Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum–mitochondria tether

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 40; pp. 11249 - 11254
• Main Authors: Naon, Deborah, Zaninello, Marta, Giacomello, Marta, Varanita, Tatiana, Grespi, Francesca, Lakshminaranayan, Sowmya, Serafini, Annalisa, Semenzato, Martina, Herkenne, Stephanie, Hernández-Alvarez, Maria Isabel, Zorzano, Antonio, De Stefani, Diego, Dorn, Gerald W., Scorrano, Luca
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.10.2016
• Subjects: Animals; Biological Sciences; Calcium; Calcium - metabolism; Calcium Channels - metabolism; Cellular biology; Embryo, Mammalian - cytology; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - ultrastructure; Fibroblasts - metabolism; Fibroblasts - ultrastructure; Fluorescence; Gene Deletion; GTP Phosphohydrolases - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Liver - metabolism; Mice, Knockout; Microscopy; Mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; Molecular Probes - metabolism; Proteins; tethering; Mfn2; interorganellar communication; Ca2; mitochondria
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1606786113

The discovery of the multiple roles of mitochondria–endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER–mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2’s role in ER–mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER–mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion. Functionally, mitochondrial uptake of Ca2+ released from the ER was reduced following acute Mfn2 ablation, as well as in Mfn2 −/− cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca2+ uptake rate and extent were normal in isolated Mfn2 −/− liver mitochondria, consistent with the finding that acute or chronic Mfn2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, Mfn2 stands as a bona fide ER–mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.