자료유형  

 학위논문

Control Number  

0016931683

International Standard Book Number  

9798379971533

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Perea, Valerie.

Publication, Distribution, etc. (Imprint  

[S.l.] : The Scripps Research Institute., 2023

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2023

Physical Description  

1 online resource(182 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-02, Section: B.

General Note  

Advisor: Wiseman, R. Luke.

Dissertation Note  

Thesis (Ph.D.)--The Scripps Research Institute, 2023.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Mitochondria are dynamic organelles that undergo rounds of fission and fusion in response to varying metabolic demands in the cell. Imbalances in mitochondrial dynamics are associated with the pathogenesis of numerous diseases. Therefore, mitochondria must be intricately regulated in order to maintain cellular homeostasis. Dysfunction the endoplasmic reticulum (ER), has also been implicated in many of the same diseases as mitochondrial dysfunction which suggests that crosstalk between both organelles may be involved in disease pathogenesis. Consistent with this, contact sites between the mitochondria and ER facilitate the exchange of metabolites such as calcium and phospholipids. However, this close coordinated contact also sensitizes mitochondria to any imbalances in ER function termed ER stress. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria during ER stress. The PERK arm of the unfolded protein response (UPR) regulates diverse aspects of mitochondrial biology during ER stress. Here, we show that PERK activity promotes adaptive remodeling of mitochondrial membrane phosphatidic acid (PA) to induce protective mitochondrial elongation during ER stress. Both PERK-dependent increases of PA and YME1L-dependent degradation of the intramitochondrial PA transporter PRELID1 lead to the accumulation of PA on the OMM where it induces mitochondrial elongation by inhibiting mitochondrial fission. We also demonstrate that PERK regulation of phospholipids extends to the YME1L-dependent degradation of the intramitochondrial phosphatidylserine (PS) transporter SLMO2 which impacts downstream phosphatidylethanolamine (PE) levels during acute stresses. These results establish a new role for PERK in the adaptive remodeling of mitochondrial phospholipids and demonstrate that PERK-dependent PA regulation adapts organellar shape in response to ER stress.Deficiencies in PERK signaling lead to mitochondrial dysfunction associated with various diseases. Here, we define the potential for pharmacologic activation of the integrated stress response (ISR) in rescuing impaired PERK signaling. The ISR is a network of eIF2α kinases, comprising of PERK, GCN2, HRI, and PKR, that induce translational and transcriptional signaling in response to diverse pathologic insults. We demonstrate that the strategy of enhancing compensatory arms of the ISR in PERK deficient cells through pharmacologic activation of other ISR kinases rescues ISR signaling and promotes mitochondrial adaptation.

Subject Added Entry-Topical Term  

Biochemistry.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Molecular biology.

Index Term-Uncontrolled  

Endoplasmic reticulum stress

Index Term-Uncontrolled  

Integrated stress response

Index Term-Uncontrolled  

Mitochondria

Index Term-Uncontrolled  

Mitochondrial morphology

Index Term-Uncontrolled  

Unfolded protein response

Added Entry-Corporate Name  

The Scripps Research Institute Biochemistry

Host Item Entry  

Dissertations Abstracts International. 85-02B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:642848