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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）是心血管和全因死亡率的预测因子