title: Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration.
abstract: 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.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China.
authors.forename: Weili
authors.initials: W
authors.lastname: Xue
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China.
authors.forename: Zhiyin
authors.initials: Z
authors.lastname: Song
authors.affiliation: Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China. kunhuang2008@hotmail.com.
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China. lzheng217@hotmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D039823:Iridoids / Q000627:therapeutic use; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D055351:Retinal Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D039823:Iridoids; D020033:Protein Isoforms; C007834:genipin; D020558:GTP Phosphohydrolases; C498811:Opa1 protein, rat
keywords: Apoptosis and necrosis; Genipin; Neurodegeneration; Opa1; Retinal injury