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Mcl-1 rescues a glitch in the matrix

Nature Cell Biology volume 14, pages 563–565 (2012)Cite this article

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Bcl-2 family proteins are known to control cell death and influence mitochondrial function. The function of Mcl-1, an anti-apoptotic Bcl-2 protein, is now shown to depend on its subcellular localization. Mcl-1 at the mitochondrial outer membrane inhibits mitochondrial permeabilization to block apoptosis. However, a cleaved form of Mcl-1 localizes to the mitochondrial matrix and controls inner mitochondrial morphology and oxidative phosphorylation, without directly modulating apoptosis.

The past two decades of apoptosis research have revealed cell death signalling pathways that can be triggered by perturbations in many areas of the cell (the plasma membrane, various organelles and the nucleus) and, with few exceptions, these pathways ultimately converge on the nexus of apoptotic signalling: the mitochondria. Here, apoptosis is regulated by the balance of anti-apoptotic Bcl-2 family proteins (for example, Bcl-2, Bcl-xL and Mcl-1), which bind and inhibit their pro-apoptotic counterparts (for example, Bax, Bak, Bim, Bad and Noxa). By various mechanisms, apoptotic stimuli can tilt this balance, overriding the effects of the anti-apoptotic family members to trigger Bax- and/or Bak-mediated release of mitochondrial cytochrome c into the cytosol, which promotes caspase activation and cell death. Of course, this conceptually simple model belies the complexity of apoptotic regulation at the mitochondria and the emerging notion that Bcl-2 family proteins not only regulate mitochondrial permeabilization in the face of death signalling, but also have physiological roles in fundamental mitochondrial processes. On page 575 of this issue, Perciavalle et al. show that distinct forms of the anti-apoptotic Bcl-2 family protein Mcl-1 reside in the mitochondrial outer membrane and the mitochondrial matrix to control cell death and cellular metabolism, respectively1.

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Figure 1: The dual functions of Mcl-1 and Bcl-xL.

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Authors and Affiliations

  1. Joshua L. Andersen is at the Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA,

    Joshua L. Andersen

  2. Sally Kornbluth is at the Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA,

    Sally Kornbluth

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  1. Joshua L. Andersen
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  2. Sally Kornbluth
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Correspondence to Sally Kornbluth.

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Andersen, J., Kornbluth, S. Mcl-1 rescues a glitch in the matrix. Nat Cell Biol 14, 563–565 (2012). https://doi.org/10.1038/ncb2511

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