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Connexin hemichannels regulate redox potential via metabolite exchange and protect lens against cellular oxidative damage.

ABSTRACT: Increased oxidative stress contributes to cataract formation during aging. Anterior epithelial cells are a frontline antioxidant defense system with powerful capacities to maintain redox homeostasis and lens transparency. In this study, we report a new molecular mechanism of connexin (Cx) hemichannels (HCs) in lens epithelial cells to protect lens against oxidative stress. Our results showed haploinsufficiency of Cx43 elevated oxidative stress and susceptibility to cataracts in the mouse lens. Cx43 HCs opened in response to hydrogen peroxide (H₂O₂) or ultraviolet radiation (UVR) in human lens epithelium HLE-B3 cells, and this activation contributed to a cellular protective mechanism against oxidative stress-induced apoptotic cell death. Furthermore, we found that Cx43 HCs mediated the exchange of oxidants and antioxidants in lens epithelial cells undergoing oxidative stress. These transporting activities facilitated a reduction of intracellular reactive oxygen species (ROS) accumulation and maintained the intracellular glutathione (GSH) level through the exchange of redox metabolites and change of anti-oxidative gene expression. In addition, we show that Cx43 HCs can be regulated by the intracellular redox state and this regulation is mediated by residue Cys260 located at the Cx43 C-terminus. Together, our results demonstrate that Cx43 HCs activated by oxidative stress in the lens epithelial cells play a key role in maintaining redox homeostasis in lens under oxidative stress. Our findings contribute to advancing our understanding of oxidative stress induced lens disorders, such as age-related non-congenital cataracts.

SUBMITTER: Quan Y

PROVIDER: S-EPMC8408634 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Data on Connexin 43 hemichannels regulation of cellular redox in lens.

Project description:This article describes a dataset that is related to the research paper "Connexin hemichannels regulate redox potential via metabolite exchange and protect lens against cellular oxidative damage". Growing evidence demonstrates that oxidative stress is a key event in cataract formation. Hemichannels (HCs) formed by Connexin (Cx) 43, a Cx subtype only present in the epithelium of lens tissue, mediate the exchange of small molecules between the intracellular and extracellular environments, including redox-related metabolic molecules, such as glutathione (GSH) and reactive oxygen species (ROS). Here, we used a Cx43 heterozygous mouse model, Cx43E2 antibody (a specific Cx43 HC blocker), and knocked down Cx43 expression by siRNA in human lens epithelial HLE-B3 cells to assess the oxidative response of Cx43 HCs to H2O2 and UVB radiation. Western blot analysis of heterozygous Cx43-null (Cx43+/-) mouse lenses showed the haploinsufficiency of Cx43 protein. We further assessed anti-oxidative gene expression in response to H2O2 and UVB radiation treatment in the Cx43-deficient lens epithelial cells. This dataset will be useful for understanding the critical role of Cx43 HCs in maintaining redox homeostasis in the lens under oxidative stress.

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