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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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.
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).
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).
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.
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.