Investigating the roles of cyclin C in the mammalian heart

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and around the world. In 2016, approximately 62,000 individuals died every month from CVD in the United States alone. CVD is a class of diseases that involve the heart or blood vessels. The human heart is a muscle that is approximately the size of a closed fist. Although not the largest organ in the body, the heart is one of the most vital, second only to the brain. Every 24 hours, this muscle constantly contracts and relaxes, beating roughly 100,000 times and pumping about 5,000 gallons of blood through the body to deliver oxygen and nutrient rich blood to our tissues and carry away waste. The persistent electrical impulses and mechanical activities of the heart require a continuous energy supply met by a rich stockpile of mitochondria, the energy factories in our cells. The subcellular compartments known as mitochondria function to process oxygen and convert substances from the food we eat into energy and is responsible for making 90 percent of the energy our body needs to function. In order to adequately perform, mitochondria are constantly undergoing two processes- fission and fusion, which are important to keep a healthy population of mitochondria. Fusion is a process in which of two mitochondria becomes one, whereas fission is when one mitochondrion splits into two. One major complication associated with CVD is decreased mitochondrial production and function in heart and skeletal muscle. Defects in mitochondria lead to energy deficits and declined cardiac function. Although many studies are dedicated to CVD research, there remains a current gap in knowledge between the pathogenesis of CVD and mitochondrial dysfunction in the human heart.

Cyclin C is a component of the Mediator kinase complex, a cluster of proteins in the nucleus of the cell that regulates transcription of genes involved in cardiac metabolism, energy balance and responsiveness of the heart to stress. The overall goal of this project is to define the roles of cyclin C in the heart. Our data shows that cyclin C physically moves from the nucleus to the cytoplasm in response to stress in heart cells. We also show that cyclin C localization regulates mitochondria function and fission and fusion events in cell culture and in whole mouse hearts. These findings suggest that cyclin C is essential to maintaining normal mitochondria function in the heart. Our studies provide new insights into the regulation of cardiac energy metabolism and may yield novel therapeutic strategies for controlling these processes in the settings of heart disease.