Dynamics of the mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis

Chen Wang, Cheng Ma, Yuanyou Xu, Shenghai Chang, Hangjun Wu, Chunlan Yan, Jinghua Chen, Yongping Wu, Shaoya An, Jiaqi Xu, Qin Han, Yujie Jiang, Zhinong Jiang, Xiakun Chu, Haichun Gao (), Xing Zhang () and Yunjie Chang ()
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Chen Wang: Zhejiang University School of Medicine
Cheng Ma: Zhejiang University School of Medicine
Yuanyou Xu: Zhejiang University
Shenghai Chang: Zhejiang University School of Medicine
Hangjun Wu: Zhejiang University School of Medicine
Chunlan Yan: Zhejiang University School of Medicine
Jinghua Chen: Zhejiang University
Yongping Wu: Zhejiang A&F University
Shaoya An: Zhejiang University School of Medicine
Jiaqi Xu: Zhejiang University School of Medicine
Qin Han: Zhejiang University School of Medicine
Yujie Jiang: Zhejiang University School of Medicine
Zhinong Jiang: Zhejiang University School of Medicine
Xiakun Chu: The Hong Kong University of Science and Technology (Guangzhou)
Haichun Gao: Zhejiang University
Xing Zhang: Zhejiang University School of Medicine
Yunjie Chang: Zhejiang University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The multi-enzyme pyruvate dehydrogenase complex (PDHc) links glycolysis to the citric acid cycle and plays vital roles in metabolism, energy production, and cellular signaling. Although all components have been individually characterized, the intact PDHc structure remains unclear, hampering our understanding of its composition and dynamical catalytic mechanisms. Here, we report the in-situ architecture of intact mammalian PDHc by cryo-electron tomography. The organization of peripheral E1 and E3 components varies substantially among the observed PDHcs, with an average of 21 E1 surrounding each PDHc core, and up to 12 E3 locating primarily along the pentagonal openings. In addition, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, and the interaction interfaces were further analyzed by molecular dynamics simulations. By revealing intrinsic dynamics of PDHc peripheral compositions, our findings indicate a distinctive activity regulation mechanism, through which the number of E1, E3 and functional LDs may be coordinated to meet constantly changing demands of metabolism.

Date: 2025
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DOI: 10.1038/s41467-025-56171-8

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