Abstract：
Calcium (Ca2+) has been observed as the most important ion involved in a series of cellular processes and its homeostasis is critical for normal cellular functions. Mitochondrial calcium uniporter (MCU) complex has been recognized as the most important calcium-specific channel located in the inner mitochondrial membrane and is one of the major players in maintaining the Ca2+ homeostasis by transporting Ca2+ across the mitochondrial membrane. Furthermore, dysregulation of the mitochondrial Ca2+ homeostasis has been orchestrated to neurodegenerative response. This necessitates quantitative evaluation of the MCU-dependent mROS production and subsequent cellular responses for more specific therapeutic interventions against neurodegenerative disorders. Towards this goal, here we present a biological regulatory network of MCU to dynamically simulate the MCU-mediated ROS production and its response in neurodegeneration. Previously, ruthenium complex RuRed and its derivatives have been reported to show low nM to high µM potency against MCU to maintain cytosolic Ca2+ (cCa2+) homeostasis by modulating mitochondrial Ca2+ (mCa2+) uptake. Therefore, structural modeling and dynamic simulation of MCU pore-forming subunit is performed to probe the interaction profiling of previously reported Ru265 and its derivatives compounds with MCU. The current study highlighted MCU as a potential drug target in neurodegenerative disorders. Furthermore, ASP261 and GLU264 amino acid residues in DIME motif of MCU pore-forming subunits are identified as crucial for modulating the activity of MCU in neurodegenerative disorders.
摘要：
已观察到钙（Ca2）是一系列细胞过程中最重要的离子，其稳态对于正常的细胞功能至关重要。线粒体钙单蛋白（MCU）复合物已被认为是位于线粒体内膜中最重要的钙特异性通道，并且是通过跨线粒体膜运输Ca2来维持Ca2稳态的主要参与者之一。此外，线粒体Ca2稳态的失调已被编排为神经退行性反应。这需要对MCU依赖性mROS的产生和随后的细胞反应进行定量评估，以进行针对神经退行性疾病的更具体的治疗干预。为了这个目标,在这里，我们提出了MCU的生物调节网络，以动态模拟MCU介导的ROS产生及其在神经变性中的反应。以前,据报道，钌络合物RuRed及其衍生物显示出对MCU的低nM至高µM效力，可通过调节线粒体Ca2（mCa2）摄取来维持细胞溶质Ca2（cCa2）稳态。因此,进行了MCU成孔亚基的结构建模和动态模拟，以探测先前报道的Ru265及其衍生物与MCU的相互作用。目前的研究强调MCU是神经退行性疾病的潜在药物靶点。此外，MCU孔形成亚基的DIME基序中的ASP261和GLU264氨基酸残基被认为对于调节神经退行性疾病中MCU的活性至关重要。
