Abstract
Contact sites between the mitochondria and endoplasmic reticulum (ER) are irregulates the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Mitofusin 2 (Mfn2) has been shown as one of the major components tethering these two organelles. Several post-translational modifications (PTMs) of Mfn2 have been identified to modulate canonical (i.e., mitochondrial fusion) and non- canonical functions, such as mitophagy and activation of ER stress signaling, however there is little information whether any PTMs can regulate mitochondrial and ER tethering. Basal tyrosine phosphorylation of Mfn2 was detected by mass spectroscopy, but it is unknown whether Mfn2 is a substrate of mitochondria-localized tyrosine kinases. Here we show that the mitochondria-localized Src family tyrosine kinases including c-Src can phosphorylate Mfn2, which decreases distance between the mitochondria and ER, and increases Ca2+ transfer from the ER to mitochondria, followed by changes in ROS generation and mitochondrial bioenergetics. Our findings suggest that tyrosine phosphorylation of Mfn2 may uniquely work to fine-tune ER- mitochondrial Ca2+ transport under physiological conditions, without activating mitophagy or ER stress signaling.