Regulation of metabolite transport by acid/base transporters and carbonic anhydrase
Cellular production and consumption of energy is tightly linked to the production of acid/base equivalents within the cell. Acid/base transport across cell membranes includes a variety of carriers, some of which are important for pH regulation or cellular import and export of metabolites. One class of these acid/base-coupled metabolite transporters are the monocarboxylate transporters (MCTs), carriers of high-energy metabolites like lactate, pyruvate and ketone bodies. MCTs are highly expressed in tissues with large energy consumption like muscle and brain, but also have been shown to play a profound role in tumor metabolism.
Our research focuses on the interplay between different MCT isoforms and other acid/base-regulatory proteins like sodium/bicarbonate co-transporters (NBCs) and carbonic anhydrases (CAs). CAs are a family of ubiquitously expressed enzymes that play a central role in the regulation of acid/base homeostasis of most cells and tissues. We have shown that different isoforms of CA can directly bind to MCTs and enhance lactate transport in a non-catalytic manner by acting as a “proton-collecting antenna” for the carrier, a type of interaction that has never been observed before for this enzyme. To study the mechanism of these interactions and their relevance for metabolite and acid/base transport within living tissue, we apply various physiological and molecular biological techniques including real-time proton- and lactate-imaging on cancer cells, astrocytes, and cardiomyocytes, ion-selective microelectrodes, Co-IP studies, heterologous protein expression in Xenopus oocytes as well as structural modeling of protein complexes.