Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras

Communication between endoplasmic reticulum (ER) and mitochondria is crucial for Ca2+ homeostasis, lipid biosynthesis and therefore for the regulation of mitochondrial metabolism and apoptosis. The mitochondrial GTPase mitofusin (MFN) 2 is enriched in mitochondria associated membranes (MAM) and localizes also on the ER, where it interacts with mitofusins on mitochondria to form interorganellar bridges. MFN2 also binds and inhibits the proto-oncogene Ras that controls proliferation, cell cycle and morphology. Mutants of MFN2 lacking the Ras-binding domain fail to tether the two organelles, raising the question of whether signaling cascades downstream of Ras can influence its ability to juxtapose ER and mitochondria. Here we show that extracellular regulated kinase (ERK) 1 is hyperactivated in cells lacking MFN2. However, genetic or pharmacological manipulation of the Ras-MAPK-ERK cascade does not influence the morphology of ER and mitochondria or their tethering. Thus, sustained Ras signaling is not the mechanism through which loss of MFN2 affects organelle shape and juxtaposition, solidifying a direct role for MFN2 in these processes.