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; Haoqiang Ying

doi:10.1038/s41467-023-37924-9

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 GaoGiannicola Genovese, Andrea Viale, Wantong Yao, Costas A. Lyssiotis, Joseph R. Marszalek, Giulio F. Draetta, Haoqiang Ying

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Article number	2194
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-37924-9
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Chen, Z., Ho, I. L., Soeung, M., Yen, E. Y., Liu, J., Yan, L., Rose, J. L., Srinivasan, S., Jiang, S., Edward Chang, Q., Feng, N., Gay, J. P., Wang, Q., Wang, J., Lorenzi, P. L., Veillon, L. J., Wei, B., Weinstein, J. N., Deem, A. K., ... Ying, H. (2023). Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis. Nature communications, 14(1), Article 2194. https://doi.org/10.1038/s41467-023-37924-9

Chen, Z , Ho, IL, Soeung, M, Yen, EY, Liu, J, Yan, L, Rose, JL , Srinivasan, S, Jiang, S, Edward Chang, Q , Feng, N, Gay, JP, Wang, Q, Wang, J, Lorenzi, PL, Veillon, LJ, Wei, B , Weinstein, JN, Deem, AK, Gao, S, Genovese, G , Viale, A , Yao, W, Lyssiotis, CA, Marszalek, JR, Draetta, GF & Ying, H 2023, 'Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis', Nature communications, vol. 14, no. 1, 2194. https://doi.org/10.1038/s41467-023-37924-9

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title = "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.",

author = "Ziheng Chen and Ho, {I. Lin} and Melinda Soeung and Yen, {Er Yen} and Jintan Liu and Liang Yan and Rose, {Johnathon L.} and Sanjana Srinivasan and Shan Jiang and {Edward Chang}, Q. and Ningping Feng and Gay, {Jason P.} and Qi Wang and Jing Wang and Lorenzi, {Philip L.} and Veillon, {Lucas J.} and Bo Wei and Weinstein, {John N.} and Deem, {Angela K.} and Sisi Gao and Giannicola Genovese and Andrea Viale and Wantong Yao and Lyssiotis, {Costas A.} and Marszalek, {Joseph R.} and Draetta, {Giulio F.} and Haoqiang Ying",

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year = "2023",

month = dec,

doi = "10.1038/s41467-023-37924-9",

language = "English (US)",

volume = "14",

journal = "Nature communications",

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T1 - Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis

AU - Chen, Ziheng

AU - Ho, I. Lin

AU - Soeung, Melinda

AU - Yen, Er Yen

AU - Liu, Jintan

AU - Yan, Liang

AU - Rose, Johnathon L.

AU - Srinivasan, Sanjana

AU - Jiang, Shan

AU - Edward Chang, Q.

AU - Feng, Ningping

AU - Gay, Jason P.

AU - Wang, Qi

AU - Wang, Jing

AU - Lorenzi, Philip L.

AU - Veillon, Lucas J.

AU - Wei, Bo

AU - Weinstein, John N.

AU - Deem, Angela K.

AU - Gao, Sisi

AU - Genovese, Giannicola

AU - Viale, Andrea

AU - Yao, Wantong

AU - Lyssiotis, Costas A.

AU - Marszalek, Joseph R.

AU - Draetta, Giulio F.

AU - Ying, Haoqiang

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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