离子通道 Piezo1 可诱导小梁网状结构细胞铁突变:原发性开角型青光眼发病机制的新发现

IF 5 2区 生物学 Q2 CELL BIOLOGY
Kexin Liu, Jing Xu, Rufei Yang, Feng Wang, Ying Su
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引用次数: 0

摘要

目的:本研究旨在阐明机械敏感分子 Piezo1 在原发性开角型青光眼(POAG)(造成不可逆视力损伤的主要原因)小梁网细胞(TMCs)中的作用。小梁网(TM)功能障碍是导致原发性开角型青光眼(POAG)眼压升高的关键因素,但导致小梁网功能障碍的具体机制尚未完全明了:我们对人小梁网状细胞(HTMC)进行了细胞拉伸,并用 Yoda1 对 HTMC 进行了药理激活,以研究 Piezo1 在 HTMC 中的作用。我们重点评估了细胞存活率、线粒体变化、脂质过氧化以及与铁变态反应相关的靶标(如酰基-CoA合成酶长链家族成员4(ACSL4)和谷胱甘肽过氧化物酶4(GPX4))的表达:结果:细胞拉伸可诱导 HTMCs 发生铁变态反应,而 Piezo1 基因敲除可逆转这一现象。此外,药理激活 Piezo1 也会导致 HTMC 中的铁蛋白沉积。此外,我们还发现抑制 JNK/p38 信号通路可减轻 Yoda1 诱导的铁变态反应,从而证实 Piezo1 可通过该通路诱导 TMCs 中的铁变态反应。值得注意的是,我们的实验表明 Yoda1 可能会引发小鼠眼球 TM 中的铁梭形细胞增多症:我们的研究结果表明,Piezo1 通路是 TMC 中铁细胞凋亡的关键介质,为青光眼,尤其是 POAG 的致病机制提供了新的见解。这项研究强调了靶向 Piezo1 通路作为减轻 TM 功能障碍和控制 POAG 的治疗方法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Ion channel Piezo1 induces ferroptosis of trabecular meshwork cells: a novel observation in the pathogenesis in primary open angle glaucoma.

This study aims to elucidate the role of Piezo1, a mechanosensitive molecule, in trabecular meshwork cells (TMCs) in the context of primary open angle glaucoma (POAG), a leading cause of irreversible visual impairment. Dysfunction of the trabecular meshwork (TM) is a key factor in the elevated intraocular pressure (IOP) observed in POAG, yet the specific mechanisms leading to TM dysfunction are not fully understood. We performed cell stretching on human trabecular meshwork cells (HTMCs) and pharmacologically activated HTMCs with Yoda1 to study the role of Piezo1 in HTMCs. We focused on assessing cell viability, mitochondrial changes, lipid peroxidation, and the expression of ferroptosis-related targets such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4). Cell stretching induces ferroptosis in HTMCs, and this phenomenon is reversed by Piezo1 knockdown. In addition, pharmacological activation of Piezo1 also leads to ferroptosis in HTMCs. Furthermore, inhibiting the JNK/p38 signaling pathway was found to mitigate the ferroptotic response induced by Yoda1, thereby confirming that Piezo1 induces ferroptosis in TMCs through this pathway. Notably, our experiments suggest that Yoda1 may trigger ferroptosis in the TM of mouse eyes. Our findings demonstrate that the Piezo1 pathway is a crucial mediator of ferroptosis in TMCs, providing new insights into the pathogenic mechanisms of glaucoma, particularly POAG. This study highlights the potential of targeting the Piezo1 pathway as a therapeutic approach for mitigating TM dysfunction and managing POAG.NEW & NOTEWORTHY This study is the first to show that cell stretching induces ferroptosis in trabecular meshwork cells (TMCs), dependent on Piezo1 activation. Targeting the Piezo1 pathway offers new therapeutic potential for mitigating trabecular meshwork dysfunction and managing primary open angle glaucoma (POAG). The study also reveals Piezo1 induces ferroptosis via the JNK/p38 signaling pathway.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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