粒線體相關降解途徑(MAD)在支鏈胺基酸(BCAA)生合成中的作用

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研究生：	簡士宏 Chien, Shih-Hung
論文名稱：	粒線體相關降解途徑(MAD)在支鏈胺基酸(BCAA)生合成中的作用 The role of the mitochondria-associated degradation (MAD) pathway in branched-chain amino acid (BCAA) biosynthesis
指導教授：	廖品超 Liao, Pin-Chao
口試委員:	李岳倫 Lee, Yueh-Luen 張壯榮 Chang, Chuang-Rung 徐子勝 Hsu, Tzu-Sheng
學位類別：	碩士 Master
系所名稱：	生命科學暨醫學院 - 分子醫學研究所 Institute of Molecular Medicine
論文出版年：	2024
畢業學年度：	112
語文別：	英文
論文頁數：	73
中文關鍵詞：	粒線體品質控管、蛋白質恆定、粒線體蛋白酶、釀酒酵母、Doa1 、Pim1
外文關鍵詞：	Mitochondrial quality control, Protein homeostasis, Mitochondrial protease, Saccharomyces cerevisiae, Doa1, Pim1
相關次數：	點閱：50 下載：0
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粒線體是生成ATP和代謝物生產必要的胞器。許多粒線體品質調控路徑，如粒線體自噬、粒線體蛋白酶和粒線體相關降解（Mitochondria-associated degradation, MAD）參與維持粒線體的健康和功能。在MAD中，未折疊的蛋白質會被泛素化，由保守的蛋白質複合體AAA-ATPase Cdc48（在哺乳動物中為VCP/p97）及其輔因子Doa1識別，從粒線體中移除並送往蛋白酶體降解。我們先前的研究顯示，兩種粒線體基質蛋白，Kgd1（α-酮戊二酸脫氫酶）和Pim1（Lon蛋白酶）是MAD的受質。由於Pim1是一種粒線體蛋白酶，我們研究MAD和Pim1是否以及如何共同調節Pim1受質的降解。我們針對Pim1的受質Ilv2，此為一種參與釀酒酵母支鏈氨基酸（BCAA）生合成的酶。我們首先確認了Pim1的降解在發酵和非發酵條件下都受到MAD的調控。接著，在正常或氧化壓力條件下時，MAD抑制導致參與BCAA生物合成的酶，包括Ilv2、Ilv3和Ilv6的量都會下降。此外，在呼吸條件下，doa1∆細胞中Ilv2的量下降可以透過突變的Pim1恢復。這一結果支持了，Ilv2降解增加是由於MAD抑制所導致Pim1增加所致。我們還發現，MAD的抑制會導致ILV2基因表現量的下降。最後，MAD的抑制導致粒線體膜電位（∆Ѱ）和BCAA水平的下降。因此，我們的研究顯示，在呼吸條件下，MAD可透過調節Ilv2生合成和降解的平衡狀態來調控BCAA的生合成。

Mitochondria are essential organelles for the generation of ATP and metabolite production. Several quality control pathways such as mitophagy, mitochondrial proteases and mitochondria-associated degradation (MAD) are involved in maintaining mitochondrial fitness and function. In MAD, unfolded proteins are ubiquitinated, recognized by a conserved protein complex AAA-ATPase Cdc48 (VCP/p97 in mammals) with its adapter Doa1, removed from mitochondria and degraded by proteasomes. Our previous study revealed that two matrix proteins, Kgd1 (alpha-ketoglutarate dehydrogenase) and Pim1 (Lon protease) are MAD substrates. Since Pim1 is a mitochondrial protease, we investigated whether and how MAD and Pim1 coordinate to regulate the turnover of Pim1 substrates. We focused on Pim1 substrates Ilv2, an enzyme involved in branched-chain amino acid (BCAA) biosynthesis in Saccharomyces cerevisiae. We first confirmed that the turnover of Pim1 was regulated by MAD under both fermentative and non-fermentative conditions. Next, enzymes involved in BCAA biosynthesis including Ilv2, Ilv3 and Ilv6 are decreased when MAD is inhibited under basal or oxidative stress conditions. Furthermore, under respiratory conditions, the reduced protein level of Ilv2 in doa1∆ cells can be restored by the catalytic domain-mutated Pim1. This result supports the idea that the degradation of Ilv2 is due to the increased functional Pim1 upon MAD inhibition. Additionally, we found that inhibition of MAD results in a decrease of ILV2 expression levels. Finally, inhibition of MAD leads to reduced mitochondrial membrane potential (ΔѰ) and BCAA levels. Collectively, our study reveals that MAD regulates BCAA biosynthesis by maintaining the homeostasis of Ilv2 biogenesis and degradation that is regulated by Pim1 under respiratory conditions.

Abstract    I
中文摘要    II
Acknowledgments    III
Table of contents    1
Chapter 1. Introduction    4
1.1 Mitochondria functions    4
1.2 Mitochondrial quality control pathway: Mitochondrial fission and fusion    5
1.4 Mitochondrial quality control pathway: Mitochondria-associated degradation (MAD)    6
1.5 Mitochondrial quality control pathway: Mitochondrial protease    8
1.6 Branched-chain amino acid (BCAA) biosynthesis in Saccharomyces cerevisiae    9
1.7 Hypothesis    10
Chapter 2. Materials and Methods    12
2.1 Yeast growth conditions    12
2.2 Yeast strain construction    12
2.3 CRISPR for pim1S1015A mutation    13
2.4 MG132 treatment    14
2.5 Total cell lysate preparation    15
2.6 Isolation of mitochondria    15
2.7 Proteinase K treatment    16
2.8 Western blot analysis    17
2.9 Membrane potential measurement using DiOC6 staining    18
2.10 Branched-chain amino acid levels    19
2.11 RNA extraction, cDNA synthesis and quantitative PCR    19
2.12 Statistical analysis    20
Chapter 3. Results    21
3.1 MAD contributes to the mitochondrial membrane potential (ΔѰ)    21
3.2 MAD is responsible for the degradation of mitochondria matrix protein Pim1    21
3.3 MAD regulates Pim1 substrate Ilv2    22
3.4 MAD regulates BCAA biosynthesis enzymes Ilv2, Ilv6 and Ilv3    23
3.5 Accumulated Pim1 resulted from MAD inhibition contributes to the degradation of Ilv2 under respiratory conditions    24
3.6 MAD and Lon protease Pim1 contributes to ILV2 gene expression    25
3.7 MAD contributes to BCAA production    25
Chapter 4. Discussion    27
4.1 MAD pathway regulation of BCAA biosynthesis enzyme Ilv2 is by turnover of mitochondrial Lon protease Pim1    27
4.2 Inhibition of MAD or Pim1 results in reduced Ilv2 biogenesis    28
4.3 Inhibition of MAD results in lower BCAA levels    28
4.4 Ilv2 tagged with 13Myc at the C-terminus has mitochondrial import defects    29
Figures    31
Figure 1. The MAD pathway and mitochondrial protease Pim1    31
Figure 2. BCAA biosynthesis in Saccharomyces cerevisiae    32
Figure 3. Generation of pim1S1015A using CRISPR    33
Figure 4. Deletion of DOA1 resulted in a decrease of the mitochondrial membrane potential (ΔѰ)    35
Figure 5. MAD substrate Pim1 accumulated in mitochondria in doa1∆ cells    40
Figure 6. Ilv2 tagged with 13Myc has a non-imported precursor and growth defect    43
Figure 7. BCAA biosynthesis enzymes Ilv2, Ilv3 and Ilv6 are decreased in doa1∆ cells    47
Figure 8. MAD-inhibition induced Pim1 accumulation contributes to the reduced Ilv2 levels    51
Figure 9. Deletion of DOA1 or PIM1 mutant resulted in reduced Ilv2 biogenesis    52
Figure 10. Deletion of DOA1 resulted in a decrease of BCAA production    53
Figure 11. Schematic of MAD regulation of BCAA biosynthesis    54
Tables    55
Table 1. Saccharomyces cerevisiae strain list    55
Table 2. Primer list    62
Abbreviation    65
References    67
                                

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