Journal article
Stress-Induced Cyclin C Translocation Regulates Cardiac Mitochondrial Dynamics
Journal of the American Heart Association, Vol.9(7), pp.e014366-e014366
04/07/2020
DOI: 10.1161/JAHA.119.014366
PMCID: PMC7428645
PMID: 32248761
Abstract
Background Nuclear-to-mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. In this study, we determined that cyclin C, a component of the Mediator complex, regulates cardiac and mitochondrial function in part by modifying mitochondrial fission. We tested the hypothesis that cyclin C functions as a transcriptional cofactor in the nucleus and a signaling molecule stimulating mitochondrial fission in response to stimuli such as cardiac ischemia. Methods and Results We utilized gain- and loss-of-function mouse models in which the
(cyclin C) gene was constitutively expressed (transgenic, CycC cTg) or deleted (knockout, CycC cKO) in cardiomyocytes. The knockout and transgenic mice exhibited decreased cardiac function and altered mitochondria morphology. The hearts of knockout mice had enlarged mitochondria with increased length and area, whereas mitochondria from the hearts of transgenic mice were significantly smaller, demonstrating a role for cyclin C in regulating mitochondrial dynamics in vivo. Hearts from knockout mice displayed altered gene transcription and metabolic function, suggesting that cyclin C is essential for maintaining normal cardiac function. In vitro and in vivo studies revealed that cyclin C translocates to the cytoplasm, enhancing mitochondria fission following stress. We demonstrated that cyclin C interacts with Cdk1 (cyclin-dependent kinase 1) in vivo following ischemia/reperfusion injury and that, consequently, pretreatment with a Cdk1 inhibitor results in reduced mitochondrial fission. This finding suggests a potential therapeutic target to regulate mitochondrial dynamics in response to stress. Conclusions Our study revealed that cyclin C acts as a nuclear-to-mitochondrial signaling factor that regulates both cardiac hypertrophic gene expression and mitochondrial fission. This finding provides new insights into the regulation of cardiac energy metabolism following acute ischemic injury.
Details
- Title: Subtitle
- Stress-Induced Cyclin C Translocation Regulates Cardiac Mitochondrial Dynamics
- Creators
- Jessica M Ponce - Interdisciplinary Graduate Program in Genetics University of Iowa Iowa City IAGrace Coen - Abboud Cardiovascular Research Center Division of Cardiovascular Medicine Department of Internal Medicine Carver College of Medicine University of Iowa Iowa City IAKathryn M Spitler - Department of Biochemistry Carver College of Medicine University of Iowa Iowa City IANikola Dragisic - Stead Family Department of Pediatrics University of Iowa Iowa City IAInes Martins - Abboud Cardiovascular Research Center Division of Cardiovascular Medicine Department of Internal Medicine Carver College of Medicine University of Iowa Iowa City IAAntentor Hinton Jr - Fraternal Order of Eagles Diabetes Research Center Division of Endocrinology and Metabolism Carver College of Medicine University of Iowa Iowa City IAMargaret Mungai - Fraternal Order of Eagles Diabetes Research Center Division of Endocrinology and Metabolism Carver College of Medicine University of Iowa Iowa City IASatya Murthy Tadinada - Department of Pharmacology and Iowa Neuroscience Institute Carver College of Medicine University of Iowa Iowa City IAHao Zhang - Mazankowski Alberta Heart Institute Canada Research Chair in Heart Failure Division of Cardiology 2C2 Walter Mackenzie Health Sciences Centre Edmonton Alberta CanadaGavin Y Oudit - Mazankowski Alberta Heart Institute Canada Research Chair in Heart Failure Division of Cardiology 2C2 Walter Mackenzie Health Sciences Centre Edmonton Alberta CanadaLong-Sheng Song - Iowa City Veterans Affairs Medical Center Iowa City IANa Li - Department of Genetics Harvard Medical School Boston MAPeter Sicinski - Department of Genetics Harvard Medical School Boston MAStefan Strack - Department of Pharmacology and Iowa Neuroscience Institute Carver College of Medicine University of Iowa Iowa City IAE Dale Abel - Fraternal Order of Eagles Diabetes Research Center Division of Endocrinology and Metabolism Carver College of Medicine University of Iowa Iowa City IAColleen Mitchell - Department of Mathematics and Delta Center University of Iowa Iowa City IADuane D Hall - Abboud Cardiovascular Research Center Division of Cardiovascular Medicine Department of Internal Medicine Carver College of Medicine University of Iowa Iowa City IAChad E Grueter - Fraternal Order of Eagles Diabetes Research Center Division of Endocrinology and Metabolism Carver College of Medicine University of Iowa Iowa City IA
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.9(7), pp.e014366-e014366
- DOI
- 10.1161/JAHA.119.014366
- PMID
- 32248761
- PMCID
- PMC7428645
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Publisher
- England
- Grant note
- S10 RR018998 / NCRR NIH HHS S10 OD019941 / NIH HHS R25 GM058939 / NIGMS NIH HHS R01 HL125436 / NHLBI NIH HHS F31 HL140884 / NHLBI NIH HHS R01 HL127764 / NHLBI NIH HHS S10 RR026293 / NCRR NIH HHS S10 RR025439 / NCRR NIH HHS
- Language
- English
- Date published
- 04/07/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Craniofacial Anomalies Research Center; Fraternal Order of Eagles Diabetes Research Center; Mathematics; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984071694002771
Metrics
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