臺灣博碩士論文加值系統

ATP合成酶是一個位在粒線體內膜上的蛋白質，在能量生合成中扮演著不可或缺的角色。我們發現ATP合成酶在某些癌細胞例如肺癌細胞與神經母細胞瘤癌細胞的細胞膜上也會出現，這些在細胞膜上的ATP合成酶，我們稱之為異位表達ATP合成酶。而有趣的是，這個現象在正常細胞膜上並不常見。而在我們的分析中，我們也發現，愈惡性的癌細胞會比相對較良性的癌細胞有著更多的異位表達ATP合成酶。此外，若把癌細胞處理異位表達ATP合成酶抑制劑的話，其生長會被抑制。因此，最近也越來越多的報導指出，抑制癌細胞的異位表達ATP合成酶將可能成為一個具高效用的癌症標靶治療手段。即使異位表達ATP合成酶的研究已經不勝枚舉，但它如何被運輸到細胞膜上的機制仍保留許多未解之謎。ATP合成酶位於粒腺體內膜，這意味著ATP合成酶必須透過某些機制從粒腺體內釋出，進一步運送至膜上。而近期的研究指出，有些細胞內的蛋白質例如ATG16L1會透過細胞自噬的方式運送至細胞膜。這似乎也暗示著ATP合成酶有可能透過粒線體的計畫性凋亡—粒腺體自噬，來達成釋出ATP合成酶的條件，並進一步運送至細胞膜上。此外，我們也根據異位表達ATP合成酶多與少的細胞之基因表現量變化，透過生物資訊學方法分析，找到粒腺體自噬以外的可能途徑—粒線體直接運送至細胞膜上，這個假說由syntaphilin做為穿梭其中的關鍵蛋白，調控著粒腺體的運輸，進而影響異位表達ATP合成酶。而整體分析結果顯示，粒線體直接運送的可能性明顯高於粒腺體自噬途徑。經過一系列的實驗，我們也證實異位表達ATP合成酶並不是經過粒腺體自噬的途徑來運送。總結來說，我們透過資訊分析的方式找到兩條可能的異位表達ATP合成酶運送途徑：粒線體直接運送途徑與粒腺體自噬途徑。並且透過實驗證實異位表達ATP合成酶的運送是不依靠粒腺體自噬途徑的。

ATP synthase is a critical transmembrane protein complex on mitochondria inner membrane and plays an essential role in biological energy conversion. We showed that ATP synthases is also located on several cancer cell surfaces (named as ectopic ATP synthase) such as lung cancer and neuroblastoma, whereas it was not observed in normal cells. Moreover, inhibition of ectopic ATP synthase with citreoviridin is able to repress cancer cell proliferation. Many reports show that targeting ectopic ATP synthase provides a powerful cancer therapeutic strategy, however, the mechanism of ectopic ATP synthase trafficking to cell surface remains unclear. Previous studies showed that the intracellular proteins such as ATG16L1 translocate to plasma membrane during autophagy. This phenomenon may infer that ATP synthase is released from mitochondria and subsequently transported to cell surface under mitochondria-specific autophagy, mitophagy. To further confirm our hypothesis, we performed a series of experiments and finally found that ectopic ATP synthase trafficking pathway was not dependent on mitophagy. On the other side, we analyzed RNA-sequencing data of neuroblastoma and discovered the other pathway, mitophagy-independent pathway, which mitochondria directly transported to cell surface and fused with plasma membrane. In addition, we performed differential expression analysis of various clinical patient datasets of neuroblastoma and indicated that syntaphilin, which can modulate mitochondrial trafficking, involved in ectopic ATP synthase trafficking by mitophagy-independent manner. Taken together, we reveal the ectopic ATP synthase trafficking pathway may not mitophagy-dependent but syntaphilin-modulated.

致謝 II
中文摘要 IV
Abstract V
Contents VII
List of Figures XI
Chapter 1 Introduction 1
1.1 ATP synthase 1
1.2 Ectopic ATP synthase 2
1.3 Protein sorting 4
1.3.1 General protein sorting mechanism 4
1.3.2 Co-translational translocation 4
1.3.3 Post-translational translocation 5
1.3.4 Trafficking of ectopic ATP synthase 5
1.4 Mitophagy 8
1.5 Gene expression analysis 9
1.6 Motivation 9
Chapter 2 Material & Methods 11
2.1 Cell Culture 11
2.2 Construction of pATP5B-EGFP and pATP5B-PAGFP plasmid 11
2.2.1 Total RNA extraction 11
2.2.2 ATP5B amplification 12
2.2.3 Restriction enzyme digestion 13
2.2.4 Ligation 14
2.2.5 Bacteria strains and culture 14
2.2.6 Transformation 14
2.2.7 Colony PCR 15
2.2.8 Plasmid DNA purification 15
2.2.9 Transfection 17
2.2.10 Stable clone selection 17
2.3 Immunocytochemistry (ICC) 17
2.3.1 Sample Preparation 17
2.3.2 Confocal microscope 18
2.3.3 DeltaVision microscope 19
2.4 Live imaging 19
2.5 Flow cytometry (FACS) 20
2.6 Western blotting 20
2.7 Mitophagy induction 22
2.8 Plasma membrane extraction 22
2.9 Gene expression analysis 22
2.10 Gene Ontology enrichment analysis 23
2.11 Gene set enrichment analysis (GSEA) 23
2.12 Analysis of MYCN chromatin immunoprecipitation (ChIP) sequencing 24
Chapter 3 Results 26
3.1 Different abundance of ectopic ATP synthase in different cancer cells 26
3.2 Malignant cancer cells have more ectopic ATP synthase 27
3.3 ATP synthase was transported to plasma membrane in A549 lung cancer cells 28
3.4 Two hypothesized pathways of ATP synthase trafficking: mitophagy and mitochondrial trafficking pathway 30
3.5 GSEA results supported the mitochondrial trafficking pathway 32
3.6 SNPH might be the possible gene to regulate ectopic ATP synthase during mitochondrial trafficking 33
3.7 Mitophagy did not affect ectopic ATP synthase abundance 35
Chapter 4 Discussion 38
4.1 Mitophagy pathway independent 38
4.2 CCCP-induced mitophagy pathway 38
4.3 GSEA results supported mitochondrial trafficking pathway but not mitophagy pathway 38
4.4 Mitochondrial trafficking pathway 39
4.5 SNPH decreased along with higher stage of neuroblastoma patients tissue 41
Chapter 5 Conclusion 42
Chapter 6 References 44
Figures 53
Appendix 84

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