The Correlation of the Average Increase in Blood Magnesium Levels with the Incidence of Preeclampsia After Magnesium Supplementation in Hypomagnesemic Pregnant Women at the Padang City Health Center

Preeclampsia is a hypertensive disorder in pregnancy that occurs in 5-10% of pregnancies and occurs after 20 weeks of gestation and recovers spontaneously after delivery. Several studies have stated that one of the risks of hypertension in pregnancy is related to magnesium homeostasis. Magnesium plays an important role in forming new tissues (maternal and fetal). Pregnant women need a higher intake of magnesium than non-pregnant women of the same age. Magnesium deficiency during pregnancy not only causes problems for the nutrition of pregnant women and fetuses, but also associated with the occurrence of preeclampsia, preterm labor and muscle cramps during pregnancy. This study aims to determine the relationship between the average increase in blood magnesium levels with the incidence of preeclampsia in hypomagnesemic pregnant women.Keywords: preeclampsia, hypertension, blood magnesium levels

Magnesium Deficiency Alters Expression of Genes Critical for Muscle Magnesium Homeostasis and Physiology in Mice

Chronic Mg2+ deficiency is the underlying cause of a broad range of health dysfunctions. As 25% of body Mg2+ is located in the skeletal muscle, Mg2+ transport and homeostasis systems (MgTHs) in the muscle are critical for whole-body Mg2+ homeostasis. In the present study, we assessed whether Mg2+ deficiency alters muscle fiber characteristics and major pathways regulating muscle physiology. C57BL/6J mice received either a control, mildly, or severely Mg2+-deficient diet (0.1%; 0.01%; and 0.003% Mg2+ wt/wt, respectively) for 14 days. Mg2+ deficiency slightly decreased body weight gain and muscle Mg2+ concentrations but was not associated with detectable variations in gastrocnemius muscle weight, fiber morphometry, and capillarization. Nonetheless, muscles exhibited decreased expression of several MgTHs (MagT1, CNNM2, CNNM4, and TRPM6). Moreover, TaqMan low-density array (TLDA) analyses further revealed that, before the emergence of major muscle dysfunctions, even a mild Mg2+ deficiency was sufficient to alter the expression of genes critical for muscle physiology, including energy metabolism, muscle regeneration, proteostasis, mitochondrial dynamics, and excitation–contraction coupling.

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

Cyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like GTPase 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction between CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 and CNBH domains. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the endoplasmic reticulum, Golgi apparatus and the plasma membrane. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

The Combined Influence of Magnesium and Insulin on Central Metabolic Functions and Expression of Genes Involved in Magnesium Homeostasis of Cultured Bovine Adipocytes

At the onset of lactation, dairy cows suffer from insulin resistance, insulin deficiency or both, similar to human diabetes, resulting in lipolysis, ketosis and fatty liver. This work explored the combined effects of different levels of magnesium (0.1, 0.3, 1 and 3 mM) and insulin (25, 250 and 25,000 pM) on metabolic pathways and the expression of magnesium-responsive genes in a bovine adipocyte model. Magnesium starvation (0.1 mM) and low insulin (25 pM) independently decreased or tended to decrease the accumulation of non-polar lipids and uptake of the glucose analog 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-deoxyglucose (6-NBDG). Activity of glycerol 3-phosphate dehydrogenase (GPDH) was highest at 25 pM insulin and 3 mM magnesium. Expression of SLC41A1 and SLC41A3 was reduced at 0.1 mM magnesium either across insulin concentrations (SLC41A1) or at 250 pM insulin (SLC41A3). MAGT1 expression was reduced at 3 mM magnesium. NIPA1 expression was reduced at 3 mM and 0.1 mM magnesium at 25 and 250 pM insulin, respectively. Expression of SLC41A2, CNNM2, TRPM6 and TRPM7 was not affected. We conclude that magnesium promotes lipogenesis in adipocytes and inversely regulates the transcription of genes that increase vs. decrease cytosolic magnesium concentration. The induction of GAPDH activity by surplus magnesium at low insulin concentration can counteract excessive lipomobilization.

Molecular Mechanisms of Renal Magnesium Reabsorption

Magnesium is an essential cofactor in many cellular processes, and aberrations in magnesium homeostasis can have life-threatening consequences. The kidney plays a central role in maintaining serum magnesium within a narrow range (0.70 to 1.10 mmol/L). Along the proximal tubule and thick ascending limbs, magnesium reabsorption occurs via paracellular pathways. Members of the claudin family form the magnesium pores in these segments, and also regulate magnesium reabsorption by adjusting the transepithelial voltage that drives it. Along the distal convoluted tubule transcellular reabsorption via heteromeric TRPM6/7 channels predominates, though paracellular reabsorption may also occur. In this segment, the NaCl cotransporter plays a critical role in determining transcellular magnesium reabsorption. While the general machinery involved in renal magnesium reabsorption has been identified by studying genetic forms of magnesium imbalance, the mechanisms regulating it are poorly understood. This review discusses pathways of renal magnesium reabsorption by different segments of the nephron, emphasizing newer findings that provide insight into regulatory process, and outlining critical unanswered questions.

Limitation of phosphate assimilation maintains cytoplasmic magnesium homeostasis

Phosphorus (P) is an essential component of core biological molecules. In bacteria, P is acquired mainly as inorganic orthophosphate (Pi) and assimilated into adenosine triphosphate (ATP) in the cytoplasm. Although P is essential, excess cytosolic Pi hinders growth. We now report that bacteria limit Pi uptake to avoid disruption of Mg2+-dependent processes that result, in part, from Mg2+ chelation by ATP. We establish that the MgtC protein inhibits uptake of the ATP precursor Pi when Salmonella enterica serovar Typhimurium experiences cytoplasmic Mg2+ starvation. This response prevents ATP accumulation and overproduction of ribosomal RNA that together ultimately hinder bacterial growth and result in loss of viability. Even when cytoplasmic Mg2+ is not limiting, excessive Pi uptake increases ATP synthesis, depletes free cytoplasmic Mg2+, inhibits protein synthesis, and hinders growth. Our results provide a framework to understand the molecular basis for Pi toxicity. Furthermore, they suggest a regulatory logic that governs P assimilation based on its intimate connection to cytoplasmic Mg2+ homeostasis.

ARL15 modulates magnesium homeostasis through N-glycosylation of CNNMs

ABSTRACTCyclin M (CNNM1-4) proteins maintain cellular and body magnesium (Mg2+) homeostasis. Using various biochemical approaches, we have identified members of the CNNM family as direct interacting partners of ADP-ribosylation factor-like protein 15 (ARL15), a small GTP-binding protein. ARL15 interacts with CNNMs at their carboxyl-terminal conserved cystathionine-β-synthase (CBS) domains. In silico modeling of the interaction using the reported structures of both CNNM2 and ARL15 supports that the small GTPase specifically binds the CBS1 domain. Immunocytochemical experiments demonstrate that CNNM2 and ARL15 co-localize in the kidney, with both proteins showing subcellular localization in the Golgi-apparatus. Most importantly, we found that ARL15 is required for forming complex N-glycosylation of CNNMs. Overexpression of ARL15 promotes complex N-glycosylation of CNNM3. Mg2+ uptake experiments with a stable isotope demonstrate that there is a significant increase of 25Mg2+ uptake upon knockdown of ARL15 in multiple kidney cancer cell lines. Altogether, our results establish ARL15 as a novel negative regulator of Mg2+ transport by promoting the complex N-glycosylation of CNNMs.

Limitation of phosphate assimilation maintains cytoplasmic magnesium homeostasis

Phosphorus (P) is an essential component of several core biological molecules. In bacteria, P is mainly acquired as inorganic orthophosphate (Pi). Once in the cytoplasm, Pi is incorporated into adenosine triphosphate (ATP), which exists primarily as a Mg2+ salt. Notably, whereas P is essential, excess of cytosolic Pi hinders growth. Here we demonstrate that cytotoxic effects of excessive Pi uptake result from its assimilation into ATP and subsequent disruption of Mg2+ dependent processes. We show that Salmonella enterica cells experiencing cytoplasmic Mg2+ starvation restrict Pi uptake, thereby limiting the availability of an ATP precursor. This response prevents excessive ATP synthesis, overproduction of ribosomal RNA, chelation of free cytoplasmic Mg2+ and the destabilization of Mg2+-dependent core processes that ultimately hinder bacterial growth and leads to loss of cellular viability. We demonstrate that, even when cytoplasmic Mg2+ is not limiting, excessive Pi uptake leads to increased ATP synthesis, depletion of free cytoplasmic Mg2+, inhibition of translation and growth. Our results establish that bacteria must restrict Pi uptake to prevent the depletion of cytoplasmic Mg2+. Furthermore, they provide a framework to understand the molecular basis of Pi cytotoxicity and reveal a regulatory logic employed by bacterial cells to control P assimilation.ImportancePhosphorus (P) is essential for life. As the fifth most abundant element in living cells, P is required for the synthesis of an array of biological molecules including (d)NTPs, nucleic acids and membranes. Organisms typically acquire environmental P as inorganic phosphate. While essential for growth and viability, excessive intracellular Pi is toxic for both bacteria and eukaryotes. Using the bacterium Salmonella enterica as a model, we demonstrate that Pi cytotoxicity is manifested following its assimilation into ATP, which acts as a chelating agent for intracellular cations, most notably, Mg2+. These results identify physiological processes disrupted by excessive Pi and elucidate a regulatory logic employed by bacteria to prevent uncontrollable P assimilation.