurosci. 4, 727-738.
  • Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C.A., Sou, Y.S., Saiki, S., Kawajiri, S., and Sato, F. (2010). PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. 189, 211-221.
  • Matsuzaki, H., Fujimoto, T., Ota, T., Ogawa, M., Tsunoda, T., Doi, K., Hamabashiri, M., Tanaka, M., and Shirasawa, S. (2012). Tespa1 is a novel inositol 1,4,5-trisphosphate receptor binding protein in T and B lymphocytes. FEBS Open Bio. 2, 255-259.
  • Matsuzaki, H., Fujimoto, T., Tanaka, M., and Shirasawa, S. (2013). Tespa1 is a novel component of mitochondria-associated endoplasmic reticulum membranes and affects mitochondrial calcium flux. Biochem Biophys Res Commun. 433, 322-326.
  • McCormack, J.G., and Denton, R.M. (1993). Mitochondrial Ca2+ transport and the role of intramitochondrial Ca2+ in the regulation of energy metabolism. Dev Neurosci. 15, 165-173.
  • McLelland, G.L., Goiran, T., Yi, W., Dorval, G., Chen, C.X., Lauinger, N.D., Krahn, A.I., Valimehr, S., Rakovic, A., and Rouiller, I. (2018). Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy. Elife. , 7.
  • Merkwirth, C., and Langer, T. (2008). Mitofusin 2 builds a bridge between ER and mitochondria. Cell. 135, 1165-1167.
  • Mesmin, B., Bigay, J., Moser von Filseck, J., Lacas-Gervais, S., Drin, G., and Antonny, B. (2013). 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.
  • Mikoshiba, K. (2007). IP3 receptor/Ca2+ channel: from discovery to new signaling concepts. J Neurochem. 102, 1426-1446.
  • Murphy, S.E., and Levine, T.P. (2016). VAP, a versatile access point for the endoplasmic reticulum: review and analysis of FFAT-like motifs in the VAPome. Biochim Biophys Acta. 1861, 952-961.
  • Myhill, N., Lynes, E.M., Nanji, J.A., Blagoveshchenskaya, A.D., Fei, H., Simmen, K.C., Cooper, T.J., Thomas, G., Simmen, T., and Linstedt, A. (2008). The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell. 19, 2777-2788.
  • Nguyen, M., Breckenridge, D.G., Ducret, A., and Shore, G.C. (2000). Caspase-resistant BAP31 inhibits fas-mediated apoptotic membrane fragmentation and release of cytochrome c from mitochondria. Mol Biol Cell. 20, 6731-6740.
  • Nishimura, A.L., Mitne-Neto, M., Silva, H.C., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J.R., Gillingwater, T., and Webb, J. (2004). A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 75, 822-831.
  • O’Brien, R.J., and Wong, P.C. (2011). Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 34, 185-204.
  • Ottolini, D., Cali, T., Negro, A., and Brini, M. (2013). The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering. Hum Mol Genet. 22, 2152-2168.
  • Patergnani, S., Suski, J.M., Agnoletto, C., Bononi, A., Bonora, M., De Marchi, E., Giorgi, C., Marchi, S., Missiroli, S., and Poletti, F. (2011). Calcium signaling around mitochondria associated membranes (MAMs). Cell Commun Signal. 9, 19.
  • Peretti, D., Dahan, N., Shimoni, E., Hirschberg, K., Lev, S., and Malhotra, V. (2008). 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.
  • Petronilli, V., Penzo, D., Scorrano, L., Bernardi, P., and Di Lisa, F. (2001). The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem. 276, 12030-12034.
  • Prinz, W.A. (2014). Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics. J Cell Biol. 205, 759-769.
  • Raiborg, C., Wenzel, E.M., Pedersen, N.M., Olsvik, H., Schink, K.O., Schultz, S.W., Vietri, M., Nisi, V., Bucci, C., and Brech, A. (2015). Repeated ER-endosome contacts promote endosome translocation and neurite outgrowth. Nature. 520, 234-238.
  • Rizzuto, R., Marchi, S., Bonora, M., Aguiari, P., Bononi, A., De Stefani, D., Giorgi, C., Leo, S., Rimessi, A., and Siviero, R. (2009). Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta. 1787, 1342-1351.
  • Rostovtseva, T.K., Tan, W., and Colombini, M. (2005). On the role of VDAC in apoptosis: fact and fiction. J Bioenerg Biomembr. 37, 129-142.
  • Rowland, A.A., Chitwood, P.J., Phillips, M.J., and Voeltz, G.K. (2014). ER contact sites define the position and timing of endosome fission. Cell. 159, 1027-1041.
  • Rowland, A.A., and Voeltz, G.K. (2012). Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol. 13, 607-625.
  • Simmen, T., Aslan, J.E., Blagoveshchenskaya, A.D., Thomas, L., Wan, L., Xiang, Y., Feliciangeli, S.F., Hung, C.H., Crump, C.M., and Thomas, G. (2005). PACS-2 controls endoplasmic reticulum–mitochondria communication and Bid-mediated apoptosis. EMBO J. 24, 717-729.
  • Stoica, R., De Vos, K.J., Paillusson, S., Mueller, S., Sancho, R.M., Lau, K.F., Vizcay-Barrena, G., Lin, W.L., Xu, Y.F., and Lewis, J. (2014). ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun. 5, 3996.
  • Stojanovski, D., Koutsopoulos, O.S., Okamoto, K., and Ryan, M.T. (2004). Levels of human Fis1 at the mitochondrial outer membrane regulate mitochondrial morphology. J Cell Sci. 117, 1201-1210.
  • Stone, S.J., and Vance, J.E. (2000). Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes. J Biol Chem. 275, 34534-34540.
  • Su, T.P., Su, T.C., Nakamura, Y., and Tsai, S.Y. (2016). The sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci. 37, 262-278.
  • Szabadkai, G., Bianchi, K., Varnai, P., De Stefani, D., Wieckowski, M.R., Cavagna, D., Nagy, A.I., Balla, T., and Rizzuto, R. (2006). Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol. 175, 901-911.
  • Van Laar, V.S., Roy, N., Liu, A., Rajprohat, S., Arnold, B., Dukes, A.A., Holbein, C.D., and Berman, S.B. (2015). Glutamate excitotoxicity in neurons triggers mitochondrial and endoplasmic reticulum accumulation of Parkin, and, in the presence of N-acetyl cysteine, mitophagy. Neurobiol Dis. 74, 180-193.
  • Vance, J.E. (2014). MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta. 1841, 595-609.
  • Wadhwa, R., Taira, K., and Kaul, S.C. (2002). An Hsp70 family chaperone, mortalin/mthsp70/PBP74/Grp75: what, when, and where?. Cell Stress Chaperones. 7, 309.
  • Wakana, Y., Takai, S., Nakajima, Ki, Tani, K., Yamamoto, A., Watson, P., Stephens, D.J., Hauri, H.P., Tagaya, M., and Linstedt, A. (2008). Bap31 is an itinerant protein that moves between the peripheral endoplasmic reticulum (ER) and a juxtanuclear compartment related to ER-associated degradation. Mol Biol Cell. 19, 1825-1836.
  • Wu, H., Carvalho, P., and Voeltz, G.K. (2018). Here, there, and everywhere: the importance of ER membrane contact sites. Science. , 361.
  • Wu, W., Lin, C., Wu, K., Jiang, L., Wang, X., Li, W., Zhuang, H., Zhang, X., Chen, H., and Li, S. (2016). FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions. EMBO J. 35, 1368-1384.
  • Wu, Z., and Bowen, W.D. (2008). Role of sigma-1 receptor C-terminal segment in inositol 1,4,5-trisphosphate receptor activation: constitutive enhancement of calcium signaling in MCF-7 tumor cells. J Biol Chem. 283, 28198-28215.
  • Xu, H., Guan, N., Ren, Y.L., Wei, Q.J., Tao, Y.H., Yang, G.S., Liu, X.Y., Bu, D.F., Zhang, Y., and Zhu, S.N. (2018). IP3R-Grp75-VDAC1-MCU calcium regulation axis antagonists protect podocytes from apoptosis and decrease proteinuria in an Adriamycin nephropathy rat model. BMC Nephrol. 19, 140.
  • Yu, C., Han, W., Shi, T., Lv, B., He, Q., Zhang, Y., Li, T., Zhang, Y., Song, Q., and Wang, L. (2008). PTPIP51, a novel 14-3-3 binding protein, regulates cell morphology and motility via Raf-ERK pathway. Cell Signal. 20, 2208-2220.
  • Zampese, E., Fasolato, C., Kipanyula, M.J., Bortolozzi, M., Pozzan, T., and Pizzo, P. (2011). Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. Proc Natl Acad Sci USA. 108, 2777-2782.

Figure 1

Composition of ER-mitochondria interface
Yeast-specific ERMES is composed by a multiprotein complex including ER protein Mmm1, cytosolic protein Mdm12, as well as mitochondrial protein Mdm34 and Mdm10. In mammalian cells, the interface between ER and mitochondria contains MFN2-MFN1/2, BAP31-Fis1, IP3R-Grp75-VDAC, and PTPIP51-VAPB or −ORP5/8 tethering complexes, which makes the two organelles close juxtaposition. Other single proteins, such as PS2, PACS-2, Tespa1, SigR1 and MCU, are also associated in the ER-mitochondria tethering complexes.

Table 1

List of protein components involved in MAM

Species Protein components Biological roles Possible related diseases Reference
Yeast Mmm1-Mdm12-Mdm34-Mdm10 Efficient phospholipid exchange Kornmann et al., 2009
Mammalian IP3R-Grp75-VDAC1 Ca2+ regulation PD Szabadkai et al., 2006; Davison et al., 2009
BAP31-Fis1 Initiation of apoptosis Iwasawa et al., 2011
VAPB-PTPIP51 Ca2+ regulation and autophagy ALS De Vos et al., 2012; Gomez-Suaga et al., 2017; Nishimura et al., 2004; De Vos et al., 2012
ORP5/8-PTPIP51 Lipid transfer Galmes et al., 2016
MFN2-MFN1/2 Physical tethering PD de Brito and Scorrano, 2008; McLelland et al., 2018
PACS-2 Regulation of apoptosis AD Simmen et al., 2005; Hedskog et al., 2013
SigR1 Ca2+ regulation by interacting with Ankyrin and BiP AD, ALS Su et al., 2016; Wu and Bowen, 2008; Hedskog et al., 2013; Al-Saif et al., 2011; Bernard-Marissal et al., 2015
Tespa1 Ca2+ regulation by interacting with IP3R and Grp75 Matsuzaki et al., 2013
FUNDC1 Regulation of mitochondrial fission and mitophagy in hypoxia condition Wu et al., 2016
PS Ca2+ regulation by interacting with MFN2 AD Filadi et al., 2016; Zampese et al., 2011; Area-Gomez et al., 2012; Cheung et al., 2008