Kolisek M1*, Montezano AC2, Sponder G1, Vormann J3, Touyz RM2, Aschenbach JR1
1Institute of Veterinary Physiology, Free University of Berlin, Oertzenweg 19b, Berlin, Germany
2Institute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, United Kingdom
3Institute for Prevention and Nutrition (IPEV), Adalperostrasse 37, Munich/Ismaning, Germany
Perturbed Mg homeostasis (MH) and increased production of reactive oxygen species (ROS) leading to oxidative stress (OS) are associated with poor clinical outcomes in patients suffering from chronic and/or degenerative diseases. It was demonstrated that Mg deficiency (MD) and increased levels of ROS correlate. However, the molecular mechanism behind it is unknown.
PARK7/DJ-1 plays a crucial role in cellular redox-homeostasis. It is also a positive regulator of androgen receptor (AR)-dependent transcription. Transcription of SLC41A1, the gene that encodes for a Na+/Mg2+ exchanger (the major ubiquitous Mg2+efflux system of the cell) is regulated by activated AR. Therefore, the assumption that the overexpression of PARK7/DJ-1 induced by OS, and the related activation of AR followed by transcription-initiation of SLC41A1 is feasible. Increased abundance of SLC41A1 increases the cellular Mg2+ efflux capacity. If this scenario is true, then the transcriptional activity of PARK7/DJ-1, AR, and SLC41A1 could be used as biomarkers of intracellular MD.
Insulin reduces the key mediators of OS. On the other hand, OS is a core factor behind dysfunction of insulin signaling and thus insulin resistance. Recently, the inhibitory effect of insulin on SLC41A1 activity has been reported. Therefore, OS could contribute to the initiation of SLC41A1-mediated Mg2+ efflux apart from the transcriptional modulation also through the functional modulation by suppressing the inhibitory effect of insulin.
The antidepressant imipramine is an inhibitor of SLC41A1 Mg2+ efflux activity. Moreover, it reduces OS. Thus, it could be further assumed that providing patients with MD-associated ailments with imipramine could be beneficial.
In summary, regulation of SLC41A1 by OS and interference of insulin signaling offers a new perspective to look at the molecular interplay between OS and MD and its relevance for the pathophysiology of various chronic and/or degenerative diseases.