Richard N. Kitsis, MD
Leducq Lab Members:
Yun Chen, PhD (Leducq Fellow)
Contribution to the network:
The Kitsis lab has long-standing expertise in molecular mechanisms of cell death and roles of cell death in human diseases including heart disease, cancer, and diabetes. The current focus of the lab in this area is to: (a) elucidate connections among various cell death programs (primarily apoptosis and necrosis); (b) understand how mitochondrial-mediated cell death mechanisms integrate with other basic mitochondrial functions such as mitochondrial dynamics; and (c) develop small molecule approaches to manipulate cell death. Although we work on fundamental questions, we are interested in translation, and our primary disease models are myocardial ischemia-reperfusions and heart failure, where our lab has done some of the initial work in elucidating relevant death mechanisms. Our roles in this network are: (a) to contribute expertise in cardiac cell death; and (b) in the execution of the first mechanistic delineation of the role of chaperone-mediated autophagy in cardiac biology and disease, a collaboration with network member Dr. Ana Maria Cuervo.
The goal of our studies in the network is to (a) understand the functional role of CMA in both cardiomyocytes and fibroblasts; (b) delineate the role of the pro-cell death protein BAX in mitochondrial mediated apoptotic and necrotic cell death; and (c) in collaboration with network member Evripidis Gavathiotis, develop small molecule BAX inhibitors that protect the heart against myocardial infarction (MI), heart failure, chemotherapy-induced cardiotoxicity.
Mitochondria play essential roles in cellular function through aerobic metabolism, which is particularly important in maintaining cardiac function in stressed states. Our central hypothesis in the cardiomyocyte CMA project is that in response to pathological stresses, CMA is activated in cardiomyocytes and negatively regulates mitochondrial function by depleting specific respiratory chain components that are CMA substrates.
Significance: We will (a) delineate the functional role of CMA in the heart; (b) elucidate the molecular mechanisms by which CMA regulates cardiac function; (c) evaluate the molecular mechanisms by which BAX mediates necrotic, as well as apoptotic, cell death; and (4) develop small molecules drugs to prevent cardiac cell death and heart damage in CVD.