The peculiar properties of mitochondrial carriers of the SLC25 family.

With 53 members, the SLC25 mitochondrial carriers form the largest solute carrier family in humans. They transport a wide variety of substrates across the mitochondrial inner membrane to generate chemical energy and to supply molecules and ions for growth and maintenance of cells. They are among the smallest transporters in nature, yet they translocate some of the largest molecules without proton leak. With one exception, they are monomeric and have an unusual three-fold pseudo-symmetric structure. These carriers also have a unique transport mechanism, which is facilitated by six structural elements, meaning that all transmembrane helices move separately, but in a co-ordinated way. In addition, there are three functional elements that are an integral part of the alternating access mechanism, which opens and closes the carrier to the mitochondrial matrix or the intermembrane space. The first is a matrix gate, comprising the matrix salt bridge network and glutamine braces on transmembrane helices H1, H3 and H5. The second is a cytoplasmic gate, containing the cytoplasmic salt bridge network and tyrosine braces on transmembrane helices H2, H4 and H6. The third functional element is a single central substrate-binding site, the access to which is controlled by the opening and closing of the two gates in an alternating way. The electrostatic properties of the binding site facilitate the exchange of charged substrates across the inner membrane in the presence of a high membrane potential. Here, we discuss the extraordinary features of mitochondrial carriers, providing new insights into one of the most complex and dynamic transport mechanisms in nature.