博碩士論文 104881609 詳細資訊



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姓名 阿南斯(PONNERI BABUHARISANKAR ANANTH)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 粒線體 Lon 蛋白在內質網-粒線體交界促進粒線體自噬並增加缺氧抗性之機制研究
(The mechanism of mitochondrial Lon-induced mitophagy benefits hypoxic resistance at the ER-mitochondria interface)
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摘要(中) 粒線體自噬作用是一種特殊的自噬過程，可以在壓力下消除受損的粒線體。ULK1（UNC51 相似激酶 1）調節的自噬/粒線體自噬作用已經被證明與腫瘤發生和耐藥性有關，而且抑制 ULK1可以產生了更好的治療反應。在本研究中，缺氧誘導的粒線體自噬作用是透過與ULK1相關的ATG13/FIP200/ATG101等傳統的自噬傳導路徑以及活化ULK1下游的Beclin1/ATG14 複合物來啟動吞噬泡團成核。為了清除受損的粒線體，ULK1磷酸化位在內質網-粒線體接觸位點 (EMC)（也稱為粒線體相關內質膜網 (MAM)）處的缺氧特異性和泛素非依賴性粒線體自噬受體 FUNDC1(S17)。然而，粒線體是如何感受到壓力並且將信號從粒線體內部發送到外部來觸發粒線體自噬的作用至今仍不清楚。
粒線體Lon是一種壓力激活蛋白，並且最近發現在內質網的壓力下出現在內質網-粒線體接觸位點，雖然其作用能不清楚。我們旨在探索於缺氧條件下，Lon是如何藉由內質網-粒線體接觸位點中穩定的 ULK1-FUNDC1 複合物來調節粒線體自噬作用的機制來促使細胞存活和癌症進展。透過我們的調查，我們發現ULK1複合體和FUNDC1是 Lon在內質網-粒線體接觸位點區域的附屬伴護蛋白，特別是ULK1的激酶功能是取決於在內質網-粒線體接觸位點中Lon的補充。有趣的是，我們還在體外和體內實驗結果中發現，粒線體鈉/鈣離子交換蛋白 (NCLX)可以促進Lon易位至內質網-粒線體接觸位點並調節粒線體自噬途徑。因此，我們的研究結果強調了一種新機制負責在缺氧下的粒線體自噬作用是藉由在粒線體中的伴護蛋白Lon透過與內質網-粒線體接觸位點中的FUNDC1-ULK1 複合物相互作用所引發。這些發現提供了 Lon 和粒線體自噬之間的直接相關性以及它們對細胞存活和癌症進展的貢獻。
摘要(英) Mitophagy, a specialized autophagic process, eliminates the damaged mitochondria upon stress. ULK1 (UNC51-like kinase-1) regulated autophagy/mitophagy was already proved to be linked with tumorigenesis, drug resistance and inhibition of ULK1 have produced a better therapeutic response. In the present study, hypoxia induced mitophagy was driven by classical autophagy pathway through the ULK1 association with ATG13/FIP200/ATG101 and ULK1 downstream activation of Beclin1/ATG14 complex to initiate the phagophore nucleation. To clear the damaged mitochondria, ULK1 phosphorylates hypoxia specific and ubiquitin independent mitophagy receptor FUNDC1(S17) at the ER (Endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon, a stress activated protein was recently reported to be localized at EMC under ER stress although the function remains unknown. We aimed to explore the mechanism of how Lon under hypoxia regulates mitophagy through the stability of ULK1-FUNDC1 complex in the EMC for cell survival and cancer progression. Through our investigation, we found that ULK1 complex and FUNDC1 were the chaperone clients of Lon at the EMC region and in particular the kinase function of ULK1 was dependent on Lon recruitment to EMC. We also found that Lon can interact with ULK1 at the ER membrane region and further regulates FUNDC1(S17) phosphorylation by ULK1 to drive the mitophagy. The ULK1 inhibitor SBI-0206965 or Lon ATPase mutant LonK529R can impair mitophagy by disrupting the association between Lon-ULK1-FUNDC1 axis. Intriguingly, we also found from our in vitro and in vivo data that mitochondrial Na+/Ca2+ exchanger (NCLX) promotes Lon translocation to EMC and regulates mitophagy pathway. Our previous study revealed that NCLX is a chaperone client of Lon and requires Lon association for its activity. Inhibiting NCLX activity by CGP371537 disrupts ULK1 complex and Lon recruitment to EMC and impairs mitophagy Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression. 
關鍵字(中) ★ 缺氧 關鍵字(英) ★ Hypoxia
★ Lon
★ Mitophagy
★ ER-mitochondria contact
★ ULK1-FUNDC1
論文目次 Abstract i
Acknowledgement…………………………………………………………………………………………iii
Table of Contents vi
List of Figures viii
List of Tables ix
Abbreviations x
Chapter I. Introduction 1
1.1 Mitochondria Quality Control 1
1.2 Autophagy – An important quality control event in cancer biology 1
1.3 Molecular mechanism in regulation of autophagy 3
1.4 Autophagy Initiation site 6
1.5 Selective Autophagy – Mitophagy turnover 9
1.6 ROS and Autophagy 13
1.7 Calcium – A complex link in regulating autophagy signaling 14
1.8 Lon protease 16
1.9 Mitophagy in cancer 18
1.10 Research objectives 20
Chapter II. Materials and Methods 21
2.1 Cell culture 21
2.2 Cell treatment 21
2.3 Plasmids and transfection 22
2.4 Reagents and Antibodies 23
2.5 Patients and clinical sample 23
2.6 Western blotting 23
2.7 Immunoprecipitation 24
2.8 Proteasome degradation assay 24
2.9 Cycloheximide chase assay 24
2.10 ROS assay 25
2.11 Subcellular fractionation 25
2.12 Fluorescence and confocal imaging of mitophagy 27
2.13 Colocalization studies 28
Abstract i
Acknowledgement…………………………………………………………………………………………iii
Table of Contents vi
List of Figures viii
List of Tables ix
Abbreviations x
Chapter I. Introduction 1
1.1 Mitochondria Quality Control 1
1.2 Autophagy – An important quality control event in cancer biology 1
1.3 Molecular mechanism in regulation of autophagy 3
1.4 Autophagy Initiation site 6
1.5 Selective Autophagy – Mitophagy turnover 9
1.6 ROS and Autophagy 13
1.7 Calcium – A complex link in regulating autophagy signaling 14
1.8 Lon protease 16
1.9 Mitophagy in cancer 18
1.10 Research objectives 20
Chapter II. Materials and Methods 21
2.1 Cell culture 21
2.2 Cell treatment 21
2.3 Plasmids and transfection 22
2.4 Reagents and Antibodies 23
2.5 Patients and clinical sample 23
2.6 Western blotting 23
2.7 Immunoprecipitation 24
2.8 Proteasome degradation assay 24
2.9 Cycloheximide chase assay 24
2.10 ROS assay 25
2.11 Subcellular fractionation 25
2.12 Fluorescence and confocal imaging of mitophagy 27
2.13 Colocalization studies 28
2.14 Transmission electron microscopy (TEM) 29
2.15 Calcium assay 29
2.16 Cell viability assay 30
2.17 Apoptosis assay 30
2.18 Immunohistochemistry (IHC) 31
2.19 Statistical analysis 32
Chapter III. Results 33
3.1 Concurrent activation of ULK1 Lon in cancer hypoxia 33
3.2 ULK1 inhibition attenuates the autophagy initiation under hypoxia 34
3.3 Hypoxia promotes mitochondrial fission and mitophagy 34
3.4 Mitochondrial Lon as a regulator of hypoxia induced ULK1dependent mitophagy 35
3.5 Regulation of ULK1 complex stability by Lon chaperone 36
3.6 Hypoxia triggers Lon and ULK1 complex recruitment to ER-mitochondria contact (EMC/MAM) 38
3.7 Mitochondrial Lon interacts with ULK1-FUNDC1 complex under hypoxia 39
3.8 Mitochondrial Lon promotes mitophagy through FUNDC1-S17 phosphorylation by ULK1 kinase 41
3.9 Mitochondrial Lon in the EMC depends NCLX activity to promote FUNDC1-ULK1 mitophagy under hypoxia 42
3.10 Lon-ROS-ULK1-FUNDC1 axis induced mitophagy benefits cell survival under hypoxia 43
Chapter IV. Discussion 45
Chapter V. Figures and Legends 51
Chapter VI. Conclusions and future directions 68
Bibliography 70
Appendix 76
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指導教授 李岳倫 高永旭(ALAN YUEH-LUEN LEE Yung-Hsi Kao) 審核日期 2023-6-17
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