利用酵母菌探討粒線體型態及功能與細胞衰老之關係

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研究生：	張可薇 Chang, Ko-Wei
論文名稱：	利用酵母菌探討粒線體型態及功能與細胞衰老之關係 Mitochondrial Morphology and Functions Associated with Cellular Senescence in Saccharomyces cerevisiae
指導教授：	張壯榮 Chang, Chuang-Rung
口試委員:	張晃猷羅椀升
學位類別：	碩士 Master
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：	2012
畢業學年度：	100
語文別：	英文
論文頁數：	79
中文關鍵詞：	粒線體、動態平衡、細胞衰老
相關次數：	點閱：3 下載：0
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粒線體藉由分裂與融合的動態平衡進行形態調控。酵母菌調控分裂的蛋白是Dnm1p及Fis1p；而Fzo1p及Mgm1p則是負責融合。粒線體分裂及融合可以進而調控腺苷三磷酸(ATP)及活性氧(ROS)的淨產量、粒線體內的物質交換、並剔除受損傷的粒線體。伴隨老化產生的神經退化性疾病與粒線體功能受損有高度相關性。然而，衰老現象與粒線體動態平衡的關聯性尚未明確，所以本篇以酵母菌的複製性衰老模式來研究粒線體的動態平衡與細胞衰老的關係。
實驗發現複製性衰老細胞粒線體呈現短小碎片狀；利用基因剔除於顯微影像實驗中，證實動態平衡調控機制參與改變複製性衰老細胞中之粒線體型態。除此之外，衰老細胞之分裂基因(FIS1)表現量較高，我們對分裂基因(FIS1)於複製性衰老細胞中表現量較高的原因加以探究。我們也發現在複製性衰老細胞中其粒線體基因數量會隨著衰老的過程增加；或許是衰老細胞為了維持粒線體之生合成及其功能所產生的補償作用。酵母菌另一個衰老模式，慢性衰老，其粒線體型態則與複製性衰老細胞之粒線體型態不同。本篇結果可以說明細胞衰老確實影響了粒線體動態平衡的調控，並且藉由改變粒線體形態，進而影響衰老細胞中粒線體生合成。

Mitochondrial morphology is in a dynamic balance between the fission and fusion. In yeast, the major fission proteins are Dnm1p and Fis1p, while Fzo1p and Mgm1p are involved in fusion. The mitochondrial fission/fusion machineries are associated with the regulation of mitochondrial functions including: the regulation of ATP production, the level of reactive oxygen species (ROS), the influx and efflux of material in mitochondria, and the removal of defective mitochondria (mitophagy). Previous studies have demonstrated that the impaired mitochondrial function is closely related to neurodegenerative diseases. In addition, many neurodegenerative disorders are progressed with aging. However, the relationship between cellular senescence and mitochondrial dynamics remains obscure. In this thesis, we applied yeast replicative senescent model to clarify the correlation between cellular senescence and mitochondria dynamics. We found that majority of senescent cells have fragmented mitochondria. By using gene deletion strains in bioimaging analyses, we found that cellular senescence associated mitochondrial fragmentation depends on conventional mitochondrial fission proteins. In addition, we found that the senescent cells have higher mRNA level of fission genes. We then examined one of the potential causes of that the higher level of fission genes in replicative senescent cells. Our results also demonstrated that the mitochondrial DNA copy number increases in replicative senescent cells. Furthermore, mitochondria dynamics in chronological senescent cells was found to be distinct from replicative senescent cells. These results indicate that cellular senescence does have effects on mitochondria dynamics.

CONTENTS
口試委員會審定書    #
誌謝    i
中文摘要    ii
ABSTRACT    iii
CONTENTS    iv
Chapter 1    Introduction    1
1.1    Senescence is an irreversible process    1
1.2    A good model to study cellular senescence    4
1.2.1    Yeast as a good model organism for studying cellular senescence    4
1.2.2    Two types of cellular senescence model in yeast- replicative and chronological senescence    5
1.3    Mitochondrial morphology is dynamic in yeast cells    7
1.4    The function of mitochondrial dynamics    9
1.5    The specific aim of the thesis    11
Chapter 2    Materials and methods    13
2.1    Special reagents & equipment    13
2.2    Microbial strains    13
2.3    Experimental protocols    13
2.3.1    E. coli transformation & plasmid mini-preparation    13
2.3.2    Competent cell preparation    14
2.3.3    Yeast transformation    15
2.3.4    Cell sorting for replicative senescent yeast    15
2.3.5    Collecting of chronological senescent yeast    16
2.3.6    Fixation of mitochondrial morphology    16
2.3.7    Yeast RNA extraction    17
2.3.8    Reverse transcription polymerase chain reaction    18
2.3.9    Polymerase chain reaction (PCR)    18
2.3.10    Real time PCR    18
2.3.11    Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting analysis    19
2.3.12    Chromatin immunoprecipitation assay    20
2.3.13    Mitochondria staining    22
Chapter 3    Results    23
3.1    Magnetically sorted cells demonstrated replicative senescent features    23
3.1.1    Cells with magnetic beads are dominated in the adsorbed sample after sorting    23
3.1.2    Sorted senescent cells have large size than unsorted cells.    23
3.1.3    More extrachromosomal rDNA circles are accumulated in adsorbed cells than unsorted young cells.    24
3.2    Mitochondrial morphology in replicative and chronological senescent yeast cells are different    24
3.2.1    Replicative senescent cells have fragmented mitochondria    24
3.2.2    Fragmented mitochondria in replicative senescent cells depend on Dnm1 and Fis1.    25
3.2.3    Expression level of FIS1 increases in replicative senescent cells    26
3.2.4    Chronological senescent cells have complicated mitochondrial morphology.    26
3.3    Mitochondrial DNA copy number is affected during replicative senescent process    27
3.4    Mitophagy is affected during senescent process    28
3.4.1    Mitophagy activation is decreased during senescent process    28
3.5    Clarifying the factors that regulate mitochondrial dynamics related genes during cellular senescence.    29
3.5.1    The acetylation status at DNM1 and FIS1 promoter region are not affected in senescent cells.    29
Chapter 4    Conclusions and Discussion    32
4.1    Conclusion    32
4.2    Discussion    32
4.2.1    Mitochondrial fragmentation in replicative senescent yeast depend on fission proteins    32
4.2.2    The physiological implications of the increased mitochondrial DNA copy number in cellular senescence.    33
4.2.3    The regulation of mitochondrial dynamic genes.    35
4.3    Perspectives of the research    37
REFERENCES    73

LIST OF FIGURES
Figure 1.    Mitochondria are a dynamic organelle.    39
Figure 2.    The definition of replicative senescent cells and the principle of sorting the replicative senescent cells from a yeast population.    41
Figure 3.    The definition of chronological senescent cells.    43
Figure 4.    Cells with magnetic beads are dominated in the adsorbed sample after sorting.    45
Figure 5.    Magnetic sorted senescent cells have larger size than non-adsorbed cells.    47
Figure 6.    More extrachromosomal rDNA circles appears to accumulate in the adsorbed cells than the log phase cells    49
Figure 7.    Replicative senescent yeast cells have more fragmented mitochondria.    51
Figure 8.    Mitochondrial fragmentation in replicative senescent cells depends on the fission protein, Dnm1p.    53
Figure 9.    Mitochondrial fragmentation in replicative senescent cells also depends on the fission protein, Fis1p.    55
Figure 10.    The expression level of Dnm1p remains the same between the replicative senescent and young cells.    57
Figure 11.    mRNA level of the fission gene, FIS1, increases in replicative senescent cells.    59
Figure 12.    The morphology of mitochondria changes mitochondrial DNA copy number in replicative senescent cells.    61
Figure 13.    The protein level of Atg8 decreases in replicative senescent cells.    63
Figure 14.    The validation of acetylation of H4K16 by chromatin immuneprecipitation assay    65
Figure 15.    The elevation of mitochondrial fission genes in replicative senescent cells is not due to H4K16 acetylation.    67
LIST OF TABLES
Table 1.    Strains of use    69
Table 2.    Primer of use    70
Table 3.    The condition of polymerase chain reaction    71
Table 4.    Abbreviations    72

                                

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