Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis

David Sebastián, María Isabel Hernández-Alvarez, Jessica Segalés, Eleanora Sorianello, Juan Pablo Muñoz, David Sala, Aurélie Waget, Marc Liesa, José C. Paz, Peddinti Gopalacharyulu, Matej Orešič, Sara Pich, R. Burcelin, Manuel Palacín, Antonio Zorzano (Corresponding Author)

Research output: Contribution to journalArticle in a proceedings journalScientificpeer-review

270 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)5523-5528
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number14
DOIs
Publication statusPublished - 2012
MoE publication typeA4 Article in a conference publication

Fingerprint

Endoplasmic Reticulum
Homeostasis
Insulin
Glucose
Liver
Mitochondria
Mitochondrial Dynamics
Muscles
Endoplasmic Reticulum Stress
Glucose Intolerance
Gluconeogenesis
Acetylcysteine
Quality Control
Organelles
Hydrogen Peroxide
Reactive Oxygen Species
Antioxidants

Keywords

  • mitochondrial dynamics
  • insulin resistance
  • metabolism
  • oxidative stress

Cite this

Sebastián, David ; Hernández-Alvarez, María Isabel ; Segalés, Jessica ; Sorianello, Eleanora ; Muñoz, Juan Pablo ; Sala, David ; Waget, Aurélie ; Liesa, Marc ; Paz, José C. ; Gopalacharyulu, Peddinti ; Orešič, Matej ; Pich, Sara ; Burcelin, R. ; Palacín, Manuel ; Zorzano, Antonio. / Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 14. pp. 5523-5528.
@article{1214e08f218341f5a5df776b9bed6e47,
title = "Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis",
abstract = "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.",
keywords = "mitochondrial dynamics, insulin resistance, metabolism, oxidative stress",
author = "David Sebasti{\'a}n and Hern{\'a}ndez-Alvarez, {Mar{\'i}a Isabel} and Jessica Segal{\'e}s and Eleanora Sorianello and Mu{\~n}oz, {Juan Pablo} and David Sala and Aur{\'e}lie Waget and Marc Liesa and Paz, {Jos{\'e} C.} and Peddinti Gopalacharyulu and Matej Orešič and Sara Pich and R. Burcelin and Manuel Palac{\'i}n and Antonio Zorzano",
year = "2012",
doi = "10.1073/pnas.1108220109",
language = "English",
volume = "109",
pages = "5523--5528",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "14",

}

Sebastián, D, Hernández-Alvarez, MI, Segalés, J, Sorianello, E, Muñoz, JP, Sala, D, Waget, A, Liesa, M, Paz, JC, Gopalacharyulu, P, Orešič, M, Pich, S, Burcelin, R, Palacín, M & Zorzano, A 2012, 'Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 14, pp. 5523-5528. https://doi.org/10.1073/pnas.1108220109

Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. / Sebastián, David; Hernández-Alvarez, María Isabel; Segalés, Jessica; Sorianello, Eleanora; Muñoz, Juan Pablo; Sala, David; Waget, Aurélie; Liesa, Marc; Paz, José C.; Gopalacharyulu, Peddinti; Orešič, Matej; Pich, Sara; Burcelin, R.; Palacín, Manuel; Zorzano, Antonio (Corresponding Author).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 14, 2012, p. 5523-5528.

Research output: Contribution to journalArticle in a proceedings journalScientificpeer-review

TY - JOUR

T1 - Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis

AU - Sebastián, David

AU - Hernández-Alvarez, María Isabel

AU - Segalés, Jessica

AU - Sorianello, Eleanora

AU - Muñoz, Juan Pablo

AU - Sala, David

AU - Waget, Aurélie

AU - Liesa, Marc

AU - Paz, José C.

AU - Gopalacharyulu, Peddinti

AU - Orešič, Matej

AU - Pich, Sara

AU - Burcelin, R.

AU - Palacín, Manuel

AU - Zorzano, Antonio

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - mitochondrial dynamics

KW - insulin resistance

KW - metabolism

KW - oxidative stress

U2 - 10.1073/pnas.1108220109

DO - 10.1073/pnas.1108220109

M3 - Article in a proceedings journal

VL - 109

SP - 5523

EP - 5528

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 - 14

ER -