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Journal of Molecular Medicine

, Volume 94, Issue 3, pp 335–346 | Cite as

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

  • Yue Sun
  • Weili Xue
  • Zhiyin Song
  • Kun HuangEmail author
  • Ling ZhengEmail author
Original Article

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

Opa1 Neurodegeneration Genipin Retinal injury Apoptosis and necrosis 

Notes

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).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

Supplementary material

109_2015_1359_MOESM1_ESM.docx (287 kb)
ESM 1 (DOCX 287 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.College of Life SciencesWuhan UniversityWuhanPeople’s Republic of China
  2. 2.Tongji School of PharmacyHuazhong University of Science and TechnologyWuhanPeople’s Republic of China

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