Mitochondrial pyruvate carrier (MPC) (MPC)

The Mitochondrial pyruvate carrier (MPC), historically known as the Mitochondrial target of thiazolidinediones (mTOT), is a hetero-oligomeric complex located in the inner mitochondrial membrane (Bricker et al., 2012, Science). It is composed of two essential subunits, MPC1 and MPC2, which facilitate the transport of pyruvate from the cytoplasm into the mitochondrial matrix (Herzig et al., 2012, Science). This transport step is a critical metabolic junction, as it determines the availability of pyruvate for the tricarboxylic acid (TCA) cycle and gluconeogenesis (Divakaruni et al., 2013, PNAS). The mTOT complex was identified as a specific binding site for thiazolidinedione (TZD) insulin sensitizers, such as pioglitazone, acting independently of the PPAR-gamma nuclear receptor (Colca et al., 2004, American Journal of Physiology-Endocrinology and Metabolism). Pharmacological inhibition of the MPC reduces the rate of hepatic gluconeogenesis and improves insulin sensitivity in peripheral tissues, offering a therapeutic pathway for Type 2 diabetes (Colca et al., 2013, American Journal of Physiology-Endocrinology and Metabolism). Beyond diabetes, the MPC is being investigated as a target for nonalcoholic steatohepatitis (NASH) and certain cancers where metabolic reprogramming is prevalent (McCommis et al., 2015, Hepatology). Novel MPC-selective inhibitors, often called mitoglitazones, are designed to retain the metabolic benefits of TZDs while minimizing side effects like weight gain and fluid retention (Chen et al., 2018, Cell Metabolism). The target also shows promise in neurodegenerative diseases, where modulating mitochondrial metabolism may provide neuroprotective effects (Ghosh et al., 2016, Journal of Alzheimer's Disease).

Other names

Mitochondrial target of thiazolidinedionesmTOTmTOT1mTOT2BRP44BRP44L

Inhibition of the mitochondrial pyruvate carrier complex, which limits the entry of pyruvate into the mitochondrial matrix, thereby modulating the TCA cycle and reducing hepatic glucose production.