Regulation of the mitochondrial calcium uniporter

线粒体钙单向转运蛋白的调节

• 批准号: 10539759
• 负责人: Dipayan Chaudhuri
• 金额: $ 56.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539759
• 关键词: ATP Synthesis Pathway; Acute; Acute Disease; Affect; Affinity; Animal Model; Architecture; Binding; Biological Assay; Biology; Calcium; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Charge; Chemicals; Chronic; Chronic Disease; Clinical Pharmacology; Complex; Cryoelectron Microscopy; Cytoplasm; Dimerization; Disease; Drug Design; Electrophysiology (science); Failure; Functional disorder; Genetic; Goals; Group Structure; Heart; Heart Injuries; Heart failure; Homeostasis; Human; Impairment; Injury; Investigation; Ischemia; Location; Mediating; Mitochondria; Mitochondrial Matrix; Molecular; Mutagenesis; Myocardial Infarction; N-terminal; Pathologic; Pathway interactions; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Positioning Attribute; Principal Investigator; Proteins; Publications; Regulation; Signal Transduction; Structure; Swelling; Testing; Vertebral column; Work; base; body system; calcium uniporter; clinical translation; improved; in vivo; inhibitor; innovation; lipophilicity; multimodality; new therapeutic target; novel; preservation; prevent; research study; skills; small molecule; stoichiometry; structural biology; targeted treatment; tool; uptake; voltage

PROJECT SUMMARY Calcium influx into the mitochondria can potently stimulate ATP synthesis, but excessive levels cause mitochondrial failure and cell death. Such calcium overload is a prominent pathological pathway in disease in multiple organ systems. In the heart, this phenomenon is noted during heart attacks, when prolonged ischemia causes calcium to accumulate in the cytoplasm and subsequently overload mitochondria. In heart failure, mitochondrial are also more susceptible to calcium overload. Calcium enters the mitochondria through a multi-subunit calcium-activated channel known as the mitochondrial calcium uniporter. In animal models, genetic inhibition of the uniporter has appeared protective in acute disease. In chronic diseases, though inhibition of calcium overload is protective, there may also be basal requirements for milder mitochondrial calcium uptake. Currently, however, there are no specific therapies to prevent calcium overload or its downstream affects. Pharmacological modulation of the uniporter in vivo is limited by agents that are poorly selective, cell impermeable, or produce off-target effects. A critical gap in the ability to better modulate the uniporter is our limited understanding of how the pore-forming subunit, MCU, is regulated. Recent elegant structural studies have revealed the architecture of the uniporter complex, and mechanisms for calcium selectivity and gating, setting the stage for structure-function investigations of further channel regulation. In this proposal, the principal investigators apply their complementary skills in structural biology and mitochondrial functional assays to define pharmacological and protein-based mechanisms for such channel regulation. First, using a combination of computational, electrophysiological, and structural approaches, we will investigate uniporter inhibitors that are cell-permeable and specific, and useful for either acute or chronic injury. Second, using new molecular tools, mutagenesis, and structural biology, we will identify how the uniporter subunit MCUB leads to inhibition of calcium uptake through the uniporter. Taken together, our studies will reveal novel forms of uniporter regulation that may be developed into therapies for cardiovascular and other disorders.

项目总结 钙离子流入线粒体可以有效地刺激三磷酸腺苷的合成，但过多的钙离子水平会导致 线粒体衰竭和细胞死亡。这种钙超载是疾病中一种突出的病理途径。 在多个器官系统中。在心脏，这种现象在心脏病发作期间被注意到，如果持续时间长的话。 缺血导致钙在细胞质中积聚，随后使线粒体超载。内心深处 失灵后，线粒体也更容易受到钙超载的影响。钙进入线粒体 通过被称为线粒体钙单转运体的多亚基钙激活通道。在动物身上 在模型中，单转运蛋白的基因抑制在急性疾病中似乎具有保护性。在慢性病方面， 虽然抑制钙超载是保护性的，但也可能对较温和的钙超载有基本要求。 线粒体钙摄取。然而，目前还没有专门的治疗方法来预防钙 过载或其下游影响。体内单转运蛋白的药理调节受到药物的限制 选择性差，细胞不渗透，或产生偏离目标的效果。在能力上存在严重差距， 调节单转运蛋白是我们对成孔亚单位MCU如何调控的有限理解。 最近优雅的结构研究揭示了单一转运体复合体的结构和机制 对于钙的选择性和门控，为进一步研究通道的结构和功能奠定了基础 监管。在这项建议中，主要研究人员将他们的互补技能应用于结构生物学。 和线粒体功能分析，以确定药理学和基于蛋白质的机制 航道整治。首先，使用计算、电生理和结构的组合 方法，我们将研究细胞渗透性和特异性的单转运蛋白抑制剂，对任何一种都有用 急性或慢性损伤。第二，使用新的分子工具、突变和结构生物学，我们将 确定单转运子亚单位MCUB如何通过单转运子抑制钙摄取。已被占用 总之，我们的研究将揭示新形式的单一转运体调控，这些形式可能会被开发成治疗 心血管疾病和其他疾病。