Mitochondrial pyruvate carrier complex (MPC)

The Mitochondrial Pyruvate Carrier (MPC) complex is a hetero-oligomeric transporter located in the inner mitochondrial membrane, primarily composed of the subunits MPC1 and MPC2 (Bricker et al., 2012; Herzig et al., 2012). Its primary biological function is to facilitate the transport of pyruvate from the cytosol into the mitochondrial matrix, a critical step that links glycolysis to the tricarboxylic acid (TCA) cycle and gluconeogenesis (McCommis & Finck, 2015; Gray et al., 2014). By controlling the entry of pyruvate into the mitochondria, the MPC serves as a key metabolic gatekeeper, influencing energy production and biosynthetic pathways (Taylor et al., 2012). MPC2 is recognized as the primary binding subunit for several classes of inhibitors, including thiazolidinedione-like insulin sensitizers (Colca et al., 2014; Divakaruni et al., 2013). In diseases such as type 2 diabetes and non-alcoholic steatohepatitis (NASH), the MPC is a strategic therapeutic target (McCommis et al., 2017; Harrison et al., 2020). Inhibition of the MPC can reduce hepatic glucose production and improve insulin sensitivity by altering mitochondrial fuel utilization (Vigueira et al., 2014; McCommis et al., 2015). In oncology, the MPC's role is context-dependent; it is often downregulated in tumors to promote the Warburg effect, but its inhibition can also be used to starve certain cancers of mitochondrial metabolites (Schell et al., 2014; Bensard et al., 2020). Clinical candidates like MSDC-0602K and MSDC-0160 target the MPC to treat metabolic and neurodegenerative conditions, respectively, by modulating systemic energy homeostasis (Shah et al., 2014; ClinicalTrials.gov NCT02784444). Recent structural studies have elucidated the rocker-switch mechanism of the MPC, providing a blueprint for the design of more selective inhibitors (Sichrovsky et al., 2024).

Other names

MPC1/MPC2 complexMitochondrial pyruvate carrier 2MPC2BRP44BRP44LMitochondrial pyruvate carrier 1MPC1

Inhibition of mitochondrial pyruvate transport