Inhibition of Pathological Mitochondrial Fission in Retinal Pigment Epithelium Mitigates Choroidal Neovascularization.

Abstract

PURPOSE: Mitochondria are highly dynamic organelles that continuously undergo fission and fusion, and their dysfunction is associated with various age-related disorders. This study aimed to elucidate the role of mitochondrial fission in the development of choroidal neovascularization (CNV), a hallmark of neovascular age-related macular degeneration (AMD), and to evaluate the therapeutic potential of its pharmacological inhibition. METHODS: The murine CNV model was created by laser photocoagulation using C57BL/6J mice. Expression changes of mitochondrial fission-related protein during CNV development were examined using western blotting and immunofluorescence. To assess the effectiveness of pharmacological inhibition of mitochondrial fission, the effects of mitochondrial division inhibitor-1 (Mdivi-1) and mitochondrial fusion promoter (M1) were evaluated by CNV area measurement, fluorescein angiography, and western blot analysis. The pro-angiogenic mechanisms associated with mitochondrial fission were further investigated in RPE cells cultured under hypoxic condition. RESULTS: In a murine laser-induced CNV model, mitochondrial fission-related proteins increased in the retinal pigment epithelium (RPE)-choroid complex, and the high expression of phosphorylated dynamin-related protein 1 (DRP1) was observed in RPE cells surrounding the CNV lesion. Additionally, intravitreal injection of Mdivi-1 or M1 suppressed CNV formation, vascular leakage, and pro-angiogenic factor production. In RPE cells exposed to hypoxia, DRP1-mediated mitochondrial fission was rapidly activated, accompanied by increased mitochondrial reactive oxygen species production. Moreover, inhibition of mitochondrial fission suppressed mitochondrial bioenergetic dysfunction and the upregulation of vascular endothelial growth factor. CONCLUSIONS: These findings support that pharmacological inhibition of activated mitochondrial fission could serve as a potential therapeutic approach for neovascular AMD.