Structure of human mitochondrial pyruvate carrier MPC1 and MPC2 complex

Yingyuan Sun, Yaru Wang, Zheng Xing, Dongyu Li, Rong Wang, Baozhi Chen, Ning Zhou, Alyssa Ayala, Benjamin P. Tu and Xiaofeng Qi ()
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Yingyuan Sun: University of Texas Southwestern Medical Center
Yaru Wang: University of Texas Southwestern Medical Center
Zheng Xing: University of Texas Southwestern Medical Center
Dongyu Li: University of Texas Southwestern Medical Center
Rong Wang: University of Texas Southwestern Medical Center
Baozhi Chen: University of Texas Southwestern Medical Center
Ning Zhou: University of Texas Southwestern Medical Center
Alyssa Ayala: University of Texas Southwestern Medical Center
Benjamin P. Tu: University of Texas Southwestern Medical Center
Xiaofeng Qi: University of Texas Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-10

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61939-z

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