자료유형  

 학위논문

Control Number  

0017163904

International Standard Book Number  

9798384098720

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Marsh, Nicole M.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of Washington., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

125 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Sancak, Yasemin S.

Dissertation Note  

Thesis (Ph.D.)--University of Washington, 2024.

Summary, Etc.  

요약Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter coordinates metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial metabolic pathways has remained unexplored. Here, we investigate the metabolic consequences of uniporter loss- and gain-of-function and find that mitochondrial calcium signaling regulates the branched-chain amino acid (BCAA) catabolism pathway. Loss of uniporter function activates the pathway through two mechanisms: increased expression of pathway proteins and stimulation of the enzyme that catalyzes the committed step of the pathway by dephosphorylation. Conversely, in the liver cancer fibrolamellar carcinoma (FLC) - which we demonstrate to have increased mitochondrial calcium levels - expression of BCAA catabolism enzymes is suppressed. The transcription factor KLF15, a master regulator of liver metabolic gene expression, is also regulated by mitochondrial calcium signaling. KLF15 is downregulated in FLC patient tumors and cellular models. The KLF15 target gene ornithine transcarbamylase (OTC) is downregulated in FLC, which is thought to contribute to urea cycle defects and hyperammonemia observed in some FLC patients, suggesting a role for mitochondrial calcium in hyperammonemia. Inhibition of uniporter activity in FLC cellular models upregulates KLF15, BCAA catabolism genes, and OTC. Collectively, we identify an important role for mitochondrial calcium signaling in metabolic adaptation through transcriptional and post-translational regulation of metabolism and elucidate its importance for BCAA and ammonia regulation in FLC.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Pharmacology.

Index Term-Uncontrolled  

Calcium

Index Term-Uncontrolled  

Fibrolamellar carcinoma

Index Term-Uncontrolled  

Mitochondria

Index Term-Uncontrolled  

Ammonia regulation

Index Term-Uncontrolled  

Hyperammonemia

Added Entry-Corporate Name  

University of Washington Pharmacology

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

로그인을 한후 보실 수 있는 자료입니다.

Control Number  

joongbu:654648