粒線體的主要作用是維持細胞功能，如能量的供給，細胞週期的調控，訊息的傳遞，抗氧化壓力，鈣離子的運輸以及細胞凋亡等。粒線體是一高度動態的胞器，不斷分裂與融合造成粒線體的形態的變化，以協調對應不同的細胞生理狀態。破壞粒線體的動態平衡會影響到腫瘤的生成、神經元退化以及不正常的老化。而目前對於衰老的現象與粒線體動態平衡間的關聯尚不明確。在本實驗中，我們利用酵母菌為模型，來研究在老化細胞中，粒線體動態平衡和其生物能量的變化。我們發現在衰老的細胞中粒線體的型態會呈現碎裂狀，兩種主要參與粒線體分裂的蛋白質的表現量會增加。此外，粒線體基因數量、粒線體膜電位、活性氧的產生以及氧氣消耗量在衰老的細胞中都有所改變。這些結果指出在細胞衰老的過程中，粒線體活性的改變和粒線體動態平衡的調控有所關聯。進一步的蛋白質體分析也顯示了在衰老的細胞中，參與壓力反應的蛋白表現量也有所改變。所有這些研究結果皆強烈表明，線粒體動態平衡的轉變是伴隨著粒線體功能的改變並且和細胞衰老的進程密切相關。

Mitochondrion maintains important cellular functions, such as energy production, cell-cycle regulation, signal transduction, oxidative stress responses, calcium transferring and apoptosis. Mitochondria are highly dynamic organelles that constantly undergo fission and fusion processes to shape mitochondria and coordinate with different cellular states. Disrupting mitochondrial dynamics would affect tumorigenesis, neurodegeneration and abnormal aging. However, little is known about the relationship between senescence and mitochondrial dynamics. In this study, we applied the replicative aging model of yeast to examine the mitochondrial dynamics and bioenergetics in cellular senescence. We found that the mitochondrial morphology turns into fragmented and major mitochondrial fission proteins’ levels are elevated in senescent cells. Moreover, the changes of mtDNA copy number, mitochondrial membrane potential, reactive oxygen species (ROS) production and oxygen consumption were found in the senescent cells. Furthermore, the proteomics analysis showed that the expressions of proteins involved in stress response were changed in senescent cells. All these findings strongly suggested that the shift of mitochondrial dynamics is accompanied with the changes of mitochondrial activities and closely associated with cellular senescence. Our results indicated that a compensative signaling network existed to strengthen the mitochondrial-related cellular activities during cellular senescence.

CONTENT
口試委員審定書 #
致謝 i
中文摘要 iii
ABSTRACT iv
CONTENT v
LIST OF TABLES ix
LIST OF FIGURES x
I. Introduction 1
1.1 Mitochondria are important organelles in a cell 1
1.1.1. Mitochondria are dynamic organelles 1
1.1.2. The fission machinery of mitochondria in yeast 2
1.1.3 The fusion machinery of mitochondria in yeast 3
1.2 The functions of mitochondria 5
1.2.1 Mitochondria are key player in pathogenesis 6
1.2.2 Mitochondrial defects and diseases 7
1.2.3 Mitochondrial efficiency and oxidative stress 9
1.3 Aging 11
1.3.1 The free radical theory of aging 12
1.3.2 Mitochondrial theory of aging 12
1.3.3 Mitochondria and aging 13
1.4. Specific aim 15
II. Materials and methods 16
2.1 Yeast strains and medium 16
2.2 Experiment protocol 16
2.2.1 Yeast transformation 16
2.2.2 Cell sorting for replicative-age mother cells 17
2.2.3 Fixation of yeasts to observe the mitochondrial morphology 18
2.2.4 Bud scar staining 18
2.2.5 Yeast gemomic DNA extraction 19
2.2.6 Yeast RNA extraction 19
2.2.7 Reverse transcription polymerase chain reaction 20
2.2.8 Real time PCR 21
2.2.9 Mitochondrial membrane potential detection 22
2.2.10 ROS level measurement 23
2.2.11 Apoptosis 23
2.2.12 Flow cytometry 24
2.2.13 The bioenergetic measurement of mitochondria 25
2.2.14 Two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption inoization-time of flight mass spectrometry (MALDI–TOF MS) 25
III. Results 27
3.1. Isolating the replicative aging yeasts as senescent models by biotin-streptavidin sorting system 27
3.2. The isolated yeast cells showed the senescence-related features 27
3.3. The mitochondrial morphology of senescent wild type yeasts turned into fragment 28
3.4. The fragmented mitochondria in senescent yeasts were caused by conventional mitochondrial dynamic pathways 29
3.5. Dnm1 and Fis1 were critical factors regulating the fission process in senescent cells 30
3.6. The senescent yeasts had higher mtDNA copy number 31
3.7. The mitochondria activity is altered in senescent yeasts 32
3.8. The mitochondrial-derived ROS production is affected in senescent cells 34
3.9. The assay of mitochondrial oxygen consumption rate (OCR) 35
3.10. The early apoptosis in senescent cells 36
3.11. Proteomic analysis between young and senescent yeast cells 38

IV. Conclusions and Discussion 40
4.1. Conclusions 40
4.2. Discussion 41
4.2.1. Mitochondrial fragmentation depends on fission-related proteins during senescence in yeasts. 41
4.2.2. The mitochondrial activity changes links to mitochondrial dynamics during cellular senescence 43
4.2.3. The fragmented mitochondria and apoptosis in senescent cells 45
4.2.4. The protein expression level changes during senescence 46
4.3. Perspective 47
References 71

LIST OF TABLES
Table 1. The primer sequence used in this study. 50
Table 2. The axial length of the log-phase and adsorbed cells. 51
Table 3. The flow cytometry analysis of apoptosis cell percentage by FITC-coupled Annexin V and PI staining. 52
Table 4. 2D-DIGE and MS analysis of the proteins I. 53
Table 5. 2D-DIGE and MS analysis of the proteins II. 54

LIST OF FIGURES
Figure 1. The fission process of mitochondrial dynamics in yeast. 55
Figure 2. The fusion process of mitochondrial dynamics in yeast. 56
Figure 3. The senescent yeast cells can be sorted by Biotin-Streptavidin system. 57
Figure 4. The percentage of the adsorbed cells with biotin-streptavidin beads. 58
Figure 5. Senescent cells have more bud scars. 59
Figure 6. Mitochondria become fragmented with culturing time in wild type cells. 60
Figure 7. Analysis of mitochondrial morphology in fusion/ fission gene deleted strains. 62
Figure 8. Analysis of the DNM1, FIS1 and FZO1 transcriptional level at different time point by RT-PCR. 63
Figure 9. Comparisons of the mtDNA copy number by real-time PCR. 65
Figure 10. Analysis of the mitochondrial membrane potential in log-phase and senescent cells. 67
Figure 11. Measurement of the mitochondria-derived ROS production level in log-phase and senescent cells. 69
Figure 12. Analysis the oxygen consumption in log-phase and senescent cells. 70

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