Mitochondrial Carriers


In eukaryotic cells, the exchange of metabolites across the inner mitochondrial membrane is performed by members of the mitochondrial carrier family (MCF), the largest family of solute transporters. Mutations in MCF genes are associated with rare genetic diseases underscoring the relevance of individual MCF members. Mitochondrial carriers have a common tripartite structure made up by tandem repeats of 100 amino acids each containing two transmembrane α‐helices and one conserved MCF signature. MCF members are present in two states, c and m, with binding sites for substrates facing either the intermembrane (c) or matrix (m) space. X‐ray crystallography of the mitochondrial ADP/ATP carrier in the c‐state has shown that the six α‐helices form a compact bundle shaping a cavity sealed on the matrix side by a salt‐bridge network. Substrate binding perturbs the salt‐bridge network triggering conformational changes that cause the opening of the carrier towards the matrix coupled to substrate transport.

Key Concepts:

  • Mitochondrial carriers perform the exchange of metabolites, nucleotides and cofactors through the inner mitochondrial membrane.

  • Mitochondrial carriers form an evolutionary conserved family present in all eukaryotic cells.

  • Mitochondrial carriers share a tripartite structure made up by repeats of 100 amino acids containing two α‐helices connected by a hydrophilic loop.

  • Phylogenetic analyses have shown the existence of a limited number of mitochondrial carrier subfamilies involved in the transport of structurally related substrates.

  • Mutations in nine mitochondrial carriers cause autosomal recessive disorders in humans.

  • Mitochondrial carriers are present in either one of two different states, c and m, in which binding sites for substrates face the intermembrane (c) or matrix (m) spaces.

  • During the transport cycle, substrate binding in each of these states induces a transition to the other state which is coupled to substrate transport.

  • The three‐dimensional structure solved for the ADP/ATP carrier in the c state is consistent with a bundle of six transmembrane α‐helices forming an aqueous cavity closed towards the matrix by electrostatic interactions. Specific interactions of substrates with the substrate‐binding site within the aqueous cavity will disturb the electrostatic interactions that maintain the carrier closed to the matrix side.

  • Substrate translocation by mitochondrial carriers occurs coupled to conformational movements of the α‐helices that open the carrier.

Keywords: mitochondria; solute transport; evolution; structure; human diseases

Figure 1.

The members of the mitochondrial carrier family showing conserved features. (a) Schematic diagram of the mitochondrial carrier secondary structure. Adapted from Pebay‐Peyroula et al. . Transmembrane helices (H), matrix helices (h), IMS loops (C) and matrix loops (M) are labelled. Odd‐numbered helices are kinked by the presence of prolines. In each repeat, the relative positions of the two parts of the MCF motif are indicated. Their consensus sequences are indicated at bottom. (b) Phylogenetic analysis of human mitochondrial carriers. The unrooted tree with relevant members of the human SLC25 family was calculated by the neighbour‐joining method using MEGA4. Clusters with high confidence, containing carriers that transport structurally related carriers are coloured. The main substrates transported for some of the carriers used in the analysis are indicated.

Figure 2.

Three‐dimensional structure of the bovine AAC. (a) A ribbon diagram viewing the carrier from the side. The structure is coloured blue to red from the N‐terminus to the C‐terminus. The transmembrane α‐helices (H1–H6) and the short α‐helices of matrix loops (h1–2, h3–4 and h5–6) are marked. (b) View from the IMS. (c) Proline‐induced kink in odd‐numbered α‐helices. Transmembrane α‐helices H3 and H4 are taken from the ADP/ATP translocase structure. The position of the P132 in H3 is indicated. (d) Top view of the matrix salt‐bridge network involving residues in odd‐numbered helices one half helix turn below the conserved prolines. Interactions among these residues lock the odd‐numbered helices towards the matrix side. All figures are drawn with the PYMOL program.

Figure 3.

The transport mechanism proposed for mitochondrial carriers. (a) The three‐dimensional structure of the AAC is shown highlighting the residues involved in the cytoplasmic (in even‐numbered H2, H4 and H6 helices) and matrix gate (in odd‐numbered H1, H3 and H5 helices, half helix below the conserved prolines of the MC motif) and substrate binding (in even‐numbered H2, H4 and H6 helices, one and a half helix above the conserved prolines). (b) Proposed model of solutes transport cycle across the mitochondrial inner membrane from the IMS. During the transport cycle the opening and closing of the carrier may be coupled to the disruption and formation of two salt‐bridge networks. Substrate(s) binding could compete with the electrostatic interactions of the salt‐bridge networks favouring the opening of the carrier towards the matrix or cytoplasmic side.



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del Arco, Araceli, and Satrústegui, Jorgina(Mar 2013) Mitochondrial Carriers. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024196]