Magnesium, mitochondria, and diastolic dysfunction

镁、线粒体和舒张功能障碍

基本信息

批准号：
10705354
负责人：
SAMUEL C DUDLEY
金额：
$ 54.44万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2022-09-22 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705354
关键词：
Affect Antioxidants Blood Pressure Calcium Calcium Channel Blockers Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cell physiology Cells DNA Data Diabetes Mellitus Divalent Cations EFRAC Electron Transport Elements Equilibrium Failure Family Functional disorder Heart failure Homeostasis Hypertension Hypomagnesemia Inner mitochondrial membrane Intake Ion Channel Kidney Lead Magnesium Magnesium Deficiency Maintenance Mediating Membrane Mg supplementation Minerals Mitochondria Mitochondrial RNA Molecular Morphology Muscle Contraction Outcome Pathologic Phosphorylation Phosphotransferases Physiological Play Production Protein Biosynthesis Proteins RNA Splicing RNA chemical synthesis Reactive Oxygen Species Regulation Reporting Resistance Role Series Serum Symptoms TRP channel Testing Therapeutic Effect Up-Regulation calcium uniporter extracellular heart rhythm improved insight knock-down mitochondrial dysfunction mitochondrial membrane mortality mouse model novel preservation prevent receptor response solute treatment strategy

项目摘要

Low serum magnesium (Mg) is a predictor for cardiovascular and all-cause mortality, while Mg supplementation has shown significant therapeutic effects in heart failure. Cardiac Mg homeostasis is maintained by a series of sarcolemmal and mitochondrial transporters such as the transient receptor potential melastatin 7 channel (TRPM7). Mitochondria act as stores of Mg. In hypomagnesemia (HypoMg), mitochondrial Ca (mitoCa) is increased and mitochondrial Mg (mitoMg) is reduced. Increased mitoCa is associated with mitochondrial reactive oxygen species (mitoROS) overproduction. Recently, we have shown that diabetes mellitus (DM)-mediated diastolic dysfunction (DD) is associated with HypoMg.31, 47, 48 Mg supplementation relieves DD by reducing mitoROS production and mitoCa overload, increasing ATP production, and improving mitochondrial morphology.18 In preliminary data, we show that HypoMg alone, without DM, is sufficient to cause DD49 by inducing electron transport chain (ETC) dysfunction and increasing mitoROS. The increase in mitoROS49 is associated with increased TRPM7 and the mitochondrial Ca uniporter (MCU), while another Mg transporter solute carrier family 41A1 is unchanged. We show that TRPM7 kinase regulates MCU phosphorylation. Again, Mg repletion, MCU knockdown, TRPM7 knockdown, and TRPM7 kinase inactivation reverse effects of HypoMg. The novel findings include that HypoMg alone can cause DD, that HypoMg can cause dysregulation of TRPM7, MCU, and mitoROS, and that Mg supplementation can act as a mitochondrial antioxidant. Hypothesis: Therefore, we hypothesize that changes in TRPM7 (both channel and kinase functions) and MCU result in mitoMg depletion, ETC dysfunction, mitoROS overproduction, and DD and that mitigating these changes will prevent mitoMg depletion and the subsequent cardiomyopathy. In this study, we will test this hypothesis in three aims. Aim 1. To determine the role of TRPM7 in HypoMg-induced mitoMg depletion, ETC dysfunction, mitoROS overproduction and DD. Aim 2. To determine the role of TRPM7 kinase activity in HypoMg-induced mitoMg depletion, ETC dysfunction, mitoROS overproduction and DD. Aim 3. To study the role of MCU in HypoMg-induced mitoMg depletion, ETC dysfunction, mitoROS overproduction and DD. The outcome of this project is expected to lead to novel understandings and treatment strategies for cardiac diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF). Moreover, elucidation of the role of TRPM7 and MCU will provide us with novel insights into the molecular basis of Mg and Ca handling under physiological and pathological conditions.

低血清镁（MG）是心血管和全因死亡率的预测因子，而MG 补充对心力衰竭显示出显着的治疗作用。维持心脏MG稳态通过一系列肌膜和线粒体转运蛋白，例如瞬态受体电势梅拉斯汀7 通道（TRPM7）。线粒体作为Mg的存储。在低磁性血症（Hypomg）中，线粒体CA（Mitoca）增加并减少线粒体MG（mitomg）。线粒体增加与线粒体有关活性氧（Moritoros）过量生产。最近，我们表明糖尿病（DM）介导的舒张功能障碍（DD）与 Hypomg.31，47，47 mg补充剂可通过减少Moritoros的产生和Mitoca超负荷来缓解DD 提高ATP的产生并改善线粒体形态。18在初步数据中，我们表明单独使用DM的Hytomg足以通过诱导电子传输链（ETC）功能障碍引起DD49 并增加身体。 MitoroS49的增加与TRPM7和线粒体增加有关 CA Uniporter（MCU），而另一个MG转运蛋白溶质载体家族41A1不变。我们证明TRPM7 激酶调节MCU磷酸化。同样，MG的补充，MCU敲低，TRPM7敲低和TRPM7 激酶失活的反向作用。新颖的发现包括单独的hytomg可能会导致DD， hytomg可能引起TRPM7，MCU和MOTOROS的失调，并且补充毫克可以充当线粒体抗氧化剂。假设：因此，我们假设TRPM7（通道和激酶函数）和MCU的变化导致MITOMG耗竭等功能障碍，Moritoros过量生产和DD，并减轻这些变化将防止丝瘤耗竭和随后的心肌病。在这项研究中，我们将以三个目标检验这一假设。目的1。确定TRPM7在Hypomg诱导的丝线耗竭等功能障碍中的作用，moritoros 过量生产和DD。目的2。确定TRPM7激酶活性在Hypomg诱导的MITOMG耗竭等中的作用功能障碍，moritoros生产过量和DD。目的3。研究MCU在Hypomg诱导的MITOMG耗竭等功能障碍中的作用，moritoros 过量生产和DD。预计该项目的结果将导致对心脏的新理解和治疗策略舒张功能障碍和心力衰竭，保留的射血分数（HFPEF）。而且，阐明角色 TRPM7和MCU将为我们提供有关MG和CA处理的分子基础的新见解生理和病理状况。