老化中代謝對粒線體動態調控之數學模型與電腦模擬

Abstract

近年來的研究指出新陳代謝對於粒線體的動態有重要的調控作用，然而現在並沒有一個能個整合複雜實驗數據和分析新陳代謝以及粒線體動態之間關係的方法。本篇論文採取電腦模擬的策略，整合目前關於粒線體動態的分子機制，其中粒線體動態包含了融合、分裂、傳輸、以及粒線體自噬。此論文利用多種的建模方式來建立數學模型，並調查老化如何對於生物能量的狀態造成影響，及生物能量狀態的轉變如何調控粒線體的整體型態組成。這篇論文的模型主要可以分成兩個部分，第一部分為粒線體代謝模型，第二部分為粒線體動態模型。粒線體代謝模型主要是以微分方程為主，並模擬出 GTP 濃度以及 ADP/ATP 比例的波動，而這兩者都被認為和粒線體動態有關。這篇論文建立出 GTP 濃度以及 ADP/ATP 比例對於粒線體動態的調控規則，並把產生出的結果用在粒線體動態模型上。第二部分的粒線體動態模型為一代理人基模擬，把各個粒線體是為獨立的代理人，並進行動態相關的事件。模擬結果顯示，在老化中的 GTP 濃度變化並未帶來明顯的粒腺體形態變化。這也顯示目前關於 GTP 調控動態的假說尚未完備。總體來說，本論文試圖藉由電腦模擬的方式，去建立一個能夠模擬在不同生理狀況下粒線體型態的模型。這不僅能夠讓我們更全面了解生物能量和粒線體動能之間的複雜關係，更有可能被應用在未來的實驗設計或是關於疾病的研究。

Recent studies have demonstrated the importance of metabolic regulations on mitochondrial dynamics. Still, existing literature lacks a methodology to assimilate different experimental data and fully understand the interplay between bioenergetics and organelle behavior. This thesis adopts an in silico method that integrates the current knowledge about the molecular mechanism of mitochondrial dynamics, including fusion, fission, transport, biogenesis, and mitophagy. Notably, a multi-method mathematical model that was implemented, simulating the bioenergetic shift in the aging process to study how the metabolic shift regulates the mitochondrial dynamics. The model contains two parts: mitochondrial metabolism and mitochondrial dynamics. The ordinary differential equation based metabolic model simulates the bioenergetics of mitochondria with an output of GTP level and ADP/ATP ratio, which regulate the mitochondrial fission-fusion cycle. Subsequently, the simulated fission-fusion parameters are applied in the stochastic agent-based mitochondrial dynamics model. Overall, this project pursues a model that not only predicts the dynamics of mitochondria under varying physiological conditions for further experimentation, but also understand the interplay between metabolism and mitochondrial dynamics. The proposed model is expected to further our understanding of alterations in mitochondrial dynamics in disease progression and aging.