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. 2012 Apr 3;109(14):5523-8.
doi: 10.1073/pnas.1108220109. Epub 2012 Mar 16.

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

David Sebastián  1 , María Isabel Hernández-Alvarez, Jessica Segalés, Eleonora Sorianello, Juan Pablo Muñoz, David Sala, Aurélie Waget, Marc Liesa, José C Paz, Peddinti Gopalacharyulu, Matej Orešič, Sara Pich, Rémy Burcelin, Manuel Palacín, Antonio Zorzano
Affiliations

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

David Sebastián et al. Proc Natl Acad Sci U S A. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Liver-specific Mfn2 ablation causes glucose intolerance and a reduced response to insulin. (A) Mfn2 protein levels from various tissues in control and L-KO mice. (B) Representative images of mitochondria in isolated hepatocytes. Mitochondria were visualized by transfecting hepatocytes with DsRed2-mito vector. (C–E) Plasma glucose insulin and glucagon levels in mice fed a normal diet (ND) or a HFD (n = 8–12). (F) Glucose tolerance test (GTT) on mice fed a normal diet (n = 15–20). (G) GTT on mice fed a HFD (n = 8–12). (H) Insulin tolerance tests on mice fed a HFD (n = 8–12). (I) Pyruvate challenge (n = 15–20). (J) Hepatic expression of gluconeogenic genes (n = 8–12). (K) CRTC2 phosphorylation in livers from fed or 4-h fasting mice. Data represent mean ± SEM. *P < 0.05. C, control; G6Pase, glucose 6-phosphatase; PC, pyruvate carboxylase.
Fig. 2.
Fig. 2.
Mfn2 KO mice show impaired glucose tolerance, high plasma insulin levels, and insulin resistance in response to aging or HFD. (A) Mfn2 protein levels in mitochondrial extracts from several tissues in control (C) and Mfn2 KO mice and densitometric quantification (n = 3–8). (B) Confocal images of intracellular localization of Mfn2 by immunofluorescence in transversal sections of gastrocnemius muscles of control and KO mice. (Scale bars: 50 μm.) (C) Mitochondrial network was visualized by confocal microscopy using longitudinal sections of tibialis anterior muscles expressing a DsRed2-Mito vector that specifically labels mitochondria. (Scale bars: 50 μm.) (D) GTT on 54-wk-old mice (n = 8). (E) Insulin levels during the GTT in 54-wk-old mice (n = 8). (F) GTT on mice subjected to a HFD for 14 wk (n = 8–12). (G) Insulin levels during the GTT in HFD-fed mice (n = 8–12). (H) Insulin tolerance test in mice subjected to a HFD for 14 wk (n = 8–12). (I) Glucose fluxes during the euglycemic-hyperinsulinemic clamp in HFD-fed mice (26 wk) (n = 5). (J) Muscle glycogen synthesis assessed during euglycemic-hyperinsulinemic clamp in mice fed a HFD (n = 5). Data represent mean ± SEM. *P < 0.05 vs. control mice.
Fig. 3.
Fig. 3.
Mfn2 loss-of-function impairs insulin signaling in liver and skeletal muscle in vivo. (A) Insulin receptor (IR) tyrosine phosphorylation, p85 subunit of PI3K bound to IRS1 or IRS2, and Akt phosphorylation were measured using specific antibodies in liver extracts from C or L-KO mice on a normal diet 5 min after portal vein insulin injection. (B) Insulin receptor (IR) tyrosine phosphorylation, p85 subunit of PI3K bound to IRS1, and Akt phosphorylation were measured in gastrocnemius extracts from C or KO mice on high-fat diet.
Fig. 4.
Fig. 4.
Mfn2 ablation causes ER stress and JNK activation. (A–B) ER stress markers were evaluated in liver from C and L-KO mice (A) and in skeletal muscle from C and KO mice (B). (C–G) Western blot analysis of pJNK was performed in liver of C and L-KO mice (C), skeletal muscle from C and KO mice (E), and L6E9 myotubes (F). Ser 307 phosphorylation of IRS1 was analyzed in livers from C and L-KO mice (D) and L6E9 myotubes (G).
See this image and copyright information in PMC

References

    1. Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845. - PubMed
    1. Twig G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27:433–446. - PMC - PubMed
    1. Yasukawa K, et al. Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci Signal. 2009;2:ra47. - PubMed
    1. Pich S, et al. The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system. Hum Mol Genet. 2005;14:1405–1415. - PubMed
    1. Hailey DW, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141:656–667. - PMC - PubMed

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