Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis

Ziheng Chen (), I-Lin Ho, Melinda Soeung, Er-Yen Yen, Jintan Liu, Liang Yan, Johnathon L. Rose, Sanjana Srinivasan, Shan Jiang, Q. Edward Chang, Ningping Feng, Jason P. Gay, Qi Wang, Jing Wang, Philip L. Lorenzi, Lucas J. Veillon, Bo Wei, John N. Weinstein, Angela K. Deem, Sisi Gao, Giannicola Genovese, Andrea Viale, Wantong Yao, Costas A. Lyssiotis, Joseph R. Marszalek, Giulio F. Draetta () and Haoqiang Ying ()
Additional contact information
Ziheng Chen: The University of Texas MD Anderson Cancer Center
I-Lin Ho: The University of Texas MD Anderson Cancer Center
Melinda Soeung: The University of Texas MD Anderson Cancer Center
Er-Yen Yen: The University of Texas MD Anderson Cancer Center
Jintan Liu: The University of Texas MD Anderson Cancer Center
Liang Yan: The University of Texas MD Anderson Cancer Center
Johnathon L. Rose: The University of Texas MD Anderson Cancer Center
Sanjana Srinivasan: The University of Texas MD Anderson Cancer Center
Shan Jiang: The University of Texas MD Anderson Cancer Center
Q. Edward Chang: The University of Texas MD Anderson Cancer Center
Ningping Feng: The University of Texas MD Anderson Cancer Center
Jason P. Gay: The University of Texas MD Anderson Cancer Center
Qi Wang: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Philip L. Lorenzi: The University of Texas MD Anderson Cancer Center
Lucas J. Veillon: The University of Texas MD Anderson Cancer Center
Bo Wei: The University of Texas MD Anderson Cancer Center
John N. Weinstein: The University of Texas MD Anderson Cancer Center
Angela K. Deem: The University of Texas MD Anderson Cancer Center
Sisi Gao: The University of Texas MD Anderson Cancer Center
Giannicola Genovese: The University of Texas MD Anderson Cancer Center
Andrea Viale: The University of Texas MD Anderson Cancer Center
Wantong Yao: The University of Texas MD Anderson Cancer Center, University of Texas
Costas A. Lyssiotis: University of Michigan
Joseph R. Marszalek: The University of Texas MD Anderson Cancer Center
Giulio F. Draetta: The University of Texas MD Anderson Cancer Center
Haoqiang Ying: The University of Texas MD Anderson Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37924-9

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