ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.
ATP synthase inhibitory factor subunit 1 regulates islet β-cell function via repression of mitochondrial homeostasis.
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DOI：
10.1038/s41374-021-00670-x
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发表时间：
2022-01
影响因子：
5
通讯作者：
Yang, Qinglin
中科院分区：
文献类型：
--
作者：
Zhang, Kailiang;Bao, Rong;Huang, Fengyuan;Yang, Kevin;Ding, Yishu;Lauterboeck, Lothar;Yoshida, Masasuke;Long, Qinqiang;Yang, Qinglin
线粒体动态平衡对胰腺β细胞的功能至关重要。三磷酸腺苷合成酶抑制因子亚基1(IF1)是一种线粒体蛋白，与三磷酸腺苷合成酶相互作用，抑制其酶活性。IF1还可能在维持ATP合酶寡聚和线粒体内膜形成方面发挥作用。最近的一项研究证实，IF1在β-细胞中表达。在培养的INS-1Eβ-细胞中，IF1基因敲除增强了葡萄糖诱导的胰岛素释放。然而，IF1在胰岛β细胞中的作用仍鲜为人知。本研究调查了新分离的具有全局IF1基因敲除(IF1−/−)和过度表达(OE)的小鼠胰岛。IF1−/−小鼠的胰岛在葡萄糖刺激下的胰岛素分泌增加，而IF1 OE小鼠的胰岛分泌减少。分离胰岛的透射电子显微镜观察显示，IF1−/−组成熟的胰岛素颗粒数(核致密)相对较多，而IF1 OE组较对照胰岛少。IF1高表达的β细胞线粒体超微结构与野生型小鼠相当，而IF1−/−β细胞的线粒体质量增加。对培养的INS-1β-细胞的线粒体网络分析显示，与IF1基因敲除细胞的线粒体网络增加类似。IF1过表达的INS-1β-细胞线粒体氧化磷酸化速率降低，细胞内三磷酸腺苷含量降低。相反，带有IF1基因敲除的INS-1细胞表现出显著的细胞呼吸增加和ATP产生的改善。这些结果支持，IF1通过抑制β细胞的线粒体质量和呼吸作用，对胰岛素的产生和分泌起负调控作用。因此，抑制IF1以改善患者的β细胞功能可能是治疗糖尿病的一种新的治疗策略。
Mitochondrial homeostasis is crucial for the function of pancreatic β-cells. ATP synthase inhibitory factor subunit 1 (IF1) is a mitochondrial protein interacting with ATP synthase to inhibit its enzyme activity. IF1 may also play a role in maintaining ATP synthase oligomerization and mitochondrial inner membrane formation. A recent study confirmed IF1 expresses in β-cells. IF1 knockdown in cultured INS-1E β-cells enhances glucose-induced insulin release. However, the role of IF1 in islet β-cells remains little known. The present study investigates islets freshly isolated from mouse lines with global IF1 knockout (IF1−/−) and overexpression (OE). The glucose-stimulated insulin secretion was increased in islets from IF1−/− mice but decreased in islets from IF1 OE mice. Transmitted Electronic Microscopic assessment of isolated islets revealed that the number of matured insulin granules (with dense core) was relatively higher in IF1−/−, but fewer in IF1 OE islets than those of controlled islets. The mitochondrial ultrastructure within β-cells of IF1 overexpressed islets was comparable with those of wild-type mice, whereas those in IF1−/− β-cells showed increased mitochondrial mass. Mitochondrial network analysis in cultured INS-1 β-cells showed a similar pattern with an increased mitochondrial network in IF1 knockdown cells. IF1 overexpressed INS-1 β-cells showed a compromised rate of mitochondrial oxidative phosphorylation with attenuated cellular ATP content. In contrast, INS-1 cells with IF1 knockdown showed markedly increased cellular respiration with improved ATP production. These results support that IF1 is a negative regulator of insulin production and secretion via inhibiting mitochondrial mass and respiration in β-cells. Therefore, inhibiting IF1 to improve β-cell function in patients can be a novel therapeutic strategy to treat diabetes.
DOI：
10.1007/978-1-62703-155-4_4
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Kim, Teayoun;Zhelyabovska, Olga;Liu, Jian;Yang, Qinglin
通讯作者：
Yang, Qinglin