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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

ABSTRACT: 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.

SUBMITTER: Chen Z

PROVIDER: S-EPMC10110566 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

Chen Ziheng Z Ho I-Lin IL Soeung Melinda M Yen Er-Yen EY Liu Jintan J Yan Liang L Rose Johnathon L JL Srinivasan Sanjana S Jiang Shan S Edward Chang Q Q Feng Ningping N Gay Jason P JP Wang Qi Q Wang Jing J Lorenzi Philip L PL Veillon Lucas J LJ Wei Bo B Weinstein John N JN Deem Angela K AK Gao Sisi S Genovese Giannicola G Viale Andrea A Yao Wantong W Lyssiotis Costas A CA Marszalek Joseph R JR Draetta Giulio F GF Ying Haoqiang H

Nature communications 20230417 1

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 i ...[more]

PMID: 37069167

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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis.

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