Control of mitochondrial functions via contacts with ER. The figure shows an overview of some of the best-studied functional contacts between the ER and mitochondrial membranes. (a) Calcium transport for homeostasis or apoptosis. In healthy cells, Ca²⁺ flows from the lumen of ER via the IP3R and through the VDAC1 channel in the outer mitochondria membrane (OMM). GRP75 binds both channels to stabilize the synapse. Inside the mitochondria, ions pass the inner mitochondria membrane (IMM) via MCU1 where Ca²⁺ is needed for the Krebs cycle. Several protein–protein interactions are required to strengthen the contact site. Examples of such contacts are the ER proteins MFN2 and VAP-B which can interact with mitochondria-resident proteins MFN1/2 and PTPIP51, respectively. During apoptosis, a membrane complex consisting of BAP31, procaspase-8, CDIP1, and FIS1 tethers mitochondria and ER together in addition to the complex required for calcium transport. BAP31 from the ER bind both CDIP1 and procaspase-8, the latter is activated by interacting via its DED domain to bind a vDED domain on BAP31. FIS1 on the mitochondria interacts with BAP31 to bridge the two organelles. These apoptotic cues lead to increased Ca²⁺ levels in the mitochondria matrix and open the PTP. This disrupts the proton gradient and eventually leads to swelling and rupture of the mitochondria membrane, allowing cytochrome c to leak into the cytosol. APAF1 binds cytochrome c and assembles the apoptosome to execute apoptosis. (b) Mitochondria fission and fusion. ER marks the position for mitochondria fission or fusion by wrapping tubules around the mitochondria. Spire1C nucleates actin filaments and binds INF2 on the ER. INF2 stimulates the mitochondrial Ca²⁺ uptake and polymerizes actin filaments to further connect ER and mitochondria, allowing the IMM to divide first. DRP1 self assembles into a spiral guided by MFF and FIS1, and with the help of actin filaments constricts to separate the OMM. The final separation of the mitochondria can be aided by lysosomes or trans-Golgi network vesicles containing PtdIns4P at the ER–mitochondria contact site. Fusion is engaged by homodimerization between MFN1 or MFN2 in the OMM through their GTPase domain. Similarly, the GTPase domain on OPA1 interacts to fuse the inner membranes. Miro can bind motor proteins on both microtubules and actin filaments, possibly to strengthen the ER–mitochondria contact by reducing mitochondria movements.