FoxO transcription factors in mitochondrial homeostasis.
FoxO transcription factors in mitochondrial homeostasis.
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DOI：
10.1042/bcj20210777
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发表时间：
2022-02-17
期刊：
影响因子：
--
通讯作者：
Cheng Z
中科院分区：
文献类型：
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作者：
Cheng Z
线粒体在细胞能量学、生物合成和信号转导中起着重要作用。线粒体功能失调与肥胖、糖尿病、心血管疾病、非酒精性脂肪性肝病、神经退行性疾病和癌症等不同疾病有关。线粒体稳态是由线粒体生物发生、动力学（融合和裂变）和自噬（线粒体自噬）三方面控制的。研究强调FoxO转录因子是关键的线粒体调节因子。具体来说，FoxOs通过直接抑制NRF1-Tfam和c-Myc-Tfam级联，以及通过诱导Hmox1或抑制Fxn和Urod间接抑制NAD-Sirt1-Pgc1α级联来调节线粒体的生物发生。此外，FoxOs介导线粒体融合（通过Mfn1和Mfn2）和裂变（通过Drp1、Fis1和MIEF2），在此过程中，FoxOs在转录、转录后（例如通过miR-484/Fis1）和翻译后（例如通过bnip3 -钙调磷酸酶介导的Drp1去磷酸化）水平上引发调控机制。此外，FoxOs在自噬体形成和成熟阶段（如起始、成核和延伸）、线粒体与自噬体连接并被自噬体吞噬（如通过PINK1和Bnip3途径）、自噬体与溶酶体融合形成自噬体进行货物降解（如通过Tfeb和组织蛋白酶蛋白）等阶段控制线粒体自噬。本文提供了FoxOs调节线粒体稳态的最新观点，并讨论了针对FoxOs的治疗潜力。
Mitochondria play essential roles in cellular energetics, biosynthesis, and signaling transduction. Dysfunctional mitochondria have been implicated in different diseases such as obesity, diabetes, cardiovascular disease, nonalcoholic fatty liver disease, neurodegenerative disease, and cancer. Mitochondrial homeostasis is controlled by a triad of mitochondrial biogenesis, dynamics (fusion and fission), and autophagy (mitophagy). Studies have underscored FoxO transcription factors as key mitochondrial regulators. Specifically, FoxOs regulate mitochondrial biogenesis by dampening NRF1-Tfam and c-Myc-Tfam cascades directly, and inhibiting NAD-Sirt1-Pgc1α cascade indirectly by inducing Hmox1 or repressing Fxn and Urod. In addition, FoxOs mediate mitochondrial fusion (via Mfn1 and Mfn2) and fission (via Drp1, Fis1, and MIEF2), during which FoxOs elicit regulatory mechanisms at transcriptional, posttranscriptional (e.g. via miR-484/Fis1), and posttranslational (e.g. via Bnip3-calcineurin mediated Drp1 dephosphorylation) levels. Furthermore, FoxOs control mitochondrial autophagy in the stages of autophagosome formation and maturation (e.g. initiation, nucleation, and elongation), mitochondria connected to and engulfed by autophagosome (e.g. via PINK1 and Bnip3 pathways), and autophagosome-lysosome fusion to form autolysosome for cargo degradation (e.g. via Tfeb and cathepsin proteins). This article provides an up-to-date view of FoxOs regulating mitochondrial homeostasis and discusses the potential of targeting FoxOs for therapeutics.