The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore.

TitleThe ADP/ATP translocator is not essential for the mitochondrial permeability transition pore.
Publication TypeJournal Article
Year of Publication2004
AuthorsKokoszka, JE, Waymire, KG, Levy, SE, Sligh, JE, Cai, J, Jones, DP, MacGregor, GR, Wallace, DC
JournalNature
Volume427
Issue6973
Pagination461-5
Date Published2004 Jan 29
ISSN1476-4687
KeywordsAdenine Nucleotide Translocator 1, Adenine Nucleotide Translocator 2, Animals, Cell Death, Gene Deletion, Hepatocytes, Ion Channels, Isoenzymes, Mice, Mice, Knockout, Mitochondria, Liver, Mitochondrial Membrane Transport Proteins
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.

DOI10.1038/nature02229
Alternate JournalNature
Citation Key10.1038/nature02229
PubMed ID14749836
PubMed Central IDPMC3049806
Grant ListR01 HD036437-03 / HD / NICHD NIH HHS / United States
U01 HD045913-01 / HD / NICHD NIH HHS / United States
R01 HD036437-02 / HD / NICHD NIH HHS / United States
R01 HD036437-05 / HD / NICHD NIH HHS / United States
R01 HD036437-04 / HD / NICHD NIH HHS / United States