Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration
Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration
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Opa1长亚型的恢复抑制视网膜损伤引起的神经变性
DOI：
10.1007/s00109-015-1359-y
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发表时间：
2016-03-01
影响因子：
4.7
通讯作者：
Zheng, Ling
中科院分区：
文献类型：
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作者：
Sun, Yue;Xue, Weili;Zheng, Ling
视神经萎缩1（Opa 1）是调节线粒体融合和其他重要功能的关键因子。Opa 1前体的N-末端线粒体靶向序列被去除，产生Opa 1长亚型（L-Opa 1），其进一步裂解为短亚型（S-Opa 1）。在本研究中，我们发现，视网膜缺血再灌注（I/R）损伤和玻璃体内注射羰基氰间氯苯腙（CCCP）都显着诱导Opa 1切割和L-Opa 1的损失。在缺氧-复氧（H/R）损伤的培养神经细胞中，Opa 1也观察到类似的变化。相反，通过过表达S1切割位点缺失Opa 1剪接体1（Opa 1-Delta S1）来恢复L-Opa 1水平不仅使H/R诱导的线粒体形态学改变正常化，而且抑制H/R诱导的细胞凋亡、坏死和细胞内ATP丢失。此外，通过玻璃体内注射京尼平或过表达Opa 1-Delta S1来恢复I/R损伤的视网膜中的L-Opa 1水平抑制了神经节细胞层中的细胞凋亡、坏死、细胞损失和视网膜厚度减小。总之，我们的数据表明，L-Opa 1的损失涉及视网膜I/R损伤的发展，表明恢复L-Opa 1水平可以被认为是I/R损伤相关疾病的治疗靶点，至少对于视网膜而言。
Optic atrophy 1 (Opa1) is a critical factor that regulates fusion and other important functions of mitochondria. In mitochondrion, the N-terminal mitochondrial targeting sequence of Opa1 precursors is removed to generate Opa1 long isoforms (L-Opa1), which are further cleaved into short isoforms (S-Opa1). In the present study, we found that retinal ischemia-reperfusion (I/R) injury and intravitreal injection of carbonylcyanide m-chlorophenyl hydrazone (CCCP) both dramatically induced Opa1 cleavage and caused loss of L-Opa1. In cultured neuronal cells under hypoxia-reoxygenation (H/R) injury, similar changes for Opa1 were also observed. In contrast, restoration of L-Opa1 level by overexpression of S1 cleavage site deletion Opa1 splice 1 (Opa1-Delta S1) not only normalized the H/R-induced mitochondrial morphology changes, but also inhibited the H/R-induced apoptosis, necrosis, and the intracellular ATP loss. Furthermore, recovering L-Opa1 level in the I/R-injured retina by intravitreal injection of genipin or overexpression of Opa1-Delta S1 inhibited apoptosis, necrosis, cell loss in the ganglion cell layer and retinal thickness reduction. Together, our data demonstrated the loss of L-Opa1 is involved in the development of retinal I/R injury, indicating restoring L-Opa1 level may be considered as a therapeutic target for I/R injury-related diseases, at least for the retina.