Role of Cullin 3 in cardiac mitochondrial quality control

Heart failure remains a global health problem affecting more than 26 million people worldwide. Mitochondria play a crucial role in regulating cardiac function in health and disease by regulating energy production and other vital cellular processes. Disruption of mitochondrial homeostasis has been closely linked to the development and pathogenesis of cardiomyopathies of different etiologies. Thus, clearly identification of novel molecular regulators of mitochondrial quality control in the heart is crucial for reducing cardiac dysfunction-related mortality. This application provides a novel link between neddylation and mitochondrial turnover in the heart. Neddylation is a post-translational modification that covalently attaches a small ubiquitin (Ub)-like protein NEDD8 to target proteins. I have recently demonstrated that neddylation is indispensable in the developing heart, and mice deficient of neddylation develop heart failure and die perinatally. Intriguingly, my preliminary data revealed that one of the major substrates of NEDD8, cullin 3 (Cul3), is a novel regulator of mitophagy in cardiomyocytes, and that mice lacking Cul3 have severe mitochondrial and functional defects in the heart. Given the known role of Cul3 as a key component of the ubiquitin ligases, I propose the central hypothesis that Cul3 mediates mitophagy and maintains cardiac function by acting as mitochondrial ubiquitin ligases downstream of neddylation. These studies will identify novel regulators/mechanisms of mitochondrial quality control and has broad implications for the understanding and treatment of heart failure and other diseases associated with mitochondrial or other metabolic dysfunctions. To achieve the goal, I will elucidate the molecular mechanisms by which Cul3 regulates mitophagy using biochemical assays, live cell imaging and fluorescent protein indicators, as well as proteomics approach. In addition, I will test whether Cul3 directs metabolic maturation and ventricular compaction using mice lacking Cul3 in the developing heart. Also, I will define the role of Cul3 in maintaining mitochondrial and cardiac integrity in physiological settings using cardiomyocyte-specific, conditional Cul3 knockout mice. Collectively, these studies and career development activities will foster my continued scientific and professional training, leading to a successful independent and academic research program. (AHA Program: Career Development Award)