Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics

Abstract

Regions of close apposition between two organelles, often referred to as membrane contact sites (MCSs), mostly form between the endoplasmic reticulum and a second organelle, although contacts between mitochondria and other organelles have also begun to be characterized. Although these contact sites have been noted since cells first began to be visualized with electron microscopy, the functions of most of these domains long remained unclear. The last few years have witnessed a dramatic increase in our understanding of MCSs, revealing the critical roles they play in intracellular signaling, metabolism, the trafficking of metabolites, and organelle inheritance, division, and transport.

Figure 1.

Proteins proposed to mediate tethering at MCSs. Mammalian proteins are shown on a yellow background, yeast proteins on a blue background, and proteins found in both mammals and yeast are on a green background. Tethering complexes not described in the text are indicated with red numbers: (1) StARD3-VAPs (Alpy et al., 2013), (2) NPC1-ORP5 (Du et al., 2011), (3) Psd2-Pdr17 (Riekhof et al., 2014), (4) Vac8-Nvj1 (Pan et al., 2000), (5) Nvj2 (Toulmay and Prinz, 2012), (6) PTPIP51-VAPs (De Vos et al., 2012), (7) Orai1-STIM1 (Nunes et al., 2012), (8) DGAT2-FATP1 (Xu et al., 2012), and (9) IncD-CERT-VAPs (Derré et al., 2011; Elwell et al., 2011).

Figure 2.

Possible mechanisms of lipid exchange at MCSs. (A) Transfer by LTPs using CERT as an example. The targeting PH domain (pink) and FFAT motif (blue) are shown. CERT could shuttle between membranes (left) or transfer while binding both membranes (right). (B) Some transfer could occur through hydrophobic channels or tunnels (in green) bridging the two membranes at a MCS. (C) Lipid exchange between hemifused membranes. Hemifusion could be promoted and regulated by proteins (red).

Figure 3.

Ca²⁺ trafficking at ER–PM MCSs. (A) In muscle cells, the interaction of the RyR in the SR and with DHPR in the PM allows the coordinated release of Ca²⁺ during muscle excitation and contraction. See text for details. (B) When STIM1 senses low Ca²⁺ concentration in the ER, it undergoes a conformational change that allows it to oligomerize and bind to the PM, to the protein Orai1, and to accumulate at ER–PM MCSs. Ca²⁺ influx at these sites facilitates Ca²⁺ import into the ER by sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA). (C) Calcium channeling from the ER lumen to the mitochondrial matrix. Calcium exits the ER through the inositol trisphosphate receptor (IP3R) channel, enters mitochondria via VDAC, and then uses the mitochondrial Ca²⁺ uniporter (MCU) to move into the mitochondrial matrix.

Figure 4.

Model of ER-mediated regulation of mitochondrial fission at sites of contact. (A) The ER and mitochondria are tethered by ERMES in yeast (other tethers are used in higher eukaryotes). (B) The ER encircles mitochondria at sites where division will occur. (C) Actin polymerization facilitated by formin 2 may cause mitochondrial constriction. (D) The dynamin-like protein Drp1 is recruited to the mitochondrial surface, where it multimerizes and causes mitochondrial scission. (E) After fission, the ER remains associated with the mitochondrion that retains the ERMES complex.