Abstract
Mitochondrial outer membrane permeabilization (MOMP) is a critical control point during apoptosis that results in the release of pro-apoptotic mitochondrial contents such as cytochrome c. MOMP is largely controlled by Bcl-2 family proteins such as Bax, which under various apoptotic stresses becomes activated and oligomerizes on the outer mitochondrial membrane. Bax oligomerization helps promote the diffusion of the mitochondrial contents into the cytoplasm activating the caspase cascade. In turn, Bax is regulated primarily by anti-apoptotic Bcl-2 proteins including Bcl-xL, which was recently shown to prevent Bax from accumulating at the mitochondria. However, the exact mechanisms by which Bcl-xL regulates Bax and thereby MOMP remain partially understood. In this study, we show that the small CHCH-domain-containing protein CHCHD2 binds to Bcl-xL and inhibits the mitochondrial accumulation and oligomerization of Bax. Our data show that in response to apoptotic stimuli, mitochondrial CHCHD2 decreases prior to MOMP. Furthermore, when CHCHD2 is absent from the mitochondria, the ability of Bcl-xL to inhibit Bax activation and to prevent apoptosis is attenuated, which results in increases in Bax oligomerization, MOMP and apoptosis. Collectively, our findings establish CHCHD2, a previously uncharacterized small mitochondrial protein with no known homology to the Bcl-2 family, as one of the negative regulators of mitochondria-mediated apoptosis.
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Accession codes
Abbreviations
- ARF:
-
alternative reading frame
- CHCHD2:
-
coiled-coil helix coiled-coil helix domain-containing 2
- IP:
-
immunoprecipitation
- MEF:
-
mouse embryonic fibroblast cells
- MOMP:
-
mitochondrial outer membrane permeabilization
- mPTP:
-
mitochondrial permeability transition pore
- PARP:
-
poly (ADP-ribose) polymerase
- PI:
-
propidium iodide
- IP:
-
immunoprecipitation
- UV:
-
ultra violet
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Acknowledgements
We thank M Deshmukh and A Cox for helpful discussions and for their generosity in sharing reagents. This work was supported by grants from the NIH (CA100302, CA127770, CA155235 and CA167637) and NSFC (No. 81272207) to YZ and from the National Cancer Institute (Cancer Cell Biology Training Grant, 5T32CA071341) to HVC.
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Liu, Y., Clegg, H., Leslie, P. et al. CHCHD2 inhibits apoptosis by interacting with Bcl-x L to regulate Bax activation. Cell Death Differ 22, 1035–1046 (2015). https://doi.org/10.1038/cdd.2014.194
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DOI: https://doi.org/10.1038/cdd.2014.194
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