Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration
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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.
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.
KeywordsOpa1 Neurodegeneration Genipin Retinal injury Apoptosis and necrosis
This work was supported by the National Basic Research Program of China (2012CB524901) and the Natural Science Foundation of China (81202557, 31271370, 81172971, and 31471208).
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interests.
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