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Updated: Jul 26, 2025

Visualization and Quantification of Endogenous Intra-Organelle Protein Interactions at ER-Mitochondria Contact Sites by Proximity Ligation Assays
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Visualization and Quantification of Endogenous Intra-Organelle Protein Interactions at ER-Mitochondria Contact Sites by Proximity Ligation Assays

Published on: October 20, 2023

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

Déborah Naón1,2,3, María Isabel Hernández-Alvarez4,5,6, Satoko Shinjo1,2

  • 1Department of Biology, University of Padua, 35121 Padova, Italy.

Science (New York, N.Y.)
|June 22, 2023
PubMed

Insights

Researchers discovered ERMIT2, an endoplasmic reticulum (ER) protein, which tethers ER and mitochondria. This interaction is crucial for cellular functions and ameliorates liver disease in mice, revealing new extramitochondrial roles for mitofusin 2 (MFN2) variants.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Organelle Biology

Background:

  • Organelle interactions at membrane contact sites are essential for cellular functions.
  • Mitochondrial mitofusin 2 (MFN2) is a known tether but its endoplasmic reticulum (ER) binding partner was unidentified.

Purpose of the Study:

  • To identify the ER-specific binding partner of mitochondrial MFN2.
  • To elucidate the function of ER-specific MFN2 splice variants in interorganelle tethering and cellular processes.

Main Methods:

  • Identification of MFN2 splice variants ERMIT2 and ERMIN2.
  • Localization studies of ERMIT2 at ER-mitochondria interfaces.
  • Analysis of ERMIT2's interaction with MFN2 and its role in calcium uptake and phospholipid transfer.
  • Assessment of ERMIT2's therapeutic potential in a liver-specific Mfn2 knockout mouse model.

Main Results:

  • The MFN2 splice variant ERMIT2 was identified as the ER tethering partner of MFN2.
  • ERMIT2 localized to ER-mitochondria contact sites and tethered these organelles.
  • This tethering facilitated efficient mitochondrial calcium ion uptake and phospholipid transfer.
  • ERMIT2 expression ameliorated ER stress, inflammation, and fibrosis in Mfn2 knockout mice.

Conclusions:

  • ER-specific MFN2 variants, ERMIT2 and ERMIN2, possess distinct extramitochondrial functions.
  • ERMIT2 plays a critical role in ER-mitochondria tethering, impacting cellular metabolism and liver health.
  • Targeting ERMIT2 may offer therapeutic benefits for liver diseases associated with MFN2 dysfunction.

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