Magnesium Extravaganza: A Critical Compendium of Current Research into Cellular Mg2+ Transporters Other than TRPM6/7

  • Martin KolisekEmail author
  • Gerhard Sponder
  • Ivana Pilchova
  • Michal Cibulka
  • Zuzana Tatarkova
  • Tanja Werner
  • Peter Racay
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 176)


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 Mg2+ 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, Mg2+ 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 Mg2+ 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 Mg2+ transporters/Mg2+ 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 Mg2+ 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 Mg2+ while constituting the major gateway for Mg2+ to enter the cell.


Carrier Channel Ion transporter Magnesium (Mg) Mg homeostasis 



Our gratitude is due to Dr. Theresa Jones for linguistic corrections. This work was supported by the grant “Return Home” issued by the Government of Slovak Republic to MK and also by the project “Creating a New Diagnostic Algorithm for Selected Cancer Diseases” (ITMS: 26220220022) co-financed from EU sources and the European Regional Development Fund.

The authors declare no conflict of interests. All authors read and approved the final version of the manuscript.


MK and GS wrote the manuscript, and IP, MC, ZT, TW, and PR contributed to the manuscript writing.


  1. Acin-Perez R, Salazar E, Kamenetsky M, Buck J, Levin LR, Manfredi G (2009) Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9(3):265–276PubMedPubMedCentralGoogle Scholar
  2. Acin-Perez R, Russwurm M, Günnewig K, Gertz M, Zoidl G, Ramos L, Buck J, Levin LR, Rassow J, Manfredi G, Steegborn C (2011a) A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. J Biol Chem 286(35):30423–30432PubMedPubMedCentralGoogle Scholar
  3. Acin-Perez R, Gatti DL, Bai Y, Manfredi G (2011b) Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. Cell Metab 13(6):712–719PubMedPubMedCentralGoogle Scholar
  4. Arjona FJ, de Baaij JH, Schlingmann KP, Lameris AL, van Wijk E, Flik G, Regele S, Korenke GC, Neophytou B, Rust S, Reintjes N, Konrad M, Bindels RJ, Hoenderop JG (2014) CNNM2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genet 10(4):e1004267PubMedPubMedCentralGoogle Scholar
  5. Bai Y, Dong L, Huang X, Zheng S, Qiu P, Lan F (2017) Associations of rs823128, rs1572931, and rs823156 polymorphisms with reduced Parkinson’s disease risks. Neuroreport 28(14):936–941PubMedPubMedCentralGoogle Scholar
  6. Bijur GN, Jope RS (2003) Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem 87(6):1427–1435PubMedPubMedCentralGoogle Scholar
  7. Bui DM, Gregan J, Jarosch E, Ragnini A, Schweyen RJ (1999) The bacterial magnesium transporter CorA can functionally substitute for its putative homologue Mrs2p in the yeast inner mitochondrial membrane. J Biol Chem 274(29):20438–20443PubMedGoogle Scholar
  8. Butland SL, Sanders SS, Schmidt ME, Riechers SP, Lin DT, Martin DD, Vaid K, Graham RK, Singaraja RR, Wanker EE, Conibear E, Hayden MR (2014) The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington’s disease. Hum Mol Genet 23(15):4142–4160PubMedPubMedCentralGoogle Scholar
  9. Cabezas-Bratesco D, Brauchi S, González-Teuber V, Steinberg X, Valencia I, Colenso C (2015) The different roles of the channel-kinases TRPM6 and TRPM7. Curr Med Chem 22(25):2943–2953PubMedGoogle Scholar
  10. Cherepanova NA, Gilmore R (2016) Mammalian cells lacking either the cotranslational or posttranslocational oligosaccharyltransferase complex display substrate-dependent defects in asparagine linked glycosylation. Sci Rep 6:20946PubMedPubMedCentralGoogle Scholar
  11. Cherepanova N, Shrimal S, Gilmore R (2016) N-linked glycosylation and homeostasis of the endoplasmic reticulum. Curr Opin Cell Biol 41:57–65PubMedPubMedCentralGoogle Scholar
  12. Corkey BE, Duszynski J, Rich TL, Matschinsky B, Williamson JR (1986) Regulation of free and bound magnesium in rat hepatocytes and isolated mitochondria. J Biol Chem 261(6):2567–2574PubMedGoogle Scholar
  13. Cui Y, Zhao S, Wang J, Wang X, Gao B, Fan Q, Sun F, Zhou B (2015) A novel mitochondrial carrier protein Mme1 acts as a yeast mitochondrial magnesium exporter. Biochim Biophys Acta 1853(3):724–732PubMedGoogle Scholar
  14. Cui Y, Zhao S, Wang X, Zhou B (2016) A novel Drosophila mitochondrial carrier protein acts as a Mg2+ exporter in fine-tuning mitochondrial Mg2+ homeostasis. Biochim Biophys Acta 1863(1):30–39PubMedGoogle Scholar
  15. de Baaij JH, Stuiver M, Meij IC, Lainez S, Kopplin K, Venselaar H, Müller D, Bindels RJ, Hoenderop JG (2012) Membrane topology and intracellular processing of cyclin M2 (CNNM2). J Biol Chem 287(17):13644–13655PubMedPubMedCentralGoogle Scholar
  16. de Baaij JH, Hoenderop JG, Bindels RJ (2015) Magnesium in man: implications for health and disease. Physiol Rev 95(1):1–46PubMedGoogle Scholar
  17. de Baaij JH, Arjona FJ, van den Brand M, Lavrijsen M, Lameris AL, Bindels RJ, Hoenderop JG (2016) Identification of SLC41A3 as a novel player in magnesium homeostasis. Sci Rep 6:28565PubMedPubMedCentralGoogle Scholar
  18. Delva PT, Pastori C, Degan M, Montesi GD, Lechi A (1996) Intralymphocyte free magnesium in a group of subjects with essential hypertension. Hypertension 28(3):433–439PubMedGoogle Scholar
  19. Delva P, Degan M, Trettene M, Lechi A (2006) Insulin and glucose mediate opposite intracellular ionized magnesium variations in human lymphocytes. J Endocrinol 190(3):711–718PubMedGoogle Scholar
  20. Dragileva E, Rubinstein S, Breitbart H (1999) Intracellular Ca2+-Mg2+-ATPase regulates calcium influx and acrosomal exocytosis in bull and ram spermatozoa. Biol Reprod 61(5):1226–1234PubMedGoogle Scholar
  21. Ducker CE, Stettler EM, French KJ, Upson JJ, Smith CD (2004) Huntingtin interacting protein 14 is an oncogenic human protein: palmitoyl acyltransferase. Oncogene 23(57):9230–9237PubMedPubMedCentralGoogle Scholar
  22. Ebel H, Hollstein M, Günther T (2002) Role of the choline exchanger in Na+-independent Mg2+ efflux from rat erythrocytes. Biochim Biophys Acta 1559(2):135–144PubMedGoogle Scholar
  23. Feeney KA, Hansen LL, Putker M, Olivares-Yañez C, Day J, Eades LJ, Larrondo LF, Hoyle NP, O’Neill JS, van Ooijen G (2016) Daily magnesium fluxes regulate cellular timekeeping and energy balance. Nature 532(7599):375–379PubMedPubMedCentralGoogle Scholar
  24. Feliciello A, Gottesman ME, Avvedimento EV (2005) cAMP-PKA signaling to the mitochondria: protein scaffolds, mRNA and phosphatases. Cell Signal 17(3):279–287PubMedGoogle Scholar
  25. Fiore C, Trézéguet V, Le Saux A, Roux P, Schwimmer C, Dianoux AC, Noel F, Lauquin GJ, Brandolin G, Vignais PV (1998) The mitochondrial ADP/ATP carrier: structural, physiological and pathological aspects. Biochimie 80(2):137–150PubMedGoogle Scholar
  26. Flatman PW (1984) Magnesium transport across cell membranes. J Membr Biol 80(1):1–14PubMedGoogle Scholar
  27. Fleig A, Schweigel-Röntgen M, Kolisek M (2013) Solute carrier family SLC41, what do we really know about it? WIREs Membr Transport Signaling 2(6).
  28. Funato Y, Yamazaki D, Miki H (2017) Renal function of cyclin M2 Mg2+ transporter maintains blood pressure. J Hypertens 35(3):585–592PubMedGoogle Scholar
  29. Garlid KD, Halestrap AP (2012) The mitochondrial K(ATP) channel – fact or fiction? J Mol Cell Cardiol 52(3):578–583PubMedPubMedCentralGoogle Scholar
  30. Gibson MM, Bagga DA, Miller CG, Maguire ME (1991) Magnesium transport in Salmonella typhimurium: the influence of new mutations conferring Co2+ resistance on the CorA Mg2+ transport system. Mol Microbiol 5(11):2753–2762PubMedGoogle Scholar
  31. Giménez-Mascarell P, Oyenarte I, Hardy S, Breiderhoff T, Stuiver M, Kostantin E, Diercks T, Pey AL, Ereño-Orbea J, Martínez-Chantar ML, Khalaf-Nazzal R, Claverie-Martin F, Müller D, Tremblay ML, Martínez-Cruz LA (2017) Structural basis of the oncogenic interaction of phosphatase PRL-1 with the magnesium transporter CNNM2. J Biol Chem 292(3):786–801PubMedGoogle Scholar
  32. Goldin AL (2006) Expression of ion channels in Xenopus oocytes. In: Clare JJ, Trezise DJ (eds) Expression and analysis of recombinant ion channels. Wiley, WeinheimGoogle Scholar
  33. Goytain A, Quamme GA (2005a) Functional characterization of human SLC41A1, a Mg2+ transporter with similarity to prokaryotic MgtE Mg2+ transporters. Physiol Genomics 21(3):337–342PubMedGoogle Scholar
  34. Goytain A1, Quamme GA (2005b) Functional characterization of the mouse solute carrier, SLC41A2. Biochem Biophys Res Commun 330(3):701–705PubMedGoogle Scholar
  35. Goytain A, Quamme GA (2005c) Identification and characterization of a novel mammalian Mg2+ transporter with channel-like properties. BMC Genomics 6:48PubMedPubMedCentralGoogle Scholar
  36. Goytain A, Quamme GA (2005d) Functional characterization of ACDP2 (ancient conserved domain protein), a divalent metal transporter. Physiol Genomics 22(3):382–389PubMedGoogle Scholar
  37. Goytain A, Quamme GA (2008) Identification and characterization of a novel family of membrane magnesium transporters, MMgT1 and MMgT2. Am J Physiol Cell Physiol 294(2):C495–C502PubMedGoogle Scholar
  38. Goytain A, Hines RM, El-Husseini A, Quamme GA (2007) NIPA1(SPG6), the basis for autosomal dominant form of hereditary spastic paraplegia, encodes a functional Mg2+ transporter. J Biol Chem 282(11):8060–8068PubMedGoogle Scholar
  39. Goytain A, Hines RM, Quamme GA (2008a) Functional characterization of NIPA2, a selective Mg2+ transporter. Am J Physiol Cell Physiol 295(4):C944–C953PubMedGoogle Scholar
  40. Goytain A, Hines RM, Quamme GA (2008b) Huntingtin-interacting proteins, HIP14 and HIP14L, mediate dual functions, palmitoyl acyltransferase and Mg2+ transport. J Biol Chem 283(48):33365–33374PubMedPubMedCentralGoogle Scholar
  41. Graschopf A, Stadler JA, Hoellerer MK, Eder S, Sieghardt M, Kohlwein SD, Schweyen RJ (2001) The yeast plasma membrane protein Alr1 controls Mg2+ homeostasis and is subject to Mg2+-dependent control of its synthesis and degradation. J Biol Chem 276(19):16216–16222PubMedGoogle Scholar
  42. Gregan J, Kolisek M, Schweyen RJ (2001a) Mitochondrial Mg2+ homeostasis is critical for group II intron splicing in vivo. Genes Dev 15(17):2229–2237PubMedPubMedCentralGoogle Scholar
  43. Gregan J, Bui DM, Pillich R, Fink M, Zsurka G, Schweyen RJ (2001b) The mitochondrial inner membrane protein Lpe10p, a homologue of Mrs2p, is essential for magnesium homeostasis and group II intron splicing in yeast. Mol Gen Genet 264(6):773–781PubMedGoogle Scholar
  44. Groisman EA, Hollands K, Kriner MA, Lee EJ, Park SY, Pontes MH (2013) Bacterial Mg2+ homeostasis, transport, and virulence. Annu Rev Genet 47:625–646PubMedPubMedCentralGoogle Scholar
  45. Günther T (1993) Mechanisms and regulation of Mg2+ efflux and Mg2+ influx. Miner Electrolyte Metab 19(4–5):259–265PubMedGoogle Scholar
  46. Günther T (2006a) Concentration, compartmentation and metabolic function of intracellular free Mg2+. Magnes Res 19(4):225–236PubMedGoogle Scholar
  47. Günther T (2006b) Mechanisms, regulation and pathologic significance of Mg2+ efflux from erythrocytes. Magnes Res 19(3):190–198PubMedGoogle Scholar
  48. Günther T (2007) Na+/Mg2+ antiport in non-erythrocyte vertebrate cells. Magnes Res 20(2):89–99PubMedGoogle Scholar
  49. Günther T, Vormann J, Cragoe EJ Jr (1990) Species-specific Mn2+/Mg2+ antiport from Mg2+-loaded erythrocytes. FEBS Lett 261(1):47–51PubMedGoogle Scholar
  50. Guo D, Ling J, Wang MH, She JX, Gu J, Wang CY (2005) Physical interaction and functional coupling between ACDP4 and the intracellular ion chaperone COX11, an implication of the role of ACDP4 in essential metal ion transport and homeostasis. Mol Pain 1:15PubMedPubMedCentralGoogle Scholar
  51. Hirata Y, Funato Y, Takano Y, Miki H (2014) Mg2+-dependent interactions of ATP with the cystathionine-β-synthase (CBS) domains of a magnesium transporter. J Biol Chem 289(21):14731–14739PubMedPubMedCentralGoogle Scholar
  52. Hmiel SP, Snavely MD, Miller CG, Maguire ME (1986) Magnesium transport in Salmonella typhimurium: characterization of magnesium influx and cloning of a transport gene. J Bacteriol 168(3):1444–1450PubMedPubMedCentralGoogle Scholar
  53. Hmiel SP, Snavely MD, Florer JB, Maguire ME, Miller CG (1989) Magnesium transport in Salmonella typhimurium: genetic characterization and cloning of three magnesium transport loci. J Bacteriol 171(9):4742–4751PubMedPubMedCentralGoogle Scholar
  54. Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP (1994) Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 77(6):869–880PubMedGoogle Scholar
  55. Huang G, Chen S, Li S, Cha J, Long C, Li L, He Q, Liu Y (2007) Protein kinase A and casein kinases mediate sequential phosphorylation events in the circadian negative feedback loop. Genes Dev 21(24):3283–3295PubMedPubMedCentralGoogle Scholar
  56. Hurd TW, Otto EA, Mishima E, Gee HY, Inoue H, Inazu M, Yamada H, Halbritter J, Seki G, Konishi M, Zhou W, Yamane T, Murakami S, Caridi G, Ghiggeri G, Abe T, Hildebrandt F (2013) Mutation of the Mg2+ transporter SLC41A1 results in a nephronophthisis-like phenotype. J Am Soc Nephrol 24(6):967–977PubMedPubMedCentralGoogle Scholar
  57. Islam Z, Hayashi N, Yamamoto Y, Doi H, Romero MF, Hirose S, Kato A (2013) Identification and proximal tubular localization of the Mg2+ transporter, Slc41a1, in a seawater fish. Am J Physiol Regul Integr Comp Physiol 305(4):R385–R396PubMedPubMedCentralGoogle Scholar
  58. Islam Z, Hayashi N, Inoue H, Umezawa T, Kimura Y, Doi H, Romero MF, Hirose S, Kato A (2014) Identification and lateral membrane localization of cyclin M3, likely to be involved in renal Mg2+ handling in seawater fish. Am J Physiol Regul Integr Comp Physiol 307(5):R525–R537PubMedPubMedCentralGoogle Scholar
  59. Iwatsuki H, Lu YM, Yamaguchi K, Ichikawa N, Hashimoto T (2000) Binding of an intrinsic ATPase inhibitor to the F1F0ATPase in phosphorylating conditions of yeast mitochondria. J Biochem 128(4):553–559PubMedGoogle Scholar
  60. Joyal JL, Aprille JR (1992) The ATP-Mg/Pi carrier of rat liver mitochondria catalyzes a divalent electroneutral exchange. J Biol Chem 267:19198–19203PubMedGoogle Scholar
  61. Jung DW, Apel L, Brierley GP (1990) Matrix free Mg2+ changes with metabolic state in isolated heart mitochondria. Biochemistry 29(17):4121–4128PubMedGoogle Scholar
  62. Jung DW, Panzeter E, Baysal K, Brierley GP (1997) On the relationship between matrix free Mg2+ concentration and total Mg2+ in heart mitochondria. Biochim Biophys Acta 1320(3):310–320PubMedGoogle Scholar
  63. Karch J, Molkentin JD (2014) Identifying the components of the elusive mitochondrial permeability transition pore. Proc Natl Acad Sci U S A 111(29):10396–10397PubMedPubMedCentralGoogle Scholar
  64. Khan MB, Sponder G, Sjöblom B, Svidová S, Schweyen RJ, Carugo O, Djinović-Carugo K (2013) Structural and functional characterization of the N-terminal domain of the yeast Mg2+ channel Mrs2. Acta Crystallogr D Biol Crystallogr 69(Pt 9):1653–1664PubMedGoogle Scholar
  65. Klingenberg M (2008) The ADP and ATP transport in mitochondria and its carrier. Biochim Biophys Acta 1778(10):1978–2021Google Scholar
  66. Koivusalo M, Steinberg BE, Mason D, Grinstein S (2011) In situ measurement of the electrical potential across the lysosomal membrane using FRET. Traffic 12(8):972–982PubMedGoogle Scholar
  67. Kolisek M, Zsurka G, Samaj J, Weghuber J, Schweyen RJ, Schweigel M (2003) Mrs2p is an essential component of the major electrophoretic Mg2+ influx system in mitochondria. EMBO J 22(6):1235–1244PubMedPubMedCentralGoogle Scholar
  68. Kolisek M, Launay P, Beck A, Sponder G, Serafini N, Brenkus M, Froschauer EM, Martens H, Fleig A, Schweigel M (2008) SLC41A1 is a novel mammalian Mg2+ carrier. J Biol Chem 283(23):16235–16247PubMedPubMedCentralGoogle Scholar
  69. Kolisek M, Nestler A, Vormann J, Schweigel-Röntgen M (2012) Human gene SLC41A1 encodes for the Na+/Mg2+ exchanger. Am J Physiol Cell Physiol 302(1):C318–C326PubMedGoogle Scholar
  70. Kolisek M, Sponder G, Mastrototaro L, Smorodchenko A, Launay P, Vormann J, Schweigel-Röntgen M (2013a) Substitution p.A350V in Na+/Mg2+ exchanger SLC41A1, potentially associated with Parkinson’s disease, is a gain-of-function mutation. PLoS One 8(8):e71096PubMedPubMedCentralGoogle Scholar
  71. Kolisek M, Galaviz-Hernández C, Vázquez-Alaniz F, Sponder G, Javaid S, Kurth K, Nestler A, Rodríguez-Moran M, Verlohren S, Guerrero-Romero F, Aschenbach JR, Vormann J (2013b) SLC41A1 is the only magnesium responsive gene significantly overexpressed in placentas of preeclamptic women. Hypertens Pregnancy 32(4):378–389PubMedGoogle Scholar
  72. Kovanich D, van der Heyden MA, Aye TT, van Veen TA, Heck AJ, Scholten A (2010) Sphingosine kinase interacting protein is an A-kinase anchoring protein specific for type I cAMP-dependent protein kinase. Chembiochem 11(7):963–971PubMedGoogle Scholar
  73. Kubota T, Shindo Y, Tokuno K, Komatsu H, Ogawa H, Kudo S, Kitamura Y, Suzuki K, Oka K (2005) Mitochondria are intracellular magnesium stores: investigation by simultaneous fluorescent imagings in PC12 cells. Biochim Biophys Acta 1744(1):19–28PubMedGoogle Scholar
  74. Kun E (1976) Kinetics of ATP-dependent Mg2+ flux in mitochondria. Biochemistry 15(11):2328–2336PubMedGoogle Scholar
  75. Kuramoto T, Kuwamura M, Tokuda S, Izawa T, Nakane Y, Kitada K, Akao M, Guénet JL, Serikawa T (2011) A mutation in the gene encoding mitochondrial Mg2+ channel MRS2 results in demyelination in the rat. PLoS Genet 7(1):e1001262PubMedPubMedCentralGoogle Scholar
  76. Kuwamura M, Inumaki K, Tanaka M, Shirai M, Izawa T, Yamate J, Franklin RJ, Kuramoto T, Serikawa T (2011) Oligodendroglial pathology in the development of myelin breakdown in the dmy mutant rat. Brain Res 1389:161–168PubMedGoogle Scholar
  77. Lambie EJ, Tieu PJ, Lebedeva N, Church DL, Conradt B (2013) CATP-6, a C. elegans ortholog of ATP13A2 PARK9, positively regulates GEM-1, an SLC16A transporter. PLoS One 8(10):e77202PubMedPubMedCentralGoogle Scholar
  78. Lee S, Russo D, Redman CM (2000) The Kell blood group system: Kell and XK membrane proteins. Semin Hematol 37(2):113–121PubMedGoogle Scholar
  79. Lefkimmiatis K, Leronni D, Hofer AM (2013) The inner and outer compartments of mitochondria are sites of distinct cAMP/PKA signaling dynamics. J Cell Biol 202(3):453–462PubMedPubMedCentralGoogle Scholar
  80. Li J, Huang Y, Tan H, Yang X, Tian L, Luan S, Chen L, Li D (2015) An endoplasmic reticulum magnesium transporter is essential for pollen development in Arabidopsis. Plant Sci 231:212–220PubMedGoogle Scholar
  81. Lin CH, Wu YR, Chen WL, Wang HC, Lee CM, Lee-Chen GJ, Chen CM (2014) Variant R244H in Na+/Mg2+ exchanger SLC41A1 in Taiwanese Parkinson’s disease is associated with loss of Mg2+ efflux function. Parkinsonism Relat Disord 20(6):600–603PubMedGoogle Scholar
  82. Luciano AK, Zhou W, Santana JM, Kyriakides C, Velazquez H, Sessa WC (2018) CLOCK phosphorylation by AKT regulates its nuclear accumulation and circadian gene expression in peripheral tissues. J Biol Chem 293(23):9126–9136PubMedPubMedCentralGoogle Scholar
  83. Maeshima K, Matsuda T, Shindo Y, Imamura H, Tamura S, Imai R, Kawakami S, Nagashima R, Soga T, Noji H, Oka K, Nagai T (2018) A transient rise in free Mg2+ ions released from ATP-Mg hydrolysis contributes to mitotic chromosome condensation. Curr Biol 28(3):444–451.e6PubMedGoogle Scholar
  84. Maguire ME (1992) MgtA and MgtB: prokaryotic P-type ATPases that mediate Mg2+ influx. J Bioenerg Biomembr 24(3):319–328PubMedGoogle Scholar
  85. Maguire ME (2006) Magnesium transporters: properties, regulation and structure. Front Biosci 11:3149–3163PubMedGoogle Scholar
  86. Mandt T, Song Y, Scharenberg AM, Sahni J (2011) SLC41A1 Mg2+ transport is regulated via Mg2+-dependent endosomal recycling through its N-terminal cytoplasmic domain. Biochem J 439(1):129–139PubMedGoogle Scholar
  87. Manning BD, Toker A (2017) AKT/PKB signaling: navigating the network. Cell 169(3):381–405PubMedPubMedCentralGoogle Scholar
  88. Mastrototaro L, Tietjen U, Sponder G, Vormann J, Aschenbach JR, Kolisek M (2015) Insulin modulates the Na+/Mg2+ exchanger SLC41A1 and influences Mg2+ efflux from intracellular stores in transgenic HEK293 cells. J Nutr 145(11):2440–2447PubMedGoogle Scholar
  89. Mastrototaro L, Smorodchenko A, Aschenbach JR, Kolisek M, Sponder G (2016) Solute carrier 41A3 encodes for a mitochondrial Mg2+ efflux system. Sci Rep 6:27999PubMedPubMedCentralGoogle Scholar
  90. McGuigan JAS, Elder HY, Günzel D, Schlue WR (2002) Magnesium homeostasis in heart: a critical reappraisal. J Clin Basic Cardiol 5(1):5–22Google Scholar
  91. Means CK, Lygren B, Langeberg LK, Jain A, Dixon RE, Vega AL, Gold MG, Petrosyan S, Taylor SS, Murphy AN, Ha T, Santana LF, Tasken K, Scott JD (2011) An entirely specific type I A-kinase anchoring protein that can sequester two molecules of protein kinase A at mitochondria. Proc Natl Acad Sci U S A 108(48):E1227–E1235PubMedPubMedCentralGoogle Scholar
  92. Merolle L, Sponder G, Sargenti A, Mastrototaro L, Cappadone C, Farruggia G, Procopio A, Malucelli E, Parisse P, Gianoncelli A, Aschenbach JR, Kolisek M, Iotti S (2018) Overexpression of the mitochondrial Mg channel MRS2 increases total cellular Mg concentration and influences sensitivity to apoptosis. Metallomics 10(7):917–928PubMedGoogle Scholar
  93. Meyer TE, Verwoert GC, Hwang SJ, Glazer NL, Smith AV et al (2010) Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six Loci influencing serum magnesium levels. PLoS Genet 6(8):e1001045PubMedPubMedCentralGoogle Scholar
  94. Mohorko E, Owen RL, Malojčić G, Brozzo MS, Aebi M, Glockshuber R (2014) Structural basis of substrate specificity of human oligosaccharyl transferase subunit N33/Tusc3 and its role in regulating protein N-glycosylation. Structure 22(4):590–601PubMedGoogle Scholar
  95. Monteilh-Zoller MK, Hermosura MC, Nadler MJ, Scharenberg AM, Penner R, Fleig A (2003) TRPM7 provides an ion channel mechanism for cellular entry of trace metal ions. J Gen Physiol 121(1):49–60PubMedPubMedCentralGoogle Scholar
  96. Montell C (2003) Mg2+ homeostasis: the Mg2+nificent TRPM chanzymes. Curr Biol 13(20):R799–R801PubMedGoogle Scholar
  97. Nadler MJ, Hermosura MC, Inabe K, Perraud AL, Zhu Q, Stokes AJ, Kurosaki T, Kinet JP, Penner R, Scharenberg AM, Fleig A (2001) LTRPC7 is a Mg.ATP-regulated divalent cation channel required for cell viability. Nature 411(6837):590–595PubMedGoogle Scholar
  98. Nishizawa Y, Morii H, Durlach J (2007) New perspectives in magnesium research. Springer, LondonGoogle Scholar
  99. Noguchi M, Hirata N, Suizu F (2018) AKT keeps the beat in CLOCK’s circadian rhythm. J Biol Chem 293(23):9137–9138PubMedPubMedCentralGoogle Scholar
  100. Nosek MT, Dransfield DT, Aprille JR (1990) Calcium stimulates ATP-Mg/Pi carrier activity in rat liver mitochondria. J Biol Chem 265(15):8444–8450PubMedGoogle Scholar
  101. Nury H, Dahout-Gonzalez C, Trézéguet V, Lauquin GJ, Brandolin G, Pebay-Peyroula E (2006) Relations between structure and function of the mitochondrial ADP/ATP carrier. Annu Rev Biochem 75:713–741PubMedGoogle Scholar
  102. Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF (2009) Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet 84(2):266–273PubMedPubMedCentralGoogle Scholar
  103. Penner R, Fleig A (2007) The Mg2+ and Mg2+-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol 179:313–328Google Scholar
  104. Pfaff E, Heldt HW, Klingenberg M (1969) Adenine nucleotide translocation of mitochondria. Kinetics of the adenine nucleotide exchange. Eur J Biochem 10(3):484–493PubMedGoogle Scholar
  105. Piskacek M, Zotova L, Zsurka G, Schweyen RJ (2009) Conditional knockdown of hMRS2 results in loss of mitochondrial Mg2+ uptake and cell death. J Cell Mol Med 13(4):693–700PubMedGoogle Scholar
  106. Qin Y, Dittmer PJ, Park JG, Jansen KB, Palmer AE (2011) Measuring steady-state and dynamic endoplasmic reticulum and Golgi Zn2+ with genetically encoded sensors. Proc Natl Acad Sci U S A 108(18):7351–7356PubMedPubMedCentralGoogle Scholar
  107. Quamme GA (2010) Molecular identification of ancient and modern mammalian magnesium transporters. Am J Physiol Cell Physiol 298(3):C407–C429PubMedGoogle Scholar
  108. Rivera A, Kam SY, Ho M, Romero JR, Lee S (2013) Ablation of the Kell/Xk complex alters erythrocyte divalent cation homeostasis. Blood Cells Mol Dis 50(2):80–85PubMedGoogle Scholar
  109. Rodríguez-Zavala JS, Moreno-Sánchez R (1998) Modulation of oxidative phosphorylation by Mg2+ in rat heart mitochondria. J Biol Chem 273(14):7850–7855PubMedGoogle Scholar
  110. Romani AM (2007) Magnesium homeostasis in mammalian cells. Front Biosci 12:308–331PubMedGoogle Scholar
  111. Romani AMP (2011) Cellular magnesium homeostasis. Arch Biochem Biophys 512(1):1–23PubMedPubMedCentralGoogle Scholar
  112. Romani AM, Scarpa A (2000) Regulation of cellular magnesium. Front Biosci 5:D720–D734PubMedGoogle Scholar
  113. Romani A, Dowell E, Scarpa A (1991) Cyclic AMP-induced Mg2+ release from rat liver hepatocytes, permeabilized hepatocytes, and isolated mitochondria. J Biol Chem 266(36):24376–24384PubMedGoogle Scholar
  114. Roulis E, Hyland C, Flower R, Gassner C, Jung HH, Frey BM (2018) Molecular basis and clinical overview of McLeod syndrome compared with other Neuroacanthocytosis syndromes: a review. JAMA Neurol.
  115. Run C, Yang Q, Liu Z, OuYang B, Chou JJ (2015) Molecular basis of MgATP selectivity of the mitochondrial SCaMC carrier. Structure 23(8):1394–1403PubMedPubMedCentralGoogle Scholar
  116. Rutter GA, Osbaldeston NJ, McCormack JG, Denton RM (1990) Measurement of matrix free Mg2+ concentration in rat heart mitochondria by using entrapped fluorescent probes. Biochem J 271(3):627–634PubMedPubMedCentralGoogle Scholar
  117. Sahni J, Scharenberg AM (2013) The SLC41 family of MgtE-like magnesium transporters. Mol Asp Med 34(2–3):620–628Google Scholar
  118. Sahni J, Nelson B, Scharenberg AM (2007) SLC41A2 encodes a plasma-membrane Mg2+ transporter. Biochem J 401(2):505–513PubMedGoogle Scholar
  119. Sardanelli AM, Signorile A, Nuzzi R, Rasmo DD, Technikova-Dobrova Z, Drahota Z, Occhiello A, Pica A, Papa S (2006) Occurrence of A-kinase anchor protein and associated cAMP-dependent protein kinase in the inner compartment of mammalian mitochondria. FEBS Lett 580(24):5690–5696PubMedGoogle Scholar
  120. Schapiro FB, Grinstein S (2000) Determinants of the pH of the Golgi complex. J Biol Chem 275(28):21025–21032PubMedGoogle Scholar
  121. Schindl R, Weghuber J, Romanin C, Schweyen RJ (2007) Mrs2p forms a high conductance Mg2+ selective channel in mitochondria. Biophys J 93(11):3872–3883PubMedPubMedCentralGoogle Scholar
  122. Schlingmann KP, Weber S, Peters M, Niemann Nejsum L, Vitzthum H, Klingel K, Kratz M, Haddad E, Ristoff E, Dinour D, Syrrou M, Nielsen S, Sassen M, Waldegger S, Seyberth HW, Konrad M (2002) Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 31(2):166–170PubMedGoogle Scholar
  123. Schönfeld P, Schüttig R, Wojtczak L (2002) Rapid release of Mg2+ from liver mitochondria by nonesterified long-chain fatty acids in alkaline media. Arch Biochem Biophys 403(1):16–24PubMedGoogle Scholar
  124. Schultheis PJ, Hagen TT, O’Toole KK, Tachibana A, Burke CR, McGill DL, Okunade GW, Shull GE (2004) Characterization of the P5 subfamily of P-type transport ATPases in mice. Biochem Biophys Res Commun 323(3):731–738PubMedGoogle Scholar
  125. Schweigel M, Martens H (2000) Magnesium transport in the gastrointestinal tract. Front Biosci 5:D666–D677PubMedGoogle Scholar
  126. Schweigel M, Martens H (2003) Anion-dependent Mg2+ influx and a role for a vacuolar H+-ATPase in sheep ruminal epithelial cells. Am J Physiol Gastrointest Liver Physiol 285(1):G45–G53PubMedGoogle Scholar
  127. Schweigel M, Lang I, Martens H (1999) Mg2+ transport in sheep rumen epithelium: evidence for an electrodiffusive uptake mechanism. Am J Phys 277(5 Pt 1):G976–G982Google Scholar
  128. Schweigel M, Vormann J, Martens H (2000) Mechanisms of Mg2+ transport in cultured ruminal epithelial cells. Am J Physiol Gastrointest Liver Physiol 278(3):G400–G408PubMedGoogle Scholar
  129. Schweigel M, Park HS, Etschmann B, Martens H (2006) Characterization of the Na+-dependent Mg2+ transport in sheep ruminal epithelial cells. Am J Physiol Gastrointest Liver Physiol 290(1):G56–G65PubMedGoogle Scholar
  130. Schweigel M, Kuzinski J, Deiner C, Kolisek M (2009) Rumen epithelial cells adapt magnesium transport to high and low extracellular magnesium conditions. Magnes Res 22(3):133–150PubMedGoogle Scholar
  131. Schweigel-Röntgen M, Kolisek M (2014) SLC41 transporters – molecular identification and functional role. Curr Top Membr 73:383–410PubMedGoogle Scholar
  132. Shrimal S, Cherepanova NA, Gilmore R (2015) Cotranslational and posttranslocational N-glycosylation of proteins in the endoplasmic reticulum. Semin Cell Dev Biol 41:71–78PubMedGoogle Scholar
  133. Smith RL, Thompson LJ, Maguire ME (1995) Cloning and characterization of MgtE, a putative new class of Mg2+ transporter from Bacillus firmus OF4. J Bacteriol 177(5):1233–1238PubMedPubMedCentralGoogle Scholar
  134. Sponder G, Svidova S, Schindl R, Wieser S, Schweyen RJ, Romanin C, Froschauer EM, Weghuber J (2010a) Lpe10p modulates the activity of the Mrs2p-based yeast mitochondrial Mg2+ channel. FEBS J 277(17):3514–3525PubMedGoogle Scholar
  135. Sponder G, Svidova S, Schweigel M, Vormann J, Kolisek M (2010b) Splice-variant 1 of the ancient domain protein 2 (ACDP2) complements the magnesium-deficient growth phenotype of Salmonella enterica sv. typhimurium strain MM281. Magnes Res 23(2):105–114PubMedGoogle Scholar
  136. Sponder G, Svidová S, Khan MB, Kolisek M, Schweyen RJ, Carugo O, Djinović-Carugo K (2013a) The G-M-N motif determines ion selectivity in the yeast magnesium channel Mrs2p. Metallomics 5(6):745–752PubMedGoogle Scholar
  137. Sponder G, Rutschmann K, Kolisek M (2013b) “Inside-in” or “inside-out”? The membrane topology of SLC41A1. Magnes Res 26(4):176–181PubMedGoogle Scholar
  138. Sponder G, Mastrototaro L, Kurth K, Merolle L, Zhang Z, Abdulhanan N, Smorodchenko A, Wolf K, Fleig A, Penner R, Iotti S, Aschenbach JR, Vormann J, Kolisek M (2016) Human CNNM2 is not a Mg2+ transporter per se. Pflugers Arch 468(7):1223–1240PubMedGoogle Scholar
  139. Sponder G, Abdulhanan N, Fröhlich N, Mastrototaro L, Aschenbach JR, Röntgen M, Pilchova I, Cibulka M, Racay P, Kolisek M (2017) Overexpression of Na+/Mg2+ exchanger SLC41A1 attenuates pro-survival signaling. Oncotarget 9(4):5084–5104PubMedPubMedCentralGoogle Scholar
  140. Stuiver M, Lainez S, Will C, Terryn S, Günzel D, Debaix H, Sommer K, Kopplin K, Thumfart J, Kampik NB, Querfeld U, Willnow TE, Němec V, Wagner CA, Hoenderop JG, Devuyst O, Knoers NV, Bindels RJ, Meij IC, Müller D (2011) CNNM2, encoding a basolateral protein required for renal Mg2+ handling, is mutated in dominant hypomagnesemia. Am J Hum Genet 88(3):333–343PubMedPubMedCentralGoogle Scholar
  141. Svenstrup K, Møller RS, Christensen J, Budtz-Jørgensen E, Gilling M, Nielsen JE (2011) NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy. Eur J Neurol 18(9):1197–1199PubMedGoogle Scholar
  142. Tewari SG, Dash RK, Beard DA, Bazil JN (2012) A biophysical model of the mitochondrial ATP-Mg/Pi carrier. Biophys J 103(7):1616–1625PubMedPubMedCentralGoogle Scholar
  143. Traba J, Satrústegui J, del Arco A (2009) Characterization of SCaMC-3-like/slc25a41, a novel calcium-independent mitochondrial ATP-Mg/Pi carrier. Biochem J 418(1):125–133PubMedGoogle Scholar
  144. Trapani V, Wolf FI (2015) Mitochondrial magnesium to the rescue. Magnes Res 28(2):79–84PubMedGoogle Scholar
  145. Tsao YT, Shih YY, Liu YA, Liu YS, Lee OK (2017) Knockdown of SLC41A1 magnesium transporter promotes mineralization and attenuates magnesium inhibition during osteogenesis of mesenchymal stromal cells. Stem Cell Res Ther 8(1):39PubMedPubMedCentralGoogle Scholar
  146. Vallipuram J, Grenville J, Crawford DA (2010) The E646D-ATP13A4 mutation associated with autism reveals a defect in calcium regulation. Cell Mol Neurobiol 30(2):233–246PubMedGoogle Scholar
  147. Vergun O, Votyakova TV, Reynolds IJ (2003) Spontaneous changes in mitochondrial membrane potential in single isolated brain mitochondria. Biophys J 85(5):3358–3366PubMedPubMedCentralGoogle Scholar
  148. Voets T, Nilius B, Hoefs S, van der Kemp AW, Droogmans G, Bindels RJ, Hoenderop JG (2004) TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 279(1):19–25PubMedGoogle Scholar
  149. Wabakken T, Rian E, Kveine M, Aasheim HC (2003) The human solute carrier SLC41A1 belongs to a novel eukaryotic subfamily with homology to prokaryotic MgtE Mg2+ transporters. Biochem Biophys Res Commun 306(3):718–724PubMedGoogle Scholar
  150. Wang CY, Shi JD, Yang P, Kumar PG, Li QZ, Run QG, Su YC, Scott HS, Kao KJ, She JX (2003) Molecular cloning and characterization of a novel gene family of four ancient conserved domain proteins (ACDP). Gene 306:37–44PubMedGoogle Scholar
  151. Wang CY, Yang P, Shi JD, Purohit S, Guo D, An H, Gu JG, Ling J, Dong Z, She JX (2004) Molecular cloning and characterization of the mouse Acdp gene family. BMC Genomics 5(1):7PubMedPubMedCentralGoogle Scholar
  152. Wiesenberger G, Waldherr M, Schweyen RJ (1992) The nuclear gene MRS2 is essential for the excision of group II introns from yeast mitochondrial transcripts in vivo. J Biol Chem 267(10):6963–6969PubMedGoogle Scholar
  153. Will C, Breiderhoff T, Thumfart J, Stuiver M, Kopplin K, Sommer K, Günzel D, Querfeld U, Meij IC, Shan Q, Bleich M, Willnow TE, Müller D (2010) Targeted deletion of murine Cldn16 identifies extra- and intrarenal compensatory mechanisms of Ca2+ and Mg2+ wasting. Am J Physiol Renal Physiol 298(5):F1152–F1161PubMedGoogle Scholar
  154. Wuttke MS, Buck J, Levin LR (2001) Bicarbonate-regulated soluble adenylyl cyclase. JOP 2(4 Suppl):154–158PubMedGoogle Scholar
  155. Xie H, Zhang Y, Zhang P, Wang J, Wu Y, Wu X, Netoff T, Jiang Y (2014) Functional study of NIPA2 mutations identified from the patients with childhood absence epilepsy. PLoS One 9(10):e109749PubMedPubMedCentralGoogle Scholar
  156. Yamanaka R, Shindo Y, Hotta K, Suzuki K, Oka K (2013) NO/cGMP/PKG signaling pathway induces magnesium release mediated by mitoKATP channel opening in rat hippocampal neurons. FEBS Lett 587(16):2643–2648PubMedGoogle Scholar
  157. Yamanaka R, Tabata S, Shindo Y, Hotta K, Suzuki K, Soga T, Oka K (2016) Mitochondrial Mg2+ homeostasis decides cellular energy metabolism and vulnerability to stress. Sci Rep 6:30027PubMedPubMedCentralGoogle Scholar
  158. Yamazaki D, Funato Y, Miura J, Sato S, Toyosawa S, Furutani K, Kurachi Y, Omori Y, Furukawa T, Tsuda T, Kuwabata S, Mizukami S, Kikuchi K, Miki H (2013) Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model. PLoS Genet 9(12):e1003983PubMedPubMedCentralGoogle Scholar
  159. Yanai A, Huang K, Kang R, Singaraja RR, Arstikaitis P, Gan L, Orban PC, Mullard A, Cowan CM, Raymond LA, Drisdel RC, Green WN, Ravikumar B, Rubinsztein DC, El-Husseini A, Hayden MR (2006) Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function. Nat Neurosci 9(6):824–831PubMedPubMedCentralGoogle Scholar
  160. Yu N, Jiang J, Yu Y, Li H, Huang X, Ma Y, Zhang L, Zou J, Zhang B, Chen S, Liu P (2014) SLC41A1 knockdown inhibits angiotensin II-induced cardiac fibrosis by preventing Mg2+ efflux and Ca2+ signaling in cardiac fibroblasts. Arch Biochem Biophys 564:74–82PubMedGoogle Scholar
  161. Zhang GH, Melvin JE (1996) Na+-dependent release of Mg2+ from an intracellular pool in rat sublingual mucous acini. J Biol Chem 271(46):29067–29072PubMedGoogle Scholar
  162. Zhang J, Wang Y, Liu X, Dagda RK, Zhang Y (2017a) How AMPK and PKA interplay to regulate mitochondrial function and survival in models of ischemia and diabetes. Oxidative Med Cell Longev 2017:4353510Google Scholar
  163. Zhang H, Kozlov G, Li X, Wu H, Gulerez I, Gehring K (2017b) PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3. Sci Rep 7(1):48PubMedPubMedCentralGoogle Scholar
  164. Zhou H, Clapham DE (2009) Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc Natl Acad Sci U S A 106(37):15750–15755PubMedPubMedCentralGoogle Scholar
  165. Zhu X, Rivera A, Golub MS, Peng J, Sha Q, Wu X, Song X, Kumarathasan P, Ho M, Redman CM, Lee S (2009) Changes in red cell ion transport, reduced intratumoral neovascularization, and some mild motor function abnormalities accompany targeted disruption of the Mouse Kell gene (Kel). Am J Hematol 84(8):492–498PubMedGoogle Scholar
  166. Zippin JH, Chen Y, Nahirney P, Kamenetsky M, Wuttke MS, Fischman DA, Levin LR, Buck J (2003) Compartmentalization of bicarbonate-sensitive adenylyl cyclase in distinct signaling microdomains. FASEB J 17(1):82–84PubMedGoogle Scholar
  167. Zsurka G, Gregán J, Schweyen RJ (2001) The human mitochondrial Mrs2 protein functionally substitutes for its yeast homologue, a candidate magnesium transporter. Genomics 72(2):158–168PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Martin Kolisek
    • 1
    Email author
  • Gerhard Sponder
    • 2
  • Ivana Pilchova
    • 1
  • Michal Cibulka
    • 3
  • Zuzana Tatarkova
    • 3
  • Tanja Werner
    • 4
  • Peter Racay
    • 1
  1. 1.Biomedical Center Martin, Division of Neurosciences, Jessenius Faculty of Medicine in MartinComenius University in BratislavaMartinSlovakia
  2. 2.Institute of Veterinary Physiology, Veterinary MedicineFree University of BerlinBerlinGermany
  3. 3.Institute of Medical Biochemistry, Jessenius Faculty of Medicine in MartinComenius University in BratislavaMartinSlovakia
  4. 4.NuOmix Research k.s.MartinSlovakia

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