c-Src-dependent phosphorylation of Mfn2 regulates endoplasmic reticulum-mitochondria tethering

Contact sites between the mitochondria and endoplasmic reticulum (ER) regulate the exchange of lipids, Ca2+, and reactive oxygen species (ROS) across the two organelles. Mitofusin 2 (Mfn2) has been identified as one of the major components tethering these two organelles together. Several post-translational modifications (PTMs) of Mfn2 have been shown to modulate canonical (i.e., mitochondrial fusion) and non-canonical Mfn2 functions, such as mitophagy and activation of ER stress signaling. However, there is little information about 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 mitochondria-localized c-Src can phosphorylate the C-terminal tail of Mfn2, which decreases the distance between the mitochondria and ER and facilitates 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 and pathological conditions.