Loss of Mitofusin 2 Promotes Endoplasmic Reticulum Stress
Loss of Mitofusin 2 Promotes Endoplasmic Reticulum Stress
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DOI：
10.1074/jbc.m112.359174
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发表时间：
2012-06-08
影响因子：
4.8
通讯作者：
Walsh, Kenneth
中科院分区：
文献类型：
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作者：
Ngoh, Gladys A.;Papanicolaou, Kyriakos N.;Walsh, Kenneth
线粒体外膜GTP酶mitofusin 2（Mfn 2）除了其线粒体融合作用外，还已知调节内质网（ER）形状。然而，其在ER应激中的作用尚不清楚。我们在这里报告，诱导ER应激与毒胡萝卜素或衣霉素在小鼠胚胎成纤维细胞中导致上调Mfn 2 mRNA和蛋白水平的线粒体成形因子Mfn 1，Opa 1，Drp 1和Fis 1的表达没有变化。在小鼠胚胎成纤维细胞或小鼠心肌细胞中Mfn 2而不是Mfn 1的遗传缺失导致ER伴侣蛋白表达的增加。小鼠胚胎成纤维细胞中Mfn 2的基因切除放大了ER应激并加剧了ER应激诱导的细胞凋亡。Mfn 2的缺失通过延长eIF 2 α磷酸化延迟翻译恢复，这与GADD 34和p58（IPK）表达降低以及晚期时间点C/EBP同源蛋白诱导升高相关。未折叠蛋白反应的这些变化与增加的细胞死亡相关联，所述细胞死亡通过增强的半胱天冬酶3/7活性、从细胞释放的乳酸脱氢酶以及响应于毒胡萝卜素或衣霉素处理的碘化丙啶阳性核的增加来反映。相反，Mfn 1基因缺失不影响ER应激介导的ER伴侣蛋白合成或eIF 2 α磷酸化的增加。此外，ER应激诱导的C/EBP同源蛋白、GADD 34和p58（IPK）诱导和细胞死亡不受Mfn 1丢失的影响。我们的结论是Mfn 2，但不是Mfn 1是一个ER应激诱导蛋白，需要适当的时间序列的ER应激反应。
The outer mitochondrial membrane GTPase mitofusin 2 (Mfn2) is known to regulate endoplasmic reticulum (ER) shape in addition to its mitochondrial fusion effects. However, its role in ER stress is unknown. We report here that induction of ER stress with either thapsigargin or tunicamycin in mouse embryonic fibroblasts leads to up-regulation of Mfn2 mRNA and protein levels with no change in the expression of the mitochondrial shaping factors Mfn1, Opa1, Drp1, and Fis1. Genetic deletion of Mfn2 but not Mfn1 in mouse embryonic fibroblasts or cardiac myocytes in mice led to an increase in the expression of the ER chaperone proteins. Genetic ablation of Mfn2 in mouse embryonic fibroblasts amplified ER stress and exacerbated ER stress-induced apoptosis. Deletion of Mfn2 delayed translational recovery through prolonged eIF2 alpha phosphorylation associated with decreased GADD34 and p58(IPK) expression and elevated C/EBP homologous protein induction at late time points. These changes in the unfolded protein response were coupled to increased cell death reflected by augmented caspase 3/7 activity, lactate dehydrogenase release from cells, and an increase in propidium iodide-positive nuclei in response to thapsigargin or tunicamycin treatment. In contrast, genetic deletion of Mfn1 did not affect ER stress-mediated increase in ER chaperone synthesis or eIF2 alpha phosphorylation. Additionally, ER stress-induced C/EBP homologous protein, GADD34, and p58(IPK) induction and cell death were not affected by loss of Mfn1. We conclude that Mfn2 but not Mfn1 is an ER stress-inducible protein that is required for the proper temporal sequence of the ER stress response.