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

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 be considered as a therapeutic target for i/r injury-related diseases, at least for the retina.