CISD (CDGSH iron-sulfur domain) 是一類鐵硫簇結合結構域，具有高度保留性且廣泛分布於原核和真核生物中，但其生物功能目前尚未被廣泛探討。在人類與老鼠中具有三個CDGSH iron-sulfur domain的蛋白，分別為CISD1、CISD2和CISD3。目前於小鼠的剔除實驗已知，缺乏Cisd1會造成粒線體的氧化能力下降，缺乏Cisd2會導致粒線體缺陷和增加自噬作用(autophagy)，進而伴隨早衰現象之發生，Cisd3尚未被探討。
本實驗是經由CDGSH domain之序列比對，發現在果蠅中具有兩個CISD蛋白，分別為CG1458和CG3420。其中CG1458具有單一CDGSH domain，且其序列相較於Cisd2比Cisd1較為相似。本研究發現，隨著年齡增長，伴隨著累積CG1458；此外，當過量表現CG1458會導致果蠅早衰並伴隨行為能力缺陷，反之，於EPG6528 背景果蠅，下調CG1458基因表現可明顯地觀察到延緩果蠅老化，並且改善其行為能力。在研究結果中發現，CG1458蛋白可能主要表現在粒線體上；因此本研究以利用需要大量能量的肌肉組織作為模式。其結果顯示，隨著年齡的增加，因蛋白質降解的衰退導致泛素化蛋白嚴重累積。因此，我們推測過量表現CG1458會導致的爬行能力缺失，可能是由於無法針對受損之蛋白進行適當降解反應所導致。此外，CG1458對於調控粒線體動態變化扮演非常重要之角色；當過量表現CG1458會誘使粒線體趨向於融合；相反地，剔減(Knockdown) CG1458基因表現則促使粒線體型態由原本桿狀改變成非典型的圓型，即呈現裂殖狀態。此外，當表現老鼠的Cisd1和Cisd2蛋白時分別會造成粒線體呈現裂殖和融合狀態，然而表現老鼠的Cisd1或Cisd2於CG1458缺陷的果蠅，其粒線體型態並無顯著之改變。
同時，我們針對此粒線蛋白和細胞凋亡之關聯性進行研究，當下調CG1458表現可抑制Reaper和Grim所誘發的細胞凋亡，然而卻不影響Hid；相反地上調CG1458表現可增強Reaper和Grim誘發之死亡。此外，有研究顯示Drosophila Bruce會抑制Reaper和Grim所誘發的細胞凋亡，然而卻不影響Hid。由於此共通性，我們探討dBruce、CG1458與Reaper之間的交互作用。研究發現，剔減dBruce表現會增強Reaper誘發之細胞凋亡，然而進一步剔減CG1458表現則可減緩細胞凋亡，可能是由於dBruce會透過抑制CG1458進而抑制Reaper所誘發之細胞凋亡。此外，由於pro-apoptotic proteins (RGH)會與 anti-apoptotic proteins (DIAP1)達到穩定平衡，我們進一步探討CG1458與DIAP1之上下游關係；結果顯示，CG1458位於DIAP1之上游調控細胞凋亡。另一方面，本實驗室也著重於Caspase非依存性凋亡途徑之探討，結果顯示，CG1458可能不參與Eiger誘發之Caspase非依存性凋亡途徑。
在本論文研究中，我利用果蠅動物研究CG1458蛋白與老化、粒線體動態改變和細胞凋亡進行相關探討。且提出CG1458為一粒線體蛋白可連接此三領域之重要因子。

CISD (CDGSH iron-sulfur domain) is a subtype of iron and sulfur cluster binding domain, which is highly conserved in prokaryotes and eukaryote; however, the biological functions are largely unclear. In human and mice, there are three CISD proteins, including CISD1, CISD2 and CISD3. In mice, it has been reported that Cisd1-null mice demonstrate a reduced oxidative capacity of mitochondria; Cisd2 knockout mice led to mitochondrial defect and an increased autophagy accompany by premature aging; Cisd3 is unclear yet. In this study, we identified that CG1458 and C3420 are CISD proteins by alignment CDGSH domain sequence in Drosophila. CG1458 contains a CDGSH domain in C-terminal region. The sequence of CG1458 is similar to those of Cisd1 and Cisd2 in mice. In Drosophila, we found that CG1458 is located on or within the mitochondria, and that it increases in abundance with aging. Using a daughterless-GAL4 driver, overexpression of CG1458 fly line was found to reduce the mean lifespan to 41% compared to that of wild-type Drosophila. The hypomorphic allele, EPG6528 mutant increased the mean lifespan of male flies by 29%, compared to that of wild-type flies. CG1458 likely is a mitochondria-associated protein, thus we use muscle tissue which has the highest energy needs and are therefore the most dependent on mitochondrial function as the tissue model. We found that aging causes protein degradation declines and accumulation of polyubiquitinated proteins, thus we proposed that overexpression of CG1458 results in loss of climbing activity due to the dysfunctional proteins cannot be degraded properly. Using ectopically express CG1458 by Mef2-Gal4 in thoracic muscle, we observed that the mitochondria were swollen, enlarged and fusion-like phenotype in flies in which CG1458 was overexpressed. By contrast, flies in which the expression of CG1458 was knocked down using Mef2-Gal4 driven micro-shRNA were found that mitochondrial morphology became fragmented and atypical round-shaped, were called fission-like phenotype. We also showed that expression of mouse Cisd1 caused the fission-like mitochondria; and expression of mouse Cisd2 caused elongated mitochondria. However, there were no significant differences of mitochondrial morphology between knockdown of CG1458 and expression of Cisd1/Cisd2 in knockdown of CG1458 background. These results indicated that CG1458 may be a regulator of mitochondrial dynamics in Drosophila. Beside aging and mitochondrial dynamics, CG1458 plays an important role in cell death way in Drosophila. In our study, we show that CG1458 involve in Rpr- and Grim-induced cell death, but not Hpo-triggered Hid-induced cell death, additionally, CG1458 may be a component to assist Rpr-dependent cell death against dBruce. The balance between of pro-apoptotic proteins and anti-apoptotic proteins is crucial for cell death regulation. These results showed that CG1458 is an upstream gene of DIAP1. On the other hand, we also focus on caspase-independent cell death and found that CG1458 might be involved in this cell death pathway. In summary, CG1458 plays important roles in aging, mitochondrial dynamics and cell death. Yet, the more detail molecular mechanism of CG1458 need to be investigated. Mostly important, we propose a novel concept that CG1458 is a bridge to link these three fields together.

ABSTRACT ........................................................................................................................................................................ II
ACKNOWLEDGEMENT ................................................................................................................................................ III
TABLE OF CONTENTS .................................................................................................................................................. IV
FIGURE LIST ................................................................................................................................................................... VI
TABLE LIST .................................................................................................................................................................... VII
ABBREVIATIONS ........................................................................................................................................................ VIII
INTRODUCTION .............................................................................................................................................................. 1
1.CDGSH iron-sulfur domain-containing (CISD) protein family ...................................................................................... 1
1.1 The CISD-like proteins, CISD1, CISD2 and CISD3 in mammals ....................................................................... 1
1.2 CG1458: a member of the CISD protein family in Drosophila ............................................................................ 3
2.Aging ................................................................................................................................................................................ 3
2.1 Introduction ........................................................................................................................................................... 3
2.2 Overview of muscle aging .................................................................................................................................... 4
2.2.1 Indirect flight muscles (IFMs) ........................................................................................................................... 4
3.Mitochondria .................................................................................................................................................................... 5
3.1 Structure and morphology of mitochondria .......................................................................................................... 5
3.2 Mitochondrial function and characterization ........................................................................................................ 6
3.3 Mitochondrial dynamics: fission and fusion ......................................................................................................... 6
3.4 Mitochondrial dynamics and aging ....................................................................................................................... 7
3.5 Mitochondrial dysfunction and disease ................................................................................................................. 8
4.Cell death ......................................................................................................................................................................... 8
4.1 Regulation of caspase-dependent signaling pathway in Drosophila .................................................................... 8
4.2 Regulation of the caspase-independent signaling pathway ..................................................................................11
4.3 Mitochondria and cell death ................................................................................................................................ 12
5.The aims of this thesis .................................................................................................................................................... 12
MATEIRALS AND METHODS ...................................................................................................................................... 14
Drosophila Genetics and strains ................................................................................................................................ 14
Generation of transgenic flies ................................................................................................................................... 14
Behavioral assay-negative gravitaxis assay .............................................................................................................. 14
Lifespan ..................................................................................................................................................................... 15
Immunoblotting ......................................................................................................................................................... 15
Muscle section and immunostaining ......................................................................................................................... 16
Eye disc and caspase-3 immunostaining ................................................................................................................... 17
V
Fluorescence and scanning electron microscopy .......................................................................................................... 18
Real time quantitative PCR (qRT-PCR) analyses ......................................................................................................... 18
S2 cell culture and immunofluorescence staining ......................................................................................................... 19
Cell culture .................................................................................................................................................................... 19
Immunofluorescence staining ....................................................................................................................................... 19
Cloning and construction of the recombinant plasmid ................................................................................................. 19
Statistical analysis ......................................................................................................................................................... 20
RESULTS .......................................................................................................................................................................... 21
The CG1458 protein possesses a unique CDGSH iron-sulfur cluster domain ............................................................. 21
CG1458 likely is a mitochondria-associated protein .................................................................................................... 21
Delay lifespan and preferable climbing performance in knockdown and EPG6528 mutant strains ................................ 22
CG1458 protein abundance with age ............................................................................................................................ 24
Progressive accumulation of polyubiquitinated protein aggregates is associated with CG1458 during aging ............ 24
Genetic defects in the CG1458 protein regulate mitochondrial fission and fusion and lead to severely altered mitochondrial shape ...................................................................................................................................................... 25
Expression of the mouse Cisd1 and Cisd2 gene in Drosophila muscle lead to an abnormal mitochondrial morphology ................................................................................................................................................................... 26
CG1458 interacts with the Drosophila pro-apoptotic protein Reaper and Grim, but not Hid ...................................... 28
Double knockdown dBruce with CG1458 enhances Reaper-induced the cell death .................................................... 29
CG1458 is upstream of Drosophila inhibitor of apoptosis protein 1 in cell death pathway. ........................................ 31
CG1458 is not involved in the Eiger-triggered JNK cell death pathway ...................................................................... 31
DISCUSSION AND CONCLUSION ............................................................................................................................... 34
REFERENCES.................................................................................................................................................................. 39
FIGURES .......................................................................................................................................................................... 48
TABLES ............................................................................................................................................................................ 69
SUPPLEMENTARY ......................................................................................................................................................... 73

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