The rough endoplasmic reticulum (RER) in mammalian cells forms an intricate network. It has long been noticed that it can be in close apposition to other organelles such as mitochondria. Electron microscopic analysis and biochemical analysis have provided insight in the functional importance and molecular composition of such organelle contact sites.

Contact sites between RER and mitochondria are exemplified in panels A–C. In a thin section from HepG2 hepatoma cells, a cisterna of the RER and a mitochondrion (M) are observed in close proximity (arrowheads in panel A). At the site of membrane contact, the RER is not covered by ribosomes. In panel B, a RER cisterna is located between two mitochondria (M). A membrane contact site with a synapse-like appearance is established with the upper mitochondrion (arrowhead). The surface of the cisterna facing the lower mitochondrion is covered by ribosomes and well separated from the outer mitochondrial membrane (arrow). At contact sites, the space between the apposing membranes is narrow. In addition, panel C shows how spatially restricted the membrane contact sites can be. Here, a RER cisterna curves along a mitochondrion (M) and forms ribosome-free contact sites only over a short distance (arrowheads). The part of the RER cisterna between the two contact sites (arrow) is covered by ribosomes. The RER-mitochondria contact sites are involved in Ca²⁺ exchange, signaling as well as lipid flipping during lipid biosynthesis.

A different type of contact site involves the RER and the plasma membrane. Panel D shows four consecutive serial sections with a branching RER cisterna and the plasma membrane (PM). In sections D2 and D3, a minuscule contact site (arrowheads) can be observed. Although the RER membrane involved in the contact site is ribosome-free, its surface towards the cytoplasm is covered by ribosomes. The RER-plasma membrane contact sites are involved in Ca²⁺ signaling, in store-operated Ca²⁺ influx or excitation-contraction coupling in muscle cells. As other organelle contact sites, they are implicated in lipid transport. Other membrane contact sites exist between the RER and endosomes, lysosomes, and the trans-Golgi apparatus (cf. Figs. 43 and 44).