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BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria
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SYSNO ASEP 0585072 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria Tvůrce(i) Gotvaldová, Klára (FGU-C) RID, ORCID
Špačková, Jitka (FGU-C) RID, ORCID
Novotný, Jiří (FGU-C)
Baslarová, Kamila (FGU-C)
Ježek, Petr (FGU-C) RID, ORCID
Rossmeislová, L. (CZ)
Gojda, J. (CZ)
Smolková, Katarína (FGU-C) RID, ORCID, SAIČíslo článku 10 Zdroj.dok. Cancer & Metabolism
Roč. 12, č. 1 (2024)Poč.str. 18 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova BCAA metabolism ; pancreatic cancer ; mitochondria ; triglycerides ; lipid droplets ; fatty acid/transport ; fluorescence microscopy ; lipidomics Obor OECD Biochemistry and molecular biology CEP NV19-01-00101 GA MZd - Ministerstvo zdravotnictví Způsob publikování Open access Institucionální podpora FGU-C - RVO:67985823 UT WOS 001191291100001 DOI 10.1186/s40170-024-00335-5 Anotace Background Pancreatic ductal adenocarcinoma (PDAC) has been associated with the host dysmetabolism of branched-chain amino acids (BCAAs), however, the implications for the role of BCAA metabolism in PDAC development or progression are not clear. The mitochondrial catabolism of valine, leucine, and isoleucine is a multistep process leading to the production of short-chain R-CoA species. They can be subsequently exported from mitochondria as short-chain carnitines (SC-CARs), utilized in anabolic pathways, or released from the cells.Methods We examined the specificities of BCAA catabolism and cellular adaptation strategies to BCAA starvation in PDAC cells in vitro. We used metabolomics and lipidomics to quantify major metabolic changes in response to BCAA withdrawal. Using confocal microscopy and flow cytometry we quantified the fluorescence of BODIPY probe and the level of lipid droplets (LDs). We used BODIPY-conjugated palmitate to evaluate transport of fatty acids (FAs) into mitochondria. Also, we have developed a protocol for quantification of SC-CARs, BCAA-derived metabolites.Results Using metabolic profiling, we found that BCAA starvation leads to massive triglyceride (TG) synthesis and LD accumulation. This was associated with the suppression of activated FA transport into the mitochondrial matrix. The suppression of FA import into mitochondria was rescued with the inhibitor of the acetyl-CoA carboxylase (ACC) and the activator of AMP kinase (AMPK), which both regulate carnitine palmitoyltransferase 1A (CPT1) activation status.Conclusions Our data suggest that BCAA catabolism is required for the import of long chain carnitines (LC-CARs) into mitochondria, whereas the disruption of this link results in the redirection of activated FAs into TG synthesis and its deposition into LDs. We propose that this mechanism protects cells against mitochondrial overload with LC-CARs and it might be part of the universal reaction to amino acid perturbations during cancer growth, regulating FA handling and storage. Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2025 Elektronická adresa https://doi.org/10.1186/s40170-024-00335-5
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