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Mitochondria-Associated Membranes and ER Stress

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Coordinating Organismal Physiology Through the Unfolded Protein Response

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 414))

Abstract

The endoplasmic reticulum (ER) is a crucial organelle for coordinating cellular Ca2+ signaling and protein synthesis and folding. Moreover, the dynamic and complex membranous structures constituting the ER allow the formation of contact sites with other organelles and structures, including among others the mitochondria and the plasma membrane (PM). The contact sites that the ER form with mitochondria is a hot topic in research, and the nature of the so-called mitochondria-associated membranes (MAMs) is continuously evolving. The MAMs consist of a proteinaceous tether that physically connects the ER with mitochondria. The MAMs harness the main functions of both organelles to form a specialized subcompartment at the interface of the ER and mitochondria. Under homeostatic conditions, MAMs are crucial for the efficient transfer of Ca2+ from the ER to mitochondria, and for proper mitochondria bioenergetics and lipid synthesis. MAMs are also believed to be the master regulators of mitochondrial shape and motility, and to form a crucial site for autophagosome assembly. Not surprisingly, MAMs have been shown to be a hot spot for the transfer of stress signals from the ER to mitochondria, most notably under the conditions of loss of ER proteostasis, by engaging the unfolded protein response (UPR). In this chapter after an introduction on ER biology and ER stress, we will review the emerging and key signaling roles of the MAMs, which have a root in cellular processes and signaling cascades coordinated by the ER.

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Abbreviations

ACAT:

acyl-CoA:cholesterol acyltransferase

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

ATG:

Autophagy-related gene

BiP:

Immunoglobulin heavy chain-binding protein

Ca2+:

Calcium

Cav-1:

Caveolin-1

cER:

Cortical endoplasmic reticulum

CHOP:

C/EBP homologous protein

DAG:

Diacylglycerol

Drp1:

Dynamin-1-like protein

eIF2α:

Eukaryotic initiation factor 2 alpha

ER:

Endoplasmic reticulum

ERAD:

ER-associated protein degradation

ERMES:

ER–mitochondria encounter structure

Ero1α:

ER oxidoreductin 1 alpha

Fis1:

Mitochondrial fission protein 1

GADD34:

Growth arrest and DNA damage-inducible gene 34

GED:

GTPase effector domain

Grp78:

Glucose-regulated protein 78

Grp75:

Glucose-regulated protein 75

GST:

Glutathione-S-tranferase

GTP:

Guanosine tri-phosphate

HO-1:

Heme-oxygenase

HSP:

Heat-shock protein

IMM:

Inner mitochondrial membrane

IP3R:

Inositol 1, 4, 5-trisphosphate receptor

IP3:

Inositol trisphosphate

IRE1:

Inositol-requiring enzyme 1

JNK:

c-Jun N-terminal kinase

MAMs:

Mitochondria-associated membranes

MCU:

Mitochondrial Ca2+ uniporter

MCUR1:

Mitochondrial Ca2+ uniporter regulator

Mff:

Mitochondrial fission factor

MFN:

Mitofusin

MOMP:

Mitochondrial outer membrane permeabilization

NLRP3:

Nucleotide-binding oligomerization domain (NOD)-like receptor family 3

NRF2:

Nuclear factor (erythroid-derived 2)-like 2

OMM:

Outer mitochondrial membrane

Orai1:

Calcium release-activated calcium channel protein 1

ORD:

OSBP-related domain

ORP:

Oxysterol-binding protein (OSBP)-related protein

PACS2:

Phosphofurin acidic pluster porting protein 2

PC:

Phosphatidylcholine

PDI:

Protein disulfide isomerase

PE:

Phosphatidylethanolamine

PERK:

Double-stranded RNA-activated protein kinase (PKR)-like ER kinase

PH:

Pleckstrin homology

PI4P:

Phosphatidylinositol 4-Phosphate

PKA:

Protein kinase A

PM:

Plasma membrane

PML:

Promyelocytic leukemia

PP1:

Protein phosphatase 1

PS:

Phosphatidylserine

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

PTPIP51:

Protein tyrosine phosphatase-interacting protein 51

RER:

Rough ER

RHOT:

Mitochondrial Rho GTPase

RIDD:

Regulated IRE1-dependent decay of mRNA

ROS:

Reactive oxygen species

RyR:

Ryanodine receptor

S1T:

Truncated form of SERCA

S1R:

Sigma R1 receptor

SER:

Smooth ER

SERCA:

Sarco/endoplasmic reticulum Ca2+ ATPase

SOCE:

Store-operated calcium entry

STIM1:

Stromal interaction molecule 1

Stx17:

Syntaxin 17

Tespa-1:

Thymocyte-expressed, positive selection-associated gene 1

TXNIP:

Thioredoxin-interacting protein

TRAF2:

TNFR-associated factor 2

UPR:

Unfolded protein response

VAP:

VAMP-associated proteins

VAPB:

Vesicle-associated membrane protein-associated protein B and C

VDAC1:

Voltage-dependent anion channel 1

XBP1:

X-box binding protein 1

References

  • Achleitner G, Gaigg B, Krasser A, Kainersdorfer E, Kohlwein SD, Perktold A, Zellnig G, Daum G (1999) Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact. Eur J Biochem 264:545–553

    Article  CAS  PubMed  Google Scholar 

  • Anelli T, Bergamelli L, Margittai E, Rimessi A, Fagioli C, Malgaroli A, Pinton P, Ripamonti M, Rizzuto R, Sitia R (2012) Ero1α regulates Ca(2+) fluxes at the endoplasmic reticulum-mitochondria interface (MAM). Antioxid Redox Signal 16:1077–1087

    Article  CAS  PubMed  Google Scholar 

  • Area-Gomez E, Castillo MDCL, Tambini MD, Guardia-Laguarta C, De Groof AJ, Madra M, Ikenouchi J, Umeda M, Bird TD, Sturley SL, Schon EA (2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31:4106–4123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berridge MJ (2002) The endoplasmic reticulum: a multifunctional signaling organelle. Cell Calcium 32:235–249

    Article  CAS  PubMed  Google Scholar 

  • Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4:517–529

    Article  CAS  PubMed  Google Scholar 

  • Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (2003) Cytochrome c binds to inositol (1, 4, 5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5:1051–1061

    Article  CAS  PubMed  Google Scholar 

  • Bononi A, Bonora M, Marchi S, Missiroli S, Poletti F, Giorgi C, Pandolfi PP, Pinton P (2013) Identification of PTEN at the ER and MAMs and its regulation of Ca(2+) signaling and apoptosis in a protein phosphatase-dependent manner. Cell Death Differ 20:1631–1643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bosch M, Mari M, Herms A, Fernandez A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, Gonzalez-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, Garcia-Ruiz C, Perez-Navarro E, Fernandez-Checa JC, Pol A (2011) Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biol 21:681–686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouman L, Schlierf A, Lutz AK, Shan J, Deinlein A, Kast J, Galehdar Z, Palmisano V, Patenge N, Berg D, Gasser T, Augustin R, Trumbach D, Irrcher I, Park DS, Wurst W, Kilberg MS, Tatzelt J, Winklhofer KF (2011) Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ 18:769–782

    Article  CAS  PubMed  Google Scholar 

  • Bravo R, Vicencio JM, Parra V, Troncoso R, Munoz JP, Bui M, Quiroga C, Rodriguez AE, Verdejo HE, Ferreira J, Iglewski M, Chiong M, Simmen T, Zorzano A, Hill JA, Rothermel BA, Szabadkai G, Lavandero S (2011) Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress. J Cell Sci 124:2143–2152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brough D, Schell MJ, Irvine RF (2005) Agonist-induced regulation of mitochondrial and endoplasmic reticulum motility. Biochem J 392:291–297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415:92–96

    Article  ADS  CAS  PubMed  Google Scholar 

  • Cali T, Ottolini D, Negro A, Brini M (2013) Enhanced parkin levels favor ER-mitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta 1832:495–508

    Article  CAS  PubMed  Google Scholar 

  • Chami M, Oules B, Szabadkai G, Tacine R, Rizzuto R, Paterlini-Brechot P (2008) Role of SERCA1 truncated isoform in the proapoptotic calcium transfer from ER to mitochondria during ER stress. Mol Cell 32:641–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu CT (2010) A pivotal role for PINK1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet 19:R28–R37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung J, Torta F, Masai K, Lucast L, Czapla H, Tanner LB, Narayanaswamy P, Wenk MR, Nakatsu F, de Camilli P (2015) Intracellular Transport. PI4P/phosphatidylserine countertransport at ORP5- and ORP8-mediated ER-plasma membrane contacts. Science 349:428–432

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Csordas G, Renken C, Varnai P, Walter L, Weaver D, Buttle KF, Balla T, Mannella CA, Hajnoczky G (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174:915–921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Csordas G, Varnai P, Golenar T, Roy S, Purkins G, Schneider TG, Balla T, Hajnoczky G (2010) Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface. Mol Cell 39:121–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  ADS  PubMed  CAS  Google Scholar 

  • Dickey AS, Strack S (2011) PKA/AKAP1 and PP2A/Bbeta2 regulate neuronal morphogenesis via Drp1 phosphorylation and mitochondrial bioenergetics. J Neurosci 31:15716–15726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dinner AR, Sali A, Smith LJ, Dobson CM, Karplus M (2000) Understanding protein folding via free-energy surfaces from theory and experiment. Trends Biochem Sci 25:331–339

    Article  CAS  PubMed  Google Scholar 

  • Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci U S A 112:E2174–E2181

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Filadi R, Greotti E, Turacchio G, Luini A, Pozzan T, Pizzo P (2016) Presenilin 2 modulates endoplasmic reticulum-mitochondria coupling by tuning the antagonistic effect of mitofusin 2. Cell Rep 15:2226–2238

    Article  CAS  PubMed  Google Scholar 

  • Fransson A, Ruusala A, Aspenstrom P (2003) Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis. J Biol Chem 278:6495–6502

    Article  CAS  PubMed  Google Scholar 

  • Fransson S, Ruusala A, Aspenstrom P (2006) The atypical Rho GTPases miro-1 and miro-2 have essential roles in mitochondrial trafficking. Biochem Biophys Res Commun 344:500–510

    Article  CAS  PubMed  Google Scholar 

  • Friedman JR, Lackner LL, West M, Dibenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334:358–362

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujimoto M, Hayashi T, Su TP (2012) The role of cholesterol in the association of endoplasmic reticulum membranes with mitochondria. Biochem Biophys Res Commun 417:635–639

    Article  CAS  PubMed  Google Scholar 

  • Furuichi T, Yoshikawa S, Miyawaki A, Wada K, Maeda N, Mikoshiba K (1989) Primary structure and functional expression of the inositol 1, 4, 5-trisphosphate-binding protein P400. Nature 342:32–38

    Article  ADS  CAS  PubMed  Google Scholar 

  • Galmes R, Houcine A, Van Vliet AR, Agostinis P, Jackson CL, Giordano F (2016) ORP5/ORP8 localize to endoplasmic reticulum-mitochondria contacts and are involved in mitochondrial function. EMBO Rep 17(6):800–810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giacomello M, Drago I, Bortolozzi M, Scorzeto M, Gianelle A, Pizzo P, Pozzan T (2010) Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels. Mol Cell 38:280–290

    Article  CAS  PubMed  Google Scholar 

  • Gilady SY, Bui M, Lynes EM, Benson MD, Watts R, Vance JE, Simmen T (2010) Ero1α requires oxidizing and normoxic conditions to localize to the mitochondria-associated membrane (MAM). Cell Stress Chaperones 15:619–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giorgi C, de Stefani D, Bononi A, Rizzuto R, Pinton P (2009) Structural and functional link between the mitochondrial network and the endoplasmic reticulum. Int J Biochem Cell Biol 41:1817–1827

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giorgi C, Ito K, Lin HK, Santangelo C, Wieckowski MR, Lebiedzinska M, Bononi A, Bonora M, Duszynski J, Bernardi R, Rizzuto R, Tacchetti C, Pinton P, Pandolfi PP (2010) PML regulates apoptosis at endoplasmic reticulum by modulating calcium release. Science 330:1247–1251

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorlach A, Klappa P, Kietzmann T (2006) The endoplasmic reticulum: folding, calcium homeostasis, signaling, and redox control. Antioxid Redox Signal 8:1391–1418

    Article  PubMed  Google Scholar 

  • Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, Lippincott-Schwartz J (2010) Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell 141:656–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, Amano A, Yoshimori T (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–393

    Article  ADS  CAS  PubMed  Google Scholar 

  • Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15:481–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harding HP, Zhang Y, Ron D (1999) Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397:271–274

    Article  ADS  CAS  PubMed  Google Scholar 

  • Hayashi T, Fujimoto M (2010) Detergent-resistant microdomains determine the localization of sigma-1 receptors to the endoplasmic reticulum-mitochondria junction. Mol Pharmacol 77:517–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi T, Rizzuto R, Hajnoczky G, Su TP (2009) MAM: more than just a housekeeper. Trends Cell Biol 19:81–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayashi T, Su TP (2003) Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther 306:718–725

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596–610

    Article  CAS  PubMed  Google Scholar 

  • Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He CC, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hendershot LM (2004) The ER function BiP is a master regulator of ER function. Mt Sinai J Med 71:289–297

    PubMed  Google Scholar 

  • Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102

    Article  CAS  PubMed  Google Scholar 

  • Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS (2009) Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 186:323–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ingerman E, Perkins EM, Marino M, Mears JA, McCaffery JM, Hinshaw JE, Nunnari J (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. J Cell Biol 170:1021–1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwasawa R, Mahul-Mellier AL, Datler C, Pazarentzos E, Grimm S (2011) Fis1 and Bap31 bridge the mitochondria-ER interface to establish a platform for apoptosis induction. EMBO J 30:556–568

    Article  CAS  PubMed  Google Scholar 

  • Jager R, Bertrand MJ, Gorman AM, Vandenabeele P, Samali A (2012) The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress. Biol Cell 104:259–270

    Article  CAS  PubMed  Google Scholar 

  • Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030

    Article  CAS  PubMed  Google Scholar 

  • Kirichok Y, Krapivinsky G, Clapham DE (2004) The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427:360–364

    Article  ADS  CAS  PubMed  Google Scholar 

  • Kornmann B, Osman C, Walter P (2011) The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections. Proc Natl Acad Sci U S A 108:14151–14156

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87:99–163

    Article  CAS  PubMed  Google Scholar 

  • Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23:7448–7459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lynes EM, Bui M, Yap MC, Benson MD, Schneider B, Ellgaard L, Berthiaume LG, Simmen T (2012) Palmitoylated TMX and calnexin target to the mitochondria-associated membrane. EMBO J 31:457–470

    Article  CAS  PubMed  Google Scholar 

  • Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18:716–731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mallilankaraman K, Cardenas C, Doonan PJ, Chandramoorthy HC, Irrinki KM, Golenar T, Csordas G, Madireddi P, Yang J, Muller M, Miller R, Kolesar JE, Molgo J, Kaufman B, Hajnoczky G, Foskett JK, Madesh M (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336–1343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuzaki H, Fujimoto T, Tanaka M, 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

    Article  CAS  PubMed  Google Scholar 

  • Maurel M, Chevet E, Tavernier J, Gerlo S (2014) Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci 39:245–254

    Article  CAS  PubMed  Google Scholar 

  • McCormack JG, Denton RM (1980) Role of calcium ions in the regulation of intramitochondrial metabolism. Properties of the Ca2+-sensitive dehydrogenases within intact uncoupled mitochondria from the white and brown adipose tissue of the rat. Biochem J 190:95–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCracken AA, Brodsky JL (2003) Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD). BioEssays 25:868–877

    Article  CAS  PubMed  Google Scholar 

  • Moenner M, Pluquet O, Bouchecareilh M, Chevet E (2007) Integrated endoplasmic reticulum stress responses in cancer. Cancer Res 67:10631–10634

    Article  CAS  PubMed  Google Scholar 

  • Muhlberg AB, Warnock DE, Schmid SL (1997) Domain structure and intramolecular regulation of dynamin GTPase. EMBO J 16:6676–6683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Munoz JP, Ivanova S, Sanchez-Wandelmer J, Martinez-Cristobal P, Noguera E, Sancho A, Diaz-Ramos A, Hernandez-Alvarez MI, Sebastian D, Mauvezin C, Palacin M, Zorzano A (2013) Mfn2 modulates the UPR and mitochondrial function via repression of PERK. EMBO J 32:2348–2361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Myhill N, Lynes EM, Nanji JA, Blagoveshchenskaya AD, Fei H, Simmen KC, Cooper TJ, Thomas G, Simmen T (2008) The subcellular distribution of calnexin is mediated by PACS-2. Mol Biol Cell 19:2777–2788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naon D, Zaninello M, Giacomello M, Varanita T, Grespi F, Lakshminaranayan S, Serafini A, Semenzato M, Herkenne S, Hernandez-Alvarez MI, Zorzano A, De Stefani D, Dorn GW 2nd, Scorrano L (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci U S A 113:11249–11254

    Google Scholar 

  • Nguyen TT, Lewandowska A, Choi JY, Markgraf DF, Junker M, Bilgin M, Ejsing CS, Voelker DR, Rapoport TA, Shaw JM (2012) Gem1 and ERMES do not directly affect phosphatidylserine transport from ER to mitochondria or mitochondrial inheritance. Traffic 13:880–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Noack J, Molinari M (2014) Protein trafficking: RESETting proteostasis. Nat Chem Biol 10:881–882

    Article  CAS  PubMed  Google Scholar 

  • Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SH, Blackstone C (2010) Further assembly required: construction and dynamics of the endoplasmic reticulum network. EMBO Rep 11:515–521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penno A, Hackenbroich G, Thiele C (2013) Phospholipids and lipid droplets. Biochim Biophys Acta 1831:589–594

    Article  CAS  PubMed  Google Scholar 

  • Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R (2008) Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene 27:6407–6418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pizzo P, Drago I, Filadi R, Pozzan T (2012) Mitochondrial Ca(2+) homeostasis: mechanism, role, and tissue specificities. Pflugers Arch 464:3–17

    Article  CAS  PubMed  Google Scholar 

  • Pizzo P, Pozzan T (2007) Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol 17:511–517

    Article  CAS  PubMed  Google Scholar 

  • Pollard MG, Travers KJ, Weissman JS (1998) Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum. Mol Cell 1:171–182

    Article  CAS  PubMed  Google Scholar 

  • Porter KR, Claude A, Fullam EF (1945) A study of tissue culture cells by electron microscopy: methods and preliminary observations. J Exp Med 81:233–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Preissler S, Rato C, Chen R, Antrobus R, Ding S, Fearnley IM, Ron D (2015) AMPylation matches BiP activity to client protein load in the endoplasmic reticulum. Elife 4:e12621

    PubMed  PubMed Central  Google Scholar 

  • Rizzuto R, Pinton P, Carrington W, Fay FS, Fogarty KE, Lifshitz LM, Tuft RA, Pozzan T (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280:1763–1766

    Article  ADS  CAS  PubMed  Google Scholar 

  • Rizzuto R, Pozzan T (2006) Microdomains of intracellular Ca2+: molecular determinants and functional consequences. Physiol Rev 86:369–408

    Article  CAS  PubMed  Google Scholar 

  • Roberts-Thomson SJ, Peters AA, Grice DM, Monteith GR (2010) ORAI-mediated calcium entry: mechanism and roles, diseases and pharmacology. Pharmacol Ther 127:121–130

    Article  CAS  PubMed  Google Scholar 

  • Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  PubMed  Google Scholar 

  • Ruby JR, Dyer RF, Skalko RG (1969) Continuities between mitochondria and endoplasmic reticulum in the mammalian ovary. Z Zellforsch Mikrosk Anat 97:30–37

    Article  CAS  PubMed  Google Scholar 

  • Rusinol AE, Cui Z, Chen MH, Vance JE (1994) 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 269:27494–27502

    CAS  PubMed  Google Scholar 

  • Rysman E, Brusselmans K, Scheys K, Timmermans L, Derua R, Munck S, van Veldhoven PP, Waltregny D, Daniels VW, Machiels J, Vanderhoydonc F, Smans K, Waelkens E, Verhoeven G, Swinnen JV (2010) De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Res 70:8117–8126

    Article  CAS  PubMed  Google Scholar 

  • Sammels E, Parys JB, Missiaen L, de Smedt H, Bultynck G (2010) Intracellular Ca2+ storage in health and disease: a dynamic equilibrium. Cell Calcium 47:297–314

    Article  CAS  PubMed  Google Scholar 

  • Sano R, Annunziata I, Patterson A, Moshiach S, Gomero E, Opferman J, Forte M, D’Azzo A (2009) GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Mol Cell 36:500–511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saotome M, Safiulina D, Szabadkai G, Das S, Fransson A, Aspenstrom P, Rizzuto R, Hajnoczky G (2008) Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci U S A 105:20728–20733

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Schrepfer E, Scorrano L (2016) Mitofusins, from Mitochondria to Metabolism. Mol Cell 61:683–694

    Article  CAS  PubMed  Google Scholar 

  • Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    Article  PubMed  CAS  Google Scholar 

  • Scorrano L (2013) Keeping mitochondria in shape: a matter of life and death. Eur J Clin Invest 43:886–893

    Article  CAS  PubMed  Google Scholar 

  • Shen WW, Frieden M, Demaurex N (2011) Remodelling of the endoplasmic reticulum during store-operated calcium entry. Biol Cell 103:365–380

    Article  CAS  PubMed  Google Scholar 

  • Shiao YJ, Balcerzak B, Vance JE (1998) A mitochondrial membrane protein is required for translocation of phosphatidylserine from mitochondria-associated membranes to mitochondria. Biochem J 331(Pt 1):217–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata Y, Shemesh T, Prinz WA, Palazzo AF, Kozlov MM, Rapoport TA (2010) Mechanisms determining the morphology of the peripheral ER. Cell 143:774–788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306:990–995

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Simmen T, Aslan JE, Blagoveshchenskaya AD, Thomas L, Wan L, Xiang Y, Feliciangeli SF, Hung CH, Crump CM, Thomas G (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24:717–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steenbergen R, Nanowski TS, Beigneux A, Kulinski A, Young SG, Vance JE (2005) Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J Biol Chem 280:40032–40040

    Article  CAS  PubMed  Google Scholar 

  • Stefan CJ, Manford AG, Baird D, Yamada-Hanff J, Mao Y, Emr SD (2011) Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites. Cell 144:389–401

    Article  CAS  PubMed  Google Scholar 

  • Stevens FJ, Argon Y (1999) Protein folding in the ER. Semin Cell Dev Biol 10:443–454

    Article  CAS  PubMed  Google Scholar 

  • Stoica R, de Vos KJ, Paillusson S, Mueller S, Sancho RM, Lau KF, Vizcay-Barrena G, Lin WL, Xu YF, Lewis J, Dickson DW, Petrucelli L, Mitchell JC, Shaw CE, Miller CC (2014) ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun 5:3996

    ADS  CAS  PubMed  Google Scholar 

  • Szabadkai G, Bianchi K, Varnai P, de Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175:901–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tooze SA, Yoshimori T (2010) The origin of the autophagosomal membrane. Nat Cell Biol 12:831–835

    Article  CAS  PubMed  Google Scholar 

  • Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287:664–666

    Article  ADS  CAS  PubMed  Google Scholar 

  • Vance JE (1990) Phospholipid synthesis in a membrane fraction associated with mitochondria. J Biol Chem 265:7248–7256

    CAS  PubMed  Google Scholar 

  • Varnai P, Balla A, Hunyady L, Balla T (2005) Targeted expression of the inositol 1, 4, 5-triphosphate receptor (IP3R) ligand-binding domain releases Ca2+ via endogenous IP3R channels. Proc Natl Acad Sci U S A 102:7859–7864

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Verfaillie T, Garg AD, Agostinis P (2013) Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett 332:249–264

    Article  CAS  PubMed  Google Scholar 

  • Verfaillie T, Rubio N, Garg AD, Bultynck G, Rizzuto R, Decuypere JP, Piette J, Linehan C, Gupta S, Samali A, Agostinis P (2012) PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ 19:1880–1891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Verkhratsky A, Toescu EC (2003) Endoplasmic reticulum Ca(2+) homeostasis and neuronal death. J Cell Mol Med 7:351–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voelker DR (1989) Reconstitution of phosphatidylserine import into rat liver mitochondria. J Biol Chem 264:8019–8025

    CAS  PubMed  Google Scholar 

  • Voelker DR (2005) Bridging gaps in phospholipid transport. Trends Biochem Sci 30:396–404

    Article  CAS  PubMed  Google Scholar 

  • Voeltz GK, Prinz WA, Shibata Y, Rist JM, Rapoport TA (2006) A class of membrane proteins shaping the tubular endoplasmic reticulum. Cell 124:573–586

    Article  CAS  PubMed  Google Scholar 

  • Voeltz GK, Rolls MM, Rapoport TA (2002) Structural organization of the endoplasmic reticulum. EMBO Rep 3:944–950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • von Filseck JM, Copic A, Delfosse V, Vanni S, Jackson CL, Bourguet W, Drin G (2015) Intracellular Transport. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate. Science 349:432–436

    Article  CAS  PubMed  Google Scholar 

  • Wang K, Klionsky DJ (2011) Mitochondria removal by autophagy. Autophagy 7:297–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang M, Kaufman RJ (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529:326–335

    Article  ADS  CAS  PubMed  Google Scholar 

  • Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, Selkoe D, Rice S, Steen J, Lavoie MJ, Schwarz TL (2011) PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893–906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei Y, Pattingre S, Sinha S, Bassik M, Levine B (2008) JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell 30:678–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wideman JG, Lackey SW, Srayko MA, Norton KA, Nargang FE (2013) Analysis of mutations in Neurospora crassa ERMES components reveals specific functions related to beta-barrel protein assembly and maintenance of mitochondrial morphology. PLoS ONE 8:e71837

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Yi M, Weaver D, Hajnoczky G (2004) Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit. J Cell Biol 167:661–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yorimitsu T, Klionsky DJ (2005) Autophagy: molecular machinery for self-eating. Cell Death Differ 12(Suppl 2):1542–1552

    Article  CAS  PubMed  Google Scholar 

  • Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281:30299–30304

    Article  CAS  PubMed  Google Scholar 

  • Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107:881–891

    Article  CAS  PubMed  Google Scholar 

  • Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, University of Leuven, KU Leuven, 3000, Leuven, Belgium

    Alexander R. van Vliet

  2. Laboratory of Cell Death Research & Therapy, University of Leuven, Campus Gasthuisberg O&N1, Herestraat 49, box 802, 3000, Leuven, Belgium

    Patrizia Agostinis

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  1. Alexander R. van Vliet
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  2. Patrizia Agostinis
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Correspondence to Patrizia Agostinis .

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  1. Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA

    R. Luke Wiseman

  2. Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Cole M. Haynes

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van Vliet, A.R., Agostinis, P. (2017). Mitochondria-Associated Membranes and ER Stress. In: Wiseman, R., Haynes, C. (eds) Coordinating Organismal Physiology Through the Unfolded Protein Response. Current Topics in Microbiology and Immunology, vol 414. Springer, Cham. https://doi.org/10.1007/82_2017_2

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