Aberrant intracellular calcium ([Ca2+]i) homeostasis has been implicated in cardiovascular diseases (CVD) which contributes to endothelial dysfunction. Ca2+ acts as a second messenger and is known to regulate several cell functions. Despite the available evidence of a link between Ca2+ signaling and endothelial dysfunction, mechanisms underlying the development of vascular disease remain incompletely understood. Besides Ca2+, reactive oxygen species have also been implicated in endothelial cell (EC) dysfunction. A growing recognition exists of a link between elevated levels of mitochondrial Ca2+ and subsequent generation of mitochondrial reactive oxygen species (mROS) in cardiovascular diseases. Mitochondria shape cytosolic Ca2+ signals by sequestering Ca2+ through uniporter and transporters. Nevertheless, the causal link between mitochondrial Ca2+ overload and mROS production is poorly understood in the context of EC dysfunction. Recently identified mitochondrial Ca2+ uniporter complex molecules MCU and MICU1 are shown to regulate the mitochondrial Ca2+ uptake, however the pathophysiological role of these molecules in endothelial function has not been studied. Our new findings show that MICU1 gates the basal mitochondrial Ca2+ accumulation by regulating MCU. Further, silencing of MICU1 facilitates constitutive mitochondrial Ca2+ overload which subsequently elevates mROS and sensitizes cells to apoptotic stimuli. Accordingly, our central hypothesis is that MICU1 gates MCU pore activity limiting basal mitochondrial Ca2+ accumulation and ROS overproduction to preserve vascular integrity. The hypothesis was formulated based on our recent publication in Cell. The hypothesis will be tested using combination of molecular and cell biology, biochemical and advanced imaging technology, primary endothelial cells, genetically-modified animals and samples from human subject with coronary artery disease. Our proposal will address these issues via three specific aims: 1) Characterize the functional role of MICU1 in EC mitochondrial Ca2+ homeostasis 2) Study the role of MICU1 in EC signaling and function, and 3) Investigate the role of MICU1 in EC biology under pathophysiological conditions. Importantly, our investigations will uncover the role of MICU1 in mitochondrial Ca2+ homeostasis and mROS production in vascular endothelium. The expected outcomes from these studies will significantly shift the focus of EC signaling by elucidating that MICU1 plays a central role in limiting mitochondrial Ca2+ load and oxidative signaling. Such findings are expected to have an immediate impact through advancing the fields of EC Ca2+ signaling and oxidative stress with a strong likelihood that the information will provide new targets for therapeutic interventions in CVD.
Both mitochondrial Ca2+ overload and elevated mitochondrial-derived ROS have been implicated in cardiovascular diseases and ischemia/reperfusion injury. Aberrant Ca2+ and mROS promote bioenergetic crisis which results in EC cell death. The proposed study will uncover the role of MICU1 in mitochondrial Ca2+ homeostasis and mROS in vascular endothelial cells, which may lead to development of new interventions in vascular disorders.
|Lee, Samuel K; Shanmughapriya, Santhanam; Mok, Mac C Y et al. (2016) Structural Insights into Mitochondrial Calcium Uniporter Regulation by Divalent Cations. Cell Chem Biol 23:1157-69|
|Bao, Lei; Chen, Shu-Jen; Conrad, Kathleen et al. (2016) Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics. J Biol Chem 291:24449-24464|
|Tomar, Dhanendra; Dong, Zhiwei; Shanmughapriya, Santhanam et al. (2016) MCUR1 Is a Scaffold Factor for the MCU Complex Function and Promotes Mitochondrial Bioenergetics. Cell Rep 15:1673-85|
|Scheitlin, Christopher G; Julian, Justin A; Shanmughapriya, Santhanam et al. (2016) Endothelial mitochondria regulate the intracellular Ca2+ response to fluid shear stress. Am J Physiol Cell Physiol 310:C479-90|
|Chu, Jin; Li, Jian-Guo; Joshi, Yash B et al. (2015) Gamma secretase-activating protein is a substrate for caspase-3: implications for Alzheimer's disease. Biol Psychiatry 77:720-8|
|Hoffman, Nicholas E; Miller, Barbara A; Wang, JuFang et al. (2015) CaÂ²âº entry via Trpm2 is essential for cardiac myocyte bioenergetics maintenance. Am J Physiol Heart Circ Physiol 308:H637-50|
|Shanmughapriya, Santhanam; Rajan, Sudarsan; Hoffman, Nicholas E et al. (2015) Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU. Sci Signal 8:ra23|
|Chu, Jin; Li, Jian-Guo; Hoffman, Nicholas E et al. (2015) Degradation of gamma secretase activating protein by the ubiquitin-proteasome pathway. J Neurochem 133:432-9|
|Woitek, Felix; Zentilin, Lorena; Hoffman, Nicholas E et al. (2015) Intracoronary Cytoprotective Gene Therapy: A Study of VEGF-B167 in a Pre-Clinical Animal Model of Dilated Cardiomyopathy. J Am Coll Cardiol 66:139-53|
|Chu, Jin; Li, Jian-Guo; Hoffman, Nicholas E et al. (2015) Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence. Sci Rep 5:11086|
Showing the most recent 10 out of 38 publications