Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells
Selective Actions of Mitochondrial Fission/Fusion Genes on Metabolism-Secretion Coupling in Insulin-releasing Cells
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DOI：
10.1074/jbc.m806251200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Wollheim, Claes B.
中科院分区：
文献类型：
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作者：
Park, Kyu-Sang;Wiederkehr, Andreas;Wollheim, Claes B.
线粒体形成经历连续裂变/融合的丝状网络。在胰腺β细胞中，线粒体对于将营养代谢与胰岛素颗粒胞吐作用联系起来的信号转导是必不可少的。在这里，我们研究了胰岛素瘤细胞系INS-1 E、原代大鼠和人类β细胞中的线粒体网络。我们进一步研究了INS-1 E细胞中线粒体分裂/融合对代谢-分泌偶联的影响。hFis 1的过度表达引起了戏剧性的线粒体片段化，而Mfn 1诱发过度融合和聚集的线粒体。过表达hFis 1或Mfn 1的细胞显示线粒体体积减少，细胞ATP水平降低，因此，葡萄糖刺激的胰岛素分泌受损。线粒体ATP生成的减少被糖酵解的增强部分补偿，如这些细胞中乳酸产生的增加所示。显性负性Mfn 1引起INS-1 E细胞线粒体的线粒体缩短和片段化，类似于hFis 1。然而，线粒体体积，胞浆ATP水平，和葡萄糖刺激的胰岛素分泌的影响不大。我们的结论是，线粒体碎片本身并不损害代谢分泌耦合。hFis 1和Mfn 1活性通过影响线粒体生物能量学和分布，影响线粒体信号产生，从而影响胰岛素胞吐。
Mitochondria form filamentous networks that undergo continuous fission/fusion. In the pancreatic beta-cells, mitochondria are essential for the transduction of signals linking nutrient metabolism to insulin granule exocytosis. Here we have studied mitochondrial networks in the insulinoma cell line INS-1E, primary rat and human beta-cells. We have further investigated the impact of mitochondrial fission/fusion on metabolism-secretion coupling in INS-1E cells. Overexpression of hFis1 caused dramatic mitochondrial fragmentation, whereas Mfn1 evoked hyperfusion and the aggregation of mitochondria. Cells overexpressing hFis1 or Mfn1 showed reduced mitochondrial volume, lowered cellular ATP levels, and as a consequence, impaired glucose-stimulated insulin secretion. Decreased mitochondrial ATP generation was partially compensated for by enhanced glycolysis as indicated by increased lactate production in these cells. Dominant-negative Mfn1 elicited mitochondrial shortening and fragmentation of INS-1E cell mitochondria, similar to hFis1. However, the mitochondrial volume, cytosolic ATP levels, and glucose-stimulated insulin secretion were little affected. We conclude that mitochondrial fragmentation per se does not impair metabolism-secretion coupling. Through their impact on mitochondrial bioenergetics and distribution, hFis1 and Mfn1 activities influence mitochondrial signal generation thereby insulin exocytosis.