In eukaryotic cells, various organelles interact at membrane contact sites stabilized by tethering factors.
The mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this study, we identified the MFN2 splicing variant known as ERMIT2 as the ER-anchoring partner of MFN2. Alternative splicing of MFN2 gives rise to ERMIT2 and ERMIN2, two ER-specific variants.
ERMIN2 regulates ER morphology, whereas ERMIT2 localizes at the ER–mitochondria interface and interacts with mitochondrial mitofusins to tether the two organelles. This tethering enables efficient mitochondrial calcium uptake and phospholipid transfer. Expression of ERMIT2 ameliorated ER stress, inflammation, and fibrosis characteristic of liver-specific Mfn2 knockout mice.
Thus, ER-specific MFN2 variants reveal fully extramitochondrial functions of MFN2 involved in inter-organelle tethering and hepatic metabolic activities.
