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Vol. 17, Issue 9, 3952-3963, September 2006

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An Internal EELD Domain Facilitates Mitochondrial Targeting of Mcl-1 via a Tom70-dependent Pathway

Chiang-Hung Chou^*, Ru-Shuo Lee, and Hsin-Fang Yang-Yen^*,,

*Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan; Graduate Institute of Cell and Molecular Biology, Taipei Medical University, Taipei 110, Taiwan; and Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan

Submitted April 18, 2006; Accepted June 26, 2006
Monitoring Editor: Janet Shaw

Mcl-1 functions at an apical step in many regulatory programs that control cell death. Although the 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. Together, our results indicate that the internal EELD domain facilitates mitochondrial targeting of Mcl-1 via a Tom70-dependent pathway.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0319) on July 5, 2006.

Address correspondence to: Hsin-Fang Yang-Yen (imbyy{at}gate.sinica.edu.tw)

Abbreviations used: co-IP, coimmunoprecipitation; GP, guinea pig; MOM, outer membrane of mitochondria.

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