Recent discovery of the molecular identity of pore-forming subunit of the mitochondrial Ca2+ uniporter (encoded by MCU gene) provides new possibilities for applying genetic approaches to study the mitochondrial Ca2+ (mtCa2+) influx mechanism. T hough the alteration of MCU function and mtCa2+ overload are frequently observed in non- cardiac human diseases, cardiomyocytes (ACMs) and MCU function contribute to the pathology . Recently, I reported that a post-translational modification (PTM) of MCU (tyrosine it is still not clear how mtCa2+ in adult phosphorylation) is one of the critical regulatory mechanisms for upregulating MCU function in ACMs. PTM of MCU initiates overload, -dependent ROS overproduction and activation of apoptotic signaling under alpha1-adrenoceptor (alpha1-AR) stimulation, suggesting that PTM of MCU plays an important role in the development of cardiac dysfunction under Gq-protein-coupled receptor (GqPCR) stimulation, which is one of the major causes of heart failure (HF) in vivo. In addition to the discovery of the PTM of MCU, I identified a form of transcriptional/post-transcriptional regulation of MCU, namely the existence of alternative transcript variants (?short- form? MCU, termed MCU-S) in human and mouse in addition to the original MCU (?long form? MCU, renamed MCU-L). Importantly, MCU-S is highly expressed in non-excitable cells including adult cardiac fibroblast (ACFs). Our preliminary data show that introduction of MCU-S enhances the formation of Ca2+-permeable channels at the plasma membrane (PM). In addition, the PM-localized MCU channel (PM-MCU) formed by MCU-S activates glycolysis followed by acceleration of ATP production in the cytoplasm, possibly due to the increase in local [Ca2+]c beneath the PM. These preliminary findings indicate an important role of PM-MCU channels for energy metabolism especially in non-excitable cells (such as ACFs). We also determined that the manipulation of MCU-S/MCU-L ratio mtCa2+ mtCa2+ can secondarily modulate the driving force of MCU-channel trafficking to IMM, which eventually inhibits the mtCa2+ uptake, mtCa2+ -dependent ROS overproduction and activation of apoptotic signaling under alpha1-AR stimulation. Therefore, I hypothesize that the MCU gene encodes two isoforms that form both mitochondrial and non- mitochondrial MCU channels; novel transcript variant MCU-S forms a PM-MCU channels that regulate cell?s metabolism and inhibits the MCU-channel trafficking to IMM. To test the hypothesis, I will investigate whether MCU-S forms Ca2+-permeable MCU channels at PM and is involved in the mechanism for the activation of glycolysis to accelerate ATP production in the cytoplasm in primary ACMs and ACFs (Aim.1). I will next test whether switching the main variant from MCU-L to MCU-S protects the heart from mtCa2+-overload-mediated apoptotic death, energy depletion and cardiac dysfunction under GqPCR stimulation in vivo (Aim.2). The outcome of this project is expected to lead to a novel treatment strategy for cases of HF under GqPCR stimulation that involve mtCa2+ overload, oxidative stress, energy depletion and ACM death. Moreover, elucidation of the role of MCU variants will provide us novel insights into the molecular basis of mtCa2+ handling in the heart.
It is our goal to understand the detailed mechanism of why heart beats become weaker when we have heart disease. We begin by using abnormal ion channel proteins found in humans with heart disease, introducing these mutant proteins into animals and examining the functional changes in the animals? heart cells. The experiments and analysis of this project will help us to find novel drugs for preventing sudden and unexplained death by heart disease.
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