The adenine nucleotide translocase: a central component of the mitochondrial permeability transition pore and key player in cell death.
In addition to its normal function, the adenine nucleotide translocase (ANT) forms the inner membrane channel of the mitochondrial permeability transition pore (MPTP). Binding of cyclophilin-D (CyP-D) to its matrix surface (probably on Pro(61) on loop 1) facilitates a calcium-triggered conformational change converting it from a specific transporter to a non-specific pore. The voltage dependent anion channel (VDAC) binds to the outer face of the ANT, at contact sites between the inner and outer membranes, and together VDAC, ANT and CyP-D probably represent the minimum MPTP configuration. The evidence for this is critically reviewed as is the structure and molecular mechanism of the carrier in its normal physiological mode. This provides helpful insights into MPTP regulation by adenine nucleotides, membrane potential and ANT ligands such as carboxyatractyloside and bongkrekic acid. Oxidative stress activates the MPTP by glutathione-mediated cross-linking of Cys(159) and Cys(256) on matrix-facing loops of the ANT that inhibits ADP binding and enhances CyP-D binding. Molecular modeling of the loop containing the ADP binding site suggests an arrangement of aspartate and glutamate residues that may provide a calcium binding site. There are other proteins that may bind to the ANT, modulating MPTP opening and hence cell death. These included members of the Bax/Bcl-2 family (both oncoproteins and tumor suppressors) and viral proteins. Vpr from HIV-1 can bind to ANT and convert it into a pro-apoptotic pore, whereas vMIA from cytomegalovirus interacts to inhibit opening. Thus the ANT may provide a molecular link between physiopathological mechanisms of infection and the regulation of MPTP function and so represents a potential therapeutic target.
Halestrap
Andrew P
AP
Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. A.Halestrap@Bristol.ac.uk
Brenner
Catherine
C
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology*; D000226:Mitochondrial ADP, ATP Translocases / Q000737:chemistry / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011485:Protein Binding; D011487:Protein Conformation; D014157:Transcription Factors / Q000378:metabolism / Q000494:pharmacology
D000081406:Peptidyl-Prolyl Isomerase F; D007473:Ion Channels; D008024:Ligands; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D014157:Transcription Factors; D000226:Mitochondrial ADP, ATP Translocases; D021983:Cyclophilins; D003545:Cysteine; D002118:Calcium