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RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis

Nature Cell Biology volume 20, pages 186–197 (2018)Cite this article

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Abstract

Receptor-interacting protein kinase 3 (RIP3)-regulated production of reactive oxygen species (ROS) positively feeds back on tumour necrosis factor (TNF)-induced necroptosis, a type of programmed necrosis. Glutamine catabolism is known to contribute to RIP3-mediated ROS induction, but the major contributor is unknown. Here, we show that RIP3 activates the pyruvate dehydrogenase complex (PDC, also known as PDH), the rate-limiting enzyme linking glycolysis to aerobic respiration, by directly phosphorylating the PDC E3 subunit (PDC-E3) on T135. Upon activation, PDC enhances aerobic respiration and subsequent mitochondrial ROS production. Unexpectedly, mixed-lineage kinase domain-like (MLKL) is also required for the induction of aerobic respiration, and we further show that it is required for RIP3 translocation to meet mitochondria-localized PDC. Our data uncover a regulation mechanism of PDC activity, show that PDC activation by RIP3 is most likely the major mechanism activated by TNF to increase aerobic respiration and its by-product ROS, and suggest that RIP3-dependent induction of aerobic respiration contributes to pathologies related to oxidative stress.

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Fig. 1: TNF induces an increase in aerobic respiration in a RIP3-dependent manner.
Fig. 2: Induction of OCR is not due to the side effect of zVAD.
Fig. 3: TNF-induced increase in aerobic respiration is responsible for ROS induction in necroptosis.
Fig. 4: PDC is positively involved in TNF-induced necroptosis.
Fig. 5: RIP3 targets PDC to upregulate aerobic respiration.
Fig. 6: RIP3 activates PDC by phosphorylating PDC-E3 on T135.
Fig. 7: MLKL is required for PDC activation.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (91429301), the National Basic Research Program of China (973 Program; 2015CB553800 and 2014CB541804), the National Natural Science Foundation of China (31420103910, 31330047 and 81788104), the 111 Project (B12001), the National Science Foundation of China for Fostering Talents in Basic Research (J1310027) and the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University.

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  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Zhentao Yang, Yan Wang, Yingying Zhang, Chuan-Qi Zhong, Hengxiao Ni, Xin Chen, Yaoji Liang, Jianfeng Wu, Dawang Zhou & Jiahuai Han

  2. State Key Laboratory of Genetic Engineering, School of Life Science and Institute of Biomedical Sciences, The Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China

    Xiadi He & Shimin Zhao

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Contributions

Z.Y. and J.H. conceived and designed the experiments. Z.Y., Y.W., Y.Z. and X.C. performed the experiments. X.H. and C.-Q.Z. performed the GC-MS and MS experiments and analysed the obtained results. H.N., Y.L. and J.W. helped to prepare cell lines for the study. S.Z. and D.Z. provided technical support. Z.Y. and J.H. interpreted the data and wrote the paper.

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Correspondence to Jiahuai Han.

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Yang, Z., Wang, Y., Zhang, Y. et al. RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis. Nat Cell Biol 20, 186–197 (2018). https://doi.org/10.1038/s41556-017-0022-y

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