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Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells

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Abstract

Mitofusin 2 (Mfn2) is a dynamin-like protein anchored in the outer mitochondrial membrane that plays a crucial role in ensuring optimal mitochondrial morphological homeostasis. It has been shown that reduced expression of Mfn2 is associated with insulin resistance, but the mechanism is still unclear. We investigated whether Mfn2 deficiency leads to impaired insulin sensitivity via elevated oxidative stress. L6 skeletal muscle cells were treated with palmitate and Mfn2 expression was repressed by transfection with antisense Mfn2. Levels of antioxidant enzymes, reactive oxygen species (ROS), the phosphorylation of c-Jun N-terminal Kinase (JNK) and nuclear factor-κB (NF-κB) and the mitochondrial membrane potential (Δψm) were measured. The results showed palmitate-induced insulin resistance of skeletal muscle cells was accompanied by Mfn2 repression. Meanwhile, the cells had decreased Δψm and activity of antioxidant enzymes which could increase production of ROS, phosphorylation of JNK and NF-κB. When Mfn2 was up-regulated in palmitate-treated cells, oxidative stress and insulin resistance was alleviated. Furthermore, knock-down of Mfn2 in control cells enhanced oxidative stress. Mfn2 deficiency led to increased superoxide concentration and activation of JNK as well as NF-κB associated with insulin signaling. In conclusion, Mfn2 is a potent repressor for oxidative stress and regulation of Mfn2 expression may prove to be a potential method to circumvent insulin resistance.

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grants No. 30971391 and 81170742).

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Department of Internal Medicine, Hebei Medical University, 348 Heping West Road, Shijiazhuang, 050051, China

    Qian Nie, Guangyao Song, Dexian Kong & Xuemei Zhang

  2. Department of Endocrinology, Hebei General Hospital, Shijiazhuang, 050051, China

    Chao Wang, Guangyao Song, Huijuan Ma, Kexin Gan & Yong Tang

  3. Clinical Medicine Research Center, Hebei General Hospital, Shijiazhuang, 050051, China

    Chao Wang

Authors
  1. Qian Nie
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  2. Chao Wang
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  3. Guangyao Song
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  4. Huijuan Ma
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  6. Xuemei Zhang
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Correspondence to Guangyao Song.

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Nie, Q., Wang, C., Song, G. et al. Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells. Mol Biol Rep 41, 6975–6983 (2014). https://doi.org/10.1007/s11033-014-3584-9

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  • DOI: https://doi.org/10.1007/s11033-014-3584-9

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