Dihydroxy-Metabolites of Dihomo-γ-linolenic Acid Drive Ferroptosis-Mediated Neurodegeneration.
Journal
ACS central science
ISSN: 2374-7943
Titre abrégé: ACS Cent Sci
Pays: United States
ID NLM: 101660035
Informations de publication
Date de publication:
24 May 2023
24 May 2023
Historique:
received:
10
01
2023
medline:
30
5
2023
pubmed:
30
5
2023
entrez:
30
5
2023
Statut:
epublish
Résumé
Even after decades of research, the mechanism of neurodegeneration remains understudied, hindering the discovery of effective treatments for neurodegenerative diseases. Recent reports suggest that ferroptosis could be a novel therapeutic target for neurodegenerative diseases. While polyunsaturated fatty acid (PUFA) plays an important role in neurodegeneration and ferroptosis, how PUFAs may trigger these processes remains largely unknown. PUFA metabolites from cytochrome P450 and epoxide hydrolase metabolic pathways may modulate neurodegeneration. Here, we test the hypothesis that specific PUFAs regulate neurodegeneration through the action of their downstream metabolites by affecting ferroptosis. We find that the PUFA dihomo-γ-linolenic acid (DGLA) specifically induces ferroptosis-mediated neurodegeneration in dopaminergic neurons. Using synthetic chemical probes, targeted metabolomics, and genetic mutants, we show that DGLA triggers neurodegeneration upon conversion to dihydroxyeicosadienoic acid through the action of CYP-EH (CYP, cytochrome P450; EH, epoxide hydrolase), representing a new class of lipid metabolites that induce neurodegeneration via ferroptosis.
Identifiants
pubmed: 37252355
doi: 10.1021/acscentsci.3c00052
pmc: PMC10214511
doi:
Types de publication
Journal Article
Langues
eng
Pagination
870-882Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM142521
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare no competing financial interest.
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