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

• DOI: 10.1126/science.adh9351
• Publication Date: 2023-06-22T20:14:26Z
• Authors: Déborah Naón; María Isabel Hern...; Satoko Shinjo; Milosz Wieczor; Saska Ivanova; Olga Martins de B...; Albert Quintana; Juan Hidalgo; Manuel Palacín; Pilar Aparicio; Juan Castellanos; Luis Lores; David Sebastián; Sonia Fernández-V...; Joan Vendrell; Jorge Joven; Modesto Orozco; Antonio Zorzano; Luca Scorrano
• Keywords: MFN2; Tethering; Organelle

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a tether that interacts with an unknown partner on the endoplasmic reticulum (ER). this work, we identified MFN2 splice variant ERMIT2 ER tethering of MFN2. Splicing produced and ERMIN2, two ER-specific variants. ERMIN2 regulated morphology, whereas localized ER-mitochondria interface interacted mitochondrial mitofusins to mitochondria. This allowed efficient calcium ion uptake phospholipid transfer. Expression ameliorated stress, inflammation, fibrosis typical liver-specific Mfn2 knockout mice. Thus, variants display entirely extramitochondrial functions involved in interorganellar liver metabolic activities.