薑黃素能夠影響許多細胞的訊息，例如抑制NF-κB、Akt、STAT3、癌細胞轉移和血管新生，因此薑黃素具有潛力成為治療藥劑。薑黃素透過粒線體調控的細胞凋亡抑制癌細胞的生長。粒線體是動態平衡的胞器，經由不斷的融合與分裂改變外觀型態。此外，粒線體動態平衡與粒線體的功能和細胞的代謝息息相關。近期的研究發現，參與粒線體動態平衡的蛋白質會影響細胞凋亡，因此能調控癌細胞對於細胞凋亡的抗性。然而，薑黃素與類薑黃素如何影粒線體功能以及粒線體動態平衡在這之中扮演甚麼角色，還尚未被釐清。本篇論文將探討薑黃素與類薑黃素對於粒線體功能和粒線體動態平衡的影響。
我們的實驗結果發現類薑黃素會造成粒線體型態改變、粒線體呼吸功能損壞並且引發細胞凋亡抑制癌細胞生長。我們的結果指出類薑黃素透過粒線體融合分裂相關的蛋白來改變粒線體型態。此外，類薑黃素導致癌細胞移動能力下降。我們的研究提供從粒線體動態平衡來探究類薑黃素治療效用上的觀點。

Curcumin/curcuminoids exhibits great potential as a therapeutic agent because of its pleiotropic activities to affect tumor progression. Curcumin inhibits cancer cells proliferation through mitochondria-mediated apoptosis. Mitochondria are highly dynamic organelles that undergo constant morphological changes by fission and fusion events. Mitochondrial dynamics is linked to mitochondrial function and cell metabolism. Recently, mitochondria-shaping proteins are found to affect apoptosis and regulate the resistance of cancer cells to apoptotic stimuli. However, the mechanisms curcumin/curcuminoids affect mitochondrial functions and the roles of mitochondrial dynamics under curcumin/curcuminoids treatment are unclear. In this study, we aim to clarify the effects of curcumin/curcuminoids on mitochondrial function and dynamics. We found curcuminoids caused mitochondrial fragmentation, mitochondrial respiration defects and induced mitochondria-mediated apoptosis. We also demonstrated that curcumin/curcuminoids disturbed mitochondrial dynamics through conventional fusion/fission pathways. Additionally, curcuminoids damaged cancer cells motility. The underlined regulatory pathways related to these adjustments were discussed. Our results provide novel insights of the role of mitochondrial dynamics in curcuminoids-mediated cell death.

中文摘要 i
ABSTRACT ii
CONTENTS iii
LIST OF FIGURES vi
Chapter 1 Introduction 1
1.1 Roles of mitochondria in cells 1
1.2 Overview of mitochondrial dynamics behavior 2
1.3 Mitochondrial fusion/fission machinery 2
1.3.1 The machinery of mitochondrial fusion 3
1.3.2 The machinery of mitochondrial fission 3
1.4 The roles of mitochondrial fission/fusion 4
1.4.1 Fusion promotes complementation of damaged mitochondria 4
1.4.2 Mitochondrial dynamics allow cells to adapt to cellular stresses 5
1.4.3 Mitochondrial dynamics maintains mtDNA stability and respiratory function 6
1.4.4 Mitochondrial fission facilitates apoptosis 6
1.5 Mitochondrial dynamics and human diseases 7
1.5.1 OPA1 mutant causes autosomal dominant optic atrophy 7
1.5.2 Mitofusin 2 mutant causes Charcot-Marie-Tooth 2A 8
1.5.3 Drp1 and neonatal lethality 8
1.5.4 Mitochondrial dynamics in neurodegenerative diseases 9
1.5.5 Mitochondrial dynamics in cancer 10
1.6 Natural products research and traditional medicines 12
1.7 The purpose of this study 13
Chapter 2 Materials and methods 14
2.1 Cell culture and transfection 14
2.2 Cell transfection 14
2.3 Curcumin/curcuminoids treatment 14
2.4 Cell viability 15
2.5 Detection of apoptotic cells 15
2.6 Measurement of cellular bioenergetics 16
2.7 Mitochondrial ROS detection 16
2.8 Measurement of mitochondrial membrane potential 17
2.9 Transwell migration assay 17
2.10 Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and western blot analysis 17
2.11 Immunofluorescence staining 18
2.12 Antibodies 19
Chapter 3 Results 20
3.1 Curcuminoids attenuated viability of human cervical adenocarcinoma cells 20
3.2 Curcuminoids induced mitochondria-mediated apoptosis 20
3.3 Curcuminoids-induced mitochondrial morphology changes 22
3.4 Effects of curcuminoids on bioenergetic and mitochondrial functions 23
3.5 Curcuminoids impaired human cervical adenocarcinoma cells migration 26
3.6 Curcumin/Curcuminoids stresses disturbed mitochondrial dynamics machinery 27
Chapter 4 Conclusion 32
Chapter 5 Discussion 33
5.1 The bioavailability of curcumin/curcuminoids 33
5.2 Curcumin/curcuminoids exhibits both beneficial and cytotoxic effects for cells 34
5.3 Mitochondrial dysfunctions may affect cell fate 34
5.4 Mitochondrial reactive oxygen species is critical for maintaining cell health 35
5.5 Abnormal mitochondrial morphology and mitochondrial dysfunction affect cell motility 36
5.6 Drp1 Ser-637 serves as predominant posttranslation modification during apoptosis 37
5.7 Mitochondrial morphological changes is accompanied with physiological condition adjustments 38
5.8 Mitochondrial dynamics is altered in cancer cells 39
5.9 Manipulation of mitochondrial dynamics leads to new therapeutic approaches 40
References 56
Appendix 66

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