The DOI matches its Crossref record; 10 of the 10 references it cites were found in a registry or an index.
Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure
Open accessAbstract
Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is up-regulated in several human cancers. MCL-1 is also highly expressed in myocardium, but its function in myocytes has not been investigated. We generated inducible, cardiomyocyte-specific Mcl-1 knockout mice and found that ablation of Mcl-1 in the adult heart led to rapid cardiomyopathy and death. Although MCL-1 is known to inhibit apoptosis, this process was not activated in MCL-1-deficient hearts. Ultrastructural analysis revealed disorganized sarcomeres and swollen mitochondria in myocytes. Mitochondria isolated from MCL-1-deficient hearts exhibited reduced respiration and limited Ca 2+-mediated swelling, consistent with opening of the mitochondrial permeability transition pore (mPTP). Double-knockout mice lacking MCL-1 and cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and extended survival. Autophagy is normally induced by myocardial stress, but induction of autophagy was impaired in MCL-1-deficient hearts. These data demonstrate that MCL-1 is essential for mitochondrial homeostasis and induction of autophagy in the heart. This study also raises concerns about potential cardiotoxicity for chemotherapeutics that target MCL-1.
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Cites
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Cited by
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
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The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
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Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies
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The BCL-2 arbiters of apoptosis and their growing role as cancer targets
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Metadata
- Authors
- Thomas, R. L., Roberts, D. J., Kubli, D. A., Lee, Y., Quinsay, M. N., Owens, J. B., Fischer, K. M., Sussman, M. A., Miyamoto, S., & Gustafsson, Å. B.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-06-15
- Volume
- 27
- Issue
- 12
- Pages
- 1365-1377
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2137240394
- Cited by
- 269
- References
- 10
- Type
- posted content
- Language
- en
- Open access
- diamond
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- Thomas, R. L., Roberts, D. J., Kubli, D. A., Lee, Y., Quinsay, M. N., Owens, J. B., Fischer, K. M., Sussman, M. A., Miyamoto, S., & Gustafsson, Å. B. (2013). Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure. Genes & Development. https://doi.org/10.1101/gad.215871.113
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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