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研究生： 李岱亭
Lee, Tai-Ting
論文名稱： 探討 Fis1 對粒線體型態以及蛋白質恆定的影響
Role of Fis1 in determining mitochondrial morphology and regulating protein homeostasis.
指導教授： 陳俊宏
Chen, Chun-Hong
汪宏達
Wang, Horng-Dar
口試委員: 詹智強
Chan, Chih-Chiang
張壯榮
Chan, Chuang-Rung
學位類別： 碩士
Master
系所名稱： 生命科學暨醫學院 - 生物科技研究所
Biotechnology
論文出版年： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 71
中文關鍵詞： 粒線體 、聚集體 、電子傳遞鏈 、蛋白質恆定
外文關鍵詞： Mitochondria, Aggresome, ETC, Protein homeostasis
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    • 粒線體透過粒線體的融合和分裂以維持生理機制的恆定性。目前已知有幾種關鍵蛋白參與這些動態過程，包括參與融合機制的Mitofusin 1和Optic Atrophy 1以及參與分裂機制的Drp1和Fis1。然而，Fis1在黑腹果蠅中的確切功能仍未能完全明朗。進一步調查Fis1的作用可能有助於提高我們對粒線體動態平衡的認識。在這項研究中，我們使用果蠅（Drosophila melanogaster）作為模式生物來探索Fis1蛋白的功能。我們發現在果蠅的四種Fis1的蛋白異構體中，長度較長的兩個蛋白異構體與哺乳類的Fis1高度相似。此外，我們採用四種Fis1蛋白異構體分別表現於果蠅胸腔的肌肉中，並且發現具有較長胺基酸序列的Fis1蛋白異構體的表現量較為穩定。被過度表現的長鏈Fis1於肌肉中會形成囊泡狀結構
    ，且此結構中充滿了被泛素化(ubiquitinated protein)的蛋白。另一方面，我們還在人類肺腺癌上皮細胞A549中表現高含量的Fis1，並發現被過度表現的Fis1會形成囊泡狀結構，且其含有聚集體(aggresome)標記物HDAC6蛋白。此外，我們發現fis1基因的突變會導致果蠅中泛素化蛋白的累積。這些結果表明Fis1可能參與聚集體的組成，進而調控果蠅的蛋白質恆定機制。此外，Fis1突變使果蠅壽命減少以及活動能力的降低，表示粒線體功能可能受到損害。同時，我們還發現Fis1突變的果蠅體內的活性氧化物（ROS）的含量在老化過程中較野生型果蠅升高的還快。利用原態膠體電泳法，我們發現Fis1的缺失造成果蠅呼吸傳遞鏈中復合物I的蛋白質表現量降低，這意味著ROS的升高與複合物I受損後的電子洩漏有關。綜合以上實驗結果，我們發現Fis1不直接參與粒線體裂變過程，但有助於維持果蠅的粒線體完整性和蛋白質恆定。Fis1如何保持復合物I結構與功能的完整性以及它在聚集體形成中所起的作用仍需要進一步研究。

    Mitochondria undergo mitochondrial fusion and fission in order to maintain physiological homeostasis. There are several key proteins known to be involved in these dynamic processes, including Mitofusin 1 and Opa1 in fusion as well as Drp1 and Fis1 in fission. The exact function of Fis1 in Drosophila melanogaster remains elusive: Further investigation into the role play by Fis1 could help to improve our understanding of mitochondrial fission. In this study, we used Drosophila melanogaster as a model to explore the function of Fis1. We found that in Fis1’s four protein splicing forms of flies, the two longer splicing forms are highly similar to the mammalian Fis1. In addition, we introduced different splicing forms of Fis1 into fly muscle and found the two stable forms of endogenous Fis1 were long forms. Moreover, high levels of long form Fis1 form an aggresome-like structure that recruited ubiquitinated proteins into the inclusion structure. On the other hand, we also found high levels of Fis1 in adenocarcinomic human alveolar basal epithelial cells, A549 cells, which enclosed the aggresome marker HDAC6 and formed the inclusion structure. Moreover, we found that fis1 mutations (Fis1 knockout) caused the aggregation of severe ubiquitinated proteins in flies. These results suggest Fis1 may play a role in protein homeostasis as an assembly of aggresomes. Furthermore, Fis1 mutants showed reduced life span and mobility, suggestive of dysfunctional mitochondria. We also found an elevation of Reactive oxygen species (ROS) during aging. Using a blue native gel assay, we showed a reduced protein level on complex I in the respiratory chain, implying that the elevation of ROS is associated with the leakage of electrons from an impaired complex I. Furthermore, we found that the deficit on the respiratory chain may lead to a decreased respiration rate in aged flies. In summary, we found that Fis1 is not directly involved in the mitochondrial fission process but helps to maintain mitochondrial integrity and protein homeostasis in flies. How Fis1 maintains Complex I integrity and its role in aggresome formation warrants further investigation.

    中文摘要 I Abstract II List of figures VII List of tables VIII List of abbreviations IX Introduction 1 1 Mitochondria 2 2 The role of Fis1 7 3 Mitochondrial dysfunction and disease 8 4 Protein homeostasis 10 Aims of thesis 13 Materials and Methods 14 Drosophila genetics and stains. 14 Lifespan assay. 14 Behavior assay -Climbing assay. 14 Western Blot. 15 1. Protein extraction. 15 2. Protein concentration. 15 3. Protein sample preparation. 15 4. SDS-PAGE. 16 5. Transfer. 16 6. Hybridization. 16 7. Stripping. 17 Adult Drosophila melanogaster muscle dissection and immunofluorescence. 17 Paraffin section of muscle 18 Mammalian A549 cell culture and plasmid 18 Cell immunofluorescence 19 Mitochondria isolation 19 Blue native gel 20 Proteomic analysis 20 1. Sample Preparation for Proteome 20 2. Dimethyl Labeling of Peptides 21 3. Strong cation exchange (SCX) chromatography. 21 4. NanoLC-MS/MS Analysis 22 5. Data Analysis for proteome 22 Electron Microscopy 23 Statistical analysis 23 Results 24 fis1 has four protein isoforms with distinct functional regions; Long forms similar to mammalian Fis1. 24 Fis1 long form levels are higher than short form levels 25 Long form 2 approximately equally distributed in the cytoplasm and mitochondria 25 Fis1 L1, S1 and S2 may regulate mitochondrial morphology 26 Cytosolic Fis1 formed specific structures outside the mitochondria. 27 Cytoplasmic Long form 1 co-localized with ubiquitinated protein and the inclusion structure of Long form 2 recapitulated ubiquitinated protein. 27 The inclusion structure of Long form 2 includes Heat Shock Protein 70. 28 Human Fis1 dis-localized with mitochondria and formed inclusive vesicles or net structure in mammalian HDAC6 in A549 cell when treated with MG132. ………………………………………………………………………….…. 28 Human Fis1 formed vesicles with the aggresome marker HDAC6 in A549 cells. ……. 29 The depletion of Fis1 led to remarkable aggregation of protein during aging. 29 Loss of Fis1 shortens life span of flies in both sexes. 29 Depletion of Fis1 reduces climbing ability in young and old flies whereas overexpression of Fis1 L2 improve mobility in young flies. 30 Fis1 mutant flies demonstrated induced muscle atrophy. 30 Loss of Fis1 increased ROS level. 31 The depletion of Fis1 decreases integrity of the mitochondrial complexes in electron transport chain. 31 Discussion and conclusion 33 References 39 Figures 48 Tables 69

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