粒線體是一種不斷進行融合與分裂的動態胞器，粒線體動態平衡對於維持粒線體的功能非常重要。老化是一種造成生理與粒線體功能損害的退化性過程，在老化的酵母菌細胞中粒線體呈現破碎的型態。白藜蘆醇是一種抗老的天然多酚，我們發現白藜蘆醇除了降低衰老酵母菌細胞中活性氧化物的含量，也減少破碎的粒線體，但對於白藜蘆醇如何調控粒線體的機制並不清楚。有研究指出，白藜蘆醇可以透過抑制磷酸二酯酶的活性來改善細胞中老化的現象，因此我們針對磷酸二酯酶對於衰老酵母菌細胞中粒線體作用加以探討。本論文的實驗結果指出，白藜蘆醇無法在缺乏磷酸二酯酶的衰老酵母菌細胞中改變粒線體型態，且其調控粒線體融合分裂基因也有不同的表現; 另外，白藜蘆醇亦無法在缺乏磷酸二酯酶的衰老酵母菌細胞中減低活性氧化物的含量。我們進一步發現磷酸二酯酶的下游因子:環腺苷酸及蛋白激酶A也參與白藜蘆醇改變粒線體型態及降低活性氧化物的機制。我們的研究結果指出，白藜蘆醇在衰老酵母菌中調控粒線體型態及降低活性氧化物的含量需要透過磷酸二酯酶來達成。

Mitochondria are dynamic organelles that continuously undergo fusion and fission. Mitochondrial dynamics is important for maintaining mitochondrial integrity and cellular function. Aging is a degenerative process that exhibit physiological and mitochondrial dysfunction. Previous studies of our lab revealed mitochondrial fragmentation was present in senescent yeast cells. Resveratrol, a polyphenol mitigated mitochondrial fragmentation and superoxide level. In addition, resveratrol elevated membrane potential in the senescent yeast cells. However, the mechanism of how resveratrol-mediated mitochondria in senescent yeast cells remains unclear. We aim to elucidate the potential mechanisms. Previous studies indicated resveratrol can ameliorate aging-related metabolic phenotypes via inhibiting phosphodiesterase activity. In this thesis, I applied biotin-streptavidin system to isolate replicative senescent yeast cells to clarify the effect of phosphodiesterase, Pde2 on mitochondria. My results demonstrated that deletion of PDE2 reverted the effects of resveratrol on mitochondria dynamics and showed different transcription level of fission/ fusion genes. In the mitochondrial activity assay, resveratrol did not mitigate the superoxide level in Δpde2 senescent cells. Those results indicated that Pde2 is required for resveratrol-mediated mitochondrial dynamics and superoxide scavenging. These evidences provide hints to elucidate resveratrol signaling pathway in the regulation of mitochondrial dynamics in cellular senescence.

Chapter 1 Introduction 1
1.1 Mitochondria are important organelles in cells. 1
1.1.1 Mitochondrial dynamics is crucial for cellular functions. 1
1.1.2 The mechanism of mitochondrial dynamics in yeast. 2
1.2 Aging is a degenerative process. 4
1.2.1 The yeast aging models 4
1.2.2 Mitochondria play important roles in aging process. 4
1.3 Resveratrol, a nature polyphenol with benefits for health. 6
1.3.1 Resveratrol prevents and delays aging. 6
1.3.2 The effects of resveratrol are associated with mitochondria. 7
1.4 Phosphodiesterase breaks down cyclic nucleotide. 8
1.4.1 The activity of phosphodiesterase is inhibited by resveratrol. 8
1.4.2 Phosphodiesterase controls cAMP/PKA pathway in yeast 9
1.5 Specific aim 10
Chapter 2 Materials and methods 11
2.1 Yeast strains, medium and reagent 11
2.2 Experiment protocol 11
2.2.1 Isolation of senescent yeast cells 11
2.2.2 The cell viability of senescent yeast model 12
2.2.3 DiOC6(3) staining to observe the mitochondrial morphology 12
2.2.4 Yeast genomic DNA extraction 13
2.2.5 Yeast RNA extraction 13
2.2.6 Reverse transcription polymerase chain reaction 14
2.2.7 Real time PCR 15
2.2.8 Mitochondrial membrane potential detection 16
2.2.9 Mitochondrial superoxide level measurement 16
2.2.10 Cytosolic superoxide level measurement 16
2.2.11 Flow cytometry 17
Chapter 3 Results 18
3.1 Using biotin-streptavidin system to enrich replicative senescent yeast cells in the population. 18
3.2 Resveratrol reverses the mitochondrial morphology in senescent cells. 19
3.2.1 Resveratrol reduces senescent cells possessing fragmented mitochondria. 19
3.2.2 Resveratrol affects the gene expression profiles of fission/ fusion proteins. 20
3.3 Resveratrol affects mitochondrial activities in senescent cells. 22
3.3.1 Resveratrol improves the decreasing trend of mitochondrial membrane potential in senescent process. 22
3.3.2 Resveratrol reduces the superoxide level in the senescent cells. 23
3.3.3 Resveratrol affects mtDNA copy numbers in the senescent cells 23
3.4 PDE2 plays a role in resveratrol mediated mitochondrial dynamics in senescent cells. 25
3.4.1 Resveratrol effects on mitochondrial dynamics is different in senescent Δpde2 cells. 25
3.4.2 Δpde2 shows different fission/ fusion gene expressions after resveratrol treatment. 26
3.5 Deletion of PDE2 shows different mitochondrial activity after resveratrol treatment. 27
3.5.1 Resveratrol also improves the membrane potential of Δpde2 senescent cells. 27
3.5.2 Deletion of PDE2 blocks the ability of resveratrol as antioxidant in senescent process. 27
3.5.3 Resveratrol treatment shows different mtDNA copy numbers in ∆pde2 senescent cells. 28
3.6 Δpde2Δtpk3 slightly restores the mitochondrial morphology after resveratrol treatment. 29
3.7 Resveratrol don’t affect the mitochondrial membrane potential and mitochondrial superoxide level in Δpde2Δtpk3. 30
Chapter 4 Discussion and Conclusion 31
4.1 Pde2 participates in resveratrol mediated mitochondrial dynamics. 31
4.2 Resveratrol affects mitochondrial function not only through Pde2 32
4.3 Pde2 plays important role in resveratrol-mediated superoxide removal. 32
4.4 Phosphodiesterase plays different role in the yeast and mammal. 34
4.5 Conclusion 34
Chapter 5 Perspective 35
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