博碩士論文 104881609 詳細資訊



以作者查詢圖書館館藏 、以作者查詢臺灣博碩士 、以作者查詢全國書目 、勘誤回報 、線上人數：85 、訪客IP：3.144.3.183
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)
檔案 [Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   [檢視]  [下載]
  1. 本電子論文使用權限為同意立即開放。
  2. 已達開放權限電子全文僅授權使用者為學術研究之目的，進行個人非營利性質之檢索、閱讀、列印。
  3. 請遵守中華民國著作權法之相關規定，切勿任意重製、散佈、改作、轉貼、播送，以免觸法。

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
參考文獻 1. Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018;20(7):745-54.
2. Lee YG, Park DH, Chae YC. Role of Mitochondrial Stress Response in Cancer Progression. Cells. 2022;11(5).
3. Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16(6):495-501.
4. Weidberg H, Shvets E, Elazar Z. Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem. 2011;80:125-56.
5. De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955;60(4):604-17.
6. Tsukada M, Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333(1-2):169-74.
7. Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221(1):3-12.
8. Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Curr Opin Cell Biol. 2010;22(2):177-80.
9. Egan D, Kim J, Shaw RJ, Guan KL. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy. 2011;7(6):643-4.
10. Matsuura A, Tsukada M, Wada Y, Ohsumi Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene. 1997;192(2):245-50.
11. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284(18):12297-305.
12. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009;20(7):1992-2003.
13. Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V, Bordi M, et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat Cell Biol. 2013;15(4):406-16.
14. Alers S, Loffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32(1):2-11.
15. Puente C, Hendrickson RC, Jiang X. Nutrient-regulated Phosphorylation of ATG13 Inhibits Starvation-induced Autophagy. J Biol Chem. 2016;291(11):6026-35.
16. Wang C, Wang H, Zhang D, Luo W, Liu R, Xu D, et al. Phosphorylation of ULK1 affects autophagosome fusion and links chaperone-mediated autophagy to macroautophagy. Nat Commun. 2018;9(1):3492.
17. Lin SY, Li TY, Liu Q, Zhang C, Li X, Chen Y, et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science. 2012;336(6080):477-81.
18. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, et al. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol. 2013;15(7):741-50.
19. Park JM, Jung CH, Seo M, Otto NM, Grunwald D, Kim KH, et al. The ULK1 complex mediates MTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy. 2016;12(3):547-64.
20. Stjepanovic G, Baskaran S, Lin MG, Hurley JH. Unveiling the role of VPS34 kinase domain dynamics in regulation of the autophagic PI3K complex. Mol Cell Oncol. 2017;4(6):e1367873.
21. Matsunaga K, Morita E, Saitoh T, Akira S, Ktistakis NT, Izumi T, et al. Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L. J Cell Biol. 2010;190(4):511-21.
22. Liu CC, Lin YC, Chen YH, Chen CM, Pang LY, Chen HA, et al. Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination. Mol Cell. 2016;61(1):84-97.
23. Dossou AS, Basu A. The Emerging Roles of mTORC1 in Macromanaging Autophagy. Cancers (Basel). 2019;11(10).
24. Karmacharya U, Jung JW. Small Molecule Inhibitors for Unc-51-like Autophagy-Activating Kinase Targeting Autophagy in Cancer. Int J Mol Sci. 2023;24(2).
25. Ktistakis NT, Tooze SA. Digesting the Expanding Mechanisms of Autophagy. Trends Cell Biol. 2016;26(8):624-35.
26. Karanasios E, Stapleton E, Manifava M, Kaizuka T, Mizushima N, Walker SA, et al. Dynamic association of the ULK1 complex with omegasomes during autophagy induction. J Cell Sci. 2013;126(Pt 22):5224-38.
27. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. 2008;182(4):685-701.
28. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol. 2009;11(12):1433-7.
29. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, et al. Autophagosomes form at ER-mitochondria contact sites. Nature. 2013;495(7441):389-93.
30. Vance JE. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res. 2008;49(7):1377-87.
31. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141(4):656-67.
32. Leal NS, Schreiner B, Pinho CM, Filadi R, Wiehager B, Karlstrom H, et al. Mitofusin-2 knockdown increases ER-mitochondria contact and decreases amyloid beta-peptide production. J Cell Mol Med. 2016;20(9):1686-95.
33. Missiroli S, Bonora M, Patergnani S, Poletti F, Perrone M, Gafa R, et al. PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development. Cell Rep. 2016;16(9):2415-27.
34. Gallagher LE, Williamson LE, Chan EY. Advances in Autophagy Regulatory Mechanisms. Cells. 2016;5(2).
35. Chaanine AH, Kohlbrenner E, Gamb SI, Guenzel AJ, Klaus K, Fayyaz AU, et al. FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress. Am J Physiol Heart Circ Physiol. 2016;311(6):H1540-H59.
36. Dhingra R, Gang H, Wang Y, Biala AK, Aviv Y, Margulets V, et al. Bidirectional regulation of nuclear factor-kappaB and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes. Circ Heart Fail. 2013;6(2):335-43.
37. Ma X, McKeen T, Zhang J, Ding WX. Role and Mechanisms of Mitophagy in Liver Diseases. Cells. 2020;9(4).
38. Chai P, Cheng Y, Hou C, Yin L, Zhang D, Hu Y, et al. USP19 promotes hypoxia-induced mitochondrial division via FUNDC1 at ER-mitochondria contact sites. J Cell Biol. 2021;220(7).
39. Wang C, Dai X, Wu S, Xu W, Song P, Huang K. FUNDC1-dependent mitochondria-associated endoplasmic reticulum membranes are involved in angiogenesis and neoangiogenesis. Nat Commun. 2021;12(1):2616.
40. Kuang Y, Ma K, Zhou C, Ding P, Zhu Y, Chen Q, et al. Structural basis for the phosphorylation of FUNDC1 LIR as a molecular switch of mitophagy. Autophagy. 2016;12(12):2363-73.
41. Lv M, Wang C, Li F, Peng J, Wen B, Gong Q, et al. Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy. Protein Cell. 2017;8(1):25-38.
42. van der Bliek AM. Mitochondria just wanna have FUN(DC1). EMBO J. 2016;35(13):1365-7.
43. Liu L, Li Y, Chen Q. The Emerging Role of FUNDC1-Mediated Mitophagy in Cardiovascular Diseases. Front Physiol. 2021;12:807654.
44. Tian W, Li W, Chen Y, Yan Z, Huang X, Zhuang H, et al. Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy. FEBS Lett. 2015;589(15):1847-54.
45. Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 2014;15(5):566-75.
46. Kimball SR, Gordon BS, Moyer JE, Dennis MD, Jefferson LS. Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell Signal. 2016;28(8):896-906.
47. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell. 2008;134(3):451-60.
48. Wang J, Gao S, Wang S, Xu Z, Wei L. Zinc oxide nanoparticles induce toxicity in CAL 27 oral cancer cell lines by activating PINK1/Parkin-mediated mitophagy. Int J Nanomedicine. 2018;13:3441-50.
49. Cui X, Luo Y, Li C, Li Y, Wang Z. Changes of intracellular Ca2+ in quercetin-induced autophagy progression. Acta Biochim Biophys Sin (Shanghai). 2015;47(11):908-14.
50. Gordon PB, Holen I, Fosse M, Rotnes JS, Seglen PO. Dependence of hepatocytic autophagy on intracellularly sequestered calcium. J Biol Chem. 1993;268(35):26107-12.
51. Luyten T, Welkenhuyzen K, Roest G, Kania E, Wang L, Bittremieux M, et al. Resveratrol-induced autophagy is dependent on IP(3)Rs and on cytosolic Ca(2). Biochim Biophys Acta Mol Cell Res. 2017;1864(6):947-56.
52. Tomar D, Elrod JW. Metabolite regulation of the mitochondrial calcium uniporter channel. Cell Calcium. 2020;92:102288.
53. Hernansanz-Agustin P, Choya-Foces C, Carregal-Romero S, Ramos E, Oliva T, Villa-Pina T, et al. Na(+) controls hypoxic signalling by the mitochondrial respiratory chain. Nature. 2020;586(7828):287-91.
54. Mammucari C, Raffaello A, Vecellio Reane D, Rizzuto R. Molecular structure and pathophysiological roles of the Mitochondrial Calcium Uniporter. Biochim Biophys Acta. 2016;1863(10):2457-64.
55. Assali EA, Sekler I. Sprinkling salt on mitochondria: The metabolic and pathophysiological roles of mitochondrial Na(+) signaling mediated by NCLX. Cell Calcium. 2021;97:102416.
56. Hori O, Ichinoda F, Tamatani T, Yamaguchi A, Sato N, Ozawa K, et al. Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J Cell Biol. 2002;157(7):1151-60.
57. Ngo JK, Davies KJ. Mitochondrial Lon protease is a human stress protein. Free Radic Biol Med. 2009;46(8):1042-8.
58. Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129(1):111-22.
59. Bernstein SH, Venkatesh S, Li M, Lee J, Lu B, Hilchey SP, et al. The mitochondrial ATP-dependent Lon protease: a novel target in lymphoma death mediated by the synthetic triterpenoid CDDO and its derivatives. Blood. 2012;119(14):3321-9.
60. Cheng CW, Kuo CY, Fan CC, Fang WC, Jiang SS, Lo YK, et al. Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species. Cell Death Dis. 2013;4:e681.
61. Liu Y, Lan L, Huang K, Wang R, Xu C, Shi Y, et al. Inhibition of Lon blocks cell proliferation, enhances chemosensitivity by promoting apoptosis and decreases cellular bioenergetics of bladder cancer: potential roles of Lon as a prognostic marker and therapeutic target in baldder cancer. Oncotarget. 2014;5(22):11209-24.
62. Jin SM, Youle RJ. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy. 2013;9(11):1750-7.
63. Thomas RE, Andrews LA, Burman JL, Lin WY, Pallanck LJ. PINK1-Parkin pathway activity is regulated by degradation of PINK1 in the mitochondrial matrix. PLoS Genet. 2014;10(5):e1004279.
64. Polo M, Alegre F, Moragrega AB, Gibellini L, Marti-Rodrigo A, Blas-Garcia A, et al. Lon protease: a novel mitochondrial matrix protein in the interconnection between drug-induced mitochondrial dysfunction and endoplasmic reticulum stress. British journal of pharmacology. 2017;174(23):4409-29.
65. Kulikov AV, Luchkina EA, Gogvadze V, Zhivotovsky B. Mitophagy: Link to cancer development and therapy. Biochem Biophys Res Commun. 2017;482(3):432-9.
66. Chi HC, Chen SL, Lin SL, Tsai CY, Chuang WY, Lin YH, et al. Thyroid hormone protects hepatocytes from HBx-induced carcinogenesis by enhancing mitochondrial turnover. Oncogene. 2017;36(37):5274-84.
67. Guan Y, Wang Y, Li B, Shen K, Li Q, Ni Y, et al. Mitophagy in carcinogenesis, drug resistance and anticancer therapeutics. Cancer Cell Int. 2021;21(1):350.
68. Hou H, Er P, Cheng J, Chen X, Ding X, Wang Y, et al. High expression of FUNDC1 predicts poor prognostic outcomes and is a promising target to improve chemoradiotherapy effects in patients with cervical cancer. Cancer Med. 2017;6(8):1871-81.
69. Li W, Li Y, Siraj S, Jin H, Fan Y, Yang X, et al. FUN14 Domain-Containing 1-Mediated Mitophagy Suppresses Hepatocarcinogenesis by Inhibition of Inflammasome Activation in Mice. Hepatology. 2019;69(2):604-21.
70. Song C, Pan S, Zhang J, Li N, Geng Q. Mitophagy: A novel perspective for insighting into cancer and cancer treatment. Cell Prolif. 2022;55(12):e13327.
71. Jang JE, Eom JI, Jeung HK, Cheong JW, Lee JY, Kim JS, et al. Targeting AMPK-ULK1-mediated autophagy for combating BET inhibitor resistance in acute myeloid leukemia stem cells. Autophagy. 2017;13(4):761-2.
72. Egan DF, Chun MG, Vamos M, Zou H, Rong J, Miller CJ, et al. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol Cell. 2015;59(2):285-97.
73. Altman JK, Szilard A, Goussetis DJ, Sassano A, Colamonici M, Gounaris E, et al. Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting. Clin Cancer Res. 2014;20(9):2400-9.
74. Sung YJ, Kao TY, Kuo CL, Fan CC, Cheng AN, Fang WC, et al. Mitochondrial Lon sequesters and stabilizes p53 in the matrix to restrain apoptosis under oxidative stress via its chaperone activity. Cell Death Dis. 2018;9(6):697.
75. Williamson CD, Wong DS, Bozidis P, Zhang A, Colberg-Poley AM. Isolation of Endoplasmic Reticulum, Mitochondria, and Mitochondria-Associated Membrane and Detergent Resistant Membrane Fractions from Transfected Cells and from Human Cytomegalovirus-Infected Primary Fibroblasts. Curr Protoc Cell Biol. 2015;68:3 27 1-3 33.
76. Tangeda V, Lo YK, Babuharisankar AP, Chou HY, Kuo CL, Kao YH, et al. Lon upregulation contributes to cisplatin resistance by triggering NCLX-mediated mitochondrial Ca(2+) release in cancer cells. Cell Death Dis. 2022;13(3):241.
77. Vargas JNS, Wang C, Bunker E, Hao L, Maric D, Schiavo G, et al. Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy. Mol Cell. 2019;74(2):347-62 e6.
78. Triantafyllou A, Liakos P, Tsakalof A, Georgatsou E, Simos G, Bonanou S. Cobalt induces hypoxia-inducible factor-1alpha (HIF-1alpha) in HeLa cells by an iron-independent, but ROS-, PI-3K- and MAPK-dependent mechanism. Free radical research. 2006;40(8):847-56.
79. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468-72.
80. Yuan Y, Hilliard G, Ferguson T, Millhorn DE. Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem. 2003;278(18):15911-6.
81. Park JM, Seo M, Jung CH, Grunwald D, Stone M, Otto NM, et al. ULK1 phosphorylates Ser30 of BECN1 in association with ATG14 to stimulate autophagy induction. Autophagy. 2018;14(4):584-97.
82. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G, et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433-46.
83. Gomes LC, Di Benedetto G, Scorrano L. During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol. 2011;13(5):589-98.
84. Saito T, Nah J, Oka SI, Mukai R, Monden Y, Maejima Y, et al. An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia. J Clin Invest. 2019;129(2):802-19.
85. Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct. 1998;23(1):33-42.
86. McWilliams TG, Prescott AR, Allen GF, Tamjar J, Munson MJ, Thomson C, et al. mito-QC illuminates mitophagy and mitochondrial architecture in vivo. J Cell Biol. 2016;214(3):333-45.
87. Kuo CL, Ponneri Babuharisankar A, Lin YC, Lien HW, Lo YK, Chou HY, et al. Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend? J Biomed Sci. 2022;29(1):74.
88. Wang WM, Shen H, Liu ZN, Chen YY, Hou LJ, Ding Y. Interaction between tumor microenvironment, autophagy, and epithelial-mesenchymal transition in tumor progression. Cancer Treat Res Commun. 2022;32:100592.
89. Kuo CL, Chou HY, Chiu YC, Cheng AN, Fan CC, Chang YN, et al. Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer letters. 2020;474:138-50.
90. Ambro L, Pevala V, Ondrovicova G, Bellova J, Kunova N, Kutejova E, et al. Mutations to a glycine loop in the catalytic site of human Lon changes its protease, peptidase and ATPase activities. FEBS J. 2014;281(7):1784-97.
91. Liu T, Lu B, Lee I, Ondrovicova G, Kutejova E, Suzuki CK. DNA and RNA binding by the mitochondrial lon protease is regulated by nucleotide and protein substrate. J Biol Chem. 2004;279(14):13902-10.
92. Kao TY, Chiu YC, Fang WC, Cheng CW, Kuo CY, Juan HF, et al. Mitochondrial Lon regulates apoptosis through the association with Hsp60-mtHsp70 complex. Cell Death Dis. 2015;6:e1642.
93. Jiao H, Su GQ, Dong W, Zhang L, Xie W, Yao LM, et al. Chaperone-like protein p32 regulates ULK1 stability and autophagy. Cell Death Differ. 2015;22(11):1812-23.
94. Koyama-Honda I, Itakura E, Fujiwara TK, Mizushima N. Temporal analysis of recruitment of mammalian ATG proteins to the autophagosome formation site. Autophagy. 2013;9(10):1491-9.
95. Kishi-Itakura C, Koyama-Honda I, Itakura E, Mizushima N. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J Cell Sci. 2014;127(Pt 18):4089-102.
96. Itakura E, Mizushima N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy. 2010;6(6):764-76.
97. Wieckowski MR, Giorgi C, Lebiedzinska M, Duszynski J, Pinton P. Isolation of mitochondria-associated membranes and mitochondria from animal tissues and cells. Nat Protoc. 2009;4(11):1582-90.
98. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12(1):9-14.
99. Johansen T, Lamark T. Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2011;7(3):279-96.
100. Rana NK, Singh P, Koch B. CoCl2 simulated hypoxia induce cell proliferation and alter the expression pattern of hypoxia associated genes involved in angiogenesis and apoptosis. Biol Res. 2019;52(1):12.
101. Dower CM, Bhat N, Gebru MT, Chen L, Wills CA, Miller BA, et al. Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma. Mol Cancer Ther. 2018;17(11):2365-76.
102. Sung YJ, Kao TY, Kuo CL, Fan CC, Cheng AN, Fang WC, et al. Mitochondrial Lon sequesters and stabilizes p53 in the matrix to restrain apoptosis under oxidative stress via its chaperone activity. Cell Death & Disease. 2018;9(6):697.
103. Yan Y, Jiang K, Liu P, Zhang X, Dong X, Gao J, et al. Bafilomycin A1 induces caspase-independent cell death in hepatocellular carcinoma cells via targeting of autophagy and MAPK pathways. Sci Rep. 2016;6:37052.
104. Ng MYW, Wai T, Simonsen A. Quality control of the mitochondrion. Dev Cell. 2021;56(7):881-905.
105. Ponneri Babuharisankar A, Kuo CL, Chou HY, Tangeda V, Fan CC, Chen CH, et al. Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca(2+)-dependent FUNDC1 phosphorylation at the ER-mitochondria interface. Cell Death Dis. 2023;14(3):199.
106. Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017;61(6):585-96.
107. Shang L, Chen S, Du F, Li S, Zhao L, Wang X. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci U S A. 2011;108(12):4788-93.
108. Chen Z, Liu L, Cheng Q, Li Y, Wu H, Zhang W, et al. Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy. EMBO Rep. 2017;18(3):495-509.
109. Lin XH, Qiu BQ, Ma M, Zhang R, Hsu SJ, Liu HH, et al. Suppressing DRP1-mediated mitochondrial fission and mitophagy increases mitochondrial apoptosis of hepatocellular carcinoma cells in the setting of hypoxia. Oncogenesis. 2020;9(7):67.
110. Chen M, Chen Z, Wang Y, Tan Z, Zhu C, Li Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy. 2016;12(4):689-702.
111. Cheng AN, Cheng LC, Kuo CL, Lo YK, Chou HY, Chen CH, et al. Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1-mediated immunoescape via STING-IFN signaling and extracellular vesicles. J Immunother Cancer 2020;8(2):e001372.
112. Diaz P, Sandoval-Borquez A, Bravo-Sagua R, Quest AFG, Lavandero S. Perspectives on Organelle Interaction, Protein Dysregulation, and Cancer Disease. Front Cell Dev Biol. 2021;9:613336.
113. Liu L, Yan L, Liao N, Wu WQ, Shi JL. A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer. Cancers (Basel). 2020;12(2).
114. Yun M, Bai HY, Zhang JX, Rong J, Weng HW, Zheng ZS, et al. ULK1: a promising biomarker in predicting poor prognosis and therapeutic response in human nasopharygeal carcinoma. PLoS One. 2015;10(2):e0117375.
115. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331(6016):456-61.
116. Laker RC, Drake JC, Wilson RJ, Lira VA, Lewellen BM, Ryall KA, et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nat Commun. 2017;8(1):548.
117. Ghislat G, Patron M, Rizzuto R, Knecht E. Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-beta (CaMKK-beta). J Biol Chem. 2012;287(46):38625-36.
118. Gueguinou M, Ibrahim S, Bourgeais J, Robert A, Pathak T, Zhang X, et al. Curcumin and NCLX inhibitors share anti-tumoral mechanisms in microsatellite-instability-driven colorectal cancer. Cell Mol Life Sci. 2022;79(6):284.
指導教授 李岳倫 高永旭(ALAN YUEH-LUEN LEE Yung-Hsi Kao) 審核日期 2023-6-17
推文 facebook   plurk   twitter   funp   google   live   udn   HD   myshare   reddit   netvibes   friend   youpush   delicious   baidu   
網路書籤 Google bookmarks   del.icio.us   hemidemi   myshare   

若有論文相關問題，請聯絡國立中央大學圖書館推廣服務組 TEL:(03)422-7151轉57407，或E-mail聯絡  - 隱私權政策聲明