Human mitochondrial carriers of the SLC25 family function as monomers exchanging substrates with a ping-pong kinetic mechanism.
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Members of the SLC25 mitochondrial carrier family link cytosolic and mitochondrial metabolism and support cellular maintenance and growth by transporting compounds across the mitochondrial inner membrane. Their monomeric or dimeric state and kinetic mechanism have been a matter of long-standing debate. It is believed by some that they exist as homodimers and transport substrates with a sequential kinetic mechanism, forming a ternary complex where both exchanged substrates are bound simultaneously. Some studies, in contrast, have provided evidence indicating that the mitochondrial ADP/ATP carrier (SLC25A4) functions as a monomer, has a single substrate binding site, and operates with a ping-pong kinetic mechanism, whereby ADP is imported before ATP is exported. Here we reanalyze the oligomeric state and kinetic properties of the human mitochondrial citrate carrier (SLC25A1), dicarboxylate carrier (SLC25A10), oxoglutarate carrier (SLC25A11), and aspartate/glutamate carrier (SLC25A13), all previously reported to be dimers with a sequential kinetic mechanism. We demonstrate that they are monomers, except for dimeric SLC25A13, and operate with a ping-pong kinetic mechanism in which the substrate import and export steps occur consecutively. These observations are consistent with a common transport mechanism, based on a functional monomer, in which a single central substrate-binding site is alternately accessible.
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Acknowledgements: This work was supported by the Medical Research Council, grant MC_UU_00028/2 to MSK and ERSK. CC-W was supported by an Aker Scholarship, DL by the Swiss National Science Foundation (Synergia project CRSII5_180326), EP by the Norges Forskningsråd (Forskningsrådet)(grant 301170), and SJB by a BBSRC-GSK CASE Fellowship. We thank Dr. Shane Palmer for multiple large-scale fermentation runs of yeast, required for this project.
Funder: Aker Scholarship
Funder: BBSRC-GSK CASE Fellowship
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1460-2075
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MRC (MC_UU_00028/2)