Molecular, Functional, and Pathological Aspects of the Mitochondrial ADP/ATP Carrier

摘要

In providing the ceil with ATP generated by oxidative phosphorylation, the mitochondrial ADP/ATP carrier plays a central role in aerobic eukaryotic cells. Combining biochemical, genetic, and structural approaches contributes to understanding the molecular mechanism of this essential transport system, the dysfunction of which is implicated in neuromuscular diseases. Most of the energy usable by aerobic eukaryotic cells is provided by the hydrolysis of ATP into ADP and inorganic phosphate. Therefore, the continuous synthesis of ATP is required to sustain the cellular energetic economy: each human being recycles the equivalent of his/her own mass of ATP every day. ATP is regenerated in the mitochondria! matrix through the oxidative phosphorylation process (FIGURE 1). The continuous uptake of electron-rich substrates, phosphate, and ADP, as well as the release of ATP into the cytosol require their crossing over mitochondrial membranes. Nonspecific porins mediate this transport through the outer membrane (7). In contrast, the inner membrane displays highly selective permeability, and hydrophilic metabolites can only cross this lipid bilayer thanks to specific carrier proteins. As a consequence, mitochondrial carrier proteins not only provide mitochondria with essential physiological metabolites but also play an important role in regulating the balance between intra- and extra-mitochondrial compartments (e.g., redoxpotential, phosphate potential). Solutes transported by theses carriers differ considerably in size and structure. They range from the smallest cation, the proton, to one of the largest anions, ATP. At physiological pH, most metabolites are anions, but some of them, including carnitine, ornithine, and glutamine, are zwitterions. To date, -20 carriers have been identified on the basis of their activity, assessed either in intact mitochondria or in reconstituted proteoliposomes (51). Some of them are involved in specialized metabolic pathways such as gluconeogenesis and urea synthesis. For anumber of them, isoforms displaying tissue-specific distribution have been identified (51). In addition, the distribution of carriers is tissue dependent, e.g., heart mitochondria, which lack the citrate carrier. On the basis of common biochemical characteristics, such as the presence in their sequence of the amino acid signature P-X-[D/E]-X-X-[K/R] found three times, -100 residues apart, mitochondrial carriers have been classified as members of the mitochondrial carrier family (68).