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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 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria Author(s) 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, SAIArticle number 10 Source Title Cancer & Metabolism
Roč. 12, č. 1 (2024)Number of pages 18 s. Language eng - English Country GB - United Kingdom Keywords BCAA metabolism ; pancreatic cancer ; mitochondria ; triglycerides ; lipid droplets ; fatty acid/transport ; fluorescence microscopy ; lipidomics OECD category Biochemistry and molecular biology R&D Projects NV19-01-00101 GA MZd - Ministry of Health (MZ) Method of publishing Open access Institutional support FGU-C - RVO:67985823 UT WOS 001191291100001 DOI 10.1186/s40170-024-00335-5 Annotation 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. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2025 Electronic address https://doi.org/10.1186/s40170-024-00335-5
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