The role of calcium entry through the mitochondrial uniporter in regulating cardiac metabolism and physiology

钙通过线粒体单转运蛋白进入在调节心脏代谢和生理学中的作用

• 批准号: 10320832
• 负责人: TOREN FINKEL
• 金额: $ 66.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320832
• 关键词: Aging; Alleles; Animals; Bioenergetics; Biology; Biophysics; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cell Death; Cells; Complex; Data; Defect; Electrophysiology (science); Enzymes; Functional disorder; Genetic; Genetic Models; Genetic Transcription; Heart; Human; Inner mitochondrial membrane; Ischemia; Link; Mediating; Membrane; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Molecular; Multiprotein Complexes; Mus; Muscle Cells; Myocardial; Myocardial Ischemia; Necrosis; Oxidation-Reduction; Pathology; Pathway interactions; Pharmacology; Phosphotransferases; Physiological; Physiology; Play; Process; Production; Proteins; RIPK1 gene; RIPK3 gene; Reperfusion Injury; Reperfusion Therapy; Role; Scaffolding Protein; Stress; Testing; VDAC1 gene; age related; calcium uniporter; cyclophilin D; experimental study; genetic approach; genetic manipulation; heart function; heart metabolism; in vivo; induced pluripotent stem cell; mitochondrial membrane; mitochondrial permeability transition pore; mouse model; normal aging; programs; response; scaffold; single-cell RNA sequencing; tissue injury; treatment strategy; uptake

The entry of calcium into the mitochondria is fundamentally important in regulating bioenergetic capacity and modulating cell death thresholds. For nearly fifty years, mitochondria were known to have a selective calcium-selective pore in the inner mitochondrial membrane. Entry of calcium through this pore, often termed the calcium uniporter, was believed to be essential in boosting ATP production by augmenting the activity of multiple calcium-sensitive mitochondrial matrix enzymes. This increase in mitochondrial calcium therefore allowed for a rapid but regulated increase in mitochondrial ATP under conditions of increased energetic demand. While under these conditions, the entry of calcium appears beneficial, additional evidence suggested that excessive calcium entry triggers a mitochondrial cell death program characterized by opening of the mitochondrial permeability transition pore (mPTP). Such situations appear to be particularly relevant to tissue injury occurring in the setting of ischemia-reperfusion injury. While considerable electrophysiological, biophysical and physiological data existed on the mitochondrial inner membrane calcium pore, its molecular identity remained elusive for over fifty years. That situation has demonstrably changed in the last five years with the rapid identification of the components of the inner mitochondrial calcium uniporter complex (MCUC) now known to be composed of at least four proteins. These components include the pore- forming protein MCU, its apparent membrane scaffold EMRE and two calcium-sensitive regulators MICU1 and MICU2. The molecular identity of the MCUC paved the way for the creation of mouse models in which one or more component of the complex has been deleted. This, in turn, allows for a more detailed and precise analysis of the physiological role of mitochondrial calcium in regulating both bioenergetics and cell death. Here, we propose to analyze the role of the MCUC in basal and stress-induced cardiovascular physiology. Our particular emphasis will be on the role of the MCUC in ischemia/reperfusion injury, metabolism and aging. This analysis, we believe, will increase our fundamental understanding of both mitochondrial biology and cardiac physiology and potentially pave the way for new treatment strategies targeting a diverse array of conditions ranging from reperfusion injury to the age- dependent decline in cardiac function.

钙进入线粒体对于调节生物能量至关重要 容量和调节细胞死亡阈值。近五十年来，线粒体已知 在线粒体膜中具有选择性钙选择性孔。进入 据认为，通过此孔经钙通常称为钙Uniporter，被认为是必不可少的 通过增强多个钙敏感的线粒体的活性来增强ATP的产生 基质酶。因此，线粒体钙的增加允许快速但 在能量需求增加的条件下，线粒体ATP的调节增加。尽管 在这些条件下，钙的进入似乎有益，提出了其他证据 过度的钙进入触发了一个以线粒体细胞死亡为特征的线粒体细胞死亡程序 线粒体通透性过渡孔（MPTP）的打开。这种情况似乎是 与在缺血再灌注损伤的情况下发生的组织损伤特别相关。尽管 存在相当大的电生理，生物物理和生理数据 线粒体内膜钙孔，其分子身份仍然难以捉摸 年。随着快速 鉴定内部线粒体钙Uniporter复合物（MCUC）的成分 现在已知至少由四种蛋白质组成。这些成分包括孔 形成蛋白质MCU，其明显的膜支架EMRE和两个钙敏感 调节器MICU1和MICU2。 MCUC的分子身份为 创建鼠标模型，其中已删除了复合物的一个或多个组成部分。 反过来，这允许对 线粒体钙在调节生物能和细胞死亡方面。在这里，我们建议 分析MCUC在基础和应力诱导的心血管生理学中的作用。我们的 特别强调MCUC在缺血/再灌注损伤，代谢中的作用 和老化。我们认为，这种分析将增加我们对两者的基本理解 线粒体生物学和心脏生理学，并有可能为新治疗铺平道路 针对从再灌注损伤到年龄各种条件的各种条件的策略 - 心脏功能的依赖下降。