Intracellular Magnesium Concentration Research Articles

Phosphatase and Pseudo-Phosphatase Functions of Phosphatase of Regenerating Liver 3 (PRL-3) Are Insensitive to Divalent Metals In Vitro.

Phosphatase of regenerating liver 3 (PRL-3) is associated with cancer metastasis and has been shown to interact with the cyclin and CBS domain divalent metal cation transport mediator (CNNM) family of proteins to regulate the intracellular concentration of magnesium and other divalent metals. Despite PRL-3's importance in cancer, factors that regulate PRL-3's phosphatase activity and its interactions with CNNM proteins remain unknown. Here, we show that divalent metal ions, including magnesium, calcium, and manganese, have no impact on PRL-3's structure, stability, phosphatase activity, or CNNM binding capacity, indicating that PRL-3 does not act as a metal sensor, despite its interaction with CNNM metal transporters. In vitro approaches found that PRL-3 is a broad but not indiscriminate phosphatase, with activity toward di- and tri-nucleotides, phosphoinositols, and NADPH but not other common metabolites. Although calcium, magnesium, manganese, and zinc-binding sites were predicted near the PRL-3 active site, these divalent metals did not specifically alter PRL-3's phosphatase activity toward a generic substrate, its transition from an inactive phospho-cysteine intermediate state, or its direct binding with the CBS domain of CNNM. PRL-3's insensitivity to metal cations negates the possibility of its role as an intracellular metal content sensor for regulating CNNM activity. Further investigation is warranted to define the regulatory mechanisms governing PRL-3's phosphatase activity and CNNM interactions, as these findings could hold potential therapeutic implications in cancer treatment.

Massive Transfusion Increases Serum Magnesium Concentration.

(1) Background: The massive transfusion of packed red blood cells (RBCs) is a lifesaving procedure, but it is associated with complications, e.g., dysmagnesemia. Since magnesium is an intracellular ion, the transfused RBCs can significantly influence the magnesium concentration in the recipient's blood. (2) Methods: A retrospective study was performed among 49 patients hospitalized in the Central Clinical Hospital of the Medical University of Warsaw who received a massive blood transfusion (≥4 units/h). Data on laboratory results and patient history were collected from the hospital database. The intracellular RBCs magnesium concentration was measured in 231 samples using the colorimetric method. (3) Results: There were statistically significant changes in the mean serum magnesium concentration preoperatively and 24 h postoperatively (0.87 ± 0.13 vs. 1.03 ± 0.14, p < 0.00001) and 48 h postoperatively (0.87 ± 0.13 vs. 1.06 ± 0.15, p < 0.00001). Patients who died had significantly higher serum magnesium concentrations (p < 0.05). The median intracellular magnesium concentration in RBCs was 0.91 (0.55-1.8) mmol/L, which is below the reference values of 1.65-2.65 mmol/L. (4) Conclusions: Transfused RBCs significantly increased the serum magnesium concentration 24 h and 48 h postoperatively. It could be a result of mild hemolysis, as the median intracellular magnesium concentration in RBCs was below the reference values.

Polarization of THP-1-Derived Macrophage by Magnesium and MAGT1 Inhibition in Wound Healing.

Background Macrophages play a major role in wound healing and prevent infection from the outside. Polarization conversion of macrophages regulates aspects of inflammation, and two macrophages, M1 (classically activated) and M2 (alternatively activated), exist at both ends of broad-spectrum macrophage polarization. Thus, we aimed to investigate whether macrophage polarization can be artificially regulated. To this end, MgSO4 and small-interfering RNA (siRNA) targeting magnesium transport 1 (MAGT1) were used to investigate the effects of intracellular magnesium (Mg2+) concentrations on the differentiation of macrophages in vitro. Methods THP-1 derived macrophages maintained in a culture medium containing 5 mM MgSO4 and siRNA to inhibit the expression of MAGT1. As comparative groups, THP-1 derived macrophages polarized into M1 and M2 macrophages by treatment with M1, M2 inducer cytokine. The polarization status of each group of cells was confirmed by cell surface antigen expression and cytokine secretion. Results We found that MgSO4 treatment increased CD163 and CD206, similar to the effect noted in the M2 group. The expression of CD80 and HLA-DR was increased in the group treated with MAGT1 siRNA, similar to the effect noted in the M1 group. Functional assays demonstrated that the group treated with MgSO4 secreted higher levels of IL-10, whereas the MAGT1 siRNA-treated group secreted higher levels of IL-6 cytokines. Additionally, the conditional medium of the Mg2+ treated group showed enhanced migration of keratinocytes and fibroblasts. Conclusion Mg2+ can help to end the delay in wound healing caused by persistent inflammation in the early stages.

Ion selectivity and gating behavior of the CorA-type channel Bpss1228.

Magnesium is an essential element to sustain all forms of life. Total intracellular magnesium content is determined by the balance of magnesium influx and efflux. CorA is a divalent selective channel in the metal ion transport superfamily and is the major Mg2+ uptake pathway in prokaryotes and eukaryotic mitochondria. Previous studies have demonstrated that CorA showed distinct magnesium bound closed conformation and Mg2+-free states. In addition, CorA is regulated by cytoplasmic magnesium ions and its gating mechanism has been investigated by electron paramagnetic resonance technique and molecular dynamic simulations. Here, we report a study of the putative CorA-type channel Bpss1228 from Burkholderia pseudomallei, which has been shown to be significantly associated with pseudomallei infection. We expressed and purified the Bpss1228 in full-length. Subsequently, electrophysiological experiments further investigated the electrical characteristics of Bpss1228 and revealed that it was a strictly cation-selective channel. We also proved that Bpss1228 not only possessed magnesium-mediated regulatory property a remarkable ability to be modulated by magnesium ions. Finally, we observed the three-step gating behavior of Bpss1228 on planar lipid bilayer, and further proposed a synergistic gating mechanism by which CorA family channels control intracellular magnesium homeostasis.

Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome.

The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells.

A chronic low-dose magnesium L-lactate administration has a beneficial effect on the myocardium and the skeletal muscles.

The purpose of this study was to determine whether magnesium L-lactate is responsible for having a beneficial effect on the myocardium and the skeletal muscles and how this substrate acts at the molecular level. Twenty seven young male Wistar rats were supplied with a magnesium L-lactate (L) solution, a magnesium chloride (M) solution and/or water (W) as a vehicle for 10weeks. The treated animals absorbed the L and M solutions as they wished since they also had free access to water. After 9weeks of treatment, in vivo cardiac function was determined ultrasonically. The animals were sacrificed at the end of the tenth week of treatment and the heart was perfused according to the Langendorff method by using a technique allowing the determination of cardiomyocyte activity (same coronary flow in the two groups). Blood was collected and skeletal muscles of the hind legs were weighed. The myocardial expressions of the sodium/proton exchange 1 (NHE1) and sodium/calcium exchange 1 (NCX1), intracellular calcium accumulation, myocardial magnesium content, as well as systemic and tissue oxidative stress, were determined. Animals of the L group absorbed systematically a low dose of L-lactate (31.5 ± 4.3µg/100g of body weight/day) which was approximately four times higher than that ingested in the W group through the diet supplied. Ex vivo cardiomyocyte contractility and the mass of some skeletal muscles (tibialis anterior) were increased by the L treatment. Myocardial calcium was decreased, as was evidenced by an increase in total CaMKII expression, without any change in the ratio between phosphorylated CaMKII and total CaMKII. Cardiac magnesium tended to be elevated. Our results suggest that the increased intracellular magnesium concentration was related to L-lactate-induced cytosolic acidosis and to the activation of the NHE1/NCX1 axis. Interestingly, systemic oxidative stress was reduced by the L treatment whereas the lipid profile of the animals was unaltered. Taken together, these results suggest that a chronic low-dose L-lactate intake has a beneficial health effect on some skeletal muscles and the myocardium through the activation of the NHE1/NCX1 axis, a decrease in cellular calcium and an increase in cellular magnesium. The treatment can be beneficial for the health of young rodents in relation to chronic oxidative stress-related diseases.

Cardiovascular Diseases in Obesity: What is the Role of Magnesium?

An excess of adipose tissue, a characteristic of obesity, has been associated with endocrine-metabolic alterations that contribute to dyslipidemias, which are characterized by an increase in the plasma concentrations of triacylglycerols, total cholesterol, and LDL-c along with a reduction in HDL-c. Some nutrients such as the mineral magnesium play important roles in lipid metabolism. Magnesium regulates the activity of HMG-CoA reductase, increasing the activity of lipoprotein lipase and lecithin-cholesterol acyltransferase. The objective of this review is to present important aspects about the contribution of obesity to the manifestation of cardiovascular risk, to bring the main physiological functions of magnesium, as well as the role of the nutrient in the protection against cardiovascular diseases. Studies have shown that individuals with obesity have low intracellular concentrations of magnesium, which can compromise the nutrient's physiological functions. Thus, this mineral appears to play an important role in protecting against cardiovascular diseases; however, changes in the nutrient metabolism in obesity may compromise the functions of this element. Further studies are needed to clarify this.

Magnesium in Combinatorial With Valproic Acid Suppressed the Proliferation and Migration of Human Bladder Cancer Cells.

Magnesium, the second most predominant intracellular cation, plays a crucial role in many physiological functions; magnesium-based biomaterials have been widely used in clinical application. In a variety of cancer types, the high intracellular concentration of magnesium contributes to cancer initiation and progression. Therefore, we initiated this study to investigate the likelihood of confounding magnesium with cancer therapy. In this study, the anti-tumor activity of magnesium and underlying mechanisms were assessed in bladder cancer both in vitro and in vivo. The results indicated that the proliferation of bladder cancer cells was inhibited by treatment with a high concentration of MgCl2 or MgSO4. The apoptosis, G0/G1 cell cycle arrest, autophagy, and ER stress were promoted following treatment with MgCl2. However, the migratory ability of MgCl2 treated cells was similar to that of control cells, as revealed by the trans-well assay. Besides, no significant difference was observed in the proportion of CD44 or CD133 positive cells between the control and MgCl2 treated cells. Thus, to improve the therapeutic effect of magnesium, VPA was used to treat cancer cells in combination with MgCl2. As expected, combination treatment with MgCl2 and VPA could markedly reduce proliferation, migration, and in vivo tumorigenicity of UC3 cells. Moreover, the Wnt signaling was down-regulated, and ERK signaling was activated in the cells treated with combination treatment. In conclusion, the accurate utilization of MgCl2 in targeting autophagy might be beneficial in cancer therapy. Although further studies are warranted, the combination treatment of MgCl2 with VPA is an effective strategy to improve the outcome of chemotherapy.

Is Intra-Cellular Magnesium Concentration Correlate with Morbidity and Mortality in Critically Ill Patients? A Cross-Sectional Study

Backgrounds: Hypomagnesemia is a common electrolyte disturbance among critically ill patient which is associated with increased morbidity and mortality. In this study, correlations between serum and intra-cellular magnesium concentrations at the time of intensive care unit (ICU) admission with ICU complications and mortality were evaluated. Methods: This cross-sectional study included 70 consecutive adult patients admitted to the intensive care unit of a tertiary referral teaching hospital during a six-month period. Serum and intra-cellular magnesium levels were measured on admission. Clinical information, morbidity, and mortality were followed and recorded during ICU stay until discharge or death. Results: On admission, 37.14% of patients suffered hypomagnesemia. Low intra-cellular magnesium level was observed in 44.28% of patients. Cardiovascular complications and mortality were significantly higher in patients with lower serum and intra-cellular magnesium levels when compared to patients with normal levels (P &lt; 0.05). There was a significant correlation between serum magnesium level on ICU admission and Acute Physiology and Chronic Health Evaluation (APACHE II) score (r = ˗0.39, P &lt; 0.001). Conclusion: Particular attention should be reserved to possible prognostic and therapeutic consequences of magnesium depletion in critically ill patients. Magnesium deficiency was associated with a higher APACHE II score on admission, higher cardiovascular complications, and increased mortality.

Analysis of Intracellular Magnesium and Mineral Depositions during Osteogenic Commitment of 3D Cultured Saos2 Cells.

In this study, we explore the behaviour of intracellular magnesium during bone phenotype modulation in a 3D cell model built to mimic osteogenesis. In addition, we measured the amount of magnesium in the mineral depositions generated during osteogenic induction. A two-fold increase of intracellular magnesium content was found, both at three and seven days from the induction of differentiation. By X-ray microscopy, we characterized the morphology and chemical composition of the mineral depositions secreted by 3D cultured differentiated cells finding a marked co-localization of Mg with P at seven days of differentiation. This is the first experimental evidence on the presence of Mg in the mineral depositions generated during biomineralization, suggesting that Mg incorporation occurs during the bone forming process. In conclusion, this study on the one hand attests to an evident involvement of Mg in the process of cell differentiation, and, on the other hand, indicates that its multifaceted role needs further investigation.

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression

Cadmium is a xenobiotic involved in neoplastic transformation. Cadmium enters the cells through divalent cation transporters including the Transient Receptor Potential Melastatin-related 7 (TRPM7) which is known to be involved in cancer cell fate. This work aimed to study the role of TRPM7 in neoplastic transformation induced by cadmium exposure in non-cancer epithelial cells. Non-cancer epithelial cells were chronically exposed to low-dose of cadmium. TRPM7 expression and function were studied by Western-Blot, Patch-Clamp and calcium and magnesium imaging. Finally, cell migration and invasion were studied by Boyden chamber assays. Chronic cadmium exposure induced TRPM7 overexpression and increased the membrane currents (P < 0.001). Cells exposed to cadmium had higher intracellular calcium and magnesium levels (P < 0.05). TRPM7 silencing restored calcium levels but strongly decreased intracellular magnesium concentration (P < 0.001). Moreover, cadmium exposure enhanced both cell migration and invasion, but TRPM7 silencing strongly decreased these features (P < 0.001). Furthermore, mammary epithelial cells exposed to cadmium became rounded and had less cell-to-cell junctions. Cadmium exposure decreased epithelial markers while the mesenchymal ones were increased. Importantly, TRPM7 silencing was able to reverse these phenotypic modifications (P < 0.05). To summarize, our data show that chronic cadmium exposure enhanced TRPM7 expression and activity in non-cancer epithelial cells. TRPM7 overexpression induced intracellular magnesium increase and stimulated cell migration and invasion. These neoplastic properties could be linked to a TRPM7-dependent epithelial-to-mesenchymal transition reprogramming in cell exposed to cadmium. These findings provide new insights into the regulation of cell fates by cadmium exposure.

Relationship between intracellular free magnesium concentration and the degree of insulin resistance in horses with equine metabolic syndrome

Relationship between intracellular free magnesium concentration and the degree of insulin resistance in horses with equine metabolic syndrome

Optimization of hypomagnesemia diagnostics as an integral element in paroxysmal atrial fibrillation management strategy

Purpose. To study magnesium status of patients having paroxysmal atrial fibrillation (AF) based on the use of an integrated clinical and laboratory approach. Methods. A prospective cohort study included 58 patients of the cardiology department of New Hospital Medical Association. The main group consisted of 32 patients having frequently recurring paroxysmal AF, the control group consisted of 26 patients without paroxysmal rhythm disturbance. The clinical status, Holter ECG monitoring data, the test results for magnesium deficiency (MD) clinical evidence, laboratory evidence of calcium, magnesium in blood plasma and formed elements, magnesium in whole blood, free fatty acids (FFA) and osmolality in blood plasma were assessed. Results. The score obtained when assessing MD clinical evidence was significantly higher in the main group patients compared with the control group (16.5 (11÷21) vs. 13 (8÷15), p&lt;0.001). A statistically significant magnesium decrease in whole blood was revealed in patients having paroxysmal AF (0.54 (0.46÷0.60) vs. 0.61 (0.59÷0.64), p&lt;0.001) and inside formed elements (0.68 (0.53÷1.07) vs. 1.31 (1.07÷1.44), p&lt;0.001), which reflected changes in their magnesium status to a greater extent than the measured plasma cation concentrations. A close correlation between magnesium content in formed elements (intracellularly) and AF paroxysms frequency (Spearman’s rank correlation -0.51, p&lt;0.001) was established. A violation of calcium to magnesium ratio in blood plasma (2.6 (2.5÷2.9) vs. 3.0 (2.8÷3.1), p=0.004) and intracellularly (4.85 (2.62÷9.3) vs. 1.85 (1.57÷2.07), p&lt;0.001) was revealed in patients having AF. It has been shown that complex forming interactions with free fatty acids may affect intracellular calcium and magnesium content.

Clinical and methodological aspects in the diagnosis of magnesium deficiency in patients with paroxysmal atrial fibrillation

Aim. To determine magnesium deficiency in patients with paroxysmal atrial fibrillation using a comprehensive clinical and laboratory approach. Methods. The prospective cohort study included 35 patients of the cardiology department of the Medical association «Novaya bolnitsa». The main group consisted of 22 patients with frequently recurrent paroxysmal atrial fibrillation, the control group - 13 patients without cardiac arrhythmias. The clinical status, Holter-monitoring of the electrocardiogram, the results of the clinical test for magnesium deficiency, laboratory parameters of calcium, magnesium in blood plasma and formed elements, magnesium in whole blood, free fatty acids and plasma osmolarity were evaluated. Results. The clinical score of magnesium deficiency was significantly higher in patients from the main group compared to the control [16.5 (11÷21) vs 13 (8÷15), p &lt;0.001]. In the main group, there was a decrease of magnesium in the whole blood [0.55 (0.5÷0.59) vs 0.61 (0.58÷0.54), p=0.002] and inside the blood cells [0.68 (0.53÷1.29) vs 1.38 (1.29÷1.44), p &lt;0.001]. In patients with atrial fibrillation there is a shift of the ratio of calcium to magnesium in blood plasma [2.5 (2.5÷3) vs 2.9 (2.8÷3.15), p=0.029] and intracellularly [4.85 (2.62÷9.3) vs 1.7 (1.4÷1.95), p=0.002]. The redistribution of calcium and magnesium is influenced not only by the initial concentration of cations, but also by free fatty acids. The best redistribution was obtained when the concentration of free fatty acids was 900 µmol/l, magnesium 1 mmol/l, and calcium 3 mmol/l, which is consistent with the optimal value of cations in the blood plasma. Conclusion. Patients with paroxysmal atrial fibrillation had a significantly lower magnesium content in whole blood and inside the blood cells; magnesium concentration in the cells and in whole blood closely correlated with the results of the clinical test for evaluating magnesium deficiency; intracellular magnesium content can be influenced by the complexing interaction with free fatty acids.

Magnesium enhances dehydration tolerance in Schizosaccharomyces pombe by promoting intracellular 5'-methylthioadenosine accumulation.

AbstractIn the present study, we analysed metabolite features during the dehydration–rehydration process for two Schizosaccharomyces pombe strains with different viability rate, in order to determine whether metabolite contents were affected by the presence of magnesium during cell rehydration. The qualitative changes of the intracellular metabolites of both strains were determined by comparing the metabolic profiles of cells before dehydration, after rehydration in water or magnesium solution, and after 2‐hr inoculation of cells in complete medium. Our results suggest that changes of metabolites from the methionine salvage pathway, in particular 5′‐methylthioadenosine, triggered by the increasing intracellular magnesium content may participate in the dehydration tolerance of Sp97 cells.

192-LB: Serum Magnesium Levels and Its Relationship with Alterations of Glucose Metabolism during Pregnancy

Intracellular magnesium contributes in the regulation of the effects of insulin and glucose uptake; its deficits strongly associated with hyperglycemia, hypertriglyceridemia and insulin resistance (IR). Studies in healthy, hypertensive, and diabetes mellitus type 2 (DM2) subjects have shown a lower concentration of intracellular magnesium, higher glucose increase. It is unknown if there is hypomagnesemia related to hyperglycemia and insulin resistance during pregnancy. Analytical cross-sectional study in pregnant women who signed consent, ≥18 years old, any trimester of pregnancy. Patients with chronic diarrhea, alcohol intake (≥30 g/day), use of diuretics and/or calcium channel blockers, reduced renal function, or supplemented with magnesium for at least six months prior to the study were not included. Clinical variables were determined, anthropometry, vital signs, serum magnesium levels, fasting glucose and 2-h plasma glucose (2-h PG) value during a 75-g oral glucose tolerance test (OGTT), lipid profile and glycosylated hemoglobin (A1C) were measured. We analyzed 84 patients with whom the 3 study groups were formed: healthy pregnant women, with IR (TyG index) and gestational diabetes (GD) (Table). Hypomagnesemia was found in all 3 groups without a clear relationship between low magnesium levels and alterations in glucose status. Disclosure A. López Castro: None. A. Zavalza Gomez: None. S. Hernandez Gonzalez: None. M.C. Espinel-Bermudez: None. J.R. Ortiz Hernandez: None.

Dose-dependent effects of magnesium supplementation on serum and intracellular magnesium concentrations in healthy horses

Dose-dependent effects of magnesium supplementation on serum and intracellular magnesium concentrations in healthy horses

Fluorescence lifetime imaging of intracellular magnesium content in live cells.

The first detailed analysis of FLIM applications for Mg cell imaging is presented. We employed the Mg-sensitive fluorescent dye named DCHQ5, a derivative of diaza-18-crown-6 ethers appended with two 8-hydroxyquinoline groups, to perform fluorescence lifetime imaging in control and Mg deprived SaOS-2 live cells, which contain different concentrations of magnesium. We found that the lifetime maps are almost uniform all over the cells and, most relevantly, we showed that the ratio of the amplitude terms is related to the magnesium intracellular concentration.

Intracellular free magnesium concentration in healthy horses.

Equine metabolic syndrome (EMS) is a worldwide disease in horses that parallels human diabetes mellitus type 2. In both diseases, patients show an altered peripheral insulin sensitivity as a key feature. In humans, multiple studies have demonstrated the beneficial effect of magnesium supplementation on insulin sensitivity. However, serum magnesium levels vary and are therefore not a reliable indicator of the patients' magnesium status. Determining the intracellular free magnesium concentration appears to be a more sensitive diagnostic indicator. In this study, the free intracellular magnesium concentration was measured using mag-fura 2 spectrophotometry in blood lymphocytes in 12 healthy, non-obese horses at 9a.m., 12a.m. and 4p.m. to establish reference ranges according to a protocol designed for human blood lymphocytes. Additionally, the serum magnesium concentration was measured. In all horses, the total serum magnesium concentration was within the reference range. The mean free magnesium concentration in blood lymphocytes of all horses was 0.291±0.067mmol/L with no significant difference between the time points. The reference range for the free intracellular magnesium concentration in equine lymphocytes was set at 0.16-0.42mmol/L. The established values are slightly lower than those in healthy humans. The designed protocol for the measurement of the intracellular free magnesium concentration might be an excellent research tool to assess the cellular magnesium status and to reliably diagnose an altered magnesium homeostasis in EMS. Further studies shall elucidate possible alterations in cellular magnesium status in horses with EMS.

PRL Phosphatases Promote Tumor Progression by Regulating the Level of Intracellular Magnesium

The Phosphatase of Regenerative Liver (PRL) enzymes (PRL‐1,‐2,‐3; gene name PTP4A1, PTP4A2, PTP4A3) are members of the protein tyrosine phosphatase family. These enzymes have been identified as key contributors to tumor progression and metastasis in several human cancers, yet the molecular basis of their pro‐oncogenic property is unclear. Using mass spectrometry studies, we identified the CNNM magnesium transporters as key binding partners of PRLs in an evolutionarily conserved complex that regulates the intracellular magnesium concentration. Structural analysis of this complex indicates that the second cystathionine β‐synthase (CBS) domain of CNNM underlines a binding loop unique to the CNNM family that only exists in organisms having PRL orthologs. Mutation of an evolutionarily conserved aspartic acid located in this CBS domain of CNNM3 was able to completely abolish the interaction with PRL‐2 resulting in reduced tumor growth. Also, either the abolishment of complex formation or PRL‐2 knockdown resulted in reduced magnesium transport. Since magnesium is a critical metabolic effector, we confirmed that mitochondrial respiration is altered in cells isolated from PRL2‐null animals and is associated with a lower ATP turnover. This is also consistent with the observed decreased body weight of PRL‐2−/− mice, suggesting that their cellular metabolism is inherently less efficient. As cellular magnesium transport is regulated by intrinsic mechanisms controlling various magnesium transporters and magnesium uptake in cells, we also aimed to examine the involvement of PRLs in the adaptive response related to changes in magnesium availability. Using various cell lines cultured under low magnesium conditions, we observed a decrease in intracellular magnesium levels correlating with a marked increase of PRL‐1 and ‐2 (PRL‐1/2) expression. Although the expression levels of the magnesium transporter CNNM3 remained unchanged after magnesium depletion, we found that the interaction between endogenous PRL‐1/2 and CNNM3 was also markedly increased, indicating a pivotal regulatory role for PRL‐1/2 in the complex to compensate for decreased magnesium availability. On the contrary, upon increasing intracellular magnesium levels by overexpressing the TRPM7 magnesium transporter, we observed a reduction of PRL‐1/2 expression. Consistent with this, using an in vivo reporter mouse model, PRL‐2 tissue expression was upregulated when dietary magnesium was limited. Overall, our findings suggest that PRL phosphatases regulate cellular magnesium levels, essential for cell survival/proliferation, which may explain much of the clinical relationship between PRLs and cancer.Support or Funding InformationThis research is supported by an operating grant from Canadian Institutes of Health Research (CIHR); CIHR MOP 142497.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.