Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 04 2023
17 04 2023
Historique:
received:
11
03
2022
accepted:
04
04
2023
medline:
19
4
2023
entrez:
17
4
2023
pubmed:
18
4
2023
Statut:
epublish
Résumé
Mitochondria are hubs where bioenergetics, redox homeostasis, and anabolic metabolism pathways integrate through a tightly coordinated flux of metabolites. The contributions of mitochondrial metabolism to tumor growth and therapy resistance are evident, but drugs targeting mitochondrial metabolism have repeatedly failed in the clinic. Our study in pancreatic ductal adenocarcinoma (PDAC) finds that cellular and mitochondrial lipid composition influence cancer cell sensitivity to pharmacological inhibition of electron transport chain complex I. Profiling of patient-derived PDAC models revealed that monounsaturated fatty acids (MUFAs) and MUFA-linked ether phospholipids play a critical role in maintaining ROS homeostasis. We show that ether phospholipids support mitochondrial supercomplex assembly and ROS production; accordingly, blocking de novo ether phospholipid biosynthesis sensitized PDAC cells to complex I inhibition by inducing mitochondrial ROS and lipid peroxidation. These data identify ether phospholipids as a regulator of mitochondrial redox control that contributes to the sensitivity of PDAC cells to complex I inhibition.
Identifiants
pubmed: 37069167
doi: 10.1038/s41467-023-37924-9
pii: 10.1038/s41467-023-37924-9
pmc: PMC10110566
doi:
Substances chimiques
Reactive Oxygen Species
0
Phospholipid Ethers
0
Phospholipids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2194Subventions
Organisme : NCI NIH HHS
ID : P50CA221707
Pays : United States
Organisme : NCI NIH HHS
ID : P01CA117969
Pays : United States
Organisme : NCI NIH HHS
ID : R01CA248160
Pays : United States
Organisme : NIH HHS
ID : S10OD012304-01
Pays : United States
Organisme : NIH HHS
ID : P01CA117969
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA214793
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258917
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244931
Pays : United States
Informations de copyright
© 2023. The Author(s).
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