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

Science. 2023 Jun 23;380(6651):eadh9351. doi: 10.1126/science.adh9351. Epub 2023 Jun 23.


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.

MeSH terms

  • Alternative Splicing
  • Animals
  • Calcium* / metabolism
  • Endoplasmic Reticulum Stress
  • Endoplasmic Reticulum* / metabolism
  • GTP Phosphohydrolases* / genetics
  • GTP Phosphohydrolases* / metabolism
  • HeLa Cells
  • Humans
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria* / metabolism
  • Mitochondrial Membranes / metabolism
  • Mitochondrial Proteins* / genetics
  • Mitochondrial Proteins* / metabolism
  • Protein Isoforms


  • Calcium
  • GTP Phosphohydrolases
  • Mitochondrial Proteins
  • Protein Isoforms
  • Mfn2 protein, mouse
  • MFN2 protein, human