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自主振荡线粒体呼吸活性:系统分析结果显示不同体外同步化癌细胞存在异质性。

Autonomous Oscillatory Mitochondrial Respiratory Activity: Results of a Systematic Analysis Show Heterogeneity in Different In Vitro-Synchronized Cancer Cells.

机构信息

Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy.

出版信息

Int J Mol Sci. 2024 Jul 16;25(14):7797. doi: 10.3390/ijms25147797.

Abstract

Circadian oscillations of several physiological and behavioral processes are an established process in all the organisms anticipating the geophysical changes recurring during the day. The time-keeping mechanism is controlled by a transcription translation feedback loop involving a set of well-characterized transcription factors. The synchronization of cells, controlled at the organismal level by a brain central clock, can be mimicked in vitro, pointing to the notion that all the cells are endowed with an autonomous time-keeping system. Metabolism undergoes circadian control, including the mitochondrial terminal catabolic pathways, culminating under aerobic conditions in the electron transfer to oxygen through the respiratory chain coupled to the ATP synthesis according to the oxidative phosphorylation chemiosmotic mechanism. In this study, we expanded upon previous isolated observations by utilizing multiple cell types, employing various synchronization protocols and different methodologies to measure mitochondrial oxygen consumption rates under conditions simulating various metabolic stressors. The results obtained clearly demonstrate that mitochondrial respiratory activity undergoes rhythmic oscillations in all tested cell types, regardless of their individual respiratory proficiency, indicating a phenomenon that can be generalized. However, notably, while primary cell types exhibited similar rhythmic respiratory profiles, cancer-derived cell lines displayed highly heterogeneous rhythmic changes. This observation confirms on the one hand the dysregulation of the circadian control of the oxidative metabolism observed in cancer, likely contributing to its development, and on the other hand underscores the necessity of personalized chronotherapy, which necessitates a detailed characterization of the cancer chronotype.

摘要

昼夜节律波动是所有生物体适应地球物理变化的一种既定过程,涉及到许多生理和行为过程。计时机制受转录翻译反馈环控制,其中涉及一组特征明确的转录因子。细胞的同步化,受大脑中央时钟在机体水平上的控制,可以在体外进行模拟,这表明所有细胞都具有自主的计时系统。代谢过程也受到昼夜节律的控制,包括线粒体末端分解代谢途径,在有氧条件下,电子通过呼吸链传递给氧气,同时根据氧化磷酸化化学渗透机制合成 ATP。在这项研究中,我们通过使用多种细胞类型、采用不同的同步化方案和不同的方法学,对模拟各种代谢应激条件下的线粒体耗氧率进行了研究,从而扩展了之前的孤立观察结果。研究结果清楚地表明,所有测试的细胞类型中的线粒体呼吸活性都经历周期性波动,无论其各自的呼吸效率如何,这表明这是一种普遍存在的现象。然而,值得注意的是,虽然原代细胞类型表现出相似的节律性呼吸特征,但癌细胞系则显示出高度异质性的节律变化。这一观察结果一方面证实了癌症中氧化代谢的昼夜节律控制失调,这可能有助于癌症的发展,另一方面强调了个性化chronotherapy 的必要性,这需要对癌症的chronotype 进行详细的特征描述。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b4e/11276763/d74d81bf72a7/ijms-25-07797-g001.jpg

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