PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY BMB Reports Pub Date : 2024-12-17
Byeong Geun Seok, Eunhee Park, Young-Jun Park, Young-Jun Park, Hyuk Nam Kwon, Su Wol Chung
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Abstract

A type of programmed cell death called ferroptosis is defined by increased iron-dependent lipid peroxidation. Mitochondria play a central role in iron metabolism. Mitochondrial defects include decreased cristae density, membrane rupture, and decreased mitochondrial membrane density, which occur as a result of ferroptosis. One of the important regulator of mitochondrial biogenesis is PGC1α. While recent studies have begun to explore the association between PGC1α and ferroptosis, the specific role of PGC1α in erastin-induced mitochondrial dysfunction during ferroptotic cell death has not been fully elucidated. In this study, we demonstrate for the first time that PGC1α is a key regulator of erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis in HT1080 fibrosarcoma cells. In this study, we examined PGC1α function in ferroptosis. Erastin, an inducer of ferroptosis, boosted the expression of PGC1α. Moreover, PGC1α down-regulation reduced erastin-induced ferroptosis. The most important biochemical feature of ferroptosis is the increase in iron ion (Fe2+)-dependent lipid peroxide (LOOH) concentration. Mitochondrial-dependent lipid peroxidation was abolished by PGC1α downregulation. In addition, PGC1α was induced during mitochondrial dysfunction in erastin-induced ferroptosis. Mitochondrial membrane potential loss and mitochondrial ROS production associated with erastin-induced mitochondrial dysfunction were blocked by PGC1α inhibition. In addition, erastin-induced lipid peroxidation in HT1080 fibrosarcoma cells was regulated by PGC1α inhibitor. This phenomenon was also consistent in HT1080 cells transfected with PGC1α shRNA transfected cells. Taken together, these results suggest that PGC1α is a key factor in erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis cell death.

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一种被称为铁变态反应的程序性细胞死亡是由铁依赖性脂质过氧化增加所决定的。线粒体在铁代谢中起着核心作用。线粒体缺陷包括嵴密度降低、膜破裂和线粒体膜密度降低,这些都是铁跃迁的结果。线粒体生物生成的重要调节因子之一是 PGC1α。虽然最近的研究已经开始探索 PGC1α 与铁凋亡之间的联系,但 PGC1α 在铁凋亡细胞死亡过程中由依拉斯特诱导的线粒体功能障碍中的具体作用尚未完全阐明。在本研究中,我们首次证明了 PGC1α 是 HT1080 纤维肉瘤细胞中麦角固醇诱导的线粒体依赖性脂质过氧化和铁中毒过程中线粒体功能障碍的关键调节因子。在这项研究中,我们考察了 PGC1α 在铁变态反应中的功能。铁变态反应诱导剂Erastin促进了PGC1α的表达。此外,PGC1α的下调可减少麦拉宁诱导的铁褐斑病。铁变态反应最重要的生化特征是铁离子(Fe2+)依赖性过氧化脂质(LOOH)浓度的增加。通过下调 PGC1α 可消除线粒体依赖性脂质过氧化。此外,在厄拉斯汀诱导的铁变态反应中,PGC1α在线粒体功能障碍过程中被诱导。抑制 PGC1α 可阻止与厄拉斯汀诱导的线粒体功能障碍相关的线粒体膜电位丧失和线粒体 ROS 生成。此外,PGC1α抑制剂还调节了厄拉斯汀诱导的 HT1080 纤维肉瘤细胞脂质过氧化反应。这一现象在转染了 PGC1α shRNA 的 HT1080 细胞中也是一致的。综上所述,这些结果表明,PGC1α是依拉斯汀诱导的线粒体依赖性脂质过氧化和铁中毒细胞死亡过程中功能障碍的关键因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
BMB Reports
BMB Reports 生物-生化与分子生物学
CiteScore
5.10
自引率
7.90%
发文量
141
审稿时长
1 months
期刊介绍: The BMB Reports (BMB Rep, established in 1968) is published at the end of every month by Korean Society for Biochemistry and Molecular Biology. Copyright is reserved by the Society. The journal publishes short articles and mini reviews. We expect that the BMB Reports will deliver the new scientific findings and knowledge to our readers in fast and timely manner.
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