Endoplasmic Reticulum-Mitochondria Contact Sites-Emerging Intracellular Signaling Hubs

Abstract

It has become apparent that our textbook illustration of singular isolated organelles is obsolete. In reality, organelles form complex cooperative networks involving various types of organelles. Light microscopic and ultrastructural studies have revealed that mitochondria-endoplasmic reticulum (ER) contact sites (MERCSs) are abundant in various tissues and cell types. Indeed, MERCSs have been proposed to play critical roles in various biochemical and signaling functions such as Ca²⁺ homeostasis, lipid transfer, and regulation of organelle dynamics. While numerous proteins involved in these MERCS-dependent functions have been reported, how they coordinate and cooperate with each other has not yet been elucidated. In this review, we summarize the functions of mammalian proteins that localize at MERCSs and regulate their formation. We also discuss potential roles of the MERCS proteins in regulating multiple organelle contacts.

Keywords: ER; mammalian protein; mitochondria; organelle contact sites; tether.

FIGURE 1

A schematic diagram of the proteins proposed to tether the ER and mitochondria. The size of each domain structure was either calculated from the structures deposited on the Protein Data Bank or estimated using the Phyre2 protein structure prediction tool. Proteins shown to be necessary (green, pink) or sufficient (yellow) for tethering the ER and mitochondria are depicted. Green indicates that tethering partners of the proteins remain to be determined. Light blue indicates that roles of the proteins need to be determined. ER, endoplasmic reticulum; FKBP8, FK506-binding protein 8; IP3R, inositol 1,4,5-trisphosphate receptor; Mfn2, mitofusin 2; PDZD8, PDZ domain-containing protein 8; RHOT1, Ras homolog family member T1; GRP75, glucose-regulated protein 75; RMDN3, regulator of microtubule dynamics protein 3; RRBP1, ribosome-binding protein 1; SYNJ2BP, synaptojanin-2-binding protein; TMX1, thioredoxin-related transmembrane protein 1; VAPB, VAMP-associated protein B; VPS13A, vacuolar protein sorting-associated protein 13 A; VDAC, voltage-dependent anion channel.