粒線體在真核細胞中的主要功能為提供生物體所需的能量。人類粒線體第一蛋白質複合體是由44個次單元蛋白所組成，其中的一個次單元NDUFS7為細胞核所編碼的，並且為此複合體中的電子傳遞鏈提供了最後一個鐵硫中心N2。之前，我們驗證了在NDUFS7的N端帶有粒線體標的序列(mitochondrial targeting sequence, MTS) ，而在靠近NDUFS7的C端的部分則帶有細胞和導入序列(nuclear localization signal, NLS)及細胞核導出序列(nuclear export signal, NES)。類小泛素化(SUMOylation)是一種可逆的轉譯後修飾,並會在目標蛋白上接上類小泛素蛋白(small ubiquitin-like modifier, SUMO)。它是一種負責調控細胞內多種生理反應的關鍵修飾作用。在之前的研究中發現，NDUFS7可以被類小泛素蛋白SUMO1及其旁系SUMO3所修飾。在本篇研究中，我們試著探討NDUFS7被SUMO蛋白修飾後在細胞中的分佈。在正常情況下，NDUFS7以未成熟以及成熟的形式出現在粒線體，另外還會有一部分未成熟的NDUFS7出現在細胞核。不過，當NDUFS7被SUMO修飾後，可以看到多種形式的NDUFS7-SUMO1和NDUFS7-SUMO3在細胞核中出現。有趣的是，在SUMO1修飾的組別中未成熟的NDUFS7在細胞核中的量有了明顯的增加。我們認為NDUFS7被SUMO1修飾後似乎會促進它進細胞核而SUMO3的修飾則不具此功能。此外，我們還比較了在缺氧及氧化壓力的條件下,未成熟、成熟以及SUMO修飾的NDUFS7在細胞中的分佈。雖然，氯化鈷(CoCl2)誘導的缺氧狀態下皆有一種形式的NDUFS7-SUMO1和NDFUS7-SUMO3出現在粒線體。不過，粒線體中未成熟及成熟的NDUFS7則沒有的顯著改變。相反的，SUMO3修飾的組別中細胞核內未成熟的NDUFS7及NDUFS7-SUMO3皆減少了，然而此現象卻沒在SUMO1修飾的組別中發現到。在H2O2所誘導的氧化壓力的實驗中，SUMO1的組別氧化壓力對其沒有特別的影響，不過氧化壓力卻對SUMO3的組別有顯著的影響。細胞核中不單是NDUFS7-SUMO3的量大幅度的減少，且未成熟NDUFS7的量也減少了。根據本篇的研究結果，我們認為在正常的情況下SUMO1的修飾對NDUFS7有促進其進入細胞核的功能，而SUMO3的修飾則無。然而在缺氧及氧化壓力下，SUMO3對NDUFS7的修飾反而會減少其在細胞核出現。其詳細的生理意義仍需要更進一步地去探討。令人失望的是，由於我們缺少靈敏可靠的NDUFS7抗體導致我們並沒有在內源性的實驗中發現被SUMO修飾的內生性NDUFS7。

Mitochondria are well recognized for energy production in eukaryotic cells. Human NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) is a nuclear-encoded core protein in mitochondrial respiratory complex I (NADH:ubiquinone oxidoreductase) which is made up of 44 different subunits. It contains an iron-sulfur cluster N2 (a [4Fe-4S] cluster), a final redox center for electron transfer in complex I. We previously identified that NDUFS7 has a mitochondrial targeting sequence (MTS) at the N-terminu’s and a nuclear localization signal (NLS) and a nuclear export signal (NES) at the C-terminus of the protein. SUMOylation is a reversible post-translational modification which can conjugate a small ubiquitin-like modifier (SUMO) on the target protein. SUMOylation has been considered as a key modification in modulating many cellular processes. In previous studies, we have shown that NDUFS7 could be modified by both SUMO1 and SUMO2/3. In this study, we tried to explore the localiztion of NDUFS7 after SUMOylation in cells. Normally, NDUFS7 is present in mitochondria as the precursor form and the mature form, and a small amount of the precursor form of NDUFS7 was found in the nucleus. However, after SUMOylation, multiple forms of NDUFS7-SUMO1 and NDUFS7-SUMO3 were observed in the nucleus. Interestingly, the precursor form of NDUFS7 in the SUMO1-modified group was also increased significantly in the nucleus, suggesting that modification with SUMO1 is likely to promote nuclear localization of NDUFS7 but not with SUMO3. In addition, we also compared the localization of the precursor, the mature and the SUMOylated form of NDUFS7 under hypoxia and oxidative stress. Although SUMOylation promoted the presence of a form of NDUFS7-SUMO1 and NDUFS7-SUMO3 in mitochondria under treatment of hypoxia-mimicking reagent CoCl2, the amount of mitochondrial localization of NDUFS7 was not changed. In contrast, both the SUMOylated forms and the precursor form of NDUFS7 were decreased in the nucleus in the SUMO3-modified group but not in the SUMO1-modified group. Oxidative stress induced by H2O2 treatment did not have a significant effect on the modificaiton of NDUFS7 with SUMO1 and its localizaiton. However, the same oxidative stress not only decreased the level of SUMO3-conjugated NDUFS7 but also reduced the NDUFS7 precursor in the nucleus. Our findings suggest that modification with SUMO1, not SUMO3, normally contributes to the nuclear localization of NDUFS7. However, under hypoxia or oxidative stress, the nuclear localization of NDUFS7 is significantly reduced in the SUMO3 modification condition. The detailed biological meaning of these phenomena need to further verify. Unfortunately, because of a lack of a reliable antibody against NDUFS7, SUMOylaiton of NDUFS7 was not observed in vivo.

Table of contents

中文摘要.............................................................................................................. I
Abstract .............................................................................................................III
Abbreviations ...................................................................................................XI
Introduction ....................................................................................................... 1
1. Mitochondria ............................................................................................. 1
1-1 Mitochondrial genome .....................................................................................2
1-2 Oxidative phosphorylation (OXPHOS) system ...............................................3
1-3 The crosstalk between mitochondria and nuclei ..............................................4
1-4 The crosstalk between mitochondria and endoplasmic reticula (ER) ..............5
1-5 Mitochondrial complex I (NADH: ubiquinone oxidoreductase) .....................6
1-6 Human NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) ........7
1-7 The association between NDUFS7 and diseases .............................................8
2. SUMOylation ..................................................................................................9
2-1 Small ubiquitin-like modifier (SUMO) proteins ............................................10
2-2 The SUMO pathway ......................................................................................10
2-3 SUMO binding sites and conjugation forms ..................................................11
2-3-1 SUMO binding motif ..............................................................................11
2-3-2 SUMO conjugation forms ......................................................................13
2-4 The effects of SUMOylation and its biological significance .........................14
2-4-1 Sumoylation and genomic homeostasis ..................................................14
2-4-2 SUMOylation and protein translocation .................................................15
2-4-3 SUMOylation and stresses ......................................................................16
2-4-3-1 SUMOylation and hypoxia ..............................................................16
2-4-3-2 SUMOylation and oxidative stress ..................................................17
2-5 SUMOylation in mitochondria .......................................................................17
The objective of this study ...............................................................................19
Materials and methods .....................................................................................20
Results ................................................................................................................26
1. NDUFS7 is modified by SUMO1 and SUMO3 ................................................. 26
2. The effects of modification with SUMO1, or SUMO3 for nuclear translocation of NDUFS7 are different.............................................................................................. 26
3. The treatment of hypoxia-mimicking reagent CoCl2 is likely to promote mitochondrial localization of SUMO1-conjugated NDUFS7 ................................. 27
4. The treatment of oxidative stress-inducing reagent H2O2 does not have a significant effect on the modification of NDUFS7 with SUMO1 and its subcellular localization .............................................................................................................. 28
5. The treatment of hypoxia-mimicking reagent CoCl2 is likely to reduce nuclear localization of NDUFS7 precursor but promote mitochondrial localization of SUMO3-conjugated NDUFS7................................................................................. 29
6. Oxidative stress not only decreases the level of SUMO3-conjugated NDUFS7 but also reduces the nuclear location of NDUFS7 precursor................................... 30
7. The identification of endogenous NDUFS7 and its subcellular distribution........30
8. SUMOylated-NDUFS7 was not found in cells in native conditions................... 31
Discussion ......................................................................................................... 32
1. NDUFS7 and its SUMOylation............................................................................32
2. NDUFS7 modification with SUMOs under various stresses...............................33
2-1 The connection between SUMOylation of NDUFS7 and hypoxia.............33
2-2 The connection between SUMOylation of NDUFS7 and oxidative stress..35
3. Poly-SUMOylation with SUMO1.........................................................................36
4. Some techniques needed to be involved in this study...........................................37
5. The crosstalk between SUMOylation an phosphorylation...................................37
6. The limitation of endogenous NDUFS7...............................................................38
7. The NDUFS7 knockdown cell lines.....................................................................38
Table ................................................................................................................. 39
Figures............................................................................................................... 40
Reference .......................................................................................................... 52
Appendixes ....................................................................................................... 59

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