Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Signaling hubs at ER/mitochondrial membrane associations

Department of Natural Sciences, Pepperdine University, Malibu CA, USA

Special Issues: Membrane Organization

Signaling between organelles has profound implications for our understanding of organelle structural organization and regulatory processes. Close regional apposition of endoplasmic reticulum (ER) and mitochondrial membranes has been known for 50 years, but only in the past 20 years have scientists begun to unravel the nature and purpose of these quasi-synaptic contact points. At these sites of association, membranes have been shown to be of unique molecular composition, defining raft domains that are densely populated with membrane proteins, sphingolipids, and cholesterol. These associations are now referred to as mitochondrial associated membranes (MAMs). MAM domains mediate a complex array of cellular processes including; exchange of macromolecules, Ca2+ transfer, physical tethering, regulation of mitochondrial division, and signaling pathways that control autophagy and apoptosis. Dysfunction of MAM function is known to have profound cellular influence, and including the activation of several neurodegenerative disorders.
  Article Metrics


1. MacLennan DH, Rice WJ, Green NM (1997) The mechanism of Ca2+ transport by sarco (endo) plasmic reticulum Ca2+-ATPases. J Biol Chem 272: 28815–28818.    

2. Clapham DE (1995) Calcium signaling. Cell 80: 259–268.    

3. Clapham DE (2007) Calcium signaling. Cell 131: 1047–1058.    

4. Kuhlbrandt W (2015) Structure and function of mitochondrial membrane protein complexes. BMC Biol 13: 89.    

5. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11: 872–884.    

6. Westermann B (2010) Mitochondrial dynamics in model organisms: what yeasts, worms and flies have taught us about fusion and fission of mitochondria. Semin Cell Dev Biol 21: 542–549.    

7. Archer SL (2013) Mitochondrial dynamics-mitochondrial fission and fusion in human diseases. N Engl J Med 369: 2236–2251.    

8. Daum B, Walter A, Horst A, et al. (2013) Age-dependent dissociation of ATP synthase dimers and loss of inner-membrane cristae in mitochondria. Proc Natl Acad Sci USA 110: 15301–15306.    

9. Robertson JD (1960) The molecular structure and contact relationships of cell membranes. Prog Biophys Mol Biol 10: 343–418.

10. Rizzuto R, Pinton P, Carrington W, et al. (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280: 1763–1766.    

11. Garcia-Perez C, Roy SS, Naghdi S, et al. (2012) Bid-induced mitochondrial membrane permeabilization waves propagated by local reactive oxygen species (ROS) signaling. Proc Natl Acad Sci USA 109: 4497–4502.    

12. Williams A, Hayashi T, Wolozny D, et al. (2016) The non-apoptotic action of Bcl-xL: regulating Ca(2+) signaling and bioenergetics at the ER-mitochondrion interface. J Bioenerg Biomembr 48: 211–225.    

13. Giorgi C, Bonora M, Sorrentino G, et al. (2015) p53 at the endoplasmic reticulum regulates apoptosis in a Ca2+-dependent manner. Proc Natl Acad Sci USA 112: 1779–1784.    

14. Haupt S, Raghu D, Haupt Y (2015) p53 Calls upon CIA (Calcium Induced Apoptosis) to Counter Stress. Front Oncol 5: 57.

15. Brisac C, Teoule F, Autret A, et al. (2010) Calcium flux between the endoplasmic reticulum and mitochondrion contributes to poliovirus-induced apoptosis. J Virol 84: 12226–12235.

16. Luciani DS, Gwiazda KS, Yang TL, et al. (2009) Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and beta-cell death. Diabetes 58: 422–432.    

17. Toglia P, Ullah G (2016) The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore. Cell Calcium 60: 13–24.    

18. Szabadkai G, Bianchi K, Varnai P, et al. (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2+ channels. J Cell Biol 175: 901–911.    

19. Csordas G, Renken C, Varnai P, et al. (2006) Structural and functional features and significance of the physical linkage between ER and mitochondria. J Cell Biol 174: 915–921.    

20. Hansford RG (1994) Physiological role of mitochondrial Ca2+ transport. J Bioenerg Biomembr 26: 495–508.    

21. Rutter GA, Burnett P, Rizzuto R, et al. (1996) Subcellular imaging of intramitochondrial Ca2+ with recombinant targeted aequorin: significance for the regulation of pyruvate dehydrogenase activity. Proc Natl Acad Sci USA 93: 5489–5494.    

22. Palty R, Hershfinkel M, Sekler I (2012) Molecular identity and functional properties of the mitochondrial Na+/Ca2+ exchanger. J Biol Chem 287: 31650–31657.    

23. Adam-Vizi V, Starkov AA (2010) Calcium and mitochondrial reactive oxygen species generation: how to read the facts. J Alzheimers Dis 20 Suppl 2: S413–S426.

24. Hansson MJ, Mansson R, Morota S, et al. (2008) Calcium-induced generation of reactive oxygen species in brain mitochondria is mediated by permeability transition. Free Radic Biol Med 45: 284–294.    

25. Varanita T, Soriano ME, Romanello V, et al. (2015) The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. Cell Metab 21: 834–844.    

26. Sonnino S, Prinetti A (2013) Membrane domains and the "lipid raft" concept. Curr Med Chem 20: 4–21.

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

28. Rusinol AE, Cui Z, Chen MH, et al. (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.

29. Tessitore A, del P Martin M, Sano R, et al. (2004) GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol Cell 15: 753–766.    

30. Sano R, Annuziata I, Patterson A, et al. (2009) GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Mol Cell 36: 500–511.    

31. Annunziata I, Patterson A, D'Azzo A (2013) Mitochondria-associated ER membranes (MAMs) and glycosphingolipid enriched microdomains (GEMs): isolation from mouse brain. J Vis Exp 73: e50215.

32. Garofalo T, Matarrese P, Manganeli V, et al. (2016) Evidence for the involvement of lipid rafts localized at the ER-mitochondria associated membranes in autophagosome formation. Autophagy 12: 917–935.    

33. Pomorski TG, Menon AK (2016) Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping. Prog Lipid Res 64: 69–84.    

34. Vance JE, Aasman EJ, Szarka R (1991) Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its sites for synthesis to the cell surface. J Biol Chem 266: 8241–8247.

35. Lev S (2010) Non-vesicular lipid transport by lipid-transfer proteins and beyond. Nat Rev Mol Cell Biol 11: 739–750.    

36. D'Angelo G, Vicinanza M, De Matteis MA (2008) Lipid-transfer proteins in biosynthetic pathways. Curr Opin Cell Biol 20: 360–370.    

37. Tatsuta T, Scharwey M, Langer T (2014) Mitochondrial lipid trafficking. Trends Cell Biol 24: 44–52.    

38. Miller WL (2013) Steroid hormone synthesis in mitochondria. Mol Cell Endocrinol 379: 62–73.    

39. Salavila A, Navarrolerida I, Sanchezalvarez M, et al. (2016) Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice. Sci Rep 6: 27351.

40. Kojima R, Endo T, Tamura Y (2016) A phospholipid transfer function of ER-mitochondria encounter structure revealed in vitro. Sci Rep 6: 30777.    

41. Kornmann B, Currie E, Collins SR, et al. (2009) An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science 325: 477–481.    

42. Kornmann B, Walter P (2010) ERMES-mediated ER-mitochondria contacts: molecular hubs for the regulation of mitochondrial biology. J Cell Sci 123: 1389–1393.    

43. Lahiri S, Chao JT, Tavassoli S, et al. (2014) A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phospholipid transfer from the ER to mitochondria. PLoS Biol 12: e1001969.    

44. Lev S, Ben Halaevy D, Peretti D, et al. (2008) The VAP protein family: from cellular functions to motor neuron disease. Trends Cell Biol 18: 282–290.    

45. Stoica R, De Vos KJ, Paillusson S, et al. (2014) ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun 5: 3996.

46. De Vos KJ, Morotz GM, Stoica R, et al. (2012) VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet 21: 1299–1311.    

47. Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114: 867–874.

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

49. Filadi R, Greotti E, Turacchio G, et al. (2015) Mitofusin 2 ablation increases endoplasmic reticulum-mitochondria coupling. Proc Natl Acad Sci USA 112: E2174–E2181.    

50. Naon D, Zaninello M, Giacomello M, et al. (2016) Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether. Proc Natl Acad Sci USA 113: 11249–11254.    

51. Ouvrier R, Grew S (2010) Mechanisms of disease and clinical features of mutations of the gene for mitofusin 2: an important cause of hereditary peripheral neuropathy with striking clinical variability in children and adults. Dev Med Child Neurol 52: 328–330.    

52. Wang B, Heath-Engel H, Zhang D, et al. (2008) BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRDeltaF508 via the derlin-1 complex. Cell 133: 1080–1092.    

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

54. Wang B, Nguyen M, Chang NC, et al. (2011) Fis1, Bap31 and the kiss of death between mitochondria and endoplasmic reticulum. EMBO J 30: 451–452.    

55. Ng FW, Nguyen M, Kwan T, et al. (1997) p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the endoplasmic reticulum. J Cell Biol 139: 327–338.    

56. Rizzuto R, Marchi S, Bonora M, et al. (2009) Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 1787: 1342–1351.

57. Breckenridge DG, Stojanovic M, Marcellus RC, et al. (2003) Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol. J Cell Biol 160: 1115–1127.

58. Heath-Engel HM, Wang B, Shore GC (2012) Bcl2 at the endoplasmic reticulum protects against a Bax/Bak-independent paraptosis-like cell death pathway initiated via p20Bap31. Biochim Biophys Acta 1823: 335–347.    

59. Nguyen M, Breckenridge DG, Ducret A, et al. (2000) Caspase-resistant BAP31 inhibits fas-mediated apoptotic membrane fragmentation and release of cytochrome c from mitochondria. Mol Cell Biol 20: 6731–6740.

60. Wu W, Li W, Chen H, et al. (2016) FUNDC1 is a novel mitochondrial-associated-membrane (MAM) protein required for hypoxia-induced mitochondrial fission and mitophagy. Autophagy 12: 1675–1676.    

61. Smirnova E, Griparic L, Shurland DL, et al. (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12: 2245–2256.    

62. Friedman JR, Lackner LL, West M, et al. (2011) ER tubules mark sites of mitochondrial division. Science 334: 358–362.    

63. Wang M, Wey S, Zhang Y, et al. (2009) Role of the unfolded protein response regulator GRP78/BiP in development, cancer, and neurological disorders. Antioxid Redox Signal 11: 2307–2316.

64. Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta 1833: 3460–3470.    

65. Lumley EC, Osborn AR, Scott JC, et al. (2017) Moderate endoplasmic reticulum stress activates a PERK and p38-dependent apoptosis. Cell Stress Chaperones 22: 43–54..    

66. Simmen T, Aslan JE, Blagoveshchenskaya AD, et al. (2005) PACS-2 controls endoplasmic reticulum-mitochondria communication and Bid-mediated apoptosis. EMBO J 24: 717–729.    

67. Cormaci G, Mori T, Hayashi T, et al. (2007) Protein kinase A activation down-regulates, whereas extracellular signal-regulated kinase activation up-regulates sigma-1 receptors in B-104 cells: Implication for neuroplasticity. J Pharmacol Exp Ther 320: 202–210.

68. 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.    

69. Mori T, Hahashi T, Hayashi E, et al. (2013) Sigma-1 receptor chaperone at the ER-mitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival. PLoS One 8: e76941.    

70. Wang J, Saul A, Roon P, et al. (2016) Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration. Proc Natl Acad Sci USA 113: E3764–E3772.    

71. Chu UB, Ruoho AE (2016) Biochemical pharmacology of the Sigma-1 receptor. Mol Pharmacol 89: 142–153.

72. Verfaillie T, Rubio N, Garg AD, et al. (2012) PERK is required at the ER-mitochondrial contact sites to convey apoptosis after ROS-based ER stress. Cell Death Differ 19: 1880–1891.

73. Hardy JA, Higgins GA (1992) Alzheimer's disease: the amyloid cascade hypothesis. Science 256: 184–185.    

74. Karran E, De SB (2016) The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem 139 Suppl 2: 237–252.

75. Herrup K (2015) The case for rejecting the amyloid cascade hypothesis. Nat Neurosci 18: 794–799.    

76. Castrillo JI, Oliver SG (2016) Alzheimer's as a systems-level disease involving the interplay of multiple cellular networks. Methods Mol Biol 1303: 3–48.    

77. Bartley MG, Marquardt K, Kirchhof D, et al. (2012) Overexpression of amyloid-beta protein precursor induces mitochondrial oxidative stress and activates the intrinsic apoptotic cascade. J Alzheimers Dis 28: 855–868.

78. Benussi L, Ghidroni R, Dal Piaz F, et al. (2017) The level of 24-Hydroxycholesteryl Esters is an Early Marker of Alzheimer's Disease. J Alzheimers Dis 56: 825–833.    

79. Area-Gomez E, de Groof AJ, Boldogh I, et al. (2009) Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria. Am J Pathol 175: 1810–1816.    

80. Leech CA, Kopp RF, Nelson HA, et al. (2016) Stromal Interaction Molecule 1 (STIM1) Regulates ATP-Sensitive Potassium (KATP) and Store-Operated Ca2+ Channels in MIN6 beta-Cells. J Biol Chem 292: 2266–2277.

81. Tong BC, Lee CS, Cheng WH, et al. (2016) Familial Alzheimer's disease-associated presenilin 1 mutants promote gamma-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. Sci Signal 9: ra89.    

82. Nelson O, Supnet C, Liu H, et al. (2010) Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J Alzheimers Dis 21: 781.

83. Rozpedek W, Markiewicz L, Diehl JA, et al. (2015) Unfolded protein response and PERK kinase as a new therapeutic target in the pathogenesis of Alzheimer's disease. Curr Med Chem 22: 3169–3184.    

84. Al-Chalabi A, van den Berg LH, Veldink J (2017) Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat Rev Neurol 13: 96–104..

85. Gregianin E, Pallafacchina G, Zanin S, et al. (2016) Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling. Hum Mol Genet 25: 3741–3753.    

86. Li X, Hu Z, Liu L, et al. (2015) A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy. Neurology 84: 2430–2437.    

87. Watanabe S, Ilieva H, Tamada H, et al. (2016) Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS. EMBO Mol Med 8: 1421–1437.    

88. Hyrskyluoto A, Pulli I, Tornqvist K, et al. (2013) Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-kappaB pathway. Cell Death Dis 4: e646.    

89. Ono Y, Tanaka H, Nagahara Y, et al. (2014) SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett 559: 174–178.    

90. Neumann M, Sampathu DM, Kwong LK, et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130–133.    

91. Ambegaokar SS, Jackson GR (2011) Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation. Hum Mol Genet 20: 4947–4977.    

Copyright Info: © 2017, Jay L. Brewster, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved