title: The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore.
abstract: A sudden increase in permeability of the inner mitochondrial membrane, the so-called mitochondrial permeability transition, is a common feature of apoptosis and is mediated by the mitochondrial permeability transition pore (mtPTP). It is thought that the mtPTP is a protein complex formed by the voltage-dependent anion channel, members of the pro- and anti-apoptotic BAX-BCL2 protein family, cyclophilin D, and the adenine nucleotide (ADP/ATP) translocators (ANTs). The latter exchange mitochondrial ATP for cytosolic ADP and have been implicated in cell death. To investigate the role of the ANTs in the mtPTP, we genetically inactivated the two isoforms of ANT in mouse liver and analysed mtPTP activation in isolated mitochondria and the induction of cell death in hepatocytes. Mitochondria lacking ANT could still be induced to undergo permeability transition, resulting in release of cytochrome c. However, more Ca2+ than usual was required to activate the mtPTP, and the pore could no longer be regulated by ANT ligands. Moreover, hepatocytes without ANT remained competent to respond to various initiators of cell death. Therefore, ANTs are non-essential structural components of the mtPTP, although they do contribute to its regulation.
authors.affiliation: Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, California 92697, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Kokoszka
authors.forename: Katrina G
authors.initials: KG
authors.lastname: Waymire
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.forename: James E
authors.initials: JE
authors.lastname: Sligh
authors.forename: Jiyang
authors.initials: J
authors.lastname: Cai
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
authors.forename: Grant R
authors.initials: GR
authors.lastname: MacGregor
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D033742:Adenine Nucleotide Translocator 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D017353:Gene Deletion; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore
chemical_list: D033741:Adenine Nucleotide Translocator 1; D033742:Adenine Nucleotide Translocator 2; D007473:Ion Channels; D007527:Isoenzymes; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore