TY - JOUR
T1 - Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether
AU - Naon, Deborah
AU - Zaninello, Marta
AU - Giacomello, Marta
AU - Varanita, Tatiana
AU - Grespi, Francesca
AU - Lakshminaranayan, Sowmya
AU - Serafini, Annalisa
AU - Semenzato, Martina
AU - Herkenne, Stephanie
AU - Hernández-Alvarez, Maria Isabel
AU - Zorzano, Antonio
AU - De Stefani, Diego
AU - Dorn, Gerald W.
AU - Scorrano, Luca
N1 - Funding Information:
We thank Drs. F. Caicci and F. Boldrin (EM Facility, Department of Biology, University of Padova) for electron microscopy. This work was supported in part by Telethon-Italy Grants GGP12162, GGP15198, and TCR02016 (to L.S.); the Associazione Italiana per la Ricerca sul Cancro Italy (to L.S.); European Research Council Grants FP7-282280 and FP7 CIG PCIG13-GA-2013-618697 (to L.S.); Ministero dell'Istruzione, dell'Universit? e della Ricerca Fondo per gli Investimenti della Ricerca di Base RBAP11Z3YA-005 (to L.S.); National Heart, Lung, and Blood Institute Grants R01 HL59888, R01 108943, and R01 128071 (to G.W.D.); Ministry of Economy and Competitiveness Grant SAF2013-40987R (to A.Z.); Generalitat de Catalunya 2014SGR48 (to A.Z.); Instituci? Catalana de Recerca i Estudis Avan?ats Academia (A.Z.); Centro de Investigaci?n Biom?dica en Red de Diabetes y Enfermedades Metab?licas Asociadas (A.Z.); and PIE14/00045 Instituto de Salud Carlos III (to A.Z.). L.S. is a Senior Scientist of the Dulbecco-Telethon Institute.
Publisher Copyright:
© 2016, National Academy of Sciences. All rights reserved.
PY - 2016/10/4
Y1 - 2016/10/4
N2 - 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.
AB - 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.
KW - Ca
KW - Interorganellar communication
KW - Mfn2
KW - Mitochondria
KW - Tethering
UR - http://www.scopus.com/inward/record.url?scp=84989964357&partnerID=8YFLogxK
U2 - 10.1073/pnas.1606786113
DO - 10.1073/pnas.1606786113
M3 - Article
C2 - 27647893
AN - SCOPUS:84989964357
VL - 113
SP - 11249
EP - 11254
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 40
ER -