Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma

Overview

Journal bioRxiv

Date 2024 Jun 10

PMID 38853984

Authors

Nicole M Marsh

Melissa J S MacEwen

Jane Chea

Heidi L Kenerson

Albert A Kwong

Timothy M Locke

Francisco Javier Miralles

Tanmay Sapre

Natasha Gozali

Madeleine L Hart

Theo K Bammler

James W MacDonald

Lucas B Sullivan

G Ekin Atilla-Gokcumen

Shao-En Ong

John D Scott

Raymond S Yeung

Yasemin Sancak

Affiliations

Soon will be listed here.

Abstract

Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation, and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate metabolic consequences of uniporter loss- and gain-of-function using uniporter knockout cells and the liver cancer fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. Our results reveal that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated metabolic pathways. Reduced uniporter function boosts expression of BCAA catabolism genes, and the urea cycle enzyme ornithine transcarbamylase (OTC). In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by reduced expression of the transcription factor KLF15, a master regulator of liver metabolism. Thus, uniporter responsive calcium signaling plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for mitochondrial calcium signaling in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism in FLC.

References

Levin S, Tomasini M, Knox J, Shirani M, Shebl B, Requena D . Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma. Sci Adv. 2023; 9(25):eadg7038. PMC: 10284549. DOI: 10.1126/sciadv.adg7038. View

Bauer T, Murphy E . Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death. Circ Res. 2020; 126(2):280-293. PMC: 8317591. DOI: 10.1161/CIRCRESAHA.119.316306. View

Fernandez Garcia E, Paudel U, Noji M, Bowman C, Rustgi A, Pitarresi J . The mitochondrial Ca channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation. Front Cell Dev Biol. 2023; 11:1082213. PMC: 10285664. DOI: 10.3389/fcell.2023.1082213. View

Auron A, Brophy P . Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2011; 27(2):207-22. DOI: 10.1007/s00467-011-1838-5. View

Jeyaraj D, Scheer F, Ripperger J, Haldar S, Lu Y, Prosdocimo D . Klf15 orchestrates circadian nitrogen homeostasis. Cell Metab. 2012; 15(3):311-23. PMC: 3299986. DOI: 10.1016/j.cmet.2012.01.020. View

Li C, Lin H, Ko C, Lai J, Chu P . A Novel Biomarker Driving Poor-Prognosis Liver Cancer: Overexpression of the Mitochondrial Calcium Gatekeepers. Biomedicines. 2020; 8(11). PMC: 7693594. DOI: 10.3390/biomedicines8110451. View

MacEwen M, Markhard A, Bozbeyoglu M, Bradford F, Goldberger O, Mootha V . Evolutionary divergence reveals the molecular basis of EMRE dependence of the human MCU. Life Sci Alliance. 2020; 3(10). PMC: 7425227. DOI: 10.26508/lsa.202000718. View

Kong A, Leprevost F, Avtonomov D, Mellacheruvu D, Nesvizhskii A . MSFragger: ultrafast and comprehensive peptide identification in mass spectrometry-based proteomics. Nat Methods. 2017; 14(5):513-520. PMC: 5409104. DOI: 10.1038/nmeth.4256. View

Mao L, Liu L, Zhang T, Qin H, Wu X, Xu Y . Histone Deacetylase 11 Contributes to Renal Fibrosis by Repressing KLF15 Transcription. Front Cell Dev Biol. 2020; 8:235. PMC: 7180197. DOI: 10.3389/fcell.2020.00235. View

10.

Grankvist N, Jonsson C, Hedin K, Sundqvist N, Sandstrom P, Bjornsson B . Global C tracing and metabolic flux analysis of intact human liver tissue ex vivo. Nat Metab. 2024; 6(10):1963-1975. PMC: 11496108. DOI: 10.1038/s42255-024-01119-3. View

11.

Huang B, Gudi R, Wu P, Harris R, Hamilton J, Popov K . Isoenzymes of pyruvate dehydrogenase phosphatase. DNA-derived amino acid sequences, expression, and regulation. J Biol Chem. 1998; 273(28):17680-8. DOI: 10.1074/jbc.273.28.17680. View

12.

Arruda A, Pers B, Parlakgul G, Guney E, Inouye K, Hotamisligil G . Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med. 2014; 20(12):1427-35. PMC: 4412031. DOI: 10.1038/nm.3735. View

13.

Tian Y, Wang Z, Zheng X, Song W, Cai L, Rane M . KLF15 negatively regulates cardiac fibrosis by which SDF-1β attenuates cardiac fibrosis in type 2 diabetic mice. Toxicol Appl Pharmacol. 2021; 427:115654. DOI: 10.1016/j.taap.2021.115654. View

14.

Shao D, Villet O, Zhang Z, Choi S, Yan J, Ritterhoff J . Glucose promotes cell growth by suppressing branched-chain amino acid degradation. Nat Commun. 2018; 9(1):2935. PMC: 6062555. DOI: 10.1038/s41467-018-05362-7. View

15.

Toyota A, Goto M, Miyamoto M, Nagashima Y, Iwasaki S, Komatsu T . Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model. Biochem Biophys Res Commun. 2022; 621:157-161. DOI: 10.1016/j.bbrc.2022.07.008. View

16.

De Chiara F, Thomsen K, Habtesion A, Jones H, Davies N, Gracia-Sancho J . Ammonia Scavenging Prevents Progression of Fibrosis in Experimental Nonalcoholic Fatty Liver Disease. Hepatology. 2019; 71(3):874-892. DOI: 10.1002/hep.30890. View

17.

McGarrah R, White P . Branched-chain amino acids in cardiovascular disease. Nat Rev Cardiol. 2022; 20(2):77-89. PMC: 10284296. DOI: 10.1038/s41569-022-00760-3. View

18.

Kanyomse Q, Le X, Tang J, Dai F, Mobet Y, Chen C . KLF15 suppresses tumor growth and metastasis in Triple-Negative Breast Cancer by downregulating CCL2 and CCL7. Sci Rep. 2022; 12(1):19026. PMC: 9643362. DOI: 10.1038/s41598-022-23750-4. View

19.

Wang B, Haldar S, Lu Y, Ibrahim O, Fisch S, Gray S . The Kruppel-like factor KLF15 inhibits connective tissue growth factor (CTGF) expression in cardiac fibroblasts. J Mol Cell Cardiol. 2008; 45(2):193-7. PMC: 2566509. DOI: 10.1016/j.yjmcc.2008.05.005. View

20.

Tomar D, Elrod J . Metabolite regulation of the mitochondrial calcium uniporter channel. Cell Calcium. 2020; 92:102288. PMC: 8017895. DOI: 10.1016/j.ceca.2020.102288. View