ER and mitochondria interact intimately to perform cellular functions. (A) ER-mitochondria contact sites mediate a variety of processes. ER-mitochondria contact sites are sites of lipid and calcium exchange, used for modifying membrane lipids and sequestering calcium ions for modulating mitochondrial function as targets of intracellular signaling cascades. Such contact sites are also thought to be regulators of mitochondrial fission in a recent hypothesis that holds that ER extensions aid in the recruitment of Mff and Drp1 to mitochondria, and furthermore provide mechanical force for fission. Additionally, recent findings show that the ER and mitochondria are inherited in a co-dependent manner in yeast, facilitated by the Mmr1 protein, which binds mitochondria to cortical ER sheets in the yeast bud tip. (B) In response to an external stimulus indicating cellular stress, calcium ions sequestered in the ER lumen are released into the cytosol by the transmembrane inositol 1,4,5-triphosphate receptor protein. Released calcium ions then enter ER-tethered mitochondria by an unknown transmembrane calcium channel located in the outer mitochondrial membrane, followed by translocation into the mitochondrial matrix by the mitochondrial calcium uniporter. The targets of calcium ions in the matrix primarily include energy-producing processes, but can also lead to apoptosis in cases of severe cellular stress.