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

Mariya Misheva, Konstantinos Kotzamanis, Luke C. Davies, Victoria J. Tyrrell, Patricia R. S. Rodrigues, Gloria A. Benavides, Christine Hinz, Robert C. Murphy, Paul Kennedy, Philip R. Taylor, Marcela Rosas, Simon A. Jones, James E. McLaren, Sumukh Deshpande, Robert Andrews, Nils Helge Schebb, Magdalena A. Czubala, Mark Gurney, Maceler Aldrovandi, Sven W. Meckelmann, Peter Ghazal, Victor Darley-Usmar, Daniel A. White () and Valerie B. O’Donnell ()
Additional contact information
Mariya Misheva: Cardiff University
Konstantinos Kotzamanis: Cardiff University
Luke C. Davies: Cardiff University
Victoria J. Tyrrell: Cardiff University
Patricia R. S. Rodrigues: Cardiff University
Gloria A. Benavides: University of Alabama at Birmingham
Christine Hinz: Cardiff University
Robert C. Murphy: University of Colorado Denver
Paul Kennedy: Cayman Chemical
Philip R. Taylor: Cardiff University
Marcela Rosas: Cardiff University
Simon A. Jones: Cardiff University
James E. McLaren: Cardiff University
Sumukh Deshpande: Cardiff University
Robert Andrews: Cardiff University
Nils Helge Schebb: University of Wuppertal
Magdalena A. Czubala: Cardiff University
Mark Gurney: Cardiff University
Maceler Aldrovandi: Cardiff University
Sven W. Meckelmann: Cardiff University
Peter Ghazal: Cardiff University
Victor Darley-Usmar: University of Alabama at Birmingham
Daniel A. White: Cardiff University
Valerie B. O’Donnell: Cardiff University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27766-8

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DOI: 10.1038/s41467-021-27766-8

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