Mitofusin 2 tethers endoplasmic reticulum to mitochondria.
Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) 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 Ca(2+) 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 Ca(2+) uptake.
de Brito
Olga Martins
OM
Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
Scorrano
Luca
L
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053140:Organelle Shape
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D015544:Inositol 1,4,5-Trisphosphate; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; D002118:Calcium