|BEJARANO, ELOY - University Of Cardenal Herrera-Ceu|
|WHITCOMB, ELIZABETH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|PFEIFFER, REBECCA - University Of Utah|
|ROSE, KRISTIE - Vanderbilt University|
|ASENSIO, MARIA - Hospital Ramon Y Cajal|
|RODRIGUEZ-NAVARRO, JOSE - Hospital Ramon Y Cajal|
|PONCE-MORA, ALEJANDRO - University Of Cardenal Herrera-Ceu|
|CANTO, ANTOLIN - University Of Cardenal Herrera-Ceu|
|ALMANSA, INMA - University Of Cardenal Herrera-Ceu|
|SCHEY, KEVIN - Vanderbilt University|
|JONES, BRYAN - University Of Utah|
|TAYLOR, ALLEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|ROWAN, SHELDON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
Submitted to: Redox Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/31/2023
Publication Date: 9/1/2023
Citation: Bejarano, E., Whitcomb, E., Pfeiffer, R.L., Rose, K.L., Asensio, M.J., Rodriguez-Navarro, J.A., Ponce-Mora, A., Canto, A., Almansa, I., Schey, K.L., Jones, B.W., Taylor, A., Rowan, S. 2023. Unbalanced redox status network as an early pathological event in congenital cataracts. Redox Biology. https://doi.org/10.1016/j.redox.2023.102869.
Interpretive Summary: Congenital cataracts cause the eye lens to lose transparency and are a major cause of worldwide blindness. The underlying basis for their formation, especially non-hereditary forms, is mostly unknown. Here, we used a mouse model to understand cataract formation. By comparing all detected proteins in clear lenses against those in cataracts, we identified proteins and pathways that were altered in cataracts. These pathways involved amino acids and an important antioxidant. Defective antioxidant production has already been linked to common age-related cataracts and more broadly to age-related diseases. Our work is the first time these pathways have been connected to congenital cataracts.
Technical Abstract: The lens proteome undergoes dramatic composition changes during development and maturation. A defective developmental process leads to congenital cataracts that account for about 30% of cases of childhood blindness. Gene mutations are associated with approximately 50% of early-onset forms of lens opacity, with the remainder being of unknown etiology. To gain a better understanding of cataractogenesis, we utilized a transgenic mouse model expressing a mutant ubiquitin protein in the lens (K6W-Ub) that recapitulates most of the early pathological changes seen in human congenital cataracts. We performed mass spectrometry-based tandem-mass-tag quantitative proteomics in E15, P1, and P30 control or K6W-Ub lenses. Our analysis identified targets that are required for early normal differentiation steps and altered in cataractous lenses, particularly metabolic pathways involving glutathione and amino acids. Computational molecular phenotyping revealed that glutathione and taurine were spatially altered in the K6W-Ub cataractous lens. High-performance liquid chromatography revealed that both taurine and the ratio of reduced glutathione to oxidized glutathione, two indicators of redox status, were differentially compromised in lens biology. In sum, our research documents that dynamic proteome changes in a mouse model of congenital cataracts impact redox biology in lens. Our findings shed light on the molecular mechanisms associated with congenital cataracts and point out that unbalanced redox status due to reduced levels of taurine and glutathione, metabolites already linked to age-related cataract, could be a major underlying mechanism behind lens opacities that appear early in life.