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

  1. Vladimir Chubanov  Is a corresponding author
  2. Silvia Ferioli
  3. Annika Wisnowsky
  4. David G Simmons
  5. Christin Leitzinger
  6. Claudia Einer
  7. Wenke Jonas
  8. Yuriy Shymkiv
  9. Harald Bartsch
  10. Attila Braun
  11. Banu Akdogan
  12. Lorenz Mittermeier
  13. Ludmila Sytik
  14. Friedrich Torben
  15. Vindi Jurinovic
  16. Emiel PC van der Vorst
  17. Christian Weber
  18. Önder A Yildirim
  19. Karl Sotlar
  20. Annette Schürmann
  21. Susanna Zierler
  22. Hans Zischka
  23. Alexey G Ryazanov
  24. Thomas Gudermann  Is a corresponding author
  1. Ludwig Maximilian University of Munich, Germany
  2. The University of Queensland, Australia
  3. Helmholtz Zentrum Munich, Germany
  4. German Institute of Human Nutrition, Germany
  5. Princeton Institute of Life Sciences, United States
  6. University of Würzburg, Germany
  7. LMU Munich, Germany
  8. Paracelsus Medical University, Austria

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 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.

Data availability

The following data sets were generated

Article and author information

Author details

  1. Vladimir Chubanov

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    For correspondence
    vladimir.chubanov@lrz.uni-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6042-4193
  2. Silvia Ferioli

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Annika Wisnowsky

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. David G Simmons

    School of Biomedical Sciences, The University of Queensland, St. Lucia, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4115-9371
  5. Christin Leitzinger

    Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Claudia Einer

    Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Wenke Jonas

    Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Yuriy Shymkiv

    Princeton Institute of Life Sciences, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Harald Bartsch

    Institute of Pathology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Attila Braun

    Department of Vascular Medicine, University Hospital and Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Banu Akdogan

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Lorenz Mittermeier

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Ludmila Sytik

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Friedrich Torben

    Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Vindi Jurinovic

    IBE, LMU Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. Emiel PC van der Vorst

    Institute for Cardiovascular Prevention, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  17. Christian Weber

    Institute for Cardiovascular Prevention, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  18. Önder A Yildirim

    Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum Munich, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  19. Karl Sotlar

    Institute of Pathology, Paracelsus Medical University, Salzburg, Austria
    Competing interests
    The authors declare that no competing interests exist.
  20. Annette Schürmann

    Department of Experimental Diabetology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Germany
    Competing interests
    The authors declare that no competing interests exist.
  21. Susanna Zierler

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4684-0385
  22. Hans Zischka

    Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum Munich, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  23. Alexey G Ryazanov

    Princeton Institute of Life Sciences, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Thomas Gudermann

    Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Munich, Germany
    For correspondence
    thomas.gudermann@lrz.uni-muenchen.de
    Competing interests
    The authors declare that no competing interests exist.

Funding

Deutsche Forschungsgemeinschaft (TRR 152-P15)

  • Vladimir Chubanov

Deutsche Forschungsgemeinschaft (TRP 152-P15)

  • Thomas Gudermann

Deutsche Forschungsgemeinschaft (TRP 152-P14)

  • Susanna Zierler

Deutsche Forschungsgemeinschaft (SFB1123-A1)

  • Emiel PC van der Vorst
  • Christian Weber

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments involving animals were done in accordance with the EU Animal Welfare Act and were approved by the local councils on animal care (permit No 55.2-1-54-2532-134-13 from Government of Oberbayern, Germany, and permit No 2347-15-2014 from State Ministry of Brandenburg, Germany).

Copyright

© 2016, Chubanov et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,526
    views
  • 549
    downloads
  • 106
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Vladimir Chubanov
  2. Silvia Ferioli
  3. Annika Wisnowsky
  4. David G Simmons
  5. Christin Leitzinger
  6. Claudia Einer
  7. Wenke Jonas
  8. Yuriy Shymkiv
  9. Harald Bartsch
  10. Attila Braun
  11. Banu Akdogan
  12. Lorenz Mittermeier
  13. Ludmila Sytik
  14. Friedrich Torben
  15. Vindi Jurinovic
  16. Emiel PC van der Vorst
  17. Christian Weber
  18. Önder A Yildirim
  19. Karl Sotlar
  20. Annette Schürmann
  21. Susanna Zierler
  22. Hans Zischka
  23. Alexey G Ryazanov
  24. Thomas Gudermann
(2016)
Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival
eLife 5:e20914.
https://doi.org/10.7554/eLife.20914

Share this article

https://doi.org/10.7554/eLife.20914

Further reading

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Joar Esteban Pinto Torres, Mathieu Claes ... Yann G-J Sterckx
    Research Article

    African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.

    1. Structural Biology and Molecular Biophysics
    Manming Xu, Sarath Chandra Dantu ... Shozeb Haider
    Research Article

    The relationship between protein dynamics and function is essential for understanding biological processes and developing effective therapeutics. Functional sites within proteins are critical for activities such as substrate binding, catalysis, and structural changes. Existing computational methods for the predictions of functional residues are trained on sequence, structural, and experimental data, but they do not explicitly model the influence of evolution on protein dynamics. This overlooked contribution is essential as it is known that evolution can fine-tune protein dynamics through compensatory mutations either to improve the proteins’ performance or diversify its function while maintaining the same structural scaffold. To model this critical contribution, we introduce DyNoPy, a computational method that combines residue coevolution analysis with molecular dynamics simulations, revealing hidden correlations between functional sites. DyNoPy constructs a graph model of residue–residue interactions, identifies communities of key residue groups, and annotates critical sites based on their roles. By leveraging the concept of coevolved dynamical couplings—residue pairs with critical dynamical interactions that have been preserved during evolution—DyNoPy offers a powerful method for predicting and analysing protein evolution and dynamics. We demonstrate the effectiveness of DyNoPy on SHV-1 and PDC-3, chromosomally encoded β-lactamases linked to antibiotic resistance, highlighting its potential to inform drug design and address pressing healthcare challenges.