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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)是心血管疾病和全因死亡率的预测因子，而补充剂在治疗心力衰竭方面显示出显著的疗效。维持心脏镁代谢平衡通过一系列肌膜和线粒体转运蛋白，如瞬时受体潜力Melastatin 7 频道(TRPM7)。线粒体起到储存镁的作用。在低镁血症(HypoMG)中，线粒体钙(MitoCa) 线粒体镁(MitoMg)含量降低。线粒体膜上线粒体钙升高活性氧(MitoROS)产生过多。最近，我们发现糖尿病(DM)介导的舒张期功能障碍(DD)与补充31，47，48毫克通过减少线粒体ROS的产生和线粒体钙超载来缓解DD，增加ATP的产生，改善线粒体的形态。18在初步数据中，我们表明在没有DM的情况下，仅HypoMG就足以通过诱导电子传递链(ETC)功能障碍而导致DD49 以及增加有丝分裂原。线粒体ROS49的增加与TRPM7和线粒体的增加有关 CA单转运体(MCU)，而另一个镁转运体溶质载体家族41A1没有变化。我们证明了TRPM7 激酶调节MCU的磷酸化。同样，镁回收、MCU击倒、TRPM7击倒和TRPM7 蛋白激酶失活逆转HypoMG的作用。新的发现包括单独的HypoMG可以引起DD，即 HypoMg可导致TRPM7、MCU和mitoROS的失调，补充镁可作为一种线粒体抗氧化剂。假设：因此，我们假设TRPM7(通道和激酶功能)和MCU的变化导致mitoMg耗竭、ETC功能障碍、mitoROS过度生产和DD，并缓解这些变化将防止线粒体镁耗竭和随后的心肌病。在这项研究中，我们将从三个方面检验这一假说。目的：1.探讨TRPM7在HypoMG引起的线粒体镁耗竭等功能障碍中的作用。生产过剩和DD。目的2.探讨TRPM7激酶活性在HypoMg诱导的线粒体镁耗竭等过程中的作用功能障碍，有丝分裂酶过度生产和DD。目的：研究MCU在低镁所致的线粒体镁耗竭等功能障碍中的作用。生产过剩和DD。这一项目的结果有望导致对心脏疾病的新理解和治疗策略。舒张期功能不全和心力衰竭并保留射血分数(HFpEF)。此外，对这一角色的阐明 TRPM7和MCU的研究将为我们提供新的见解，以了解镁和钙在不同条件下的分子基础生理和病理条件。