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Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain; Departament de Bioquímica I Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red de Diabetes Y Enfermedades Metabolicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
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2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 14, p. 5523-5528Article in journal (Refereed) Published
Abstract [en]

Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo.

Place, publisher, year, edition, pages
National Academy of Sciences , 2012. Vol. 109, no 14, p. 5523-5528
National Category
Physiology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-63665DOI: 10.1073/pnas.1108220109ISI: 000302294700081PubMedID: 22427360Scopus ID: 2-s2.0-84859448265OAI: oai:DiVA.org:oru-63665DiVA, id: diva2:1169228
Funder
EU, FP7, Seventh Framework Programme
Note

Funding agencies:

Ministerio de Educacion y Cultura SAF2008-03803 

Generalitat de Catalunya, Instituto de Salud Carlos III

 Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM) 2009SGR915 

Integration of the System Models of Mitochondrial Function and Insulin Signalling 

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-05-15Bibliographically approved

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Oresic, Matej

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