線粒體融合對於Parkin介導線粒體自噬的抑製作用

An inhibitory role for mitochondrial fusion in Parkin-mediated mitophagy

黃元平(Yuan-Ping Huang)

指導教授 ： 楊維元

國立臺灣大學/生命科學院/生化科學研究所/博士(2018年)

https://doi.org/10.6342/NTU201801617

摘要

目前已經發現透過稱為線粒體自噬的特別微調的機制是線粒體壽命的關鍵決 定因素。細胞需要確保其線粒體質量得以保持活力。這部分是通過稱為PINK/Parkin 介導的線粒體自噬途徑進行選擇性降解受損的線粒體來實現的。我們確認線粒體動力學為線粒體質量控制的另一種手段：功能受損的線粒體與附近的線粒體網絡的融合可以促進其功能的恢復。通過使用光敏劑在功能上干擾線粒體使得這一發現成為可能。在這裡，我們使用光敏劑來破壞選定的線粒體，並用可被激光活化的熒光蛋白 PAGFP 追踪它們的動態。透過針對 O-GlcNAc 轉移酶（OGT），其活性取決於葡萄糖的可用性，以及 TRAK1，Miro1 和 Miro2 的siRNA 來改變線粒體動力學，致使線粒體受損的可能性改變得以進行線粒體自噬。我們發現與附近的線粒體網絡融合可以促進受損線粒體功能的恢復。我們研究了線粒體裂變/融合和線粒體運動在線粒體自噬中的分子機制和作用。這些結果表明線粒體動力學和線粒體自噬在維持線粒體質量方面的協調。

關鍵字

粒線體 ； 粒線體運動 ； 粒線體自噬 ； 粒線體動力學 ； 光敏劑

並列摘要

It has been found that autophagy is a key determinant for the life span of mitochondria through a particularly fine-tuned mechanism called mitophagy. Cells need to ensure
their mitochondrial quality to remain viable. This is achieved in part by the selective degradation of damaged mitochondria through a well-characterized pathway termed
PINK/Parkin-mediated mitophagy. We have now identified mitochondrial dynamics as an additional means for mitochondrial quality control: fusion of a functionally-impaired mitochondrion with the nearby mitochondrial network can promote the recovery of its function. The discovery was made possible through the use of a photosensitizer to functionally disturb mitochondria. Here we used photosensitizers to damage selected mitochondria and traced their fate with PAGFP, a photoactivatable fluorescent protein. Perturbing mitochondrial dynamics through siRNA like TRAK1, Miro1 and Miro2, the enzyme O-GlcNAc Transferase (OGT), whose activity depends on glucose availability, led to alteration in the likely-hood of impaired mitochondria to undergo mitophagy. We found that fusion with nearby mitochondrial network can promote the recovery of a damaged mitochondrion’s function. We investigated on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy. These results suggest coordination between mitochondrial dynamics and mitophagy in maintaining mitochondrial quality.

並列關鍵字

Mitochondria ； mitochondrial motility ； mitophagy ； mitochondrial dynamic ； photosensitizer

參考文獻

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