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Elucidating Mechanism of Peroxisomal...

Yamashita, Akihiro.

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Elucidating Mechanism of Peroxisomal Homeostasis in Mammalian Cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Elucidating Mechanism of Peroxisomal Homeostasis in Mammalian Cells./
作者:	Yamashita, Akihiro.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2023,
面頁冊數:	122 p.
附註:	Source: Dissertations Abstracts International, Volume: 85-11, Section: B.
Contained By:	Dissertations Abstracts International85-11B.
標題:	Yeast. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31079089
ISBN:	9798382617053

Elucidating Mechanism of Peroxisomal Homeostasis in Mammalian Cells.
Yamashita, Akihiro.

Elucidating Mechanism of Peroxisomal Homeostasis in Mammalian Cells. - Ann Arbor : ProQuest Dissertations & Theses, 2023 - 122 p.

Source: Dissertations Abstracts International, Volume: 85-11, Section: B.

Thesis (Ph.D.)--McGill University (Canada), 2023.

A cell is a highly ordered and compartmentalized place with intracellular organelles, including mitochondria and peroxisomes, that carry proteins, lipids and signals throughout the cell. The importance of mitochondrial and peroxisomal homeostasis to normal human development and physiology is highlighted in rare or common disorders where mitochondria and/or peroxisomes are impaired. They share a number of proteins in common, and there are vesicle-based deliveries of proteins from mitochondria to peroxisomes both in a steady state and for the formation of newborn peroxisomes. Peroxisomes play a central role in metabolism and signalling, pathways which are often highly tuned to the biochemical needs of each specific tissue type. However, the mechanisms by which the status of peroxisomes is communicated between other organelles and integrated into cellular signalling pathways are not yet understood.Herein, I report the cellular responses to acute peroxisomal proteotoxic stress upon loss of the peroxisomal protease/chaperone LONP2. Knockdown of LONP2 triggered the accumulation of its substrates, alterations in peroxisome size and numbers, and luminal protein import failure. Gene expression changes and lipidomic analysis revealed striking cell-type specific differences in response to the depletion of LONP2. In COS-7 cells, there was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels, which were absent in U2OS cells. Common changes were also observed, including repression of the retinoic acid signalling pathway, and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These results provide insights into some unexpected consequences of peroxisomal stress that may have important implications for our understanding of the tissue-specific responses seen in multiple peroxisomal disorders.

ISBN: 9798382617053Subjects--Topical Terms:

621059
Yeast.

Elucidating Mechanism of Peroxisomal Homeostasis in Mammalian Cells.
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520 $a A cell is a highly ordered and compartmentalized place with intracellular organelles, including mitochondria and peroxisomes, that carry proteins, lipids and signals throughout the cell. The importance of mitochondrial and peroxisomal homeostasis to normal human development and physiology is highlighted in rare or common disorders where mitochondria and/or peroxisomes are impaired. They share a number of proteins in common, and there are vesicle-based deliveries of proteins from mitochondria to peroxisomes both in a steady state and for the formation of newborn peroxisomes. Peroxisomes play a central role in metabolism and signalling, pathways which are often highly tuned to the biochemical needs of each specific tissue type. However, the mechanisms by which the status of peroxisomes is communicated between other organelles and integrated into cellular signalling pathways are not yet understood.Herein, I report the cellular responses to acute peroxisomal proteotoxic stress upon loss of the peroxisomal protease/chaperone LONP2. Knockdown of LONP2 triggered the accumulation of its substrates, alterations in peroxisome size and numbers, and luminal protein import failure. Gene expression changes and lipidomic analysis revealed striking cell-type specific differences in response to the depletion of LONP2. In COS-7 cells, there was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels, which were absent in U2OS cells. Common changes were also observed, including repression of the retinoic acid signalling pathway, and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These results provide insights into some unexpected consequences of peroxisomal stress that may have important implications for our understanding of the tissue-specific responses seen in multiple peroxisomal disorders.
520 $a Une cellule est une structure hautement organisee et compartimentee avec des organites intracellulaires, comprenant les mitochondries et les peroxysomes, qui transportent proteines, lipides et signaux dans toute la cellule. L'importance de l'homeostasie mitochondriale et peroxysomale pour le developpement humain normal et la physiologie est mise en evidence dans les troubles rares ou courants ou les mitochondries et/ou les peroxysomes sont alteres. Ces organites partagent un certain nombre de proteines en commun, et il existe des transports vesiculaires de proteines des mitochondries aux peroxysomes a la fois a l'etat basal et pour la formation de nouveaux peroxysomes. Les peroxysomes jouent un role central dans le metabolisme et la signalisation, des voies qui sont souvent tres adaptees aux besoins biochimiques de chaque type de tissu. Cependant, les mecanismes par lesquels le statut des peroxysomes est communique entre organites et integre dans les voies de signalisation cellulaire ne sont pas encore compris.Ici, je rapporte les reponses cellulaires au stress proteotoxique peroxysomal aigu lors de la perte de la protease/chaperone peroxysomale LONP2. L'absencede LONP2 a declenche l'accumulation de ses substrats, des alterations de la taille et du nombre de peroxysomes et une defaillance de l'import des proteines luminales. Les changements d'expression genique et l'analyse lipidomique ont revele des differences frappantes specifiques au type de cellule en reponse a l'absence de LONP2. Dans les cellules COS-7, il y avait une forte activation de la reponse au stress integree et une regulation a la hausse des niveaux d'expression des genes de la biogenese ribosomique, qui etaient absents dans les cellules U2OS. Des changements communs aux deux types cellulaires ont egalement ete observes, notamment la repression de la voie de signalisation de l'acide retinoique et l'augmentation de la quantite des sphingolipides. Le cholesterol s'est aussi accumule dans les compartiments endomembranaires des deux lignees cellulaires, ce qui concorde avec le conceptque les peroxysomes sont necessaires au flux de cholesterol hors des endosomes tardifs. Ces resultats donnent un apercu de certaines consequences inattendues du stress peroxysomal qui peuvent avoir des implications importantes pour notre comprehension des reponses specifiques aux tissus observees dans de multiples troubles peroxysomaux.
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