Structure of mitochondrial pyruvate carrier and its inhibition mechanism

Zheng He, Jianxiu Zhang, Yan Xu, Eve J. Fine, Carl-Mikael Suomivuori, Ron O. Dror and Liang Feng ()
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Zheng He: Stanford University School of Medicine
Jianxiu Zhang: Stanford University School of Medicine
Yan Xu: Stanford University School of Medicine
Eve J. Fine: Stanford University School of Medicine
Carl-Mikael Suomivuori: Stanford University School of Medicine
Ron O. Dror: Stanford University School of Medicine
Liang Feng: Stanford University School of Medicine

Nature, 2025, vol. 641, issue 8061, 250-257

Abstract: Abstract The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate—a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation—into the mitochondrial matrix1–5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4–6. However, despite MPC’s critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC’s function and pave the way for the development of more-effective therapeutic reagents that target MPC.

Date: 2025
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DOI: 10.1038/s41586-025-08667-y

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