A novel adenine nucleotide translocase inhibitor, MT-21, induces cytochrome c release by a mitochondrial permeability transition-independent mechanism

Kiyotaka Machida, Yujiro Hayashi, Hiroyuki Osada

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

The release of cytochrome c from mitochondria is a critical step during apoptosis. In order to study this process, we have used a synthetic compound, MT-21, that is able to initiate release of cytochrome c from isolated mitochondria. We demonstrate that MT-21 significantly inhibits ADP transport activity in mitochondria and reduces binding of the adenine nucleotide translocase (ANT) to a phenylarsine oxide affinity matrix. These results suggest that ANT, one of the components of the mitochondrial permeability transition (PT) pore, is the molecular target for MT-21. In agreement with this, the MT-21-induced cytochrome c release was effectively inhibited in the presence of ANT ligands, and MT-21 could dissociate ANT from a complex with a glutathione S-transferase-cyclophilin D fusion protein. Interestingly, we also found that specific inhibitors of ANT such as MT-21 and atractyloside could induce cytochrome c release without mitochondrial swelling and that this event was highly dependent on the presence of Mg 2+. These results suggest that although ANT resides in the mitochondrial inner membrane, specific ANT inhibitors can induce cytochrome c release without having an effect on inner membrane permeability. Therefore, MT-21 can be a powerful tool for studying the mechanism of PT-independent cytochrome c release from mitochondria.

Original languageEnglish
Pages (from-to)31243-31248
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number34
DOIs
Publication statusPublished - 2002 Aug 23
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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