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Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation

Misheva, Mariya, Kotzamanis, Konstantinos, Davies, Luke C., Tyrrell, Victoria J., Rodrigues, Patricia R. S. ORCID:, Benavides, Gloria A., Hinz, Christine, Murphy, Robert C., Kennedy, Paul, Taylor, Philip R. ORCID:, Rosas, Marcela ORCID:, Jones, Simon A. ORCID:, McLaren, James E. ORCID:, Deshpande, Sumukh, Andrews, Robert, Schebb, Nils Helge, Czubala, Magdalena A. ORCID:, Gurney, Mark ORCID:, Aldrovandi, Maceler, Meckelmann, Sven W., Ghazal, Peter ORCID:, Darley-Usmar, Victor, White, Daniel A. and O'Donnell, Valerie B. ORCID: 2022. Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation. Nature Communications 13 (1) , 139. 10.1038/s41467-021-27766-8

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Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Research
ISSN: 2041-1723
Funders: Wellcome Trust
Date of First Compliant Deposit: 16 March 2022
Date of Acceptance: 12 December 2021
Last Modified: 05 Jan 2024 06:21

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