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The Roles of the CoQ10 Chaperone Protein, Cardiolipin, and Endoplasmic Reticulum-Mitochondria Contact Sites in Coenzyme Q Biosynthesis and Function.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Roles of the CoQ10 Chaperone Protein, Cardiolipin, and Endoplasmic Reticulum-Mitochondria Contact Sites in Coenzyme Q Biosynthesis and Function./
作者:	Tsui, Hui Su.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	221 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Contained By:	Dissertations Abstracts International81-02B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13897555
ISBN:	9781085656061

The Roles of the CoQ10 Chaperone Protein, Cardiolipin, and Endoplasmic Reticulum-Mitochondria Contact Sites in Coenzyme Q Biosynthesis and Function.
Tsui, Hui Su.

The Roles of the CoQ10 Chaperone Protein, Cardiolipin, and Endoplasmic Reticulum-Mitochondria Contact Sites in Coenzyme Q Biosynthesis and Function. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 221 p.

Source: Dissertations Abstracts International, Volume: 81-02, Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2019.

This item is not available from ProQuest Dissertations & Theses.

Coenzyme Q (CoQ) is an essential lipid molecule for cellular bioenergetics, cellular antioxidant defense, and is a co-factor for enzymes participating in fatty acid β-oxidation and pyrimidine biosynthesis. The biosynthetic machinery of CoQ consists of a cohort of Coq polypeptides that are organized in a multi-subunit complex known as the CoQ synthome, residing on the mitochondrial inner membrane. Although CoQ is almost exclusively produced inside the mitochondria, it exists in most cellular membranes. The hydrophobicity of CoQ, especially CoQ isoforms with long polyisoprenyl tail prevents CoQ from being distributed to cellular membranes via diffusion. Thus, protein complexes localized at the membrane contact sites between two organelles, and lipid-binding chaperones play important roles redistributing CoQ and escorting CoQ from place where it is being synthesized to places where it functions. My research uses Saccharomyces cerevisiae (hereafter termed "yeast") as the model organism because many of the enzymes involved in the yeast CoQ biosynthesis are conserved in humans. Additionally, the ability of yeast cells to survive by fermentation allows genetic manipulation of genes that are essential for respiratory growth.Chapter 1 provides an overview of the biosynthesis of CoQ in both yeast and human cells, and highlights the functional conservation of many of the enzymes involved in the CoQ production. Chapter 2 focuses on the biochemical characterization of two human steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain proteins, COQ10A and COQ10B. These two human COQ10 paralogs are co-orthologous to yeast Coq10, which is essential for CoQ function and is required for efficient de novo CoQ biosynthesis. Expression of either one of the two human COQ10 paralogs restores CoQ function in yeast coq10 deletion mutant, but neither is able to restore de novo CoQ production. This result implies divergent functions of yeast Coq10 and its human COQ10 co-orthologs for CoQ production, and the existence of a second protein that needs to function concurrently with Coq10 for efficient CoQ biosynthesis in yeast. Chapter 3 explores CoQ biosynthesis in yeast mutants lacking the endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) complex at the ER and mitochondria membrane contact sites. In collaboration with Dr. Maya Schuldiner's lab, we found that the de novo production and distribution of CoQ in the ERMES deletion mutants are distorted due to the destabilization of the CoQ synthome in the absence of ERMES complex. Fluorescent microcopy data suggests close proximity of the CoQ synthome and the ERMES complex, implying a spatially coordinated regulation of CoQ biosynthesis and distribution by two closely apposed organelles. Chapter 4 examines the antioxidant property of CoQ. In collaboration with Dr. Anne Murphy's lab and Dr. Mikhail Shchepinov from Retrotope, Inc., We showed that the yeast CoQ-less mutants are exquisitely sensitive to polyunsaturated fatty acid (PUFA)-induced lipid peroxidation, and these CoQ-less mutants can be protected from oxidative damage by substituting the exogenously supplied PUFA with isotope-reinforced PUFA with its bis-allylic hydrogen replaced with deuterium atom. Chapter 5 studies CoQ biosynthesis and CoQ synthome assembly in yeast mutants that have defects in cardiolipin biosynthesis and remodeling. Cardiolipin (CL) is a unique phospholipid that is found exclusively within the mitochondrial membranes. In yeast, unmodified CL functions almost identically to remodeled CL, and the CL remodeling process is thought to remove and repair damaged CL. The yeast mutants with defects in CL biosynthesis and remodeling synthesize CoQ less efficiently, despite that the CoQ synthome assembly is only marginally affected. Last but not least, Chapter 6 describes efforts made towards characterizing the biological function of Coq10 with preliminary data collected with help from Kate Liu, Dr. Dyna Shirasaki, Dr. Frederik Lermyte, Dr. Brendan Amer, and Alice Hsu. Collectively, my work explores the biosynthesis and molecular functions of CoQ, and provides new insight into the regulation of CoQ production.

ISBN: 9781085656061Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

CoQ production

The Roles of the CoQ10 Chaperone Protein, Cardiolipin, and Endoplasmic Reticulum-Mitochondria Contact Sites in Coenzyme Q Biosynthesis and Function.
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500 $a Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
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520 $a Coenzyme Q (CoQ) is an essential lipid molecule for cellular bioenergetics, cellular antioxidant defense, and is a co-factor for enzymes participating in fatty acid β-oxidation and pyrimidine biosynthesis. The biosynthetic machinery of CoQ consists of a cohort of Coq polypeptides that are organized in a multi-subunit complex known as the CoQ synthome, residing on the mitochondrial inner membrane. Although CoQ is almost exclusively produced inside the mitochondria, it exists in most cellular membranes. The hydrophobicity of CoQ, especially CoQ isoforms with long polyisoprenyl tail prevents CoQ from being distributed to cellular membranes via diffusion. Thus, protein complexes localized at the membrane contact sites between two organelles, and lipid-binding chaperones play important roles redistributing CoQ and escorting CoQ from place where it is being synthesized to places where it functions. My research uses Saccharomyces cerevisiae (hereafter termed "yeast") as the model organism because many of the enzymes involved in the yeast CoQ biosynthesis are conserved in humans. Additionally, the ability of yeast cells to survive by fermentation allows genetic manipulation of genes that are essential for respiratory growth.Chapter 1 provides an overview of the biosynthesis of CoQ in both yeast and human cells, and highlights the functional conservation of many of the enzymes involved in the CoQ production. Chapter 2 focuses on the biochemical characterization of two human steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain proteins, COQ10A and COQ10B. These two human COQ10 paralogs are co-orthologous to yeast Coq10, which is essential for CoQ function and is required for efficient de novo CoQ biosynthesis. Expression of either one of the two human COQ10 paralogs restores CoQ function in yeast coq10 deletion mutant, but neither is able to restore de novo CoQ production. This result implies divergent functions of yeast Coq10 and its human COQ10 co-orthologs for CoQ production, and the existence of a second protein that needs to function concurrently with Coq10 for efficient CoQ biosynthesis in yeast. Chapter 3 explores CoQ biosynthesis in yeast mutants lacking the endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) complex at the ER and mitochondria membrane contact sites. In collaboration with Dr. Maya Schuldiner's lab, we found that the de novo production and distribution of CoQ in the ERMES deletion mutants are distorted due to the destabilization of the CoQ synthome in the absence of ERMES complex. Fluorescent microcopy data suggests close proximity of the CoQ synthome and the ERMES complex, implying a spatially coordinated regulation of CoQ biosynthesis and distribution by two closely apposed organelles. Chapter 4 examines the antioxidant property of CoQ. In collaboration with Dr. Anne Murphy's lab and Dr. Mikhail Shchepinov from Retrotope, Inc., We showed that the yeast CoQ-less mutants are exquisitely sensitive to polyunsaturated fatty acid (PUFA)-induced lipid peroxidation, and these CoQ-less mutants can be protected from oxidative damage by substituting the exogenously supplied PUFA with isotope-reinforced PUFA with its bis-allylic hydrogen replaced with deuterium atom. Chapter 5 studies CoQ biosynthesis and CoQ synthome assembly in yeast mutants that have defects in cardiolipin biosynthesis and remodeling. Cardiolipin (CL) is a unique phospholipid that is found exclusively within the mitochondrial membranes. In yeast, unmodified CL functions almost identically to remodeled CL, and the CL remodeling process is thought to remove and repair damaged CL. The yeast mutants with defects in CL biosynthesis and remodeling synthesize CoQ less efficiently, despite that the CoQ synthome assembly is only marginally affected. Last but not least, Chapter 6 describes efforts made towards characterizing the biological function of Coq10 with preliminary data collected with help from Kate Liu, Dr. Dyna Shirasaki, Dr. Frederik Lermyte, Dr. Brendan Amer, and Alice Hsu. Collectively, my work explores the biosynthesis and molecular functions of CoQ, and provides new insight into the regulation of CoQ production.
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