TY - JOUR
T1 - Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria
AU - Naón, Déborah
AU - Hernández-Alvarez, María Isabel
AU - Shinjo, Satoko
AU - Wieczor, Milosz
AU - Ivanova, Saska
AU - de Brito, Olga Martins
AU - Quintana, Albert
AU - Hidalgo, Juan
AU - Palacín, Manuel
AU - Aparicio, Pilar
AU - Castellanos, Juan
AU - Lores, Luis
AU - Sebastián, David
AU - Fernández-Veledo, Sonia
AU - Vendrell, Joan
AU - Joven, Jorge
AU - Orozco, Modesto
AU - Zorzano, Antonio
AU - Scorrano, Luca
N1 - Funding Information:
We thank V. Hernandez, J. M. Seco, and L. Bardia (Advanced Digital Microscopy, IRB Barcelona) and D. Bach for technical assistance; N. Berrow (Protein Expression, IRB Barcelona) for plasmid generation; J. Comas and R. Alvarez (Cytometry Unit, UB) and R. Seminago and A. Amador (Genomics Unit, UB) for technical assistance; F. Caicci and F. Boldrin (Bioimaging Facility, Department of Biology, University of Padova) for EM samples preparation; and A. Cabrelle (FACS facility, VIMM) for flow cytometry and sorting. This study was supported by MINECO PID2019-106209RB-I00 (A.Z.); Generalitat de Catalunya grant 2017SGR1015 (A.Z.); CIBERDEM “Instituto de Salud Carlos III” (A.Z.); Fundación Ramon Areces CIVP18A3942 (A.Z.); Fundación BBVA (A.Z.); Fundació Marató de TV3 20132330 (A.Z.); the European Foundation for the Study of Diabetes (EFSD) (A.Z.); “La Caixa” Foundation (A.Z.); Health Research Grant 2021 LCF/ PR/HR21/52410007 (A.Z.); ICREA “Academia” Award Generalitat de Catalunya (A.Z.); institutional funding from MINECO through the Centres of Excellence Severo Ochoa Award (A.Z.); CERCA Programme of the Generalitat de Catalunya (A.Z. and M.O.); MICINN PDI2021-122478NB-I00 (M.O.); Generalitat de Catalunya grant 2021SGR00863, “BioExcel-3: Centre of Excellence for Computational Biomolecular Research” ref. no. 101093290 HORIZON-EUROHPC-JU-2021-COE-01, 101094651 — MDDB — HORIZON-INFRA-2022-DEV-01 (M.O.); European Research Council (ERC) GA282280 (L.S.); Muscular Dystrophy Association (MDA) 4165 (L.S.); EFSD/Novo Nordisk Program for Diabetes Research in Europe (L.S.); Fondation Leducq TNE15004 (L.S.); Ministero dell’Istruzione, dell’Università e della Ricerca RBAP11Z3YA_005 (L.S.); Ministero dell’Istruzione, dell’Università e della Ricerca 2017BF3PXZ (L.S.); Ministero dell’Università e della Ricerca 2020PKLEPN_002 (L.S.); and SOE_0000181, MUR Concession Decree no. 564 of 13/12/2022, CUP C93C22007650006, funded under the National Recovery and Resilience Plan (NRRP), Mission 4, Component 2, Investment 1.2, MUR Call for tender n. 367 of 7/10/2022 funded by the European Union – NextGenerationEU (S.S.).
Publisher Copyright:
© 2023 American Association for the Advancement of Science. All rights reserved.
PY - 2023/6/23
Y1 - 2023/6/23
N2 - 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.
AB - 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.
KW - Alternative Splicing
KW - Animals
KW - Calcium/metabolism
KW - Endoplasmic Reticulum Stress
KW - Endoplasmic Reticulum/metabolism
KW - GTP Phosphohydrolases/genetics
KW - HeLa Cells
KW - Humans
KW - Liver/metabolism
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mitochondria/metabolism
KW - Mitochondrial Membranes/metabolism
KW - Mitochondrial Proteins/genetics
KW - Protein Isoforms
UR - https://www.scopus.com/pages/publications/85162769362
UR - https://www.mendeley.com/catalogue/df5dde0b-78b2-30b6-af63-c0a64d154bb8/
U2 - 10.1126/science.adh9351
DO - 10.1126/science.adh9351
M3 - Article
C2 - 37347868
AN - SCOPUS:85162769362
SN - 0036-8075
VL - 380
SP - eadh9351
JO - Science
JF - Science
IS - 6651
M1 - eadh9351
ER -