Edmund Kunji - Dissecting the charge movements during adenine nucleotide exchange by ADP/ATP carrier

The mitochondrial ADP/ATP carrier, also called adenine nucleotide translocase or translocator, imports ADP into the mitochondrial matrix, where it is converted to ATP by the ATP synthase, and exports the newly synthesized ATP to the cytosol, where it fuels the energy-requiring processes that are vital for cell survival. They belong to the largest solute carrier family in humans, called the SLC25 Mitochondrial Carrier Family. During transport, the ADP/ATP carriers cycle between a cytoplasmic-open state and matrix-open state, both of which have been structurally resolved. Comparison of the two states shows that the carrier has six dynamic elements for state interconversions, which support an alternating access mechanism, consisting of three core elements and three gate elements. When the carrier changes from the cytoplasmic-open to the matrix-open state, the three gate elements move inwards, closing the cytoplasmic side of the carrier, whereas the three core elements move outwards, opening the matrix side. The converse occurs when the carrier changes from the matrix-open to the cytoplasmic-open state. The carrier functions as a monomer and has a single substrate binding site and two networks on either side of central cavity that open and close the carrier during the transport cycle in an alternating way. We have demonstrated recently that the carrier has a ping-pong kinetic mechanism an agreement with the structural mechanism, meaning that ADP is imported first before ATP is exported. However, this leaves a major bioenergetic challenge. How is ADP, which carries three negative charges, imported into mitochondria against the inside negative membrane potential? In this talk, we will dissect the molecular features of the carrier that contribute to the charge translocations during adenine nucleotide exchange.
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