Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma

Zhou Zeng; Mengling You; Cong Fan; Rong Rong; Haibo Li; Xiaobo Xia

doi:10.1016/j.redox.2023.102687

Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma

Redox Biol. 2023 Jun:62:102687. doi: 10.1016/j.redox.2023.102687. Epub 2023 Mar 21.

Authors

Zhou Zeng¹, Mengling You¹, Cong Fan¹, Rong Rong¹, Haibo Li², Xiaobo Xia³

Affiliations

¹ Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
² Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. Electronic address: lihaibo@csu.edu.cn.
³ Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China; Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. Electronic address: xbxia21@csu.edu.cn.

Abstract

Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular pressure (ph-IOP) is an important risk factor for glaucoma, and it triggers molecularly distinct cascades that control RGC death and axonal degeneration. Dynamin-related protein 1 (Drp1)-mediated abnormalities in mitochondrial dynamics are involved in glaucoma pathogenesis; however, little is known about the precise pathways that regulate RGC injury and death. Here, we aimed to investigate the role of the ERK1/2-Drp1-reactive oxygen species (ROS) axis in RGC death and the relationship between Drp1-mediated mitochondrial dynamics and PANoptosis in ph-IOP injury. Our results suggest that inhibiting the ERK1/2-Drp1-ROS pathway is a potential therapeutic strategy for treating ph-IOP-induced injuries. Furthermore, inhibiting Drp1 can regulate RGC PANoptosis by modulating caspase3-dependent, nucleotide-binding oligomerization domain-like receptor-containing pyrin domain 3(NLRP3)-dependent, and receptor-interacting protein (RIP)-dependent pathways in the ph-IOP model. Overall, our findings provide new insights into possible protective interventions that could regulate mitochondrial dynamics to improve RGC survival.

Keywords: Dynamin-related protein 1; Glaucoma; Mitochondrial dynamics; PANoptosis; Retinal ganglion cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Dynamins / genetics
Dynamins / metabolism
Glaucoma* / drug therapy
Glaucoma* / genetics
Humans
Intraocular Pressure
Mitochondria / metabolism
Neurodegenerative Diseases* / metabolism
Reactive Oxygen Species / metabolism
Retinal Ganglion Cells / metabolism

Substances

Reactive Oxygen Species
Dynamins