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

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

1. David Sebastián^a,^b,^c,¹,


2. María Isabel Hernández-Alvarez^a,^b,^c,¹,


3. Jessica Segalés^a,^b,^c,¹,


4. Eleonora Sorianello^a,^b,^c,


5. Juan Pablo Muñoz^a,^b,^c,


6. David Sala^a,^b,^c,


7. Aurélie Waget^d,


8. Marc Liesa^a,^b,^c,


9. José C. Paz^a,^b,^c,


10. Peddinti Gopalacharyulu^e,


11. Matej Orešič^e,


12. Sara Pich^a,^b,


13. Rémy Burcelin^d,


14. Manuel Palacín^a,^b, and


15. Antonio Zorzano^a,^b,^c,²

+ Author Affiliations

1. 
   ^aInstitute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain;
   
   


2. 
   ^bDepartament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain;
   
   


3. 
   ^cInstituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08017 Barcelona, Spain;
   
   


4. 
   ^dInstitut National de la Santé et de la Recherche Médicale Unité 1048, Institut de Recherche sur les Maladies Métaboliques et Cardiovasculaires de l'Hôpital Rangueil, 31432 Toulouse, France; and
   
   


5. 
   ^eQuantitative Biology and Bioinformatics, VTT Technical Research Centre of Finland, 02044 Espoo, Finland
   
   

1. 
   Edited* by Bruce M. Spiegelman, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, and approved February 7, 2012 (received for review June 21, 2011)
   
   

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.

• mitochondrial dynamics


• insulin resistance


• metabolism


• oxidative stress

Footnotes

• 
  ↵¹D. Sebastián, M.I.H.-A., and J.S. contributed equally to this work.
  
  


• ↵²To whom correspondence should be addressed. E-mail: antonio.zorzano@irbbarcelona.org.

• 
  Author contributions: D. Sebastián, M.I.H.-A., J.S., E.S., J.P.M., D. Sala, A.W., J.C.P., S.P., R.B., and A.Z. designed research; D. Sebastián, M.I.H.-A., J.S., E.S., J.P.M., D. Sala, J.C.P., P.G., and S.P. performed research; M.L. contributed new reagents/analytic tools; D. Sebastián, M.I.H.-A., J.S., E.S., J.P.M., D. Sala, J.C.P., M.O., S.P., R.B., M.P., and A.Z. analyzed data; and A.Z. wrote the paper.
  
  


• 
  The authors declare no conflict of interest.
  
  


• 
  ↵*This Direct Submission article had a prearranged editor.
  
  


• 
  This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1108220109/-/DCSupplemental.