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.

Mitofusin 2 ablation increases endoplasmic reticulum–mitochondria coupling

“…However, its action is crucial for cell life, possibly preventing an excess of close contacts between the two organelles that might result in a toxic transfer of Ca 2+ to mitochondria during cell stimulation (31) and eventually in cell death (38)(39)(40).…”

Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

“…Mfn2, a mitochondrial fusion protein crucial for the maintenance of the mitochondrial network architecture, is induced during myogenesis and abundantly expressed in skeletal muscle [58]. Previous studies have suggested that mfn2 deficiency in muscles leads to mtDNA depletion, impaired OXPHOS, decreased mitochondrial membrane potential, and oxidative stress [59][60][61]. Moreover, muscle mfn2 protein levels were repressed in several catabolic conditions [62][63][64][65].…”

Saturated lipids decrease mitofusin 2 leading to endoplasmic reticulum stress activation and insulin resistance in hypothalamic cells

“…In this context, in contrast to unsaturated fatty acids, saturated fats promote deregulation of food intake, increase body weight, obesity and are detrimental in the coordination of insulin sensitivity (Larsen and Tennagels, 2014). In vitro evidence has shown that stimulation with the saturated lipid, palmitic acid, promotes mitochondrial deregulation, oxidative stress and JNK and NFkB activation in muscle cells resulting in insulin resistance (Nie et al, 2014). Also, palmitic promotes ER stress activation in different cell types including neurons (Kwon et al, 2014;Nie et al, 2014;Yuzefovych et al, 2012).…”

“…In vitro evidence has shown that stimulation with the saturated lipid, palmitic acid, promotes mitochondrial deregulation, oxidative stress and JNK and NFkB activation in muscle cells resulting in insulin resistance (Nie et al, 2014). Also, palmitic promotes ER stress activation in different cell types including neurons (Kwon et al, 2014;Nie et al, 2014;Yuzefovych et al, 2012). These evidences suggest that ER and mitochondria are primary targets of lipids leading to insulin resistance states and the development of metabolic disorders including obesity and T2DM.…”

“…HFD intake in rodents decreases gene expression and MTF2 protein levels in skeletal muscle which correlates with insulin resistance state (Zhang et al, 2013). Of importance, in vitro stimulation of muscle cells with the saturated lipid palmitic acid, decreased MTF2 levels, which correlates with downregulation in the expression of antioxidant enzymes, oxidative stress activation and JNK and NF-kB activation leading to insulin resistance (Nie et al, 2014). Whether saturated lipids alter MTF2 expression at hypothalamus nucleus resulting in ER stress generation leading to insulin sensitivity during obesity is unknown.…”