Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex
Abstract The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we p...
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| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61939-z |
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| author | Yingyuan Sun Yaru Wang Zheng Xing Dongyu Li Rong Wang Baozhi Chen Ning Zhou Alyssa Ayala Benjamin P. Tu Xiaofeng Qi |
| author_facet | Yingyuan Sun Yaru Wang Zheng Xing Dongyu Li Rong Wang Baozhi Chen Ning Zhou Alyssa Ayala Benjamin P. Tu Xiaofeng Qi |
| author_sort | Yingyuan Sun |
| collection | DOAJ |
| description | Abstract The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors. |
| format | Article |
| id | doaj-art-c10cad126dc54c149fc8cfbb01e201ea |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c10cad126dc54c149fc8cfbb01e201ea2025-08-20T04:02:55ZengNature PortfolioNature Communications2041-17232025-07-0116111010.1038/s41467-025-61939-zStructure of human mitochondrial pyruvate carrier MPC1 and MPC2 complexYingyuan Sun0Yaru Wang1Zheng Xing2Dongyu Li3Rong Wang4Baozhi Chen5Ning Zhou6Alyssa Ayala7Benjamin P. Tu8Xiaofeng Qi9Department of Molecular Genetics, University of Texas Southwestern Medical CenterDepartment of Molecular Biology, University of Texas Southwestern Medical CenterDepartment of Biochemistry, University of Texas Southwestern Medical CenterDepartment of Molecular Genetics, University of Texas Southwestern Medical CenterDepartment of Molecular Genetics, University of Texas Southwestern Medical CenterDepartment of Molecular Biology, University of Texas Southwestern Medical CenterDepartment of Molecular Biology, University of Texas Southwestern Medical CenterDepartment of Molecular Biology, University of Texas Southwestern Medical CenterDepartment of Biochemistry, University of Texas Southwestern Medical CenterDepartment of Molecular Biology, University of Texas Southwestern Medical CenterAbstract The Mitochondrial Pyruvate Carrier (MPC) bridges cytosolic and mitochondrial metabolism by transporting pyruvate into mitochondria for ATP production and biosynthesis of various essential molecules. MPC functions as a heterodimer composed of MPC1 and MPC2 in most mammalian cells. Here, we present the cryogenic electron microscopy (cryo-EM) structures of the human MPC1-2 complex in the mitochondrial intermembrane space (IMS)-open state and the inhibitor-bound in the mitochondrial matrix-open state. Structural analysis shows that the transport channel of MPC is formed by the interaction of transmembrane helix (TM) 1 and TM2 of MPC1 with TM2 and TM1 of MPC2, respectively. UK5099, a potent MPC inhibitor, shares the same binding site with pyruvate at the matrix side of the transport channel, stabilizing MPC in its matrix-open conformation. Notably, a functional W82F mutation in MPC2 leads to the complex in an IMS-open conformation. Structural comparisons across different conformations, combined with yeast rescue assays, reveal the mechanisms of substrate binding and asymmetric conformational changes in MPC during pyruvate transport across the inner mitochondrial membrane (IMM) as well as the inhibitory mechanisms of MPC inhibitors.https://doi.org/10.1038/s41467-025-61939-z |
| spellingShingle | Yingyuan Sun Yaru Wang Zheng Xing Dongyu Li Rong Wang Baozhi Chen Ning Zhou Alyssa Ayala Benjamin P. Tu Xiaofeng Qi Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex Nature Communications |
| title | Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex |
| title_full | Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex |
| title_fullStr | Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex |
| title_full_unstemmed | Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex |
| title_short | Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex |
| title_sort | structure of human mitochondrial pyruvate carrier mpc1 and mpc2 complex |
| url | https://doi.org/10.1038/s41467-025-61939-z |
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