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

• 成果类型: Article
• 署名作者: Naon, Deborah; Hernandez-Alvarez, Maria Isabel; Shinjo, Satoko; Wieczor, Milosz; Ivanova, Saska; Martins de Brito, Olga; Quintana, Albert; Hidalgo, Juan; Palacin, Manuel; Aparicio, Pilar; Castellanos, Juan; Lores, Luis; Sebastian, David; Fernandez-Veledo, Sonia; Vendrell, Joan; Joven, Jorge; Orozco, Modesto; Zorzano, Antonio; Scorrano, Luca
• 署名单位: University of Padua; Veneto Institute Molecular Medicine; Barcelona Institute of Science & Technology; Institute for Research in Biomedicine - IRB Barcelona; University of Barcelona; CIBER - Centro de Investigacion Biomedica en Red; CIBERDEM; University of Barcelona; Fahrenheit Universities; Gdansk University of Technology; Autonomous University of Barcelona; Autonomous University of Barcelona; CIBER - Centro de Investigacion Biomedica en Red; CIBERER; Instituto de Salud Carlos III; Universitat Rovira i Virgili; Hospital Universitari De Tarragona Joan XXIII; Universitat Rovira i Virgili; Universitat Rovira i Virgili
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12110
• DOI: 10.1126/science.adh9351
• 发表日期: 2023-06-01
• 页码: 1237-+
• 关键词: marie-tooth-disease; er membranes; ca2+; fusion; contacts; calcium; protein; opa1; stress; mfn2

摘要

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.