Magnesium, mitochondria, and diastolic dysfunction

低血清镁（Mg）是心血管和全因死亡率的预测因子， 补充剂在心力衰竭中显示出显著的治疗效果。维持心脏镁稳态 通过一系列肌膜和线粒体转运蛋白，如瞬时受体电位melastatin 7 通道（TRPM7）。线粒体作为镁的储存器。在低镁血症（HypoMg）中，线粒体Ca（mitoCa） 增加，线粒体Mg（mitoMg）减少。线粒体Ca增加与线粒体 活性氧（mitoROS）的过度产生。 最近，我们发现糖尿病（DM）介导的舒张功能不全（DD）与下列因素有关： 低Mg 31、47、48 Mg补充通过减少线粒体ROS产生和线粒体Ca过载来缓解DD， 增加ATP产生，改善线粒体形态。18在初步数据中，我们表明， 单独的低镁，没有DM，足以通过诱导电子传递链（ETC）功能障碍引起DD 49 增加线粒体。mitoROS49的增加与TRPM7的增加有关，并且线粒体DNA的表达增加。 Ca单向转运体（MCU），而另一种Mg转运体溶质载体家族41A1不变。我们发现TRPM7 激酶调节MCU磷酸化。再次，Mg补充、MCU敲低、TRPM7敲低和TRPM7敲低 激酶失活逆转HypoMg的作用。新的发现包括，低镁单独可以导致DD， 低镁可导致TRPM7、MCU和mitoROS的调节异常，补充镁可作为一种治疗方法。 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过度产生和DD，并且减轻这些变化 可以防止线粒体镁耗竭和随后的心肌病 在这项研究中，我们将测试这一假设在三个目标。 目标1.为了确定TRPM 7在HypoMg诱导的mitoMg消耗、ETC功能障碍、mitoROS功能障碍中的作用， 生产过剩和DD。 目标2.为了确定TRPM7激酶活性在HypoMg诱导的线粒体Mg消耗中的作用，ETC 功能障碍、线粒体ROS过度产生和DD。 目标3.研究MCU在HypoMg诱导的mitoMg耗竭、ETC功能障碍、mitoROS、 生产过剩和DD。 该项目的结果有望导致对心脏病的新认识和治疗策略 舒张功能不全和射血分数正常的心力衰竭（HFpEF）。此外，阐明作用 TRPM7和MCU的研究将为我们提供新的见解，了解Mg和Ca处理的分子基础， 生理和病理条件。

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.