RT Journal Article
SR Electronic
T1 Tyrosine phosphorylation of mitofusin 2 regulates endoplasmic reticulum-mitochondria tethering
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.21.481295
DO 10.1101/2022.02.21.481295
A1 Peng Zhang
A1 Kara Ford
A1 Jae Hwi Sung
A1 Jacob Moeller
A1 Yuta Suzuki
A1 Iuliia Polina
A1 Toshiaki Tachibana
A1 Yoichiro Kusakari
A1 Michael W Cypress
A1 Isabel Chaput
A1 Kamelia Drenkova
A1 Maria Landherr
A1 Stephanie M Adaniya
A1 Jyotsna Mishra
A1 Ulrike Mende
A1 Bong Sook Jhun
A1 Jin O-Uchi
YR 2022
UL http://biorxiv.org/content/early/2022/02/21/2022.02.21.481295.abstract
AB 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.