以微分方程系統解析粒線體對細胞核傳訊的系統特性

Understanding the System Dynamics of Mitochondrial Retrograde Signaling from a Differential Equation­based Framework

邱紹庭(Shao-Ting Chiu)

指導教授 ： 魏安祺

國立臺灣大學/電機資訊學院/生醫電子與資訊學研究所/碩士(2021年)

https://doi.org/10.6342/NTU202101265

摘要

粒線體是一種存在於真核細胞中的半自主性胞器，擔任細胞的能量工廠和代謝樞紐，其功能仰賴於細胞核基因體的供給與維護。因此粒線體對細胞核的傳訊過程在修補粒線體上扮演重要的角色。文獻上的研究著重於傳訊過程參與的蛋白質種類，與在不同狀態下對於基因體的定性調控。然而對於此粒線體網路的通訊 性質仍所知甚少。本篇論文採取控制系統的角度，以酵母菌為模式生物，整合粒線體往細胞核傳訊的分子機制，其中包含蛋白質結合與轉錄因子進入細胞核的過程。透過酵素動力學理論，以常微分方程系統來探討粒線體訊號傳遞的過程。本論文分成三個部分，第一部分為粒線體傳訊的布林模型; 第二部分為常微分模型; 第三部分為隨機系統模型。模擬出蛋白分子濃度在粒線體損害的動態過程包含波型、頻率響應及在雜訊影響下的可靠性。進一步的模擬與演算顯示，粒線體傳訊網路為近似於一個雙穩態系統，並附加三個區域性的穩態點。此外，訊號蛋白競爭型結合的過程，是提升敏感度的機制。透過隨機模擬亦發現訊號噪訊比會隨著粒線體損傷訊號增強而減少。本論文提出了粒線體傳訊的數學模型，以定量的角度思考資訊傳遞的過程。這不僅能夠更了解粒線體往細胞核傳訊的機制，也可能應用於致病性酵母的藥物研發與投藥策略。

關鍵字

粒線體逆向訊號 ； 酵素動力學 ； 數學模型 ； 控制系統 ； 常微分方程

並列摘要

The mitochondrion is a semi­autonomous organelle in eukaryotic cells and partici­pates in the energy production and versatile metabolic regulations. These roles make mi­tochondrial quality control essential to maintain its functionality. While most mitochon­drial genes are located in the nucleus genome, the quality control depends on supplements from the nucleus. The mitochondrial retrograde signaling describes the communication between mitochondria and the nucleus, which plays a critical role in regulating the nucleus genome. Published studies have focused on the signaling pathway participants and the qualitative effect of knockouts on genome expressions. However, there is a lack of understanding of this pathway’s communication characteristics, and how mitochondrial signal is modulated throughout the process remains unclear. To simulate the signal prop­agation from the mitochondrial damage, we use yeast as a model organism and propose a novel mathematical model of mitochondrial retrograde signaling based on enzyme kinetics and ordinary differential equations (ODE). This study contains three parts: (1) A boolean model of mitochondrial signaling (2) Ordinary differential Equation­based model (3) Extended stochastic model. The simulation reveals the dynamics of protein localized concentration including waveforms, frequency response, and robustness under noise, in response to mitochondrial damage. Further analysis shows that the mitochondrial retro­grade signaling is a bistable system with three localized steady states and the competitive binding results in the ultrasensitivity. By applying stochastic simulation, we found that the increased mitochondrial damage signal can deteriorate the robustness. This study un­ ravels the quantitative mechanism of mitochondrial retrograde signaling and may provide drug design applications for pathogenic yeast and antifungal therapy.

並列關鍵字

Mitochondrial retrograde signaling (RTG) ； Enzyme kinetics ； Mathematical modeling ； Control systems ； Ordinary differential equations

參考文獻

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