Alterations in cardiac gene expression and metabolism result in Heart Failure (HF), one of the leading causes of morbidity and mortality in the United States. A key regulator of transcription is Mediator, a large multi-subunit complex that serves as a bridge between DNA-bound transcription factors and RNA Polymerase II. The Mediator kinase sub-complex, composed of proteins Med13, Med12, Cdk8, and Cyclin C, regulate transcription of genes involved in cardiac metabolism, energy homeostasis and responsiveness of the heart to stress. Recent studies have shown Cyclin C to function independent of Mediator by translocating to mitochondria and regulating stress-induced hyper- fission in yeast in response to oxidative damage. In humans, the constant electrical and mechanical activities of the heart require a continuous energy supply met by a rich stockpile of mitochondria. One major complication associated with HF is decreased mitochondrial biogenesis and function in the heart. Defects in mitochondrial fusion and fission dynamics lead to metabolic remodeling, deficits in cardiac energetics, and increased oxidative stress. Although many studies are dedicated to HF research, there remains a current gap in knowledge between the pathogenesis in HF that connects cardiac genetic expression and mitochondrial dysfunction. The overall goal of this project is to define the mechanisms whereby Cyclin C regulates metabolism, cell survival, and energy homeostasis in heart failure via two functions: regulating mitochondrial dynamics, as well as regulating transcription of crucial cardiac and mitochondrial genes. Our preliminary data shows that Cyclin C translocates from the nucleus to the cytoplasm in response to stress in cardiomyocytes isolated from adult mouse and neonatal rats. We also show that mitochondria fission dynamics is regulated by Cyclin C localization in vitro. We have generated a cardiac-specific Cyclin C knock out mouse (CycC-cKO) using an alpha myosin heavy chain expressing cre recombinase bred with CycC floxed mice. Echocardiographic analysis was performed and a decrease in cardiac function, increased heart mass and decreased heart rate was observed in 12-week-old CycC-cKO mice compared to wild type littermates. Our findings suggest that Cyclin C is essential to maintaining normal cardiac function. These studies will provide a novel nuclear-mitochondrial mechanism into the regulation of cardiac energy metabolism and gene expression, and may yield novel therapeutic strategies for modulating these processes in the settings of heart failure.
Heart failure (HF) is a growing public health problem with substantial morbidity and mortality, with the highest incidence and leading cause of hospitalizations in the most rapidly growing segment of the U.S. population, the elderly (over 65 years old); two major complications associated with HF are decreased mitochondrial function and altered gene expression. Our goal is to determine how Cyclin C, a protein involved in gene expression is also connected to mitochondria function, which provides energy to keep the heart pumping. With these studies, a new pathway in heart failure will be discovered in hopes of developing better treatments.
