title: Mitofusin 2 deficiency leads to oxidative stress that contributes to insulin resistance in rat skeletal muscle cells.
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.
authors.affiliation: Department of Internal Medicine, Hebei Medical University, 348 Heping West Road, Shijiazhuang, 050051, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Nie
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Guangyao
authors.initials: G
authors.lastname: Song
authors.forename: Huijuan
authors.initials: H
authors.lastname: Ma
authors.forename: Dexian
authors.initials: D
authors.lastname: Kong
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
authors.forename: Kexin
authors.initials: K
authors.lastname: Gan
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002460:Cell Line; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010168:Palmitates / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D010168:Palmitates; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; D005947:Glucose