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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 潘俊良(Chun-Liang Pan) | |
| dc.contributor.author | Chih-Ta Lin | en |
| dc.contributor.author | 林志達 | zh_TW |
| dc.date.accessioned | 2021-05-19T17:57:00Z | - |
| dc.date.available | 2021-08-26 | |
| dc.date.available | 2021-05-19T17:57:00Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-16 | |
| dc.identifier.citation | Balch, W.E., Morimoto, R.I., Dillin, A., and Kelly, J.W. (2008). Adapting proteostasis for disease intervention. Science 319, 916-919.
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Zuchner, S., Mersiyanova, I.V., Muglia, M., Bissar-Tadmouri, N., Rochelle, J., Dadali, E.L., Zappia, M., Nelis, E., Patitucci, A., Senderek, J., et al. (2004). Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36, 449-451. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7878 | - |
| dc.description.abstract | 逆境或外在壓力導致生物體內蛋白構型異常時，細胞會透過專一性的訊號傳遞機制，進行各不同胞器獨特的生理反應，藉以去除構型異常的失能蛋白或將蛋白的構型恢復正常，這些統稱為胞器內未摺疊蛋白反應 (UPR)，其中包含了細胞質的熱休克反應(HSR)和內質網(UPRER)和粒線體的未摺疊蛋白反應(UPRmt)。生物體的老化會造成蛋白恆定態的失衡或粒線體功能異常，除伴隨著細胞生理功能的下降，也可能引起異常的未摺疊蛋白反應。前人在秀麗桿狀線蟲Caenorhabditis elegans當中發現，神經細胞內粒線體的呼吸狀態會影響線蟲全身性的粒線體蛋白平衡，但是神經細胞內與不同細胞間訊息傳遞的分子機制尚不清楚。本篇研究發現線蟲中調控粒線體融合的蛋白FZO-1/Mitofusin可以影響粒線體未折疊蛋白反應。fzo-1基因的突變引發多形性的性狀，包含生長遲緩、生殖能力下降、神經老化加速和粒線體未摺疊蛋白反應的異常上升。我們發現在神經細胞內專一表現FZO-1，除可以改善神經內粒線體型態的缺失和神經元細胞的過度老化外，亦可以有效改善fzo-1突變所引發的全身性粒線體未摺疊蛋白反應的異常上升，及減緩fzo-1突變所引發的生長遲緩。在腸道內專一表現FZO-1則可改善粒線體未摺疊蛋白反應在腸細胞內的異常上升。本篇研究發現神經細胞內粒線體型態的調控可以影響全身粒線體蛋白的平衡，有助於了解神經細胞內粒線體如何透過訊號傳遞來調控全身粒線體蛋白的平衡和生物體老化過程中蛋白質的恆定性。 | zh_TW |
| dc.description.abstract | Compartment-specific stress responses, including cytosolic heat shock response (HSR), the endoplasmic reticulum unfolded protein response (UPRER), and the mitochondrial unfolded protein response (UPRmt), protect animals against proteotoxic stress. Age-dependent decline in cellular functions and organismal physiology is associated with dysregulated protein homeostasis and mitochondrial function. Systemic proteostasis in the nematode Caenorhabditis elegans could be regulated by mitochondrial respiration in the neurons, but the molecular mechanisms of such intercellular control of protein homeostasis remains unclear. Here we report that the C. elegans mitochondrial fusion protein FZO-1/Mitofusin controlled UPRmt in a cell non-autonomous manner. Mutations of fzo-1 caused pleiotropic phenotypes, including slow development, reduced fecundity, accelerated neuronal aging, and maladapted UPRmt. Neuronal mitochondrial defects and aging signs of the neurites were rescued by neuron-autonomous FZO-1 functions. The maladapted UPRmt in the intestine was moderately rescued by intestinal FZO-1 expression. Unexpectedly, aberrant intestinal UPRmt of the fzo-1 mutants was significantly ameliorated by neuronal FZO-1. Neuronal FZO-1 also partially rescued the slow development of the fzo-1 mutant. We are now exploring neuron-derived signals that potentially mediate such non-autonomous effects on systemic mitochondrial proteostasis. Progress in this proposal could further our understanding of how mitochondria-mediated, neuron-derived signals control systemic protein homeostasis and cellular aging at the organismal level. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-19T17:57:00Z (GMT). No. of bitstreams: 1 ntu-105-R03448012-1.pdf: 7904516 bytes, checksum: 1289400a353504a172d17d49c5558181 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 口試委員會審定書 #
ACKNOWLEDGEMENT i 中文摘要 iii ABSTRACT iv CONTENTS v Chapter 1 INTRODUCTION 1 1.1 FZO-1/Mitofusins and Mitochondrial Dynamics 2 1.2 Regulation of Mitochondrial Proteome Homeostasis: the UPRmt 3 1.3 Cell Non-Autonomous UPRmt Regulation 5 1.4 Current Study: Neuronal Mitochondrial Dynamics and Systemic UPRmt Regulation 6 Chapter 2 MATERIALS and METHODS 9 2.1 C. elegans Strains and Genetics 9 2.2 Brood Size and Development Test 10 2.3 Feeding RNA Interference 10 2.4 Single Molecule RNA Fluorescence in situ Hybridization (smFISH) 11 2.5 Quantification of Heat Shock Responses of GFP-Based Stress Reporters 11 2.6 Fluorescence Microscopy and Quantification of Fluorescence Signal 12 2.7 Oxygen Consumption Assay 12 2.8 Mitochondrial Morphology 12 Chapter 3 RESULTS 15 3.1 Mutations of fzo-1/Mitofusin Caused Pleiotropic Defects in C. elegans 15 3.2 Mitochondrial and Neuronal Defects in the fzo-1 Mutant 16 3.3 The fzo-1 Mutation Specifically Induced Aberrant Mitochondrial Unfolded Protein Response 17 3.4 Mutations of fzo-1 Triggered Maladapted UPRmt Consistently throughout Development 19 3.5 Mitochondrial Fragmentation Triggered Systemic UPRmt 20 3.6 fzo-1 Functions Autonomously and Non-autonomously to Regulate Systemic UPRmt 21 3.7 Loss of Neuronal fzo-1 Triggers Systemic UPRmt Via Neurotransmitters and Neuropeptides 23 Chapter 4 DISCUSSION 25 4.1 Communication of Neurons with Distal Tissues in the Regulation of Stress Responses 26 4.2 The Physiological Significance of UPRmt 27 Chapter 5 FIGURES 29 Figure 1. Characterization of the fzo-1 mutant. 30 Figure 2. Pleiotropic defects in the fzo-1 mutant. 32 Figure 3. Mitochondria in the touch neurons were fragmented in the fzo-1 mutant. 34 Figure 4. Mitochondrial morphology is regulated by FZO-1. 36 Figure 5. Mitochondria in the intestine were fragmented in the fzo-1 mutant. 38 Figure 6. The fzo-1 mutant showed robust UPRmt induction in early adulthood. 40 Figure 7. The fzo-1 mutant showed intact UPRER activation. 42 Figure 8. The fzo-1 mutant showed intact HSR activation. 44 Figure 9. fzo-1 knockdown induced maladapted UPRmt. 46 Figure 10. hsp-6 transcripts were increaseded in somatic tissues of the fzo-1 mutant. 48 Figure 11. The fzo-1 mutant showed increased hsp-60 expression. 50 Figure 12. Maladapted UPRmt in the fzo-1 mutant requires canonical UPRmt genes. 52 Figure 13. UPRmt is constitutively activated throughout embryogenesis and larval development in the fzo-1 mutant. 54 Figure 14. UPRmt activation persisted during aging in the fzo-1 mutant. 56 Figure 15. fzo-1 mutation may induce maladapted UPRmt in part through respiratory inhibition. 58 Figure 16. Mitochondrial dynamics influenced respiration. 60 Figure 17. Mitochondrial dynamics controlled UPRmt activation. 62 Figure 18. Intestine-specific fzo-1 knockdown triggered UPRmt. 64 Figure 19. Muscle-specific fzo-1 knockdown did not induce UPRmt. 66 Figure 20. Intestine-specific cco-1 knockdown triggered UPRmt induction. 68 Figure 21. Muscle-specific cco-1 knockdown failed to induce UPRmt. 70 Figure 22. Neuron-specific fzo-1 knockdown triggered UPRmt. 72 Figure 23. Tissue-specific fzo-1 expression and the rescue of UPRmt. 74 Figure 24. Intestinal mitochondrial fragmentation were partially rescued by tissue-specific FZO-1 expression. 76 Figure 25. Models of autonomous and non-autonomous UPRmt control by FZO-1. 78 Figure 26. cco-1 knockdown induced UPRmt in the unc-13 and unc-31 mutants. 80 Figure 27. Cell non-autonomous induction of UPRmt requires both neurotransmitters and neuropeptides. 82 Figure 28. Model of systemic UPRmt regulation by fzo-1 in the neurons. 84 Chapter 6 REFERENCE 87 | |
| dc.language.iso | en | |
| dc.title | 線蟲神經系統調控粒線體壓力反應的分子機制 | zh_TW |
| dc.title | Neural Regulation of Mitochondrial Stress Response in Caenorhabditis elegans | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 許翱麟(Ao-Lin Hsu),吳益群(Yi-Chun Wu) | |
| dc.subject.keyword | 線蟲,粒線體,粒線體融合蛋白FZO-1/Mitofusin,未摺疊蛋白反應,神經訊號, | zh_TW |
| dc.subject.keyword | C. elegans,Mitochondria,FZO-1/Mitofusin,Unfolded protein response,Neuronal signal, | en |
| dc.relation.page | 95 | |
| dc.identifier.doi | 10.6342/NTU201602858 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2016-08-17 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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