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Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration

Nature Cell Biology volume 14, pages 575583 (2012) | Download Citation

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Abstract

MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, an MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure and maintenance of oligomeric ATP synthase. Our results provide insight into how the surprisingly diverse salutary functions of MCL-1 may control the survival of both normal and cancer cells.

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Change history

  • 17 May 2012

    In the version of this article initially published online, the x axes for Fig. 4b,c were incorrectly labelled. The correct units are μM. This has been corrected.

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Acknowledgements

We thank the St Jude Cell and Tissue Imaging Facility for assistance with live-cell imaging and S. Frase for assistance with electron micrographs; the W. M. Keck Foundation Biotechnology Resource Laboratory at Yale University for Edman sequencing; B. Xia, E. Parganas and D. Gable for technical assistance; C. Shaner for animal husbandry; and members of the St Jude Biochemistry Department, S. Oakes, J. Ihle and C. Sherr for helpful discussions. J.T.O. is supported by the Pew Scholars Program in the Biomedical Sciences; the National Institutes of Health HL-102175; the American Cancer Society RSG-10-255-01-LIB; a Cancer Center Support Grant P30CA021765; and the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital.

Author information

Affiliations

  1. Department of Biochemistry, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA

    • Rhonda M. Perciavalle
    • , Daniel P. Stewart
    • , Brian Koss
    • , Madhavi Bathina
    • , Stéphane Pelletier
    •  & Joseph T. Opferman
  2. Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA

    • Rhonda M. Perciavalle
  3. Pharmaceutical Sciences, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA

    • John Lynch
    •  & John D. Schuetz
  4. Immunology, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA

    • Sandra Milasta
    • , Stéphane Pelletier
    •  & Douglas R. Green
  5. Cell and Tissue Imaging Facility, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA

    • Jamshid Temirov
  6. Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA

    • Megan M. Cleland
    •  & Richard J. Youle

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Contributions

R.M.P. and J.T.O. conceived the study, designed the experiments and wrote the manuscript. R.M.P. performed the experiments, analysed data and prepared figures. D.P.S., B.K. and M.B. generated reagents and performed experiments. J.L. and J.D.S. carried out electron-transport-chain enzymatic assays. J.T. assisted in imaging data acquisition and quantification of mitochondrial morphology. M.M.C. and R.J.Y. carried out pilot experiments on mitochondrial morphology and provided reagents. S.P. assisted in acquisition of immunofluorescence micrographs. S.M. and D.R.G. carried out experiments on oxygen consumption and provided reagents. J.T.O. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Joseph T. Opferman.

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DOI

https://doi.org/10.1038/ncb2488

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