TRANSPORTERS OF MONOCARBOXYLATES: CHARACTERIZAITON AND FUNCTIONAL ROLES

Abstract

The rapid transport of monocarboxylates, such as lactate, pyruvate and β-hydroxybutyrate, across membranes is essential for maintaining cellular homeostasis. They are mainly transported by three well-characterized protein carrier families: SLC16/monocarboxylate transporters (MCTs), SLC5/sodium-coupled monocarboxylate transporters (SMCTs), and mitochondrial pyruvate carriers (MPCs). There are 14 members in the SLC16 family (MCT1-14), however, only 5 of them (MCT1-4 and MCT7) can transport monocarboxylates. This transport process is proton-linked, electroneutral and driven by a concentration gradient of their substrates. MCT1, MCT2 and MCT4 have a broad expression pattern in various tissues with affinities in the order of MCT2>MCT1>MCT4. They play important roles in local functions and malfunctions of MCTs have been associated with devastating disorders such as cancer, obesity and ischemia. Two members of the SLC5 family, SLC5A8 (SMCT1) and SLC5A12 (SMCT2), transport monocarboxylates in a Na+-dependent, electrogenic manner with a stoichiometry being 2:1 for Na+/substrate. They play particularly important roles in short-chain fatty acids uptake in large intestine and regulation of uric acid reabsorption in kidney. MPCs (MPC1-2) form a large heterocomplex at the inner membrane of mitochondria and are mainly responsible for pyruvate transport into mitochondrial matrix to fuel Krebs cycle. Genetic mutations within these monocarboxylates carrier genes have been identified as causal factors for many diseases. Thus, a better understanding of their functions and regulations will help advance novel therapeutic interventions under certain pathological conditions.