Publications by authors named "Martin Kolisek"

43 Publications

A Possible Preventive Role of Physically Active Lifestyle during the SARS-CoV-2 Pandemic; Might Regular Cold-Water Swimming and Exercise Reduce the Symptom Severity of COVID-19?

Int J Environ Res Public Health 2021 07 4;18(13). Epub 2021 Jul 4.

Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 036 01 Martin, Slovakia.

The objective of this study was to investigate the incidence and course of COVID-19 and the risk of an upper respiratory tract infection in a group of people with physically active lifestyles. Data were collected anonymously using an online survey platform during December 2020. The age of participants ranged from 18 to 65 years. Out of 2343 participants, 11.5% overcame COVID-19 infection. Relative to the control group (CTRL), physically active, cold-water swimmers (PACW) did not exhibit a lower risk of incidence for COVID-19 (RR 1.074, CI 95% (0.710-1.625). However, PACW had a higher chance of having an asymptomatic course of COVID-19 (RR 2.321, CI 95% (0.836-6.442); < 0.05) and a higher chance of only having an acute respiratory infection once or less per year than CTRL (RR 1.923, CI 95% (1.1641-2.253); < 0.01). Furthermore, PACW exhibited a lower incidence of acute respiratory infection occurring more than twice per year (RR 0.258, CI 95% (0.138-0.483); < 0.01). Cold-water swimming and physical activity may not lessen the risk of COVID-19 in recreational athletes. However, a physically active lifestyle might have a positive effect on the rate of incidence of acute respiratory infection and on the severity of COVID-19 symptoms.
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http://dx.doi.org/10.3390/ijerph18137158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297290PMC
July 2021

Strenuous Physical Training, Physical Fitness, Body Composition and Bacteroides to Prevotella Ratio in the Gut of Elderly Athletes.

Front Physiol 2021 22;12:670989. Epub 2021 Jun 22.

Department of Biological and Medical Science, Faculty of Physical Education and Sport, Comenius University in Bratislava, Bratislava, Slovakia.

Regular physical activity seems to have a positive effect on the microbiota composition of the elderly, but little is known about the added possible benefits of strenuous endurance training. To gain insight into the physiology of the elderly and to identify biomarkers associated with endurance training, we combined different omics approaches. We aimed to investigate the gut microbiome, plasma composition, body composition, cardiorespiratory fitness, and muscle strength of lifetime elderly endurance athletes (LA) age 63.5 (95% CI 61.4, 65.7), height 177.2 (95% CI 174.4, 180.1) cm, weight 77.8 (95% CI 75.1, 80.5) kg, VO2max 42.4 (95% CI 39.8, 45.0) ml.kg.min ( = 13) and healthy controls age 64.9 (95% CI 62.1, 67.7), height 174.9 (95% CI 171.2, 178.6) cm, weight 83.4 (95% CI 77.1, 89.7) kg, VO2max 28.9 (95% CI 23.9, 33.9), ml.kg.min ( = 9). Microbiome analysis was performed on collected stool samples further subjected to 16S rRNA gene analysis. NMR-spectroscopic analysis was applied to determine and compare selected blood plasma metabolites mostly linked to energy metabolism. The machine learning (ML) analysis discriminated subjects from the LA and CTRL groups using the joint predictors 1.8E + 00 (95% CI 1.1, 2.5)%, 3.8E + 00 (95% CI 2.7, 4.8)% ( = 0.002); 1.3 (95% CI 0.28, 2.4)%, 0.1 (95% CI 0.07, 0.3)% ( = 0.02); 1.3E-02 (95% CI 9.3E-03, 1.7E-02)%, 5.9E-03 (95% CI 3.9E-03, 7.9E-03)% ( = 0.002), 7.9E-02 (95% CI 2.5E-02, 1.3E-02)%, 3.2E-02 (95% CI 1.8E-02, 4.6E-02)% ( = 0.02); and the ratio of to 133 (95% CI -86.2, 352), 732 (95% CI 385, 1079.3) ( = 0.03), leading to an ROC curve with AUC of 0.94. Further, random forest ML analysis identified VO2max, BMI, and the to ratio as appropriate, joint predictors for discriminating between subjects from the LA and CTRL groups. Although lifelong endurance training does not bring any significant benefit regarding overall gut microbiota diversity, strenuous athletic training is associated with higher cardiorespiratory fitness, lower body fat, and some favorable gut microbiota composition, all factors associated with slowing the rate of biological aging.
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http://dx.doi.org/10.3389/fphys.2021.670989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257935PMC
June 2021

Bioaccessibility and Bioavailability of Minerals in Relation to a Healthy Gut Microbiome.

Int J Mol Sci 2021 Jun 24;22(13). Epub 2021 Jun 24.

Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia.

Adequate amounts of a wide range of micronutrients are needed by body tissues to maintain health. Dietary intake must be sufficient to meet these micronutrient requirements. Mineral deficiency does not seem to be the result of a physically active life or of athletic training but is more likely to arise from disturbances in the quality and quantity of ingested food. The lack of some minerals in the body appears to be symbolic of the modern era reflecting either the excessive intake of empty calories or a negative energy balance from drastic weight-loss diets. Several animal studies provide convincing evidence for an association between dietary micronutrient availability and microbial composition in the gut. However, the influence of human gut microbiota on the bioaccessibility and bioavailability of trace elements in human food has rarely been studied. Bacteria play a role by effecting mineral bioavailability and bioaccessibility, which are further increased through the fermentation of cereals and the soaking and germination of crops. Moreover, probiotics have a positive effect on iron, calcium, selenium, and zinc in relation to gut microbiome composition and metabolism. The current literature reveals the beneficial effects of bacteria on mineral bioaccessibility and bioavailability in supporting both the human gut microbiome and overall health. This review focuses on interactions between the gut microbiota and several minerals in sport nutrition, as related to a physically active lifestyle.
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http://dx.doi.org/10.3390/ijms22136803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268569PMC
June 2021

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

Int J Mol Sci 2021 May 31;22(11). Epub 2021 May 31.

Institute of Veterinary Physiology, Freie Universität Berlin, 14163 Berlin, Germany.

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 and was reduced at 0.1 mM magnesium either across insulin concentrations () or at 250 pM insulin (). expression was reduced at 3 mM magnesium. expression was reduced at 3 mM and 0.1 mM magnesium at 25 and 250 pM insulin, respectively. Expression of , , and 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.
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http://dx.doi.org/10.3390/ijms22115897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199494PMC
May 2021

The Efficacy of Short-Term Weight Loss Programs and Consumption of Natural Probiotic Bryndza Cheese on Gut Microbiota Composition in Women.

Nutrients 2021 May 21;13(6). Epub 2021 May 21.

Department of Biological and Medical Science, Faculty of Physical Education and Sport, Comenius University in Bratislava, 814 69 Bratislava, Slovakia.

Weight loss interventions with probiotics have favourable effects on gut microbiota composition and derived metabolites. However, little is known about whether the consumption of natural probiotics, such as Bryndza cheeses, brings similar benefits. The purpose of the study was to find the effect of short-term weight loss programs and Bryndza cheese consumption on the structure of the gut microbiota, microbiota-derived metabolites and body composition in middle-aged women. We conducted a randomised controlled intervention study. Twenty-two female participants with a body fat percentage ≥25% underwent a short weight loss program (4 weeks). Subjects were randomised to either the control or intervention group according to diet. The intervention group comprised 13 participants, whose diet contained 30 g of "Bryndza" cheese daily (WLPB). The control group comprised nine participants without the regular consumption of Bryndza cheese (WLP) in their diet. Both interventions lead to a significant and favourable change of BMI, body fat, waist circumference and muscle mass. Moreover, the relative abundance of significantly increased in both groups. However, the relative abundance of lactic acid bacteria (, , and ) significantly increased only in the WLPB group. Furthermore, short-chain fatty acid producers and increased significantly in the WLPB group. A short-term weight loss program combined with Bryndza cheese consumption improves body composition and increases the abundance of lactic acid bacteria and short-chain fatty acid producers in middle-aged women.
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http://dx.doi.org/10.3390/nu13061753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224276PMC
May 2021

Beneficial effects of an alkaline topical treatment in patients with mild atopic dermatitis.

J Cosmet Dermatol 2021 Jan 14. Epub 2021 Jan 14.

Division of Neurosciences, Biomedical Center in Martin, Jessenius Faculty of Medicine in Martin, Comenius University, Bratislava, Slovakia.

Background: Atopic dermatitis (AD) is the most common cause of eczema. The skin condition affects millions of people worldwide. Severe cases of AD demand systemic treatment, but most AD cases rely on local therapy with topical corticosteroids, emollients, and moisturizing agents to alleviate eczema. Commonly, derma-cosmetics with a pH around 5.5 are used to treat eczematous lesions (EL). However, evidence is currently amassing that the use of mildly alkaline topical creams is beneficial for AD-related eczema treatment because of its effect on the inflammation in the skin.

Aims: To test an alkaline two-phase care concept for the treatment of eczema.

Patients/methods: An open-label study of 25 patients with eczema associated with mild AD. Patients were treated with Alkaline Build Up Caring Cream INTENSIVE and Alkaline Build Up Caring Cream PLUS+ (both Siriderma ) for eight weeks. Dermatological, biochemical, and questionnaire-based examinations were conducted prior to the trial and after its completion.

Results: Topical administration of slightly alkaline creams led to small and statistically insignificant increases of skin pH. Clinical examination at the end of the observation period revealed a significant decrease of total eczematous-affected skin area, a significant decrease in average severity scores of EL, and significant improvements in patient-reported outcome parameters. Blood tests did not reveal any significant changes, except for small but significant increases in IL-8 and monocytes.

Conclusion: Mildly alkaline topical creams seem to provide soothing effects on eczema-related skin inflammation and thus might contribute to treatment of local symptoms of eczema in patients with mild AD.
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http://dx.doi.org/10.1111/jocd.13936DOI Listing
January 2021

Dietary Mg Intake and the Na/Mg Exchanger SLC41A1 Influence Components of Mitochondrial Energetics in Murine Cardiomyocytes.

Int J Mol Sci 2020 Nov 3;21(21). Epub 2020 Nov 3.

Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Mala Hora 4D, 036 01 Martin, Slovakia.

Cardiomyocytes are among the most energy-intensive cell types. Interplay between the components of cellular magnesium (Mg) homeostasis and energy metabolism in cardiomyocytes is poorly understood. We have investigated the effects of dietary Mg content and presence/functionality of the Na/Mg exchanger SLC41A1 on enzymatic functions of selected constituents of the Krebs cycle and complexes of the electron transport chain (ETC). The activities of aconitate hydratase (ACON), isocitrate dehydrogenase (ICDH), α-ketoglutarate dehydrogenase (KGDH), and ETC complexes CI-CV have been determined in vitro in mitochondria isolated from hearts of wild-type (WT) and mice fed a diet with either normal or low Mg content. Our data demonstrate that both, the type of Mg diet and the genotype largely impact on the activities of enzymes of the Krebs cycle and ETC. Moreover, a compensatory effect of genotype on the effect of low Mg diet on activities of the tested Krebs cycle enzymes has been identified. A machine-learning analysis identified activities of ICDH, CI, CIV, and CV as common predictors of the type of Mg diet and of CII as suitable predictor of genotype. Thus, our data delineate the effect of dietary Mg content and of SLC41A1 functionality on the energy-production in cardiac mitochondria.
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http://dx.doi.org/10.3390/ijms21218221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663288PMC
November 2020

Current Methods of Magnetic Resonance for Noninvasive Assessment of Molecular Aspects of Pathoetiology in Multiple Sclerosis.

Int J Mol Sci 2020 Aug 25;21(17). Epub 2020 Aug 25.

Clinic of Neurology, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 036 01 Martin, Slovakia.

Multiple sclerosis (MS) is an autoimmune disease with expanding axonal and neuronal degeneration in the central nervous system leading to motoric dysfunctions, psychical disability, and cognitive impairment during MS progression. The exact cascade of pathological processes (inflammation, demyelination, excitotoxicity, diffuse neuro-axonal degeneration, oxidative and metabolic stress, etc.) causing MS onset is still not fully understood, although several accompanying biomarkers are particularly suitable for the detection of early subclinical changes. Magnetic resonance (MR) methods are generally considered to be the most sensitive diagnostic tools. Their advantages include their noninvasive nature and their ability to image tissue in vivo. In particular, MR spectroscopy (proton H and phosphorus P MRS) is a powerful analytical tool for the detection and analysis of biomedically relevant metabolites, amino acids, and bioelements, and thus for providing information about neuro-axonal degradation, demyelination, reactive gliosis, mitochondrial and neurotransmitter failure, cellular energetic and membrane alternation, and the imbalance of magnesium homeostasis in specific tissues. Furthermore, the MR relaxometry-based detection of accumulated biogenic iron in the brain tissue is useful in disease evaluation. The early description and understanding of the developing pathological process might be critical for establishing clinically effective MS-modifying therapies.
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http://dx.doi.org/10.3390/ijms21176117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504207PMC
August 2020

Assessment of bioavailability of Mg from Mg citrate and Mg oxide by measuring urinary excretion in Mg-saturated subjects.

Magnes Res 2019 Aug;32(3):63-71

Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Biomedical Center Martin, Division of Neurosciences, MartinSlovakia, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Institute of Medical Biochemistry, MartinSlovakia.

Background: Low magnesium (Mg) levels are linked to many diseases. Studies suggest that organic salts of Mg are more readily bioavailable than its oxide or inorganic salts used for supplements production. Unfortunately, the plethora of variables in the previous study designs complicates the making of any clear and reliable conclusions.

Methods: 14 healthy males were supplemented for five days with 400 mg Mg to saturate Mg pools before intake of the test products. Bioavailability of 400 mg Mg from Mg citrate (MgC) and Mg oxide (MgO) after single-dose administration was assessed by measuring renal Mg excretion in 24-h urine and blood plasma [Mg] at time points 0, 2, 4, 8, and 24 h.

Results: Single-dose MgC supplementation led to a significant (P < 0.05) increase in 24 h urinary Mg excretion, but this was not significant following MgO. Plasma [Mg] was also significantly higher for MgC than for MgO at 4 h (P < 0.05) and 8 h (P < 0.05). Compared with baseline levels, MgC supplementation showed a significant increase in plasma [Mg] at all time points, in contrast to MgO.

Conclusions: MgC shows higher bioavailability compared with MgO. Furthermore, urinary Mg excretion should be determined as the primary endpoint of Mg bioavailability studies.
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http://dx.doi.org/10.1684/mrh.2019.0457DOI Listing
August 2019

Optimizing adipogenic transdifferentiation of bovine mesenchymal stem cells: a prominent role of ascorbic acid in induction.

Adipocyte 2020 12;9(1):35-50

Institute of Veterinary-Physiology, Freie Universität Berlin, Berlin, Germany.

Adipocyte differentiation of bovine adipose-derived stem cells (ASC) was induced by foetal bovine serum (FBS), biotin, pantothenic acid, insulin, rosiglitazone, dexamethasone and 3-isobutyl-1-methylxanthine, followed by incubation in different media to test the influence of ascorbic acid (AsA), bovine serum lipids (BSL), FBS, glucose and acetic acid on transdifferentiation into functional adipocytes. Moreover, different culture plate coatings (collagen-A, gelatin-A or poly-L-lysine) were tested. The differentiated ASC were subjected to Nile red staining, DAPI staining, immunocytochemistry and quantitative reverse transcription PCR (for ). Nile red quantification showed a significant increase in the development of lipid droplets in treatments with AsA and BSL without FBS. The presence of BSL induced a prominent increase in mRNA abundance and in FABP4 immunofluorescence signals in coincubation with AsA. The abundance of and mRNA decreased or tended to decrease in the absence of FBS, and ENG was additionally suppressed by AsA. DAPI fluorescence was higher in cells cultured in poly-L-lysine or gelatin-A coated wells. In additional experiments, the multi-lineage differentiation potential to osteoblasts was verified in medium containing ß-glycerophosphate, dexamethasone and 1,25-dihydroxyvitamin D using alizarin red staining. In conclusion, bovine ASC are capable of multi-lineage differentiation. Poly-L-lysine or gelatin-A coating, the absence of FBS, and the presence of BSL and AsA favour optimal transdifferentiation into adipocytes. AsA supports transdifferentiation via a unique role in induction, but this is not linearly related to the primarily BSL-driven lipid accumulation.: AcA: acetic acid; AsA: ascorbic acid; ASC: adipose-derived stem cells; BSL: bovine serum lipids; DAPI: 4´,6-diamidino-2-phenylindole; DLK: delta like non-canonical notch ligand; DMEM: Dulbecco's modified Eagle's medium; DPBS: Dulbecco's phosphate-buffered saline; ENG: endoglin; FABP: fatty acid binding protein; FAS: fatty acid synthase; GLUT4: glucose transporter type 4; IBMX: 3-isobutyl-1-methylxanthine; LPL: lipoprotein lipase; MSC: mesenchymal stem cells; α-MEM: α minimum essential medium; NT5E: ecto-5'-nucleotidase; PDGFRα: platelet derived growth factor receptor α; PPAR: peroxisome proliferator activated receptor γ; RPS19: ribosomal protein S19; SEM: standard error of the mean; THY1: Thy-1 cell surface antigen; TRT: treatment; TRT-Con: treatment negative control; YWHAZ: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta.
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http://dx.doi.org/10.1080/21623945.2020.1720480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999845PMC
December 2020

SNPs rs11240569, rs708727, and rs823156 in Do Not Discriminate Between Slovak Patients with Idiopathic Parkinson's Disease and Healthy Controls: Statistics and Machine-Learning Evidence.

Int J Mol Sci 2019 Sep 21;20(19). Epub 2019 Sep 21.

Division of Neurosciences, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 03601 Martin, Slovakia.

Gene () is localized within Parkinson's disease-(PD)-susceptibility locus and encodes for the Na/Mg-exchanger. The association of several SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG/AG/AA is significantly ( < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible.
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http://dx.doi.org/10.3390/ijms20194688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801379PMC
September 2019

Magnesium-responsive genes are downregulated in diabetic patients after a three-month exercise program on a bicycle ergometer.

J Chin Med Assoc 2019 Jun;82(6):495-499

Department of Physical Medicine and Rehabilitation, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, ROC.

Background: Exercise is an effective therapy for the management of diabetes because it helps regulate glucose and magnesium homeostasis. Nevertheless, the mechanisms by which exercise exerts effects on magnesium transport remain unclear. This study investigated the expression of genes encoding magnesium transporters (GMTs) after a three-month exercise program in diabetic patients.

Methods: This study was conducted with a within-subject pre-post design. A total of 15 adult patients with type 2 diabetes mellitus (T2DM) were recruited and underwent a three-month indoor bicycle exercise program. The expression of five GMTs (CNNM2, TRPM6, TRPM7, SLC41A1, and SLC41A3) was determined in blood samples. Relevant anthropometric values and biochemical parameters were also determined.

Results: Although the body weight and body mass index decreased after three months exercise, there were no significant differences. Fasting blood glucose, glycated hemoglobin (HbA1c), waist circumference, and magnesium levels decreased after the exercise program (p < 0.05). The expression of SLC41A1 and SLC41A3 were downregulated after exercise, but only CNNM2, TRPM6, and TRPM7 showed significantly decreased expression levels compared with those before the exercise program (p < 0.05).

Conclusion: The three-month exercise program ameliorated blood glucose levels and downregulated the expression of magnesium-responsive genes in patients with T2DM.
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http://dx.doi.org/10.1097/JCMA.0000000000000112DOI Listing
June 2019

Magnesium Extravaganza: A Critical Compendium of Current Research into Cellular Mg Transporters Other than TRPM6/7.

Rev Physiol Biochem Pharmacol 2019 ;176:65-105

Biomedical Center Martin, Division of Neurosciences, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.

Magnesium research has boomed within the last 20 years. The real breakthrough came at the start of the new millennium with the discovery of a plethora of possible Mg homeostatic factors that, in particular, included putative Mg transporters. Until that point, Mg research was limited to biochemical and physiological work, as no target molecular entities were known that could be used to explore the molecular biology of Mg homeostasis at the level of the cell, tissue, organ, or organism and to translate such knowledge into the field of clinical medicine and pharmacology. Because of the aforementioned, Mg and Mg homeostasis, both of which had been heavily marginalized within the biomedical field in the twentieth century, have become overnight a focal point of many studies ranging from primary biomedical research to translational medicine.The amount of literature concerning cellular Mg transport and cellular Mg homeostasis is increasing, together with a certain amount of confusion, especially about the function(s) of the newly discovered and, in the majority of instances, still only putative Mg transporters/Mg homeostatic factors. Newcomers to the field of Mg research will thus find it particularly difficult to orient themselves.Here, we briefly but critically summarize the status quo of the current understanding of the molecular entities behind cellular Mg homeostasis in mammalian/human cells other than TRPM6/7 chanzymes, which have been universally accepted as being unspecific cation channel kinases allowing the flux of Mg while constituting the major gateway for Mg to enter the cell.
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http://dx.doi.org/10.1007/112_2018_15DOI Listing
May 2019

Overexpression of the mitochondrial Mg channel MRS2 increases total cellular Mg concentration and influences sensitivity to apoptosis.

Metallomics 2018 07;10(7):917-928

Transfusion Medicine Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, 42123, Italy.

The mechanism of action of the mitochondrial Mg channel MRS2 and its involvement in cell viability remain unclear. Deletion of MRS2 has been reported to abolish Mg influx into mitochondria, to induce functional defects in mitochondrial organelles, and to result in cell death. We evaluated whether MRS2 expression had an impact on total Mg cellular content by inducing the overexpression of MRS2 in HEK-293 cells. We observed a remarkable increase of total intracellular Mg concentration in cells overexpressing MRS2 compared with control cells. In order to investigate whether and in what manner the detected Mg increment was involved in the MRS2 influence on cell viability, we treated MRS2-overexpressing cells with two known apoptotic inducers. We found that cells overexpressing the MRS2 channel became less responsive to these pharmacological insults. Our experimental evidence indicates that the MRS2 channel controls overall intracellular Mg levels, the alteration of which might have a role in the molecular signaling leading to apoptotic cell death.
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http://dx.doi.org/10.1039/c8mt00050fDOI Listing
July 2018

Overexpression of Na/Mg exchanger SLC41A1 attenuates pro-survival signaling.

Oncotarget 2018 Jan 22;9(4):5084-5104. Epub 2017 Dec 22.

Institute of Veterinary-Physiology, Free University of Berlin, Berlin, Germany.

The Na/Mg exchanger SLC41A1 (A1), a key component of intracellular Mg homeostasis (IMH), is the major cellular Mg efflux system, and its overexpression decreases [Mg]. IMH plays an important role in the regulation of many cellular processes, including cellular signaling. However, whether the overexpression of A1 and the consequent drop of [Mg] impact on intracellular signaling is unknown. To examine the latter, we utilized dynamic mass redistribution (DMR) assay, PathScan RTK signaling antibody (PRSA) array, confirmatory Western blot (WB) analyses of phosphorylation of kinases selected by PRSA, and mag-fura 2-assisted fast filter spectrometry (FFS). We demonstrate here that the overexpression of A1 quantitatively and qualitatively changes the DMR signal evoked by the application of PAR-1-selective activating peptide and/or by changing [Mg] in HEK293 cells. PRSA profiling of the phosphorylation of important signaling nodes followed by confirmatory WB has revealed that, in HEK293 cells, A1 overexpression significantly attenuates the phosphorylation of Akt/PKB on Thr and/or Ser and of Erk1/2 on Thr/Tyr in the presence of 0 or 1 mM (physiological) Mg in the bath solution. The latter is also true for SH-SY5Y and HeLa cells. Overexpression of A1 in HEK293 cells significantly lowers [Mg] in the presence of [Mg] = 0 or 1 mM. This correlates with the observed attenuation of prosurvival Akt/PKB - Erk1/2 signaling in these cells. Thus, A1 expression status and [Mg] (and consequently also [Mg]) modulate the complex physiological fingerprint of the cell and influence the activity of kinases involved in anti-apoptotic and, hence, pro-survival events in cells.
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http://dx.doi.org/10.18632/oncotarget.23598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797035PMC
January 2018

Magnesium and Other Biometals in Oxidative Medicine and Redox Biology.

Oxid Med Cell Longev 2017;2017:7428796. Epub 2017 Oct 4.

University of Palermo, Palermo 90144, Italy.

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http://dx.doi.org/10.1155/2017/7428796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646342PMC
January 2019

Influence of Bovine Serum Lipids and Fetal Bovine Serum on the Expression of Cell Surface Markers in Cultured Bovine Preadipocytes.

Cells Tissues Organs 2017 12;204(1):13-24. Epub 2017 May 12.

Institute of Veterinary Physiology, Free University of Berlin, Berlin, Germany.

To establish the influence of fetal bovine serum (FBS) and bovine serum lipids (BSL) on cell differentiation marker expression, bovine adipose-derived stem cells from subcutaneous tissue were incubated for 14 days in 4 types of differentiation media containing 10% FBS and 10 µL/mL BSL (TRT-1), no FBS and 10 µL/mL of BSL (TRT-2), 10% FBS and no BSL (TRT-3), or no supplements (TRT-4). Cells were subjected to Nile red staining, immunocytochemistry (CD73, CD90, CD105, DLK1, FabP4), and quantitative real-time PCR (CD73, CD90, CD105, FabP4). The number of cells presenting FabP4 and the percentage of mature adipocytes with large lipid droplets were increased in TRT-2, accompanied by a robust increase in FabP4 mRNA abundance and a decrease in DLK1-positive cells. In preadipocytes, CD73 was present around the nucleus and translocated towards cell membranes during differentiation. Although the percentage of CD73-positive cells was not different among treatments, its mRNA abundance, immunocytochemical staining intensity, and translocation towards cell membranes were decreased when the medium contained no FBS (TRT-2 and TRT-4). All cells showed a diffuse distribution of CD90 and CD105 and remained positive for these markers irrespective of the treatment. However, the CD90 and CD105 mRNA abundance was decreased in TRT-2 and TRT-4; i.e., in media containing no FBS. The presence of FBS increased the absolute number of cell nuclei as assessed by DAPI fluorescence. Our results suggest that bovine subcutaneous preadipocytes display typical stem cell markers. The differentiation into mature adipocytes is promoted by BSL, whereas FBS endorses cell proliferation.
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http://dx.doi.org/10.1159/000472708DOI Listing
March 2018

Molecular and functional heterogeneity of early postnatal porcine satellite cell populations is associated with bioenergetic profile.

Sci Rep 2017 03 27;7:45052. Epub 2017 Mar 27.

Leibniz Institute for Farm Animal Biology, Institute for Muscle Biology and Growth, Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.

During postnatal development, hyperplastic and hypertrophic processes of skeletal muscle growth depend on the activation, proliferation, differentiation, and fusion of satellite cells (SC). Therefore, molecular and functional SC heterogeneity is an important component of muscle plasticity and will greatly affect long-term growth performance and muscle health. However, its regulation by cell intrinsic and extrinsic factors is far from clear. In particular, there is only minor information on the early postnatal period which is critical for muscle maturation and the establishment of adult SC pools. Here, we separated two SC subpopulations (P40/50, P50/70) from muscle of 4-day-old piglets. Our results characterize P40/50 as homogeneous population of committed (high expression of Myf5), fast-proliferating muscle progenitors. P50/70 constituted a slow-proliferating phenotype and contains high numbers of differentiated SC progeny. During culture, P50/70 is transformed to a population with lower differentiation potential that contains 40% Pax7-positive cells. A reversible state of low mitochondrial activity that results from active down-regulation of ATP-synthase is associated with the transition of some of the P50/70 cells to this more primitive fate typical for a reserve cell population. We assume that P40/50 and P50/70 subpopulations contribute unequally in the processes of myofiber growth and maintenance of the SC pool.
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http://dx.doi.org/10.1038/srep45052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366807PMC
March 2017

Solute carrier 41A3 encodes for a mitochondrial Mg(2+) efflux system.

Sci Rep 2016 06 15;6:27999. Epub 2016 Jun 15.

Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, Berlin, D-14163, Germany.

The important role of magnesium (Mg(2+)) in normal cellular physiology requires flexible, yet tightly regulated, intracellular Mg(2+) homeostasis (IMH). However, only little is known about Mg(2+) transporters of subcellular compartments such as mitochondria, despite their obvious importance for the deposition and reposition of intracellular Mg(2+) pools. In particular, knowledge about mechanisms responsible for extrusion of Mg(2+) from mitochondria is lacking. Based on circumstantial evidence, two possible mechanisms of Mg(2+) release from mitochondria were predicted: (1) Mg(2+) efflux coupled to ATP translocation via the ATP-Mg/Pi carrier, and (2) Mg(2+) efflux via a H(+)/Mg(2+) exchanger. Regardless, the identity of the H(+)-coupled Mg(2+) efflux system is unknown. We demonstrate here that member A3 of solute carrier (SLC) family 41 is a mitochondrial Mg(2+) efflux system. Mitochondria of HEK293 cells overexpressing SLC41A3 exhibit a 60% increase in the extrusion of Mg(2+) compared with control cells. This efflux mechanism is Na(+)-dependent and temperature sensitive. Our data identify SLC41A3 as the first mammalian mitochondrial Mg(2+) efflux system, which greatly enhances our understanding of intracellular Mg(2+) homeostasis.
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http://dx.doi.org/10.1038/srep27999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908428PMC
June 2016

Human CNNM2 is not a Mg(2+) transporter per se.

Pflugers Arch 2016 07 11;468(7):1223-1240. Epub 2016 Apr 11.

Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.

CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellular localization of Iso1 and Iso2, (3) the ability of Iso1 and Iso2 to transport Mg(2+), and (4) the complex-forming ability and spectra of potential interactors of Iso1 and Iso2. The five main findings are as follows. (1) Mg-starvation induces CNNM2 overexpression that is markedly higher in JVM-13 cells (lymphoblasts) compared with Jurkat cells (T-lymphocytes). (2) Iso1 and Iso2 localize throughout various subcellular compartments in transgenic HEK293 cells overexpressing Iso1 or Iso2. (3) Iso1 and Iso2 do not transport Mg(2+) in an electrogenic or electroneutral mode in transgenic HEK293 cells overexpressing Iso1 or Iso2. (4) Both Iso1 and Iso2 form complexes of a higher molecular order. (5) The spectrum of potential interactors of Iso1 is ten times smaller than that of Iso2. We conclude that sensitivity of CNNM2 expression to extracellular Mg(2+) depletion depends on cell type. Iso1 and Iso2 exhibit a dispersed pattern of cellular distribution; thus, they are not exclusively integral to the cytoplasmic membrane. Iso1 and Iso2 are not Mg(2+) transporters per se. Both isomorphs form protein complexes, and divergent spectra of potential interactors of Iso1 and Iso2 indicate that each isomorph has a distinctive function. CNNM2 is therefore the first ever identified Mg(2+) homeostatic factor without being a Mg(2+) transporter per se.
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http://dx.doi.org/10.1007/s00424-016-1816-7DOI Listing
July 2016

PARK7/DJ-1 dysregulation by oxidative stress leads to magnesium deficiency: implications in degenerative and chronic diseases.

Clin Sci (Lond) 2015 Dec 28;129(12):1143-50. Epub 2015 Sep 28.

Institute of Veterinary Physiology, Free University of Berlin, Oertzenweg 19b, 14163 Berlin, Germany

Disturbed magnesium (Mg(2+)) homoeostasis and increased levels of OS (oxidative stress) are associated with poor clinical outcomes in patients suffering from neurodegenerative, cardiovascular and metabolic diseases. Data from clinical and animal studies suggest that MD (Mg(2+) deficiency) is correlated with increased production of ROS (reactive oxygen species) in cells, but a straightforward causal relationship (including molecular mechanisms) between the two conditions is lacking. The multifactorial protein PARK7/DJ-1 is a major antioxidant protein, playing a key role in cellular redox homoeostasis, and is a positive regulator of AR (androgen receptor)-dependent transcription. SLC41A1 (solute carrier family 41 member 1), the gene encoding a ubiquitous cellular Mg(2+)E (Mg(2+)efflux) system, has been shown to be regulated by activated AR. We hypothesize that overexpression/up-regulation of PARK7/DJ-1, attributable to OS and related activation of AR, is an important event regulating the expression of SLC41A1 and consequently, modulating the Mg(2+)E capacity. This would involve changes in the transcriptional activity of PARK7/DJ-1, AR and SLC41A1, which may serve as biomarkers of intracellular MD and may have clinical relevance. Imipramine, in use as an antidepressant, has been shown to reduce the Mg(2+)E activity of SLC41A1 and OS. We therefore hypothesize further that administration of imipramine or related drugs will be beneficial in MD- and OS-associated diseases, especially when combined with Mg(2+) supplementation. If proved true, the OS-responsive functional axis, PARK7/DJ-1-AR-SLC41A1, may be a putative mechanism underlying intracellular MD secondary to OS caused by pro-oxidative stimuli, including extracellular MD. Furthermore, it will advance our understanding of the link between OS and MD.
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http://dx.doi.org/10.1042/CS20150355DOI Listing
December 2015

Insulin Modulates the Na+/Mg2+ Exchanger SLC41A1 and Influences Mg2+ Efflux from Intracellular Stores in Transgenic HEK293 Cells.

J Nutr 2015 Nov 9;145(11):2440-7. Epub 2015 Sep 9.

Institute of Veterinary Physiology, Freie Universität, Berlin, Germany; and

Background: Magnesium deficiency is a common complication of diabetes with an unclear molecular background.

Objective: We investigated the effect of the insulin (INS)-signaling pathway (ISP) on the regulation of Mg(2+) efflux (Mg(2+)E) conducted by solute carrier family 41, member A1 (SLC41A1; activated by protein kinase A) in transgenic human embryonic kidney (HEK) 293 cells.

Methods: HEK293 cells overexpressing SLC41A1 were loaded with the Mg(2+) fluorescent indicator mag-fura-2 and Mg(2+). Measurements of Mg(2+)E were conducted in Mg(2+)-free buffer by using fast-filter fluorescence spectrometry. We examined the effects of INS, inhibitors of ISP or p38 mitogen-activated protein kinase (p38 MAPK), an activator of adenylate cyclase (ADC), and their combinations on SLC41A1-attributed Mg(2+)E.

Results: The application of 400 μU/mL INS inhibited SLC41A1-mediated Mg(2+)E by up to 50.6% compared with INS-untreated cells (P < 0.001). Moreover, INS evoked the early onset of Mg(2+) release from intracellular stores. The application of 0.1 μM wortmannin or 10 μM zardaverine (both ISP inhibitors) restored SLC41A1 Mg(2+)E capacity in the presence of INS to the same levels in INS-untreated cells. The simultaneous application of 10 μM forskolin, an ADC activator, and INS resulted in a reduction of Mg(2+)E of up to 59% compared with untreated cells (P < 0.001), which was comparable to that in cells treated with INS alone. Inhibition of p38 MAPK with 10 μM SB 202190 (SB) in the absence of INS resulted in a decrease (P < 0.001) of SLC41A1-dependent Mg(2+)E (by up to 49%) compared with Mg(2+)E measured in untreated cells. Simultaneous exposure of cells to SB and INS had a stronger inhibitory effect on SLC41A1 activity than INS alone (P < 0.05).

Conclusions: INS affects intracellular Mg(2+) concentration in transgenic HEK293 cells by regulating SLC41A1 activity (via ISP) and by influencing the compartmentalization and cellular distribution of Mg(2+). In addition, p38 MAPK activates SLC41A1 independently of INS action.
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http://dx.doi.org/10.3945/jn.115.213918DOI Listing
November 2015

SLC41 transporters--molecular identification and functional role.

Curr Top Membr 2014 ;73:383-410

Institute of Veterinary Physiology, Free University Berlin, Berlin, Germany.

The solute carrier family 41 (SLC41) encompasses three members A1, A2, and A3. Based on their distant homology to the bacterial Mg²⁺ channel MgtE, all have been linked to Mg²⁺ transport. There is only very limited knowledge on the molecular biology and exact functions of SLC41A2 and SLC41A3. SLC41A1 is ubiquitously expressed and data on its functional and molecular properties, regulation, complex-forming ability, and spectrum of binding partners are available. SLC41A1 was recently identified as being the Na⁺/Mg²⁺ exchanger (NME)-a predominant Mg²⁺ efflux system. Mg²⁺-dependent and hormonal regulation of NME activity is now known to depend on the intracellular N terminus of SLC41A1 that is involved in Mg²⁺ sensing and contains phosphorylation sites for protein kinase (PK) A and PKC. Data showing a link between SLC41A1 and human disorders such as Parkinson's disease, nephronophthisis (induced by the null mutation c.698G>T in renal SLC41A1), and preeclampsia make the protein a candidate therapeutic target.
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http://dx.doi.org/10.1016/B978-0-12-800223-0.00011-6DOI Listing
November 2014

"Inside-in" or "inside-out"? The membrane topology of SLC41A1.

Magnes Res 2013 Oct-Dec;26(4):176-81

Institute of Veterinary-Physiology, Freie Universität Berlin, Berlin, Germany.

Membrane topology is an important parameter for understanding the function and regulation of any integral protein. This aspect of the NME SLC41A1 is currently under debate. The most probable model, which has been computer-predicted, exhibits ten TMh with both termini being oriented intracellularly. However, other freely accessible online prediction programs predict that SLC41A1 possesses eleven ("outside-in" configuration), nine ("outside-in" configuration), or eight ("inside-in" configuration) TMh. The consensus based on published experimental data acquired by independent research teams is that the N-terminal flanking region is located intracellularly. However, controversy remains about the orientation of the C-terminus, which has lately been proposed to be extracellular in peer-reviewed bibliography. Here, we performed split-ubiquitin functional assays with transgenic SLC41A1 fused N- or C-terminally to a Cub-LexA-VP16 reporter cassette. The bait constructs were co-expressed in S. cerevisiae st. NMY51 with positive recombinant membrane markers (Ost1, Fur4, Alg5, Tom20) tagged with NubI (or NubG). Ubiquitin could only be reconstituted if the reporter moiety was exposed to the cytosol. Functional reconstitution of ubiquitin was observed when SLC41A1 C-terminally tagged with Cub was co-expressed with NubI-tagged membrane markers, thereby, indicating a cytosolic orientation of the C-terminus of SLC41A1. Thus, our experimental data are in favor of the - the in silico analyses being strongly preferred - ten TMh model of SLC41A1 topology, with both termini being oriented intracellularly.
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http://dx.doi.org/10.1684/mrh.2014.0351DOI Listing
October 2014

Blood pressure in pregnancy and magnesium sensitive genes.

Pregnancy Hypertens 2014 Jan 17;4(1):41-5. Epub 2013 Sep 17.

Department of Obstetrics and Gynaecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg and Södra Älvsborgs Hospital, 501 82 Borås, Sweden. Electronic address:

Objectives: High blood pressure during the last part of pregnancy is a risk indicator of pre-eclampsia and eclampsia which augment infant and maternal morbidity and mortality. Magnesium deficiency has been related to the risk of hypertension. A study was performed to assess the relation between pregnancy induced hypertension, excretion of urinary magnesium and expression of magnesium sensitive genes (MgSG).

Methods: A cohort of healthy, nulliparous women with singleton pregnancies was recruited. Blood pressure was recorded throughout pregnancy. Urinary magnesium excretion and expression of MgSGs in leukocytes were determined.

Results: The expression of the gene TRPM6 was higher among pregnant women compared to non-pregnant controls at week 12. All other genes had lower expressions in pregnant women. At week 37 the expressions of all genes were lower than at week 12. The expressions of SLC41A1, SLC41A3, and TRPM7 were related to the systolic and diastolic blood pressures. Furthermore, the expression of TRPM6 was related to the urinary excretion of magnesium and the change in diastolic blood pressure weeks 12-37 was inversely related to the change in magnesium excretion.

Conclusions: Systolic and diastolic blood pressure and the excretion of magnesium during pregnancy were related to the expression of different MgSGs. The results suggest that magnesium is involved in the regulation of blood pressure during pregnancy.
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http://dx.doi.org/10.1016/j.preghy.2013.09.003DOI Listing
January 2014

Solute Carrier Family SLC41, what do we really know about it?

Wiley Interdiscip Rev Membr Transp Signal 2013 ;2(6)

Laboratory of Cell and Molecular Signalling, Center for Biomedical Research at The Queen's Medical Center, Honolulu, HI USA.

The 41 family of solute carriers (SLC41) comprises three members A1, A2 and A3, which are distantly homologous to bacterial Mg channel MgtE. SLC41A1 was recently characterized as being an Na/Mg exchanger (NME; a predominant cellular Mg efflux system). Little is known about the exact function of SLC41A2 and SLC41A3, although, these proteins have also been linked to Mg transport in human (animal) cells. The molecular biology (including membrane topology, cellular localization, transcriptomics and proteomics) of SLC41A2 and SLC41A3 compared with SLC41A1 has only been poorly explored. Significantly more data with regard to function, functional regulation, involvement in cellular signalling, complex-forming ability, spectrum of binding partners and involvement in the pathophysiology of human diseases are available for SLC41A1. Three recent observations namely the identification of the null mutation, c.698G>T, in SLC41A1 underlying the nephronophthisis-like phenotype, the recognition of a putative link between SLC41A1 and Parkinson's disease, and the observation that nearly 55% of preeclamptic placental samples overexpress marks the protein as a possible therapeutic target of these diseases. A potential role of the SLC41 family of Mg transporters in the pathophysiology of human diseases is further substantiated by the finding that SLC41A3 knockout mice develop abnormal locomotor coordination.
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http://dx.doi.org/10.1002/wmts.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855994PMC
January 2013

Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation.

PLoS One 2013 15;8(8):e71096. Epub 2013 Aug 15.

Institute of Veterinary-Physiology, Free University Berlin, Berlin, Germany.

Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na⁺/Mg²⁺ exchanger (NME, Mg²⁺ efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na⁺-dependent Mg²⁺ efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na⁺ (145 mM) and completely Mg²⁺-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg²⁺-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg²⁺-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071096PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744568PMC
April 2014

SLC41A1 is the only magnesium responsive gene significantly overexpressed in placentas of preeclamptic women.

Hypertens Pregnancy 2013 Nov 11;32(4):378-89. Epub 2013 Jul 11.

Department Molecular Physiology, Institute of Veterinary-Physiology, Free University of Berlin , Germany .

Objective: To examine expression profile of magnesium responsive genes (MRGs) in placentas of normoevolutive and preeclamptic women.

Methods: The expression profiles of MRGs were determined in placentas of normoevolutive (N=26) and preeclamptic (N=25) women by RT-qPCR.

Results: Among all tested MRGs (9) only SLC41A1 (encoding for Na(+)/Mg(2+) exchanger) was significantly overexpressed in ~54.2% of preeclamptic (n=24) and in ~9.5% of normoevolutive (n=21) specimens. On average, SLC41A1 was overexpressed sixfold in the preeclamptic group. Presence of SLC41A1 in placentas was confirmed by Western blot analysis. CONCLUSION. SLC41A1 is significantly overexpressed in nearly 55% of preeclamptic placentas. This may indicate a direct contribution of changed Mg homeostasis in the development of preeclampsia.
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http://dx.doi.org/10.3109/10641955.2013.810237DOI Listing
November 2013

Nature of SLC41A1 complexes: report on the split-ubiquitin yeast two hybrid assay.

Magnes Res 2013 Apr-Jun;26(2):56-66

Institute of Veterinary-Physiology, Freie Universität Berlin, Berlin, Germany.

The Na(+)/Mg(2+) exchanger SLC41A1 is involved in the pathophysiology of various disease conditions. It forms high-molecular-mass, possibly hetero-oligomeric protein complexes in transgenic HEK293 cells. Therefore, we attempted to identify binding partners of SLC41A1 by utilizing the split-ubiquitin modification of the yeast two-hybrid assay. As the most prominent binding partners in our experimental system, we identified 3-beta-hydroxysteroid-Δ(8),Δ(7)-isomerase and B-cell receptor associated-protein 31. Other polytons (interactors appearing in the screen more than once) included: IER3IP1, PPIB, UPF0480 protein C15orf24, SPINT2, C14orf1/PEBP28, NIFIE14, YIPF6, and KCP2. In total, 20 polytons and 38 singletons (interactors appearing in the screen only once) were identified. The polytons identified were mostly endoplasmic reticulum-located, integral proteins involved in protein maturation, N-glycosylation, protein folding, anterograde transport of proteins, protein secretion, and the regulation of apoptosis. Among the singletons, we identified SLC31A2, SLC35B1, SLC39A13, CRACM1, and MTCH2 as putative binding partners of SLC41A1. Interestingly, we did not identify interactions among SLC41A1 molecules. Most of the identified interactors are integral proteins localized in cellular compartments other than the cytoplasmic membrane, whereas SLC41A1 is targeted to the cytoplasmic membrane where it performs its core function. None of the interactors was confirmed by mass spectrometry. Instead, we identified among the proteins co-purified with strep-tagged SLC41A1: ACCA1, UBB, ATX2L, HSP7C and TBB. We therefore conclude that: (1) identified interactors form transient rather than stable complexes with SLC41A1, (2) the molecular interactors identified primarily among the polytons might contribute to the production, proper folding, and maturation of SLC41A1 in the endoplasmic reticulum and Golgi apparatus, (3) most of the interactors identified among singletons might undergo similar maturation steps (post-translational modification), anterograde transport, and protein sorting as SLC41A1.
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http://dx.doi.org/10.1684/mrh.2013.0339DOI Listing
June 2014

Magnesium supplementation to prevent high blood pressure in pregnancy: a randomised placebo control trial.

Arch Gynecol Obstet 2013 Dec 30;288(6):1269-74. Epub 2013 May 30.

Department of Obstetrics and Gynaecology, at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,

Purpose: To assess if hypertension during the last part of pregnancy could be prevented by magnesium supplementation.

Methods: Pregnant primagravida women from a local antenatal care unit were given an oral supply of 300 mg magnesium as citrate or placebo from pregnancy week 25 in a randomised double-blind setup. Blood pressure was recorded during pregnancy as well as pregnancy outcome.

Results: In the magnesium-supplemented group, the average diastolic blood pressure at week 37 was significantly lower than in the placebo group (72/1.4 mean/SEM vs 77/1.4, p = 0.031). The number of women with an increase in diastolic blood pressure of ≥15 mmHg was significantly lower in the magnesium group compared with the women who received placebo (p = 0.011). There was an inverse relation between the urinary excretion of magnesium during pregnancy and the diastolic blood pressure (p = 0.005).

Conclusions: Magnesium supplementation prevented an increase in diastolic blood pressure during the last weeks of pregnancy. The relation between diastolic blood pressure and urinary excretion of magnesium suggests that magnesium is involved in the regulation of blood pressure and that the increase in diastolic blood pressure in pregnancy could be due to a lack of magnesium.
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http://dx.doi.org/10.1007/s00404-013-2900-2DOI Listing
December 2013
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