In response to stress, cellular damage must first be recognized then a signal transduced to the nucleus to install the correct gene expression program. In addition, the cell must coordinate its stress response with other organelles in the cell such as the ER and mitochondria. In particular, the mitochondria are a critical regulatory node for the stress response. In response to excessive cellular damage, the mitochondria undergo extensive fragmentation followed by mitochondrial outer membrane permeability (MOMP), which triggers the release of sequestered pro-apoptotic proteins from the mitochondria. MOMP is considered the point of no return for execution of the programmed cell death (PCD) pathway. My laboratory has identified cyclin C as a factor that connects changes in gene expression to mitochondrial fission and PCD. Cyclin C, along with its cyclin dependent kinase partner Cdk8, associates with the RNA polymerase holoenzyme to regulate transcription. In particular, cyclin C-Cdk8p are repressors of many stress responsive genes. To relieve this repression, cyclin C, but not Cdk8p, translocates from the nucleus to the cytoplasm in cells exposed to pro-oxidants and other stressors. In the cytoplasm, cyclin C interacts with the fission machinery and is both necessary and sufficient to induce extensive mitochondrial fragmentation. In addition, we identified a cytoplasmic role for cyclin C promoting PCD. These results suggest that cyclin C function connects mitochondrial fission to the cell death pathway. These activities are well conserved as we have demonstrated that the mammalian cyclin C also translocates to the mitochondria to direct fission and PCD in mammalian model systems. Therefore, the information obtained in this proposal will be applicable to higher systems as well. To elucidate the role of cyclin C in triggering mitochondrial fission and PCD, the following Aims are proposed:
AIM 1. Define the role cyclin C plays in stress-induced mitochondrial fission.
AIM 2. Determine the role mitochondria-ER junctions play in stress-induced fission.
AIM 3. Dissect the requirement of cyclin C in PCD execution.

Public Health Relevance

Mitochondrial morphology is controlled by the opposing activities of fission and fusion machines. In response to stress, this balance is shifted dramatically toward fission. We have identified a protein (cyclin C) that mediates only stress-induced fission. This proposal will investigate the role of cyclin C in mitochondrial fission and determine the relationship between fission and programmed cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM113052-01
Application #
8801338
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2014-09-15
Project End
2018-04-30
Budget Start
2014-09-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rowan University School/Osteopathic Med
Department
Biochemistry
Type
Schools of Osteopathic Medicine
DUNS #
City
Stratford
State
NJ
Country
United States
Zip Code
08084
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Stieg, David C; Willis, Stephen D; Ganesan, Vidyaramanan et al. (2018) A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13. Mol Biol Cell 29:363-375
Smethurst, Daniel G J; Cooper, Katrina F (2017) ER fatalities-The role of ER-mitochondrial contact sites in yeast life and death decisions. Mech Ageing Dev 161:225-233
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Lardenois, Aurélie; Becker, Emmanuelle; Walther, Thomas et al. (2015) Global alterations of the transcriptional landscape during yeast growth and development in the absence of Ume6-dependent chromatin modification. Mol Genet Genomics 290:2031-46
Wang, Kun; Yan, Ruilan; Cooper, Katrina F et al. (2015) Cyclin C mediates stress-induced mitochondrial fission and apoptosis. Mol Biol Cell 26:1030-43
Becker, Emmanuelle; Liu, Yuchen; Lardenois, Aurélie et al. (2015) Integrated RNA- and protein profiling of fermentation and respiration in diploid budding yeast provides insight into nutrient control of cell growth and development. J Proteomics 119:30-44
Gong, Haibo; Anasori, Babak; Dennison, Chris R et al. (2015) Fabrication, biodegradation behavior and cytotoxicity of Mg-nanodiamond composites for implant application. J Mater Sci Mater Med 26:110
Strich, Randy (2015) Programmed Cell Death Initiation and Execution in Budding Yeast. Genetics 200:1003-14
Gong, Haibo; Wang, Kun; Strich, Randy et al. (2015) In vitro biodegradation behavior, mechanical properties, and cytotoxicity of biodegradable Zn-Mg alloy. J Biomed Mater Res B Appl Biomater 103:1632-40