학술논문
Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.
Document Type
Academic Journal
Author
Marsh NM; Department of Pharmacology, University of Washington, Seattle, WA, United States.; MacEwen MJS; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Chea J; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Kenerson HL; Department of Surgery, University of Washington Medical Center, Seattle, WA, United States.; Kwong AA; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Locke TM; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Miralles FJ; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Sapre T; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Gozali N; Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY, United States.; Atilla-Gokcumen GE; Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY, United States.; Ong SE; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Scott JD; Department of Pharmacology, University of Washington, Seattle, WA, United States.; Yeung RS; Department of Surgery, University of Washington Medical Center, Seattle, WA, United States.; Sancak Y; Department of Pharmacology, University of Washington, Seattle, WA, United States.
Source
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Metabolic 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 identify a key transcriptional regulator that mediates these effects. Using gene expression profiling and proteomic, we find that loss of uniporter function increases the expression of proteins in the branched-chain amino acid (BCAA) catabolism pathway. Activity is further augmented through phosphorylation of the enzyme that catalyzes this pathway's committed step. Conversely, in the liver cancer fibrolamellar carcinoma (FLC)-which we demonstrate to have high mitochondrial calcium levels- expression of BCAA catabolism enzymes is suppressed. We also observe uniporter-dependent suppression of the transcription factor KLF15, a master regulator of liver metabolic gene expression, including those involved in BCAA catabolism. Notably, loss of uniporter activity upregulates KLF15, along with its transcriptional target ornithine transcarbamylase (OTC), a component of the urea cycle, suggesting that uniporter hyperactivation may contribute to the hyperammonemia observed in FLC patients. Collectively, we establish that FLC has increased mitochondrial calcium levels, and identify an important role for mitochondrial calcium signaling in metabolic adaptation through the transcriptional regulation of metabolism.
Competing Interests: CONFLICT OF INTEREST STATEMENT The authors have no conflicts of interest to disclose.
Competing Interests: CONFLICT OF INTEREST STATEMENT The authors have no conflicts of interest to disclose.