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

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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.

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Acknowledgments

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).

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Authors and Affiliations

  1. College of Life Sciences, Wuhan University, Wuhan, Hubei, 430072, People’s Republic of China

    Yue Sun, Weili Xue, Zhiyin Song & Ling Zheng

  2. Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China

    Kun Huang

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Sun, Y., Xue, W., Song, Z. et al. Restoration of Opa1-long isoform inhibits retinal injury-induced neurodegeneration. J Mol Med 94, 335–346 (2016). https://doi.org/10.1007/s00109-015-1359-y

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