RT Journal Article
SR Electronic
T1 Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.08.17.252007
DO 10.1101/2020.08.17.252007
A1 Mariya Misheva
A1 Konstantinos Kotzamanis
A1 Luke C Davies
A1 Victoria J Tyrrell
A1 Patricia R S Rodrigues
A1 Gloria A Benavides
A1 Christine Hinz
A1 Robert C Murphy
A1 Paul Kennedy
A1 Philip R Taylor
A1 Marcela Rosas
A1 Simon A Jones
A1 Sumukh Deshpande
A1 Robert Andrews
A1 Magdalena A Czubala
A1 Mark Gurney
A1 Maceler Aldrovandi
A1 Sven W Meckelmann
A1 Peter Ghazal
A1 Victor Darley-Usmar
A1 Daniel White
A1 Valerie B O’Donnell
YR 2020
UL http://biorxiv.org/content/early/2020/11/03/2020.08.17.252007.abstract
AB Oxylipins are potent mediators requiring strict control. How they are removed en masse during infection/inflammation is unknown. Herein, lipopolysaccharide (LPS) dynamically increased their mitochondrial β-oxidation, impacting leukocyte bioactivity. Genetic/pharmacological targeting of CPT1 showed <50 oxylipins were robustly removed by macrophage mitochondria during inflammation in vitros and in vivo. Stable isotope-lipidomics demonstrated secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Oxylipin β-oxidation was uncoupled from oxidative phosphorylation. Transcriptional interrogation of human neonatal sepsis revealed significant upregulation of many candidates, encoding proteins for mitochondrial uptake and β-oxidation of long-chain fatty acyls (ACSL1,3,4, ACADVL, CPT1B, CPT2, HADHB). ACSL1/Acsl1 upregulation was a signature in multiple human/murine macrophage datasets. In summary, mitochondrial β-oxidation is a regulatory metabolic checkpoint for oxylipins during infection. This has implications for patients with CPT1 deficiency, at higher risk of mortality during respiratory infections. We propose that mitochondrial β-oxidation capacity to remove oxylipins during infection may directly influence development of inflammation.Competing Interest StatementThe authors have declared no competing interest.