Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier. Trends Biochem Sci 2026 Feb;51(2):142-157
Date
12/07/2025Pubmed ID
41353022DOI
10.1016/j.tibs.2025.11.002Scopus ID
2-s2.0-105024324581 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.
Author List
Lacabanne D, Ruprecht JJ, Sichrovsky M, Forrest LR, Leone V, Tavoulari S, Kunji ERSAuthor
Vanessa Leone PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBinding Sites
Humans
Mitochondria
Mitochondrial Membrane Transport Proteins
Models, Molecular
Monocarboxylic Acid Transporters
Pyruvic Acid
