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J. Biol. Chem., Vol. 277, Issue 34, 31243-31248, August 23, 2002
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From 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 Mg2+. 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.
A Novel Adenine Nucleotide Translocase Inhibitor, MT-21, Induces
Cytochrome c Release by a Mitochondrial Permeability
Transition-independent Mechanism*
,¶
The Antibiotics Laboratory, Riken, Hirosawa 2-1,
Saitama 351-0198 and the § Department of Industrial
Chemistry, Faculty of Engineering, Science University of Tokyo,
Kagura-zaka, Shinjuku-ku, Tokyo 162-8601, Japan
*
This work was supported in part by a grant-in-aid from the
Ministry of Education, Science, Sports, and Culture of Japan, by the
Multibioprobe project (RIKEN), and by funding for a Special Postdoctoral Researchers Program (to K. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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