Physiology and Pathophysiology of the Mitochondrial ADP/ATP Carrier

In eukaryotic cells, ATP generated by mitochondrial oxidative phosphorylation is exported to the cytoplasm in exchange for ADP by a protein located in the inner mitochondrial membrane, the ADP/ATP carrier. The transport capacity of the ADP/ATP carrier is very high: in an adult human body at rest, between 50 and 60 kg of ADP and ATP are transported across the mitochondrial membranes each day. Their amount increases markedly under working conditions, which means that the capacity of the carrier can be adjusted to metabolic conditions and is large enough to cope with a high energy demand. In the late 1970s, the ADP/ATP carrier was purified and reconstituted into liposomes. Its sequence revealed the presence of three repeated homologous domains. At that time, preliminary experiments aimed at deciphering its functioning and structure benefited from the use of two specific inhibitors, atractyloside and bongkrekic acid. In the 1980s, through chemical approaches, including chemical modifications, controlled proteolysis and immunochemical detection of extramembraneous loops, the structural organisation of the ADP/ATP carrier protein began to be unravelled with much focus on the nucleotide and inhibitor binding sites. The early studies had led to the characterisation of two conformers of the carrier, trapped by atractyloside and bongkrekic acid, respectively. More recently, experiments carried out with yeast mitochondria and using genetic and molecular biology, were able to pinpoint strategic amino acid residues responsible for conformational changes inherent in ADP/ATP transport.