Sun Yue, Xue Weili, Song Zhiyin, Huang Kun, Zheng Ling
College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China.
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China.
J Mol Med (Berl). 2016 Mar;94(3):335-46. doi: 10.1007/s00109-015-1359-y. Epub 2015 Nov 4.
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-ΔS1) 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-ΔS1 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. Key messages: Retinal ischemia-reperfusion (I/R) or hypoxia-reoxygenation (H/R) injury induces L-Opa1 loss. Opa1-ΔS1 overexpression inhibits H/R-induced L-Opa1 loss. Opa1-ΔS1 overexpression inhibits H/R-induced mitochondria morphology change. Opa1-ΔS1 and genipin inhibit retinal I/R injury-induced necroptosis. Opa1-ΔS1 and genipin inhibit retinal I/R injury-induced neurodegeneration.
视神经萎缩蛋白1（Opa1）是调节线粒体融合及其他重要功能的关键因子。在线粒体中，Opa1前体的N端线粒体靶向序列被去除，从而产生Opa1长亚型（L - Opa1），L - Opa1进一步被切割成短亚型（S - Opa1）。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化物间氯苯腙（CCCP）均显著诱导Opa1切割并导致L - Opa1丢失。在缺氧复氧（H/R）损伤的培养神经元细胞中，也观察到了Opa1的类似变化。相反，通过过表达S1切割位点缺失的Opa1剪接变体1（Opa1 - ΔS1）来恢复L - Opa1水平，不仅使H/R诱导的线粒体形态变化正常化，还抑制了H/R诱导的细胞凋亡、坏死以及细胞内ATP的损失。此外，通过玻璃体内注射京尼平或过表达Opa1 - ΔS1来恢复I/R损伤视网膜中的L - Opa1水平，可抑制神经节细胞层中的细胞凋亡、坏死、细胞丢失以及视网膜厚度的减少。总之，我们的数据表明L - Opa1的丢失参与了视网膜I/R损伤的发展，这表明恢复L - Opa1水平可被视为I/R损伤相关疾病（至少对于视网膜而言）的治疗靶点。关键信息：视网膜缺血再灌注（I/R）或缺氧复氧（H/R）损伤诱导L - Opa1丢失。Opa1 - ΔS1过表达抑制H/R诱导的L - Opa1丢失。Opa1 - ΔS1过表达抑制H/R诱导的线粒体形态变化。Opa1 - ΔS1和京尼平抑制视网膜I/R损伤诱导的坏死性凋亡。Opa1 - ΔS1和京尼平抑制视网膜I/R损伤诱导的神经退行性变。
