Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mol Biol Cell. 2011 Jul 1;22(13):2235-45. doi: 10.1091/mbc.E10-12-0933. Epub 2011 May 5.
Previous studies using in vitro cell culture systems have shown the role of the dynamin-related GTPase Opa1 in apoptosis prevention and mitochondrial DNA (mtDNA) maintenance. However, it remains to be tested whether these functions of Opa1 are physiologically important in vivo in mammals. Here, using the Cre-loxP system, we deleted mouse Opa1 in pancreatic beta cells, in which glucose-stimulated ATP production in mitochondria plays a key role in insulin secretion. Beta cells lacking Opa1 maintained normal copy numbers of mtDNA; however, the amount and activity of electron transport chain complex IV were significantly decreased, leading to impaired glucose-stimulated ATP production and insulin secretion. In addition, in Opa1-null beta cells, cell proliferation was impaired, whereas apoptosis was not promoted. Consequently, mice lacking Opa1 in beta cells develop hyperglycemia. The data suggest that the function of Opa1 in the maintenance of the electron transport chain is physiologically relevant in beta cells.
先前的研究使用体外细胞培养系统表明了动力相关 GTP 酶 Opa1 在防止细胞凋亡和维持线粒体 DNA（mtDNA）中的作用。然而，其在哺乳动物体内是否具有生理意义仍有待检验。在此，我们使用 Cre-loxP 系统在胰岛β细胞中敲除了小鼠的 Opa1，在胰岛β细胞中，线粒体中葡萄糖刺激的 ATP 生成对于胰岛素分泌起着关键作用。缺乏 Opa1 的β细胞保持了 mtDNA 的正常拷贝数；然而，电子传递链复合物 IV 的含量和活性显著降低，导致葡萄糖刺激的 ATP 生成和胰岛素分泌受损。此外，在 Opa1 缺失的β细胞中，细胞增殖受损，而细胞凋亡未被促进。因此，缺乏胰岛β细胞 Opa1 的小鼠会出现高血糖。数据表明，Opa1 在维持电子传递链中的功能在β细胞中具有生理相关性。
