Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival.

Vladimir Chubanov,Ludmila Sytik,Claudia Einer,Yuriy Shymkiv,Banu Akdogan,Annika Wisnowsky,Lorenz Mittermeier,Karl Sotlar,Christin Leitzinger,Friedrich Torben,Harald Bartsch,Attila Braun,Wenke Jonas,Susanna Zierler,Silvia Ferioli,Hans Zischka,Thomas Gudermann,Önder Yildirim ,Emiel P C Van Der Vorst ,Vindi Jurinović ,David G Simmons ,A Schürmann ,Alexey G Ryazanov

doi:10.7554/elife.20914

Abstract

Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.

Highlights

Mg2+ is the most abundant intracellular divalent cation and is essential for the regulation of a broad spectrum of metabolic and signalling pathways (de Baaij et al, 2015)
Using a mouse strain carrying a gene-trap mutation in Trpm6 (Trpm6bgeo) (Table 1), we found that Trpm6bgeo/bgeo embryos were present at embryonic days (e) 8.5–10.5 (Figure 1A)
Only eLife digest A balanced diet contains a variety of minerals such as magnesium ions, which are required for many chemical reactions in our body

Summary

Introduction

Mg2+ is the most abundant intracellular divalent cation and is essential for the regulation of a broad spectrum of metabolic and signalling pathways (de Baaij et al, 2015). Direct association with Mg2+ fosters the structural integrity of key metabolites (such as ATP), proteins, lipid membranes and nucleic acids (de Baaij et al, 2015) implying that organismal Mg2+ deficiency, a surprisingly common condition in humans (King et al, 2005; Rosanoff et al, 2012), may be especially harmful during prenatal development and early postnatal life, when the production of and the demand for Mg2+-bound metabolites is high. Deletion of Trpm in mice has resulted in neural tube closure defects and embryonic death (Walder et al, 2009) indicating a direct role of TRPM6 in developmental processes and calling into question the simplistic view on the human TRPM6 phenotype. By integrating systematic phenotyping of Trpm gene-modified mice with biochemical analysis, gene expression, metabolomics, and cell biological approaches, we decipher the molecular and organismal roles of TRPM6 in prenatal development and postnatal survival

Results

E Muscle

Discussion

Materials and methods

Evaluation of atherosclerosis development

Funding Funder