Juxtaposition between endoplasmic reticulum (ER) and mitochondria provides physical basis for their intercommunication during Ca²⁺ signalling and apoptosis. Molecular mechanisms controlling this interaction are unknown. Mitofusin-2 (MFN2), a mitochondrial dynamin-related protein mutated in Charcot-Marie-Tooth type IIa (CMTIIa), localized also at the ER and was required for ER shape and its interaction with mitochondria. Localization of MFN2 at the ER proved essential to complement morphology of the organelle and interaction with mitochondria. Conversely, CMTIIa mutants of MFN2 restored morphology of mitochondria, but not of ER and juxtaposition of these organelles. ER-MFN2 bridged the two organelles via homo and heterotypic interactions with mitochondrial MFN 1 and 2. Thus, MFN2 physically links ER and mitochondria, suggesting a role for ER and ER-mitochondria tethering in pathogenesis of CMTIIa.