Regulation of the mitochondrial calcium uniporter

线粒体钙单向转运蛋白的调节

基本信息

批准号：
10668475
负责人：
Dipayan Chaudhuri
金额：
$ 48.4万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10668475
关键词：
ATP Synthesis Pathway Acute Acute Disease Affect Affinity Animal Model Architecture Binding Biological Assay Biology Calcium Calcium Binding Calcium Signaling 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 Membrane Mitochondria Mitochondrial Matrix Molecular Mutagenesis Myocardial Infarction N-terminal Pathologic Pathway interactions Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phenotype Physiological Positioning Attribute Predisposition Principal Investigator Proteins Publications Regulation Structure Swelling Testing Vertebral column Work body system calcium uniporter clinical translation improved in vivo inhibitor innovation lipophilicity multimodality new therapeutic target novel pharmacologic preservation prevent research study skills small molecule stoichiometry structural biology targeted treatment tool uptake voltage

项目摘要

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.

项目概要钙流入线粒体可以有效刺激 ATP 合成，但过量会导致线粒体衰竭和细胞死亡。这种钙超载是疾病的一个重要病理途径在多个器官系统中。在心脏中，当心脏病发作时间较长时，会注意到这种现象缺血导致钙在细胞质中积聚，随后线粒体超载。在心里衰竭时，线粒体也更容易受到钙超载的影响。钙进入线粒体通过称为线粒体钙单向转运蛋白的多亚基钙激活通道。在动物中在模型中，单向转运蛋白的基因抑制在急性疾病中表现出保护作用。在慢性疾病中，尽管抑制钙超载具有保护作用，但也可能存在对较温和的基础需求线粒体钙吸收。然而，目前尚无专门的疗法来预防钙过载或其下游影响。体内单向转运蛋白的药理学调节受到药物的限制选择性差、细胞不可渗透或产生脱靶效应。能力上的关键差距调节单向转运蛋白是我们对如何调节成孔亚基 MCU 的有限了解。最近的优雅结构研究揭示了单转运蛋白复合物的结构和机制用于钙选择性和门控，为进一步通道的结构功能研究奠定基础规定。在这项提案中，主要研究人员应用了他们在结构生物学方面的互补技能和线粒体功能测定来定义此类药物的药理学和基于蛋白质的机制渠道监管。首先，结合计算、电生理和结构方法，我们将研究具有细胞渗透性和特异性的单向转运蛋白抑制剂，并且可用于急性或慢性损伤。其次，利用新的分子工具、诱变和结构生物学，我们将确定单向转运蛋白亚基 MCUB 如何导致抑制通过单向转运蛋白的钙摄取。采取我们的研究将共同揭示单转运蛋白调节的新形式，这些形式可能被开发成治疗方法心血管和其他疾病。