Molecular basis of pyruvate transport and inhibition of the human mitochondrial pyruvate carrier
The mitochondrial pyruvate carrier transports pyruvate, produced by glycolysis from sugar molecules, into the mitochondrial matrix, as a crucial transport step in eukaryotic energy metabolism. The carrier is a drug target for the treatment of cancers, diabetes mellitus, neurodegeneration, and metabolic dysfunction-associated steatotic liver disease. We have solved the structure of the human MPC1L/MPC2 heterodimer in the inward- and outward-open states by cryo-electron microscopy, revealing its alternating access rocker-switch mechanism. The carrier has a central binding site for pyruvate, which contains an essential lysine and histidine residue, important for its ΔpH-dependent transport mechanism. We have also determined the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state by mimicking pyruvate interactions and by using aromatic stacking interactions.
Authors
- Jan Steyaert (ORCID: https://orcid.org/0000-0002-3825-874X)
- Els Pardon (ORCID: https://orcid.org/0000-0002-2466-0172)
- Sotiria Tavoulari (ORCID: https://orcid.org/0000-0002-4263-8905)
- Shane M. Palmer (ORCID: https://orcid.org/0000-0002-6457-0761)
- Jonathan J. Ruprecht (ORCID: https://orcid.org/0000-0002-1838-7245)
- Lee R. Cooper (ORCID: https://orcid.org/0000-0003-4000-8237)
- Denis Lacabanne (ORCID: https://orcid.org/0000-0002-8911-3794)
- Giulia Paris (ORCID: https://orcid.org/0000-0002-5610-2722)
- Mariangela Dionysopoulou (ORCID: https://orcid.org/0000-0002-1042-0020)
- Ian M. Fearnley (ORCID: https://orcid.org/0000-0002-8510-1219)
- Vanessa Leone (ORCID: https://orcid.org/0000-0001-7017-4020)
- Dimitri Y. Chirgadze (ORCID: https://orcid.org/0000-0001-9942-0993)
- Steven W. Hardwick (ORCID: https://orcid.org/0000-0001-9246-1864)
- Edmund R.S. Kunji (ORCID: https://orcid.org/0000-0002-0610-4500)
- Lucy R. Forrest (ORCID: https://orcid.org/0000-0003-1855-7985)
- Martin King (ORCID: https://orcid.org/0000-0001-6030-5154)
- Scott A. Jones (ORCID: https://orcid.org/0000-0001-9991-5603)
- Alice P. Sowton (ORCID: https://orcid.org/0000-0002-3718-7783)
- Maximilian Sichrovsky (ORCID: https://orcid.org/0009-0006-6644-8694)
- Shujing Ding
- Klaudia Stanik (ORCID: https://orcid.org/0009-0005-9006-6445)
- J. L. Rana (ORCID: https://orcid.org/0000-0003-0357-4619)
Institutions
- Vrije Universiteit Brussel (BE)
- Medical College of Wisconsin (US)
- University of Cambridge (GB)
- National Institute of Neurological Disorders and Stroke (US)
- VIB-VUB Center for Structural Biology (BE)
- MRC Mitochondrial Biology Unit (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-18
- DOI
- https://doi.org/10.1126/sciadv.adw1489
- Citations
- 12
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 9.67