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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis

Author

Listed:
  • 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
    The University of Texas MD Anderson Cancer Center)

  • Sanjana Srinivasan

    (The University of Texas MD Anderson Cancer Center
    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
    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
    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
    University of Michigan Rogel Cancer Center, University of Michigan
    University of Michigan)

  • Joseph R. Marszalek

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Giulio F. Draetta

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Haoqiang Ying

    (The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • 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 Wa, 2023. "Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37924-9
    DOI: 10.1038/s41467-023-37924-9
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    References listed on IDEAS

    as
    1. Evan C. Lien & Anna M. Westermark & Yin Zhang & Chen Yuan & Zhaoqi Li & Allison N. Lau & Kiera M. Sapp & Brian M. Wolpin & Matthew G. Vander Heiden, 2021. "Low glycaemic diets alter lipid metabolism to influence tumour growth," Nature, Nature, vol. 599(7884), pages 302-307, November.
    2. Andrea Viale & Piergiorgio Pettazzoni & Costas A. Lyssiotis & Haoqiang Ying & Nora Sánchez & Matteo Marchesini & Alessandro Carugo & Tessa Green & Sahil Seth & Virginia Giuliani & Maria Kost-Alimova &, 2014. "Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function," Nature, Nature, vol. 514(7524), pages 628-632, October.
    3. Yilong Zou & Whitney S. Henry & Emily L. Ricq & Emily T. Graham & Vaishnavi V. Phadnis & Pema Maretich & Sateja Paradkar & Natalie Boehnke & Amy A. Deik & Ferenc Reinhardt & John K. Eaton & Bryan Ferg, 2020. "Plasticity of ether lipids promotes ferroptosis susceptibility and evasion," Nature, Nature, vol. 585(7826), pages 603-608, September.
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