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Mitofusin 2 tethers endoplasmic reticulum to mitochondria

Author

Listed:
  • Olga Martins de Brito

    (Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy)

  • Luca Scorrano

    (Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy
    University of Geneva Medical School, 1 Rue M. Servet, 1211 Geneve, Switzerland)

Abstract

Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca2+ signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot–Marie–Tooth type IIa, is enriched at the ER–mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER–mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca2+ uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca2+ uptake.

Suggested Citation

  • Olga Martins de Brito & Luca Scorrano, 2008. "Mitofusin 2 tethers endoplasmic reticulum to mitochondria," Nature, Nature, vol. 456(7222), pages 605-610, December.
    • Handle: RePEc:nat:nature:v:456:y:2008:i:7222:d:10.1038_nature07534
    DOI: 10.1038/nature07534
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    1. Foozhan Tahmasebinia & Yinglu Tang & Rushi Tang & Yi Zhang & Will Bonderer & Maisa Oliveira & Bretton Laboret & Songjie Chen & Ruiqi Jian & Lihua Jiang & Michael Snyder & Chun-Hong Chen & Yawei Shen &, 2025. "The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    2. Gautham Yepuri & Lisa M. Ramirez & Gregory G. Theophall & Sergei V. Reverdatto & Nosirudeen Quadri & Syed Nurul Hasan & Lei Bu & Devi Thiagarajan & Robin Wilson & Raquel López Díez & Paul F. Gugger & , 2023. "DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
    3. Delfina Larrea & Kirstin A. Tamucci & Khushbu Kabra & Kevin R. Velasco & Taekyung D. Yun & Marta Pera & Jorge Montesinos & Rishi R. Agrawal & Carmen Paradas & John W. Smerdon & Emily R. Lowry & Anna S, 2025. "Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    4. Hongming Su & Hong Guo & Xiaoxue Qiu & Te-Yueh Lin & Chao Qin & Gail Celio & Peter Yong & Mark Senders & Xianlin Han & David A. Bernlohr & Xiaoli Chen, 2023. "Lipocalin 2 regulates mitochondrial phospholipidome remodeling, dynamics, and function in brown adipose tissue in male mice," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Felix Evers & Rona Roverts & Cas Boshoven & Mariska Kea-te Lindert & Julie M. J. Verhoef & Nico Sommerdijk & Robert E. Sinden & Anat Akiva & Taco W. A. Kooij, 2025. "Comparative 3D ultrastructure of Plasmodium falciparum gametocytes," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    6. Eunbyul Cho & Youngsik Woo & Yeongjun Suh & Bo Kyoung Suh & Soo Jeong Kim & Truong Thi My Nhung & Jin Yeong Yoo & Tran Diem Nghi & Su Been Lee & Dong Jin Mun & Sang Ki Park, 2023. "Ratiometric measurement of MAM Ca2+ dynamics using a modified CalfluxVTN," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Vaibhav Sidarala & Jie Zhu & Elena Levi-D’Ancona & Gemma L. Pearson & Emma C. Reck & Emily M. Walker & Brett A. Kaufman & Scott A. Soleimanpour, 2022. "Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Isshin Shiiba & Naoki Ito & Hijiri Oshio & Yuto Ishikawa & Takahiro Nagao & Hiroki Shimura & Kyu-Wan Oh & Eiki Takasaki & Fuya Yamaguchi & Ryoan Konagaya & Hisae Kadowaki & Hideki Nishitoh & Takehito , 2025. "ER-mitochondria contacts mediate lipid radical transfer via RMDN3/PTPIP51 phosphorylation to reduce mitochondrial oxidative stress," Nature Communications, Nature, vol. 16(1), pages 1-18, December.

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