Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities. Inside eukaryotic cells, different types of organelles interact at membrane contact sites that arestabilized by protein bridges called tethers. The mitochondrial fusion protein mitofusin 2 (MFN2) links mitochondria to an unknown partner on the endoplasmic reticulum (ER). Naón et al. found two splice variants of mitofusin 2, ERMIT2 and ERMIN2. ERMIN2 affected ER morphology, and ERMIT2 was localized to the ER and enriched at the contact sites with mitochondria. Treatment with adenovirus encoding for ERMIT2 allowed for the transfer of calcium and lipids between the two organelles and reduced liver damage in models of reduced MFN2 expression. ?Stella M. Hurtley Endoplasmic reticulum?specific variants explain MFN2 function beyond mitochondria and its role in the pathogenesis of nonalcoholic steatohepatitis.In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the MFN2 splice variant ERMIT2 as the ER tethering partner of MFN2. Splicing of MFN2 produced ERMIT2 and ERMIN2, two ER-specific variants. ERMIN2 regulated ER morphology, whereas ERMIT2 localized at the ER-mitochondria interface and interacted with mitochondrial mitofusins to tether ER and mitochondria. This tethering allowed efficient mitochondrial calcium ion uptake and phospholipid transfer. Expression of ERMIT2 ameliorated the ER stress, inflammation, and fibrosis typical of liver-specific Mfn2 knockout mice. Thus, ER-specific MFN2 variants display entirely extramitochondrial MFN2 functions involved in interorganellar tethering and liver metabolic activities. Inside eukaryotic cells, different types of organelles interact at membrane contact sites that arestabilized by protein bridges called tethers. The mitochondrial fusion protein mitofusin 2 (MFN2) links mitochondria to an unknown partner on the endoplasmic reticulum (ER). Naón et al. found two splice variants of mitofusin 2, ERMIT2 and ERMIN2. ERMIN2 affected ER morphology, and ERMIT2 was localized to the ER and enriched at the contact sites with mitochondria. Treatment with adenovirus encoding for ERMIT2 allowed for the transfer of calcium and lipids between the two organelles and reduced liver damage in models of reduced MFN2 expression. ?Stella M. Hurtley Endoplasmic reticulum?specific variants explain MFN2 function beyond mitochondria and its role in the pathogenesis of nonalcoholic steatohepatitis.