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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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.
The authors declare no competing financial interests.
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Perciavalle, R., Stewart, D., Koss, B. et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol 14, 575–583 (2012). https://doi.org/10.1038/ncb2488
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