Heart disease is the single largest killer of the American. A growing body of evidence has shown that there is a close relationship between Ca2+ handling abnormalities and development of heart disease. Therefore it is fundamentally important to understand the regulation of Ca2+ signaling under pathological conditions. Local control of Ca2+-induced Ca2+ release (CICR) depends on the spatial organization of L-type Ca2+ channels and ryanodine receptors (RyR) in the dyad. Analogously, Ca2+ uptake by mitochondria is facilitated by their close proximity to the Ca2+ release sites, a process required for stimulating oxidative phosphorylation during changes in work. Mitochondrial feedback on CICR, however, is less well understood. Since mitochondria are a primary source of reactive oxygen species (ROS), they could potentially influence the cytosolic redox state, in turn altering RyR open probability. In this proposed study, a two photon laser microscope system will be used to directly examine how acute changes in energy state dynamically influence Ca2+ spark properties under various experimental conditions. Cytosolic Ca2+ (or ROS), A^m, and NADH will be recorded simultaneously in isolated guinea pig cardiomyocytes and analyzed offline using imaged. The spatiotemporal coupling between mitochondria! depolarization and Ca2+ sparks will be analyzed using a quantitative approach. Furthermore, a computational model of mitochondria and Ca2+ release unit will be developed to quantitatively investigate the interaction between mitochondrial energetics and local Ca2+ handling. Finally, an integrated model of the cardiomyocyte incorporating substrate metabolism, cellular electrophysiology, pH regulation and E-C coupling will be developed to investigate the mechanisms underlying alterations in energy production, ion channels, Ca2+ handling and pH, as well as the resulting reduction of cardiac contractile function during ischemia-reperfusion. By combining the experimental and computational results, these studies will allow for a complete understanding the origin of post-ischemic injury and development of heart failure, and significantly spur the development of novel heart disease therapies.
Sudden Cardiac Death (SCO) cause about 20% of all annual mortality in the U.S. It is therefore critically important to work towards a more complete understanding of the molecular basis of the arrhythmic causes of SCO, such as alterations in calcium handling under disease. This would help to identify the fundamental mechanisms and translate this knowledge into the design of more effective diagnostics and therapeutics.
|Goh, Kah Yong; Qu, Jing; Hong, Huixian et al. (2016) Impaired mitochondrial network excitability in failing guinea-pig cardiomyocytes. Cardiovasc Res 109:79-89|
|Yancey, Danielle M; Guichard, Jason L; Ahmed, Mustafa I et al. (2015) Cardiomyocyte mitochondrial oxidative stress and cytoskeletal breakdown in the heart with a primary volume overload. Am J Physiol Heart Circ Physiol 308:H651-63|
|Ma, Chao; Kojima, Kyoko; Xu, Ningning et al. (2015) Comparative proteomics analysis of high n-butanol producing metabolically engineered Clostridium tyrobutyricum. J Biotechnol 193:108-19|
|Li, Qince; Su, Di; O'Rourke, Brian et al. (2015) Mitochondria-derived ROS bursts disturb Ca²? cycling and induce abnormal automaticity in guinea pig cardiomyocytes: a theoretical study. Am J Physiol Heart Circ Physiol 308:H623-36|
|Collins, Helen E; He, Lan; Zou, Luyun et al. (2014) Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function. Am J Physiol Heart Circ Physiol 306:H1231-9|
|Liu, Jian; Wang, Peipei; Zou, Luyun et al. (2014) High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats. Am J Physiol Heart Circ Physiol 307:H598-608|
|Li, Qince; Pogwizd, Steven M; Prabhu, Sumanth D et al. (2014) Inhibiting Na+/K+ ATPase can impair mitochondrial energetics and induce abnormal Ca2+ cycling and automaticity in guinea pig cardiomyocytes. PLoS One 9:e93928|
|Zhou, Lufang; Xu, Ningning; Sun, Yan et al. (2014) Targeted biopharmaceuticals for cancer treatment. Cancer Lett 352:145-51|
|Zhou, Lufang; Solhjoo, Soroosh; Millare, Brent et al. (2014) Effects of regional mitochondrial depolarization on electrical propagation: implications for arrhythmogenesis. Circ Arrhythm Electrophysiol 7:143-51|
|Zhou, Lufang; O'Rourke, Brian (2012) Cardiac mitochondrial network excitability: insights from computational analysis. Am J Physiol Heart Circ Physiol 302:H2178-89|
Showing the most recent 10 out of 14 publications