Mitofusin 2 tethers endoplasmic reticulum to mitochondria

A Corrigendum to this article was published on 10 September 2014

This article has been updated

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.

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Figure 1: MFN2 regulates morphology of the endoplasmic reticulum.
Figure 2: MFN2 is required at the endoplasmic reticulum to juxtapose it to mitochondria.
Figure 3: Juxtaposition between ER and mitochondria requires ER MFN2 and mitochondrial MFN2 or MFN1.
Figure 4: ER MFN2 engages in homotypic or heterotypic interactions with mitochondrial MFNs.
Figure 5: MFN2 regulates ER Ca 2+ levels and its transfer to mitochondria.

Change history

  • 10 September 2014

    Nature 456, 605–610 (2008); doi:10.1038/nature07534 In Fig. 1a of this Article, the representative image of a volume-rendered three-dimensional reconstruction of a z-stack of confocal images of endoplasmic-reticulum-targeted yellow fluorescent protein (ER-YFP) in a Mfn2−/− cell expressing MFN2IYFFT and that of a Mfn1−/− cell appear to be duplicated.

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Acknowledgements

O.M.d.B. received a ‘Bolsa de Doutoramento’ of FCT Portugal. L.S. is senior scientist of the Dulbecco-Telethon Institute and EMBO YIP. This work was supported by Telethon Italy, Compagnia di San Paolo Italy, United Mitochondrial Disease Foundation USA, Muscular Distrophy Association USA and Swiss National Science Foundation 3100A0-118171.

Author Contributions O.M.d.B. and L.S. conceived and designed the experiments and wrote the manuscript. O.M.d.B. performed all the experiments.

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Correspondence to Luca Scorrano.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-12, Supplementary Methods and Supplementary Notes. (PDF 8474 kb)

Supplementary Movie 1

Supplementary Movie 1. ER-mitochondria interaction in wt MEF. 180° rotation along the y-axis of a 3D-reconstruction of a z-axis stack of a wt MEF expressing erYFP (green) and mtRFP (red). (MOV 228 kb)

Supplementary Movie 2

Supplementary Movie 2. ER-mitochondria interaction in Mfn2-/- MEF. 180° rotation along the y-axis of a 3D-reconstruction of a z-axis stack of a Mfn2-/- MEF expressing erYFP (green) and mtRFP (red). (MOV 172 kb)

Supplementary Movie 3

Supplementary Movie 3. Electron tomography showing ER-mitochondria interaction in a wt MEF. Rotation along the y and x-axis of a 3D-rendered reconstruction of representative area from an electron tomogram of a wt MEF. Orange objects represent mitochondria, cyan ones cisternae of ER. (MOV 886 kb)

Supplementary Movie 4

Supplementary Movie 4. Electron tomography showing ER-mitochondria interaction in a Mfn2-/- MEF. Rotation along the y and x-axis of a 3D-rendered reconstruction of representative area from an electron tomogram of Mfn2-/- MEF. Orange objects represent mitochondria, cyan ones cisternae of ER. (MOV 815 kb)

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de Brito, O., Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008). https://doi.org/10.1038/nature07534

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