Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.
Mitochondrial mRNA localization is governed by translation kinetics and spatial transport.
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线粒体mRNA定位由翻译动力学和空间运输控制。
DOI：
10.1371/journal.pcbi.1010413
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发表时间：
2022-08
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
对于许多核编码的线粒体基因，在新生肽上的线粒体靶向序列 (MTS) 与线粒体输入复合物的关联的帮助下，mRNA 通过共翻译定位到线粒体表面。对于这些共翻译定位的 mRNA 的一个子集，它们的定位取决于细胞的代谢状态，而其他的则为组成型定位。为了探索这两种 mRNA 类型之间的差异，我们开发了一种随机定量模型，用于 MTS 介导的 mRNA 定位到酵母细胞中的线粒体。该模型包括翻译，应用源自实验数据的基因特异性动力学；以及在细胞质中的扩散。尽管两种 mRNA 类型都是共翻译定位的，但我们发现 mRNA 上核糖体的稳态数量或密度不足以区分这两种 mRNA 类型。相反，条件定位的 mRNA 具有更快的翻译动力学，可以结合代谢状态下扩散搜索动力学的变化来调节定位。我们的模型还表明 MTS 需要一段成熟时间才能有能力结合线粒体。我们的工作表明，酵母细胞可以通过控制线粒体体积分数（影响扩散搜索时间）和基因翻译动力学（调整 mRNA 结合能力）来调节 mRNA 定位到线粒体，而不需要 mRNA 特异性结合蛋白。这些结果揭示了全局和基因特异性机制，使细胞能够改变 mRNA 定位以响应不断变化的代谢条件。线粒体是三磷酸腺苷 (ATP) 的重要产生者，ATP 是细胞的能量货币。在啤酒酵母（酿酒酵母）中，细胞可以根据环境将 ATP 生成转向或远离线粒体。了解细胞如何进行线粒体功能的这种转换可能有助于深入了解线粒体功能的丧失，这是许多与年龄相关的疾病的标志。许多编码线粒体蛋白质的 mRNA 在细胞核中合成，但在蛋白质生产过程中定位于线粒体表面。虽然其中一些 mRNA 总是定位于线粒体，但其他 mRNA 只对某些驱动能量产生的食物来源作出反应。在这项研究中，我们创建了 mRNA 定位到线粒体的数学模型，以了解区分这两种 mRNA 的因素。我们的分析表明蛋白质翻译动力学以及线粒体体积是控制 mRNA 是否定位于线粒体的关键因素。这项工作提供了关于线粒体内容的整体改变和蛋白质合成动力学的基因特异性调节如何耦合在一起以调整 mRNA 定位和潜在的线粒体功能的见解。
For many nuclear-encoded mitochondrial genes, mRNA localizes to the mitochondrial surface co-translationally, aided by the association of a mitochondrial targeting sequence (MTS) on the nascent peptide with the mitochondrial import complex. For a subset of these co-translationally localized mRNAs, their localization is dependent on the metabolic state of the cell, while others are constitutively localized. To explore the differences between these two mRNA types we developed a stochastic, quantitative model for MTS-mediated mRNA localization to mitochondria in yeast cells. This model includes translation, applying gene-specific kinetics derived from experimental data; and diffusion in the cytosol. Even though both mRNA types are co-translationally localized we found that the steady state number, or density, of ribosomes along an mRNA was insufficient to differentiate the two mRNA types. Instead, conditionally-localized mRNAs have faster translation kinetics which modulate localization in combination with changes to diffusive search kinetics across metabolic states. Our model also suggests that the MTS requires a maturation time to become competent to bind mitochondria. Our work indicates that yeast cells can regulate mRNA localization to mitochondria by controlling mitochondrial volume fraction (influencing diffusive search times) and gene translation kinetics (adjusting mRNA binding competence) without the need for mRNA-specific binding proteins. These results shed light on both global and gene-specific mechanisms that enable cells to alter mRNA localization in response to changing metabolic conditions. Mitochondria are important generators of adenosine triphosphate (ATP), the energy currency of the cell. In the brewer’s yeast, Saccharomyces cerevisiae, cells can switch ATP generation towards or away from mitochondria depending on the environment. Understanding how cells carry out this switch of mitochondrial function may provide insight into the loss of mitochondrial function, a hallmark of many age-related diseases. Many mRNAs that encode mitochondrial proteins are synthesized in the nucleus, but become localized to the mitochondrial surface during protein production. While some of these mRNAs always localize to the mitochondria, others do so only in response to certain food sources driving energy production. In this study we created a mathematical model of mRNA localization to the mitochondria to understand what factors differentiate these two mRNA classes. Our analysis implicates protein translation kinetics as well as the mitochondrial volume as the key factors that control whether mRNA localize to mitochondria. This work provides insight into how global alteration in mitochondrial content and gene-specific modulation of protein synthesis kinetics can couple together to adjust mRNA localization and potentially mitochondrial function.
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影响因子：
9.8
作者：
Charneski CA;Hurst LD
通讯作者：
Hurst LD
DOI：
10.1083/jcb.201708044
发表时间：
2018-04-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Backes S;Hess S;Boos F;Woellhaf MW;Gödel S;Jung M;Mühlhaus T;Herrmann JM
通讯作者：
Herrmann JM
影响因子：
11.6
作者：
Calderwood, Alexander;Kopriva, Stanislav;Morris, Richard J.
通讯作者：
Morris, Richard J.
影响因子：
5.7
作者：
Biever, Anne;Donlin-Asp, Paul G.;Schuman, Erin M.
通讯作者：
Schuman, Erin M.
影响因子：
64.8
作者：
Couvillion MT;Soto IC;Shipkovenska G;Churchman LS
通讯作者：
Churchman LS