3 years ago

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

RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis
Yaoji Liang, Xin Chen, Dawang Zhou, Chuan-Qi Zhong, Shimin Zhao, Jiahuai Han, Zhentao Yang, Yan Wang, Xiadi He, Yingying Zhang, Jianfeng Wu, Hengxiao Ni
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.

Publisher URL: https://www.nature.com/articles/s41556-017-0022-y

DOI: 10.1038/s41556-017-0022-y

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