Fifty years of the mitochondrial pyruvate carrier: New insights into its structure, function, and inhibition

Abstract

The mitochondrial pyruvate carrier (MPC) resides in the mitochondrial inner membrane, where it links cytosolic and mitochondrial metabolism by transporting pyruvate produced in glycolysis into the mitochondrial matrix. Due to its central metabolic role, it has been proposed as a potential drug target for diabetes, non‐alcoholic fatty liver disease, neurodegeneration, and cancers relying on mitochondrial metabolism. Little is known about the structure and mechanism of MPC, as the proteins involved were only identified a decade ago and technical difficulties concerning their purification and stability have hindered progress in functional and structural analyses. The functional unit of MPC is a hetero‐dimer comprising two small homologous membrane proteins, MPC1/MPC2 in humans, with the alternative complex MPC1L/MPC2 forming in the testis, but MPC proteins are found throughout the tree of life. The predicted topology of each protomer consists of an amphipathic helix followed by three transmembrane helices. An increasing number of inhibitors are being identified, expanding MPC pharmacology and providing insights into the inhibitory mechanism. Here, we provide critical insights on the composition, structure, and function of the complex and we summarize the different classes of small molecule inhibitors and their potential in therapeutics.

Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins

“…This emphasizes the importance of understanding transporter function and characteristics of endogenous substrates that are translocated. So far, the ADP/ATP exchanger and uncoupling proteins (SLC25 family), are the only functional carriers with a characterized structure 187–191 …”

Membrane transporters in cell physiology, cancer metabolism and drug response

“…The mitochondrial pyruvate carrier (MPC), whose molecular identity remained elusive for many years, was identified by two groups in 2012 ( Bricker et al, 2012 ; Herzig et al, 2012 ) and shown to be conserved from yeast to mammals. It is a heterodimeric complex formed of MPC1 and MPC2 (also known as SLC54A1 and SLC54A2, respectively) within the inner mitochondrial membrane (see Tavoulari et al, 2019 ; and the recent review by Tavoulari et al, 2023 ). By regulating the transport of pyruvate into the mitochondria, MPC sits at the interface between glycolysis and glucose oxidation, directly influencing the relative rates of each pathway.…”