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A more recent version of this article appeared on September 1, 2006
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Submitted on April 18, 2006
Accepted on June 26, 2006

*Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan;
Graduate Institute of Cell and Molecular Biology, Taipei Medical University, Taipei 101, Taiwan;
Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan
Monitoring Editor: Janet Shaw
Mcl-1 functions at an apical step in many regulatory programs that control cell death. Although mitochondrion is one major subcellular organelle where Mcl-1 functions, the molecular mechanism by which Mcl-1 is targeted to mitochondria remains unclear. Here, we demonstrate that Mcl-1 is loosely associated with the outer membrane of mitochondria. Furthermore, we demonstrate that Mcl-1 interacts with the mitochondrial import receptor Tom70 and such interaction requires an internal domain of Mcl-1 that contains an EELD motif. A Tom70 antibody that blocks Mcl-1-Tom70 interaction blocks mitochondrial import of Mcl-1 in vitro. Furthermore, Mcl-1 is significantly less targeted to mitochondria in Tom70 knockdown than in the control cells. Similar targeting preference is also observed for the DM mutant of Mcl-1 whose mutation at the EELD motif markedly attenuates its Tom70 binding activity. Taken together, our results indicate that the internal EELD domain facilitates mitochondrial targeting of Mcl-1 via a Tom70 dependent pathway.
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