Srv2蛋白在酵母菌粒線體的動態平衡所扮演的角色

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研究生：	陳英傑 CHEN, Ying-Chieh
論文名稱：	Srv2蛋白在酵母菌粒線體的動態平衡所扮演的角色 The Role of Srv2 in Yeast Mitochondrial Fusion and Fission Regulation
指導教授：	張壯榮 Chang, Chuang-Rung
口試委員:	呂俊毅 Leu, Jun-Yi 林敬哲 Lin, Jing-Jer 王慧菁 Wang, Hui-Ching 高茂傑 Kao, Mou-Chieh
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物科技研究所 Biotechnology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	62
中文關鍵詞：	酵母菌、粒線體、融合、分裂、動態平衡
外文關鍵詞：	Yeast, Mitochondria, Fission, Fusion, Dynamics
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粒線體在細胞內能進行氧化磷酸化合成ATP，同時參與許多攸關細胞存亡的訊息傳遞，因此對細胞非常重要。粒線體透過各種調控機制來進行融合、分裂及細胞內的移動不斷改變其形態，稱之粒線體動態平衡。粒線體的動態平衡與其功能調控有緊密的關聯，粒線體動態平衡失調在能量需求高的細胞中常常造成嚴重的疾病，例如：神經退化疾病及心血管疾病，顯示出粒線體動態平衡的重要性。粒線體動態平衡的調控機制目前仍未完全明瞭。本篇論文是以酵母菌為模式生物釐清未知的粒線體動態平衡調控機制。我們利用基因篩選，找到一個能與酵母菌中粒線體分裂蛋白Dnm1交互作用的蛋白Srv2。Srv2是一個在演化上具高度保留性的蛋白，在酵母菌中能調節肌動蛋白動態平衡及環磷酸腺苷/ 蛋白激酶A相關的訊息傳遞。實驗結果指出Srv2 能與Dnm1在粒線體上交互作用，同時也發現Srv2是透過調節肌動蛋白來維持粒線體的動態平衡。此外，剔除SRV2基因會使粒線體氧化磷酸化的功能嚴重受損。本篇論文結果指出Srv2可以藉由整合粒線體分裂蛋白及肌動蛋白動態調控來調節粒線體的動態平衡及功能。此研究提出並解釋Srv2在細胞中促進粒線體分裂的新角色，同時也是調控粒線體及細胞骨架動態平衡的蛋白。

Mitochondria are critical organelles because they produce ATP by oxidative phosphorylation and regulate survival through miscellaneous metabolisms. Mitochondria morphology changes continuously through fission, fusion and movement by various mechanisms. Disturbance of mitochondria dynamics is associated with neuronal and cardiac diseases. Mitochondria dynamics have been found and studied for decades; however, the complicated mechanisms are not fully dissolved. The goal of the study is to elucidate the underlying regulatory mechanism of mitochondria dynamics. We identified Srv2 that interacts with mitochondria fission protein Dnm1 by genetic screen. Srv2 is a highly conserved protein that regulates actin dynamics and cAMP/ PKA signaling. Our data demonstrated that Srv2 interacts with Dnm1 specifically on mitochondria. Genetic manipulation results indicated Srv2 contributes to mitochondria dynamics through its function on actin dynamics. In addition, Srv2 depletion negatively affects mitochondria respiratory activity. Our results suggest that Srv2 mediates mitochondria dynamics through its role in conjugating the fission machinery and actin assembly. This work characterized a novel pro-fission factor, and unveiled the link between mitochondria and cytoskeleton system.

CONTENTS

口試委員會審定書    #
致謝    i
ABSTRACT    ii
中文摘要    iii
CONTENTS    iv
LIST OF TABLES    vi
LIST OF FIGURES    1
Chapter 1    Introduction    3
Chapter 2    Material and methods    7
2.1    Strains and genotypes    7
2.2    Plasmids construction    7
2.3    Phylogenetic analysis    9
2.4    Tandem affinity purification (TAP) tag co-precipitation    9
2.5    Microscopy    9
2.6    Mitochondria isolation    11
2.7    G-actin assay    11
2.8    Flow cytometry    12
2.9    High resolution respirometry    12
Chapter 3    Results    14
3.1    Srv2 interacts with mitochondria fission protein Dnm1    14
3.2    Srv2 shapes mitochondria in yeast Saccharomyces cerevisiae    15
3.2.1    SRV2 deletion results in hyperfused mitochondria    15
3.2.2    Srv2 depletion has no effects on mitochondria morphology in FZO1 or DNM1 deletion strains.    16
3.3    Srv2 regulates mitochondria dynamics through modulating actin cytoskeleton    17
3.3.1    Srv2 promotes mitochondria fission through modulating actin dynamics    17
3.3.2    SRV2 mutant alleles fail to rescue mitochondria dynamics in Δsrv2 yeasts    18
3.3.3    Srv2 depletion impairs actin polymerization    18
3.3.4    Srv2 regulates mitochondria dynamics likely through its function in actin cable formation.    19
3.3.5    Possible mechanism that Srv2 regulates mitochondria dynamics    20
3.4    Srv2 is required for mitochondria functionality    21
3.4.1    Srv2 depletion dampens the reserved capacity of mitochondria    21
Chapter 4    Discussion    24
4.1    Srv2 depletion impairs actin polymerization    24
4.2    Actin dynamics is closely associated with mitochondria dynamics    25
4.3    Srv2 regulates mitochondria dynamics through a novel regulatory mechanism.    26
4.4    Srv2 serves unknown functions in maintaining mitochondria respiration    27
Chapter 5    Perspective    29
REFERENCES    30


LIST OF TABLES
Table 1.  Yeast strains and their genotypes used in this study    37
Table 2.  Plasmids used in this study    38

LIST OF FIGURES
Figure 1. Phylogenetic tree of Srv2/CAP proteins in different organisms.    39
Figure 2. Srv2 co-immunoprecitates with Dnm1.    40
Figure 3. Srv2-GFP does not colocalize with mitochondria in yeast cells.    41
Figure 4. Srv2-Dnm1 interaction complex associates with mitochondria.    42
Figure 5. FIS1 deletion dissociates Srv2-Dnm1 interaction complex from mitochondria.    43
Figure 6. SRV2 deletion causes mitochondrial hyperfusion.    44
Figure 7. Srv2/ Fis1 overexpression does not alter mitochondria morphology.    45
Figure 8. Srv2 induction rescues the mitochondrial morphology in ∆srv2 yeasts    46
Figure 9. Srv2 depletion increases FIS1 transcription.    47
Figure 10. Srv2 regulates mitochondria dynamics dependent on canonical mitochondrial fission/ fusion machinery.    48
Figure 11. Srv2 regulates mitochondrial morphology closely related with actin dynamics.    49
Figure 12. srv2 mutant alleles can not rescue mitochondrial dynamics    50
Figure 13. SRV2 deletion decreases F/ G-actin ratio    51
Figure 14. Disrupting actin polymerization by Latrunculin A causes hyperfused mitochondria due to defective actin cables.    52
Figure 15. Actin cable counts in different yeast strains.    53
Figure 16. SRV2 deletion does not affect Dnm1 recruitment to mitochondria.    54
Figure 17. SRV2 deletion does not affect the Dnm1 level in mitochondria fraction.    55
Figure 18. SRV2 deletion increases occurrence of mitochondrial branching and lateral fusion.    56
Figure 19. Srv2-Dnm1 interaction occurs at mitochondrial branches and nets.    57
Figure 20. SRV2 deletion negatively affects mitochondrial reserve capacity.    58
Figure 21. Srv2 depletion declines mitochondria respiration capacity.    59
Figure 22. Srv2 depletion diminishes membrane potential increase after shifting from dextrose to raffinose.    60
Figure 23. Srv2 depletion increases mtDNA copy number.    61
Figure 24. The hypothetic model that Srv2 regulates mitochondria dynamics.    62
                                

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