Table 1.
Organelle interaction, MCS components and physiological role. ABCD1/3, ATP-binding cassette sub-family D member 1/3; ACBD2/4/5, acyl-coenzyme A binding domain containing protein 2/4/5; ACSL1, long chain fatty-acid-CoA ligase 1; AMPK, 5' AMP-activated protein kinase; ATF6α, activating transcription factor 6α; DGAT2, diacylglycerol O-acyltransferase 2; DMT1, divalent metal transporter 1; ENDO, endosome; ER, endoplasmic reticulum; ERMES, ER-mitochondria encounter structure; FAPP1, phosphatidyl-four-phosphate-adaptor-protein-1; FATP1, fatty acid transporter protein 1; GRP75, glucose regulated protein 75; INF2, inverted formin 2; IP3R, 1,4,5-trisphosphate receptor; LD, lipid droplet; LYS, lysosome; MAVS, mitochondrial anti-viral signalling protein; MIGA2, mitoguardin 2 protein; MITO, mitochondria; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; OSBP1/ORP5/8/9/10/11, oxysterol-binding protein/OSBP-related protein family; PEX, peroxin; PI(4,5)P2, phosphatidylinositol-4,5-bisphosphate; PLIN5, perilipin 5 protein; PM, plasma membrane; PO, peroxisome; STARD3, StAR related lipid transfer domain containing protein 3; STIM1, stromal interaction molecule 1; TBC1D15, TBC1 domain family member 15; TMEM135, transmembrane protein 135; VAP, vesicle-associated membrane protein; VDAC, voltage dependent anion channel; VPS13, vacuole protein sorting-associated protein 13. MCS proteins are mammalian unless otherwise stated. * MCS components listed are those mentioned in the text; this is not a complete list of all MCS components identified so far.
| Organelles (MCS) | MCS components* | Physiological role | References |
|---|---|---|---|
Mitochondria – endoplasmic reticulum
|
SigmaR1 (MITO), SEL1L (ER) | Regulation of mitochondrial fission | [50] |
| Spire1C (MITO) – INF2 (ER) tether | [[45], [46], [47]] | ||
| IP3R (ER) – GRP75 – VDAC (MITO) tether | Transfer of Ca2+ between ER and MITO; Ca2+ signalling via MITO-ER contacts | [56,57] | |
| PDZD8 (MITO/LYS?) – Unknown protein (ER) tether | Dendritic Ca2+ homeostasis in mammalian neurons? | [60,62] | |
| Mmm1, Mdm12 and Mdm34 (ERMES, MITO), VPS13 (yeast) | Lipid transfer; phospholipid synthesis | [33,70,71] | |
| VPS13A (MITO) – VAP (ER) | Lipid transfer | [73,127] | |
| PTPIP51 (MITO) – ORP5/8 (ER) | Transport of phosphatidylserine from the ER to MITO | [78,79] | |
| NLRP3 (ER) – MAVS (MITO) | Immune signalling and inflammation | [[82], [83], [84], [85]] | |
| PTPIP51 (MITO) – VAPB (ER) tether | Autophagosome formation/autophagy | [[87], [88], [89]] | |
Mitochondria – lysosome
|
Tethers unknown | Regulation of mitochondrial dynamics/fission | [41] |
| STARD3 (LYS) – tether? | Cholesterol transport to MITO (compensatory mechanism for impaired LYS-ER cholesterol transport) | [109] | |
| Regulated by RAB7, TBC1D15 (binds FIS1 at MITO) | [103,105,106] | ||
| DMT1 (ENDO/LYS, MITO) | Iron transport from ENDO/LYS to MITO | [[119], [120], [121], [122]] | |
Mitochondria – lipid droplets
|
SNAP23, Unknown tether | Lipid transfer between LD and MITO for mitochondrial β-oxidation; energy metabolism | [124,126] |
| Regulated by AMPK | [124] | ||
| DGAT2 (ER/LD), FATP1 (ER) | LD expansion and biogenesis | [128,133,134] | |
| Unknown protein (MITO) – PLIN5 (LD) | Regulation of LD hydrolysis | [129,[135], [136], [137]] | |
| MIGA2 (MITO) – unknown protein (LD), VAPB (ER) (triple contact site?) | Lipogenesis | [139] | |
Peroxisomes– endoplasmic reticulum
|
ACBD4/5(PO) – VAPA/B (ER) tether, ACSL1 | Coordination of fatty acid β-oxidation (PO) and elongation (ER); lipid transfer for ether-phospholipid synthesis; (phospho)lipid transfer for PO biogenesis (PO membrane expansion; regulation of PO positioning and mobility) | [[149], [150], [151]] |
| Lipid synthesis for virus replication | [171] | ||
| PI(4,5)P2 (PO) – E-SYTs | Transport of cholesterol | [207] | |
| ABCD3 (PO) – ATF6α (ER) tether | Regulation of ER stress; control of cellular stress response | [167] | |
| Pex3 (PO/ER) – Inp1 tether (yeast) | PO inheritance in yeast; control of PO abundance | [147,148] | |
| Pex24, Pex32 (ER) – Pex11 (PO) tether (yeast) | PO biogenesis and proliferation; positioning at the cell cortex; proper segregation to mother cells and buds | [146] | |
Peroxisomes – lipid droplets
|
ABCD1 (PO) – M1 spastin (LD) tether, ESCRTIII proteins IST1 and CHMP1B (LD) | Fatty acid trafficking between LDs and PO; lipolysis | [178] |
Peroxisomes – mitochondria
|
Pex11 (PO) – Mdm34 (ERMES, MITO) (yeast) | Metabolic signalling? | [164] |
| Pex34(PO), Fzo1 (MITO) tether (yeast) | Regulation of fatty acid β-oxidation in yeast (metabolite transfer) | [7] | |
| ACBD2 (PO/MITO) | Promotion of steroid biosynthesis (Leydig cells) | [193] | |
Peroxisomes – lysosomes/endosomes
|
PI(4,5)P2 (PO) – SYT7 (LYS) tether | Cholesterol transport from LYS to PO | [207] |
| TMEM135 (PO) | Cholesterol transport; intracellular cholesterol distribution; regulation of ciliogenesis (cholesterol dependent) | [204] | |
| PxdA (ENDO) (fungi) | PO movement via endosome ‘hitch-hiking’ | [213,214] | |
| Pex3 (PO - vacuole) tether (yeast) | PO growth/expansion; lipid transfer? | [146] | |
Golgi complex – endoplasmic reticulum
|
PI(4)P (TGN) – OSBP1/ORP9/10/11 – VAP (ER) | Direct transport of sterols | [20,219,[222], [223], [224]] |
| PI(4)P (TGN) – CERT – VAP (ER) | Translocation of ceramide from the ER to TGN | [218,226] | |
| PI(4)P (TGN) – FAPP1 – SAC1 (ER) – VAP (ER) | PI4P homeostasis | [228] | |
Plasma membrane – endoplasmic reticulum
|
Osh2/3/6/7 (PM) Osh2/3 (PM) – VAP (ER) tether (?) (yeast) |
Transport of sterols from the ER to the PM in yeast | [233] |
| Scs2/Scs22 (ER), Sac1 (ER), Ist2 (ER), Tcb1/2/3 (ER) (yeast) | Phosphoinositide metabolism in yeast | [238] | |
| NIR2 C2CD2L/TMEM24 |
Phosphatidylinositol transport between the ER and the PM. | [239,240] | |
| ORAI1 (PM) – STIM1 (ER) | Maintenance of Ca2+ homeostasis; CRAC channel activation and Ca2+ entry | [243] | |
Plasma membrane – mitochondrian
|
PI(4,5)P2 (PM) – Num1 – Mdm36 (MITO)/cardiolipin (MITO)/Scs2 (ER) tether (=MITO-PM-ER triple contact) (yeast) | MITO inheritance; regulation of MITO distribution in yeast | [247,249] |
| Mmr1 (MITO/ER) (yeast) | [254] | ||
| Mfb1 (MITO) (yeast) | [255] | ||
| MFN1 (MITO) – PKCζ (PM) tether (?) | Epithelial-mesenchymal transition (EMT) in mammals. | [256] | |
| Tethers unknown | Regulation of Ca2+ influx; mitochondrial Ca2+ import | [257] |