title: PARK7/DJ-1 dysregulation by oxidative stress leads to magnesium deficiency: implications in degenerative and chronic diseases.
abstract: 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.
authors.affiliation: Institute of Veterinary Physiology, Free University of Berlin, Oertzenweg 19b, 14163 Berlin, Germany martink@zedat.fu-berlin.de rhian.touyz@glasgow.ac.uk joerg.aschenbach@fu-berlin.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolisek
authors.affiliation: Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, U.K.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Montezano
authors.affiliation: Institute of Veterinary Physiology, Free University of Berlin, Oertzenweg 19b, 14163 Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sponder
authors.affiliation: Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, U.K.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Anagnostopoulou
authors.affiliation: Institute for Prevention and Nutrition (IPEV), Adalperostrasse 37, Munich/Ismaning, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Vormann
authors.affiliation: Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, U.K. martink@zedat.fu-berlin.de rhian.touyz@glasgow.ac.uk joerg.aschenbach@fu-berlin.de.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Touyz
authors.affiliation: Institute of Veterinary Physiology, Free University of Berlin, Oertzenweg 19b, 14163 Berlin, Germany martink@zedat.fu-berlin.de rhian.touyz@glasgow.ac.uk joerg.aschenbach@fu-berlin.de.
authors.forename: Joerg R
authors.initials: JR
authors.lastname: Aschenbach
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002908:Chronic Disease; D006801:Humans; D007099:Imipramine / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008275:Magnesium Deficiency / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D008659:Metabolic Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D058990:Molecular Targeted Therapy; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D015513:Oncogene Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D000071617:Protein Deglycase DJ-1; D011944:Receptors, Androgen / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D027682:Cation Transport Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D011944:Receptors, Androgen; C476304:SLC41A1 protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D007099:Imipramine
keywords: Mg2+ homoeostasis; PARK7/DJ-1; androgen receptor; magnesium; oxidative stress; protein–protein interaction; signalling pathway