Table 1.
Molecular determinants for inter-organellar tethering.
| YEAST | |||
|---|---|---|---|
| Tethering complexes | Mammalian/human homologs | Functional property | References |
| ERMES | |||
| Mdm10 - Mdm12 - Mdm34 - Mmm1 | n.a. - n.a. - n.a. - PDZD8 (paralog) | All members contain a SMP domain and form a channel-like structure to facilitate phospholipid transport |
Kornmann et al., 2009; Jeong et al., 2016 |
| Lam6 - Tom70/71 | GRAMD1(A-C)/GRAMD2 - TOMM70 | Controls the equilibrium and expansion of contact sites |
Elbaz-Alon et al., 2015; Murley et al., 2015 |
| EMC | |||
| Emc1/2/3/4/5/6 - Tom5 | EMC1/2/3/4/MMGT1/EMC6 - TOMM5 |
The complex is a transmembrane-domain insertase that sustains phospholipid import into mitochondria |
Lahiri et al., 2014 |
| vCLAMP | |||
| Ypt7 - Vam6 - Tom40 | RAB7 - VPS39 - TOMM40 | Ypt7 and Vam6 are core components of HOPS required to maintain viability in the absence of ERMES |
Elbaz-Alon et al., 2014; Hönscher et al., 2014; González Montoro et al., 2018 |
| Vps13 - Mcp1 | VPS13A/C - n.a. | Vps13 is a lipid transporter that forms a distinct vacuolar-mitochondrial contact required to bypass ERMES |
Lang et al., 2015; John Peter et al., 2017; González Montoro et al., 2018; Dziurdzik and Conibear, 2021 |
| Vac8 - Lam6 - Tom70/71 | ARVCF - GRAMD1(A-C)/GRAMD2 - TOMM70 |
Controls the equilibrium and expansion of contact sites |
Elbaz-Alon et al., 2015 |
| ER-vacuole (NVJ) | LDs biogenesis | ||
| Vac8 - Nvj1 | ARVCF - n.a. | Pan et al., 2000; Levine and Munro, 2001; Toulmay and Prinz, 2012; Elbaz-Alon et al., 2015; Henne et al., 2015; Bean et al., 2018; Hariri et al., 2018; Weber-Boyvat et al., 2021 |
|
| Mdm1 | SNX14 | Henne et al., 2015; Hariri et al., 2018 | |
| Osh1/Swh1 - Scs2 | OSBP1/2 - VAPA/B | Levine and Munro, 2001; Weber-Boyvat et al., 2021 |
|
| Vps13 - Ypt35 | VPS13A/C - SNX16 | Bean et al., 2018 | |
| Vac8 - Lam6 | ARVCF - GRAMD1(A-C)/GRAMD2 | Elbaz-Alon et al., 2015 | |
| Nvj2 | TEX2 | Toulmay and Prinz, 2012 | |
| Nvj3 | n.a. | Henne et al., 2015 | |
| Lipid droplet contacts | Lipid storage and trafficking | ||
| Sei1/Fld1 | BSCL2 | Fei et al., 2008; Grippa et al., 2015; Hariri et al., 2018 |
|
| Mdm1 | SNX14 | Hariri et al., 2018 | |
| Pah1 | LPIN1/2/3 | Barbosa et al., 2015 | |
| MAMMALIAN | |||
| Tethering complexes | Yeast homologs | Functional property | References |
| MAM | |||
| IP3R3 - GRP75 - VDAC | n.a. - Ecm10 - Por1/2 | Ca2+ transfer between ER and mitochondria |
Rizzuto et al., 1998; Szabadkai et al., 2006 |
| Mfn2 - Mfn2 or Mfn2 - Mfn1 | Fzo1 | Ca2+ transfer between ER and mitochondria |
de Brito and Scorrano, 2008; Cosson et al., 2012 |
| Miro1/2 cluster | Gem1 | Controls ER and mitochondria Ca2+transfer via interaction with IP3R3 and VDAC; interacts with MICOS complex |
Lee et al., 2016; Modi et al., 2019 |
| BAP31 - FIS1 | Yet1/2/3 - Fis1 | Involved in transmission of apoptotic signals from mitochondria to ER |
Iwasawa et al., 2011 |
| VAPA - VPS13A | Scs2/22 - Vps13 | Phospholipid (PA, PS and PE) transfer | Kumar et al., 2018; Muñoz-Braceras et al., 2019; Yeshaw et al., 2019 |
| VAPB - PTPIP51 | Scs2/22 - n.a. | Ca2+ transfer between ER and mitochondria; regulates autophagy/mitophagy |
De Vos et al., 2012; Gomez-Suaga et al., 2017 |
| ORP5/8 - PTPIP51 | Osh2/3 - n.a. | Sterol sensing and phospholipid transfer |
Galmes et al., 2016; Leal et al., 2020 |
| PDZD8 | Mmm1 (paralog) | Ca2+ transfer between ER and mitochondria |
Hirabayashi et al., 2017 |
| EMC | |||
| EMC1/2 - SLC25A46 | Emc1/2 - n.a. (Ugo1-like) | Maintenance of mitochondrial phospholipid levels |
Janer et al., 2016 |
| Mito-LE/Lys | |||
| RAB7 - VPS13A | Ypt7 - Vps13 | Required for optimal lysosome degradation capacity |
Muñoz-Braceras et al., 2019 |
| GDAP1 - LAMP1 | n.a. - n.a. | May regulate the duration and number of mito-LE/Lys contacts |
Cantarero et al., 2021 |
| ER-LE/Lys | Ca2+ and cholesterol transfer between ER and LE/Lys, endolysosomal maturation |
||
| VAPA - ORP1L | Scs2/22 - Osh1-7 | Rocha et al., 2009 | |
| VAPs - STARD3 | Scs2/22 - n.a. | Alpy et al., 2013; Wilhelm et al., 2016; Kumar et al., 2018 |
|
| VAPs - VPS13C | Scs2/22 - Vps13 | Leonzino et al., 2021 | |
| Protrudin - RAB7/PI3P - PDZD8 | n.a.- Ypt7 - Mmm1 | Raiborg et al., 2015; Elbaz-Alon et al., 2020; Khan et al., 2021 |
|
| RTN3L - RAB9 | Rtn1/2 - n.a. | Wu and Voeltz, 2021 | |
| ORP5 - NPC1 | Osh6 - Ncr1 | Du et al., 2011 | |
| Gramd1b - NPC1 | Lam6 - Ncr1 | Höglinger et al., 2019 | |
| TPC1 | n.a. | Kilpatrick et al., 2017 | |
| Lipid droplet contacts | Lipid transfer and homeostasis | ||
| Seipin (BSCL2) | Sei1/Fld1 | Sui et al., 2018; Benador et al., 2019 | |
| Mfn2 - PLIN1/5 | Fzo1 - n.a. | Benador et al., 2019 | |
| SNX14 | Mdm1 | Datta et al., 2019 |
Known tethers and modulators of MCSs between (i) ER and mitochondria, (ii) mitochondria and vacuole/endolysosome, (iii) ER and vacuole/endolysosome, and (iv) ER-mitochondria-vacuole/endolysosome and lipid droplets are displayed in yeast and mammalian cells respectively. Homologs based on data available in the Saccharomyces Genome Database (www.yeastgenome.org) and Alliance Genome Resources (www.alliancegenome.org) are indicated where applicable. The main functional properties of each contact are summarized to indicate their possible disruption in association with cellular dyshomeostasis. n.a., not available/applicable.