Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer’s disease

Organelle Pub Date : 2024-05-15 DOI:10.61747/0ifp.202403001
Yasin Asadi, Hongmin Wang
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Abstract

Transcriptional control is a pivotal mechanism governing various cellular processes. FOXO proteins, a subgroup of the forkhead family of transcription factors, play a key role in determining cell fate. The localization and function of FOXO proteins are regulated by post-translational modifications to control target gene expression, with a pronounced impact on various aspects of mitochondrial function, including mitochondrial dynamics, biogenesis, and quality control. Mitochondria stand out as the primary target of FOXO transcription factors, which recruit downstream signaling factors to govern mitochondrial processes. Essential signaling pathways are modulated by FOXOs, exemplified by their regulation of mitochondrial biogenesis through SIRT1-Pgc1a and NRF1-TFAM, as well as their influence on mitochondrial dynamics involving Mfn1, Mfn2, Drp1, and Fis1. Furthermore, FOXOs demonstrate the ability to upregulate and downregulate genes that serve as modulators in oxidative and apoptosis cascades. The functional role of FOXO proteins is highly context-dependent, varying with cell type, organ, and specific FOXO isoform. Notably, FOXOs emerge as prominent players in various pathological conditions, including ischemic conditions, neurodegenerative diseases, cancer, and metabolic disorders. Unraveling the complex role of FOXOs in mammalian cell pathology positions them as promising therapeutic targets receptive to pharmacological treatment. This review aims to provide insights into the intricate roles of FOXOs in mitochondria, illuminating their potential as therapeutic targets amenable to pharmacological intervention in diverse pathological contexts, particularly in ischemic stroke and Alzheimer’s disease.
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缺血性中风和阿尔茨海默病中 FOXOs 对线粒体功能的调控
转录控制是管理各种细胞过程的关键机制。FOXO 蛋白是转录因子叉头家族的一个亚群,在决定细胞命运方面发挥着关键作用。FOXO 蛋白的定位和功能受翻译后修饰的调控,从而控制目标基因的表达,对线粒体功能的各个方面(包括线粒体动力学、生物生成和质量控制)都有明显的影响。线粒体是 FOXO 转录因子的主要靶标,FOXO 转录因子可招募下游信号因子来控制线粒体过程。FOXO调节重要的信号通路,例如通过SIRT1-Pgc1a和NRF1-TFAM调节线粒体生物生成,以及通过Mfn1、Mfn2、Drp1和Fis1影响线粒体动力学。此外,FOXOs 还能上调和下调在氧化和细胞凋亡级联中起调节作用的基因。FOXO 蛋白的功能作用高度依赖于环境,因细胞类型、器官和特定 FOXO 同工酶而异。值得注意的是,FOXO 在缺血性疾病、神经退行性疾病、癌症和代谢紊乱等各种病理情况中发挥着重要作用。揭示 FOXOs 在哺乳动物细胞病理学中的复杂作用,使它们成为有希望接受药物治疗的治疗靶点。本综述旨在深入探讨 FOXOs 在线粒体中的复杂作用,揭示它们作为治疗靶点的潜力,以便在不同病理情况下,特别是在缺血性中风和阿尔茨海默病中进行药物干预。
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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Regulation of mitochondrial function by FOXOs in ischemic stroke and Alzheimer’s disease Intricate roles of spacers and stickers of Arg-rich C9ORF72 dipeptide repeat proteins; from toxicity to targeting to membraneless organelles
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