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Cyclin C mediates stress-induced mitochondrial fission and apoptosis

Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission. Cyclin C–Cdk8 kinase regulates transcription of diverse gene sets. Using knockout mouse embryonic fibroblasts (MEFs), we demonstra...

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Detalles Bibliográficos
Autores principales: Wang, Kun, Yan, Ruilan, Cooper, Katrina F., Strich, Randy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357504/
https://www.ncbi.nlm.nih.gov/pubmed/25609094
http://dx.doi.org/10.1091/mbc.E14-08-1315
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author Wang, Kun
Yan, Ruilan
Cooper, Katrina F.
Strich, Randy
author_facet Wang, Kun
Yan, Ruilan
Cooper, Katrina F.
Strich, Randy
author_sort Wang, Kun
collection PubMed
description Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission. Cyclin C–Cdk8 kinase regulates transcription of diverse gene sets. Using knockout mouse embryonic fibroblasts (MEFs), we demonstrate that cyclin C directs the extensive mitochondrial scission induced by the anticancer drug cisplatin or oxidative stress. This activity is independent of transcriptional regulation, as Cdk8 is not required for this activity. Furthermore, adding purified cyclin C to unstressed permeabilized MEF cultures induced complete mitochondrial fragmentation that was dependent on the fission factors Drp1 and Mff. To regulate fission, a portion of cyclin C translocates from the nucleus to the cytoplasm, where it associates with Drp1 and is required for its enhanced mitochondrial activity in oxidatively stressed cells. In addition, although HeLa cells regulate cyclin C in a manner similar to MEF cells, U2OS osteosarcoma cultures display constitutively cytoplasmic cyclin C and semifragmented mitochondria. Finally, cyclin C, but not Cdk8, is required for loss of mitochondrial outer membrane permeability and apoptosis in cells treated with cisplatin. In conclusion, this study suggests that cyclin C connects stress-induced mitochondrial hyperfission and programmed cell death in mammalian cells.
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spelling pubmed-43575042015-05-30 Cyclin C mediates stress-induced mitochondrial fission and apoptosis Wang, Kun Yan, Ruilan Cooper, Katrina F. Strich, Randy Mol Biol Cell Articles Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission. Cyclin C–Cdk8 kinase regulates transcription of diverse gene sets. Using knockout mouse embryonic fibroblasts (MEFs), we demonstrate that cyclin C directs the extensive mitochondrial scission induced by the anticancer drug cisplatin or oxidative stress. This activity is independent of transcriptional regulation, as Cdk8 is not required for this activity. Furthermore, adding purified cyclin C to unstressed permeabilized MEF cultures induced complete mitochondrial fragmentation that was dependent on the fission factors Drp1 and Mff. To regulate fission, a portion of cyclin C translocates from the nucleus to the cytoplasm, where it associates with Drp1 and is required for its enhanced mitochondrial activity in oxidatively stressed cells. In addition, although HeLa cells regulate cyclin C in a manner similar to MEF cells, U2OS osteosarcoma cultures display constitutively cytoplasmic cyclin C and semifragmented mitochondria. Finally, cyclin C, but not Cdk8, is required for loss of mitochondrial outer membrane permeability and apoptosis in cells treated with cisplatin. In conclusion, this study suggests that cyclin C connects stress-induced mitochondrial hyperfission and programmed cell death in mammalian cells. The American Society for Cell Biology 2015-03-15 /pmc/articles/PMC4357504/ /pubmed/25609094 http://dx.doi.org/10.1091/mbc.E14-08-1315 Text en © 2015 Wang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Wang, Kun
Yan, Ruilan
Cooper, Katrina F.
Strich, Randy
Cyclin C mediates stress-induced mitochondrial fission and apoptosis
title Cyclin C mediates stress-induced mitochondrial fission and apoptosis
title_full Cyclin C mediates stress-induced mitochondrial fission and apoptosis
title_fullStr Cyclin C mediates stress-induced mitochondrial fission and apoptosis
title_full_unstemmed Cyclin C mediates stress-induced mitochondrial fission and apoptosis
title_short Cyclin C mediates stress-induced mitochondrial fission and apoptosis
title_sort cyclin c mediates stress-induced mitochondrial fission and apoptosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357504/
https://www.ncbi.nlm.nih.gov/pubmed/25609094
http://dx.doi.org/10.1091/mbc.E14-08-1315
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AT strichrandy cyclincmediatesstressinducedmitochondrialfissionandapoptosis