BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F24%3A00585072" target="_blank" >RIV/67985823:_____/24:00585072 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/24:10478958 RIV/00216208:11120/24:43926897 RIV/60461373:22330/24:43929558 RIV/00064173:_____/24:43926897

Result on the web

<a href="https://doi.org/10.1186/s40170-024-00335-5" target="_blank" >https://doi.org/10.1186/s40170-024-00335-5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s40170-024-00335-5" target="_blank" >10.1186/s40170-024-00335-5</a>

Result language

angličtina

Original language name

BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/NV19-01-00101" target="_blank" >NV19-01-00101: Pancreatic cancer: metabolic derangements assiocated with insulin resistance</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Cancer & Metabolism

ISSN

2049-3002

e-ISSN

2049-3002

Volume of the periodical

12

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

18

Pages from-to

10

UT code for WoS article

001191291100001

EID of the result in the Scopus database

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