The molecular basis for calcium-dependent regulation of cardiac structure and function.

摘要

Calcium homeostasis is essential for regulating a wide spectrum of biological processes. In the heart, Ca2+ plays a key role in excitation-contraction coupling, electrophysiological processes, activation of contractile proteins, energy metabolism, cell death, and transcriptional regulation. Alteration of Ca2+ homeostasis is often associated with cardiac pathology such as contractile dysfunction, arrhythmias and heart failure. In order to discover novel molecular mechanisms by which Ca2+ regulates cardiac structure and function, I have utilized a zebrafish mutant tremblor (tre), as a model for cardiac defects induced by aberrant Ca2+ homeostasis. With this model system, I discovered a new mechanism by which Ca2+ homeostasis is regulated in cardiomyocytes and revealed its implication in normal and diseased physiology. First, I found that mitochondria play a critical role in modulating Ca2+ homeostasis and maintaining cardiac rhythmicity. By a multidisciplinary approach including biochemistry, genetics and physiology, I demonstrated that Ca2+ transfer into mitochondria through the outer mitochondrial membrane protein, voltage-dependent anion channel (VDAC2), is an essential fine-tuning mechanism of normal intracellular Ca2+ homeostasis that prevents the propagation of arrhythmogenic Ca2+ waves. Second, I discovered that normal Ca2+ homeostasis is required to maintain myofibrillar integrity in cardiomyocytes. Aberrant Ca2+ homeostasis leads to upregulation of an E3 ubiquitin ligase, Muscle-specific RING Finger protein 1 (MuRF1), and induces degradation of contractile proteins via a proteasome-dependent protein degradation mechanism. Taken together, my dissertation research has revealed diverse roles of Ca2+ homeostasis in the heart and its regulatory mechanism. These findings provide new insights into cardiac diseases associated with Ca2+ mishandling in cardiomyocytes and may lead to the development of novel therapeutic approaches for these diseases.