The ER (endoplasmic reticulum) is composed of multiple domains including the nuclear envelope, ribosome-studded rough ER and the SER (smooth ER). The SER can also be functionally segregated into domains that regulate ER–Golgi traffic (transitional ER), ERAD (ER-associated degradation), sterol and lipid biosynthesis and calcium sequestration. The last two, as well as apoptosis, are critically regulated by the close association of the SER with mitochondria. Studies with AMFR (autocrine motility factor receptor) have defined an SER domain whose integrity and mitochondrial association can be modulated by ilimaquinone as well as by free cytosolic calcium levels in the normal physiological range. AMFR is an E3 ubiquitin ligase that targets its ligand directly to the SER via a caveolae/raft-dependent pathway. In the present review, we will address the relationship between the calcium-dependent morphology and mitochondrial association of the SER and its various functional roles in the cell.

Structural organization of the ER (endoplasmic reticulum)

The ER is a continuous membrane system that consists of multiple domains that perform different functions [1]. These include translocation of secretory proteins across the ER membrane, integration of proteins into the membrane, folding and modification of proteins in the ER lumen, synthesis of phospholipids and steroids, detoxification, storage of calcium ions in the ER lumen and their release in the cytosol as well as segregation of nuclear contents from the cytoplasm [2].

The ER is composed of at least three morphologically defined subcompartments: the nuclear envelope, the ribosome-studded RER (rough ER) and the SER (smooth ER). The RER, involved in translation and translocation of newly synthesized proteins across the ER membrane, is distinguished by the presence of ribosomes and exhibits a tubular and granular appearance compared with the more convoluted and dilated SER [3]. The non-uniform distribution of calcium-handling proteins, ranging from Ca2+-dependent chaperones to calcium pumps, throughout the ER is indicative of a complex subdomain structure within the ER, beyond the presence of ribosomes, that regulates protein synthesis and co-translational protein folding and quality control [4]. The transitional ER, smooth extensions of the RER, is involved in packaging proteins for transport from the ER to the Golgi apparatus [5] and is enriched in proteins required for this process [6]. ERAD (ER-associated degradation) is associated with SER domains that can express components of the ERGIC (ER–Golgi intermediate compartment) [7,8]. Expression of a more abundant SER is associated with steroid hormone biosynthesis in various endocrine cells, detoxification of hydrophobic substances in the liver and calcium release and uptake in neurons and the SR (sarcoplasmic reticulum) of skeletal muscle [2].

Membrane domain formation occurs by a combination of hierarchical assembly processes and protein exclusion [9]. For example, HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase, an enzyme implicated in cholesterol biosynthesis, is found on both RER and SER membranes, but its overexpression leads to a crystalloid SER highly enriched in HMG-CoA reductase [10]. Although many proteins are uniformly distributed throughout the ER, other proteins show a specific localization to the SER, such as epoxide hydrolase, a liver enzyme whose induction is associated with hyperproliferation of the SER induced by phenobarbital treatment [11]. In steroidogenic cells, syntaxin 17 is abundantly expressed in the SER and forms complexes with SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) proteins that function in a vesicle-trafficking step to the smooth-surfaced tubular ER membranes [12]. Within the SR, at least two domains are morphologically distinguishable: terminal cisternae containing RyR (ryanodine receptor) Ca2+ release channels and longitudinal tubules composed of the SERCA (sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase) [13]. In cultured cells, antibodies to AMFR (autocrine motility factor receptor; also known as gp78) selectively label a SER domain (Figure 1) that extends from RER tubules but is distinct from the ERGIC and the calnexin-labelled ER [1416].

Anti-AMFR labelling is localized to a mitochondrial-associated SER domain

Figure 1
Anti-AMFR labelling is localized to a mitochondrial-associated SER domain

(A) Post-embedding immunoelectron microscopy with the 3F3A anti-AMFR monoclonal antibody followed by 12 nm gold-conjugated anti-rat secondary antibodies shows that most of the membrane-bound gold particles are associated with SER compared with RER with variable plasma membrane (PM) labelling in MDCK, NIH-3T3 and HeLa cells. (B) In both NIH-3T3 and HeLa cells labelled with the 3F3A anti-AMFR antibody, the density of gold particles per μm membrane is enhanced in SER and caveolae (Cav) relative to flat portions of the plasma membrane (Flat PM) and significantly reduced in RER. Data taken from [14,54]. (C) Representative anti-AMFR-labelled SER tubule in proximity to mitochondria. Scale bar, 0.1 μm. Reproduced from The Journal of Cell Biology, 2000, 150, 1489–1498 by copyright permission of The Rockefeller University Press.

Figure 1
Anti-AMFR labelling is localized to a mitochondrial-associated SER domain

(A) Post-embedding immunoelectron microscopy with the 3F3A anti-AMFR monoclonal antibody followed by 12 nm gold-conjugated anti-rat secondary antibodies shows that most of the membrane-bound gold particles are associated with SER compared with RER with variable plasma membrane (PM) labelling in MDCK, NIH-3T3 and HeLa cells. (B) In both NIH-3T3 and HeLa cells labelled with the 3F3A anti-AMFR antibody, the density of gold particles per μm membrane is enhanced in SER and caveolae (Cav) relative to flat portions of the plasma membrane (Flat PM) and significantly reduced in RER. Data taken from [14,54]. (C) Representative anti-AMFR-labelled SER tubule in proximity to mitochondria. Scale bar, 0.1 μm. Reproduced from The Journal of Cell Biology, 2000, 150, 1489–1498 by copyright permission of The Rockefeller University Press.

Mitochondrial association of the ER

Contacts between the ER membrane and the mitochondrial outer membrane have long been observed [17,18] and electron tomography studies have more recently identified 15 nm diameter sites of close contact between the membranes of these two organelles [19]. Subcellular fractionation studies identified ER membranes co-purifying with mitochondria [20,21], and the specific ER compartment that interacts with mitochondria has been labelled MAM (mitochondrial-associated membranes) [22].

Compared with RER tubules, SER tubules, both unlabelled and labelled for AMFR, are found preferentially within 200 nm of mitochondria using electron microscopy, corroborating the close association of the AMFR-labelled SER domain and mitochondria observed by confocal microscopy (Figure 1) [16]. In muscle, the ER in close contact with mitochondria is usually de-enriched in ribosomes and enriched in IP3Rs {IP3 [inositol (1,4,5)-trisphosphate] receptors} and RyRs [23]. It is now widely accepted that ER sites of calcium release channels are localized to mitochondria-associated microdomains, generating high Ca2+ concentrations to enable calcium exchange between the two organelles [24]. Using organelle-specific calcium probes, ER–mitochondria interaction was found to be stable and indicative of the existence of specific, selective mechanisms that regulate interaction between the two organelles [25]. Co-localization studies performed on oligodendrocytes showed that mitochondria are found in intimate association with sites possessing a high density of specific ER proteins, in particular IP3R calcium release channels [26]. Proximity of calcium release channels to mitochondria has been established in various cell types, including cardiomyocytes [27] and pancreatic acinar cells [28], as well as in striated cardiac muscle cells where RyR has been localized to the feet structures of the SR membranes in close apposition (37–270 nm) to mitochondria [29]. Moreover, the SERCA ER Ca2+ pump has also been found to be in proximity to individual mitochondria [30].

The transfer of calcium between the two organelles regulates cellular processes ranging from ER chaperone-assisted folding of newly synthesized proteins to the regulation of mitochondrial dehydrogenases involved in ATP production and activation of Ca2+-dependent enzymes and signals that induce cell death programmes [31]. Cleavage by caspases of BAP31 (B-cell-receptor-associated protein 31) to produce p20 induces calcium transfer between ER and mitochondria, recruitment of dynamin-related protein-1 inducing scission of the outer mitochondrial membrane and fragmentation of the mitochondrial network [32]. Numerous enzymes involved in phospholipid biosynthesis are integral membrane proteins of the ER, and physical apposition between ER and mitochondria is important for the synthesis of various lipids [33]. Phosphatidylserine synthase activity has recently been shown to be calcium-dependent [34], revealing a link between ER–mitochondria association, phospholipid synthesis and calcium signalling.

Regulation of SER–mitochondria interaction

During maturation of hamster and Xenopus oocytes, increases in cytosolic calcium concentrations correlate respectively with restructuring of the ER and redistribution of IP3R [35,36] and ER fragmentation [37]. Furthermore, artificial increases in cytosolic calcium concentrations caused fragmentation of the ER, giving it a punctate appearance [38,39]. Even though artificial, those conditions reflect physiological conditions as the increase in calcium concentration occurring during fertilization induces a loss in the continuity of the ER network [40]. Addition of rat liver cytosol to digitonin-permeabilized MDCK (Madin–Darby canine kidney) cells stimulates the mitochondrial dissociation of the AMFR-labelled SER that is inhibited by increasing free cytosolic calcium concentrations [16]. In intact cells, a window of free cytosolic calcium concentration between 100 and 200 nM promotes dissociation of the AMFR-labelled SER from mitochondria. Moreover, stimulation of IP3-sensitive calcium stores using ATP induced a transient dissociation of SER and mitochondria, demonstrating that the dissociation of the two organelles occurs in response to physiological variations in free cytosolic Ca2+ concentrations (H. Genty, J.G. Goetz, R. Sauvé and I.R. Nabi, unpublished work). Therefore SER–mitochondria dissociation induced by increases in calcium concentration could reflect physiological conditions such as mitotic disruption of the ER. Increases in cytosolic calcium concentration also inhibit mitochondrial motility [41]. Co-ordinate regulation of both SER–mitochondria interaction and mitochondrial motility by increasing cytosolic calcium levels may serve to regulate both spatial and temporal aspects of intracellular calcium signalling.

The mechanisms that regulate ER–mitochondria interaction remain unknown. PACS-2 (phospho-acidic cluster sorting protein 2) is a novel sorting protein whose depletion results in mitochondrial fragmentation and uncoupling from the ER [42]. PACS-2 regulates the amount of MAM-localized lipid-synthesizing enzymes, ER homoeostasis and Ca2+ signalling as well as translocation of the pro-apoptotic factor Bid, following an apoptotic stimulus, to mitochondria. Disruption of the ER–mitochondria axis by PACS-2 depletion leads to increased levels of the ER chaperone BiP (immunoglobulin heavy-chain-binding protein) as well as IP3R-stimulated calcium release, confirming that interaction between the two organelles regulates ER homoeostasis [42].

A candidate mitochondrial receptor is the VDAC (voltage-dependent anion channel; also known as porin), whose expression enhances calcium transfer to mitochondria and that has been localized to both ER and mitochondrial outer membranes and is enriched in the zone of apposition [43,44]. ER candidate receptors include IP3R, RyR and AMFR that are concentrated on mitochondrial opposed ER domains. Interestingly, AMFR overexpression following transfection results in loss of mitochondrial proximity of the AMFR-labelled ER domain that may reflect saturation of a putative mitochondrial receptor or reorganization and proliferation of the SER [45]. gp78/AMFR is an E3 ubiquitin ligase involved in ERAD of various substrates such as CD3-δ [46], the T-cell receptor and ApoB (apolipoprotein B) lipoprotein [47] and HMG-CoA reductase [48]. gp78/AMFR physically interacts with VCP (valosin-containing protein)/p97, an AAA (ATPase associated with various cellular activities) involved in dislodging the ubiquitinated proteins from the ER and chaperones them to the cytosol [49,50]. ATP hydrolysis is required by p97 to catalyse the release of ubiquitinated proteins to the cytosol and could be provided by recruitment of p97 by AMFR to the mitochondria-associated SER. p97 is involved not only in ERAD but also in ER and Golgi fusion processes [51], and recruitment of p97 to the SER by AMFR may serve to regulate the cellular distribution and mitochondrial association of the SER. Interestingly, p97 complex formation with p47 is implicated in Golgi fusion [52], whereas ilimaquinone, a fungal metabolite that induces Golgi vesiculation [53], also induces increased fenestration of the AMFR-labelled SER [15].

AMFR is a cell surface receptor localized at the cell surface to caveolae and internalized via a receptor-mediated caveolae/raft-dependent pathway to the SER [5456]. SV40 (simian virus 40) is also internalized via caveolae to the SER [57,58]. IBV (infectious bronchitis virus) 3a is a membrane protein expressed along SER membranes [59], and ER–mitochondria contact has recently been shown to mediate mitochondrial transfer of the HCV (hepatitis C virus) core protein during HCV infection [60]. Indeed, the interferon-induced Mx anti-viral dynamin-related protein has been localized to the SER [61]. Accessibility of the SER from the plasma membrane argues that regulation of endocytic access to this organelle, through receptor activation and a raft-dependent pathway, could impact on SER–mitochondrial interaction and on various cellular processes associated with SER–mitochondria interaction including calcium-dependent cell signalling, lipid biosynthesis, ERAD and apoptosis.

Non-Vesicular Intracellular Traffic: Biochemical Society Focused Meeting held at Goodenough College, London, U.K., 15–16 December 2005. Organized and edited by S. Cockcroft (University College London, U.K.) and T. Levine (Institute of Ophthalmology, London, U.K.).

Abbreviations

     
  • AMFR

    autocrine motility factor receptor

  •  
  • ER

    endoplasmic reticulum

  •  
  • ERAD

    ER-associated degradation

  •  
  • ERGIC

    ER–Golgi intermediate compartment

  •  
  • HCV

    hepatitis C virus

  •  
  • HMG-CoA

    3-hydroxy-3-methylglutaryl-CoA

  •  
  • IP3

    inositol (1,4,5)-trisphosphate

  •  
  • IP3R

    IP3 receptor

  •  
  • MAM

    mitochondrial-associated membranes

  •  
  • MDCK cell

    Madin–Darby canine kidney cell

  •  
  • PACS-2

    phospho-acidic cluster sorting protein 2

  •  
  • RER

    rough ER

  •  
  • RyR

    ryanodine receptor

  •  
  • SER

    smooth ER

  •  
  • SERCA

    sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase

  •  
  • SR

    sarcoplasmic reticulum

I.R.N. is an Investigator of the CIHR (Canadian Institutes of Health Research) and work in his laboratory is supported by the CIHR. J.G.G. holds a doctoral fellowship from the Ministère de la Recherche et des Technologies for his doctoral studies to be submitted jointly to the Université de Montréal and the Université Louis Pasteur de Strasbourg (UMR CNRS 7034).

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