Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract

• 成果类型: Article
• 署名作者: Wei, Zongbo; Hao, Caili; Radeen, Kazi Rafsan; Hao, Zheng; Kettimuthu, Kavitha; Maner-Smith, Kristal; Toyokuni, Shinya; Fan, Xingjun
• 署名单位: University System of Georgia; Augusta University; Nagoya University; Emory University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9957
• DOI: 10.1073/pnas.2407842121
• 发表日期: 2024-11-26
• 关键词: oxidized phospholipids; superoxide-dismutase; lipid-peroxidation; eye; catalase; differentiation; ORGANIZATION; ferroptosis; disruption; oxidation

摘要

The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis- independent but ferroptosis- mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens- specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.