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J Mol Med (Berl). 2016 Mar;94(3):335-46. doi: 10.1007/s00109-015-1359-y. Epub 2015 Nov 4.

Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration.

Author information

1
College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China.
2
Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People's Republic of China. kunhuang2008@hotmail.com.
3
College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People's Republic of China. lzheng217@hotmail.com.

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.

KEYWORDS:

Apoptosis and necrosis; Genipin; Neurodegeneration; Opa1; Retinal injury

PMID:
26530815
DOI:
10.1007/s00109-015-1359-y
[Indexed for MEDLINE]

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