# Magnesium flux compendium: Discover ligands, channels, and metabolic signals

> **NIH NIH R35** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $249,813

## Abstract

ABSTRACT/SUMMARY
Free ionized intracellular Mg2+ (iMg2+) is estimated to be in the range of 0.5–1.2 mM. In general, it is accepted
that under resting conditions, the concentration of ionized cytosolic Mg2+ is `muffled' by phosphometabolites,
nucleic acids and proteins. For example, ATP binds with a Kd value of 50 μM-70 ȝM and therefore Mg2+ in the
cytosol and the mitochondrial matrix is primarily complexed with ATP (Mg-ATP2-). Because of its abundance (~5
mM), ATP is considered to be the largest iMg2+ `store'. Fluctuations in free cytosolic (cMg2+) following hormonal
stimuli have been touted as passive adjustments of Mg2+ dissociating from the exuberant Mg-ATP contingent
and other `buffered' pools of Mg2+. Apart from iMg2+ `buffering' mechanism, Mg2+ ion channels and transporters
controlling Mg2+ entry as well as efflux across the plasma membrane are thought to maintain the equilibrium of
free cMg2+. Currently, several candidates are correlated to Mg2+ entry machinery (TRPM6, TRPM7, MagT1), but
are still awaiting convincing evidence for such roles. The Mg2+/Na+ exchanger SLC41A1 was proposed to
contribute Mg2+ efflux from the cell, whereas Mrs2 was proposed as a mitochondrial Mg2+ transporter. Very little
is known about the molecular details of Mg2+ transport into/from cellular organelles like the ER, mitochondria,
endosomes and lysosomes. A few studies have speculated that free [Mg2+] in the ER and mitochondria are likely
to be similar to [cMg2+]. However, the temporal and spatial dynamics, let alone the biological relevance of iMg2+
mobilization, remain a mystery in cell biology. Nevertheless, Mg2+ is an essential cation controlling many
biochemical reactions. Our recent work has shown that L-lactate acts as an activator that triggers a dynamic
transfer of Mg2+ between the ER and mitochondria to shape bioenergetics and cellular metabolism (Cell 2020).
The mitochondrial localized Mrs2 transporter was found to be responsible for the accumulation of Mg2+ in
mitochondria. However, the L-lactate-induced ER release molecular machinery remains unidentified. I propose
to identify ER Mg2+ release component, plasma membrane entry machinery and the resultant molecular signaling
pathways. I will take advantage of unbiased RNAi screen and targeted CRISPR/Cas9 editing approaches to
answer these mysteries in the Mg2+ signaling field. Identification of these molecular machineries would aid in our
understanding of iMg2+ dynamics and the cause-effect relationships that exist between iMg2+ flux and cellular
processes. Additionally, I will test and define the Mg2+-dependent signaling events based on the cellular and
mouse model phenotypes. It is thrilling to define the molecular link between cellular Mg2+ homeostasis and
physiological function. Our identification and characterization of the Mg2+ flux components will further investigate
how, and if, these signaling routes impinge on the pathophysiology of a growing number of Mg2+ deficiency
diseases in humankind. O...

## Key facts

- **NIH application ID:** 11095144
- **Project number:** 3R35GM145294-03S1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** MADESH MUNISWAMY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,813
- **Award type:** 3
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11095144

## Citation

> US National Institutes of Health, RePORTER application 11095144, Magnesium flux compendium: Discover ligands, channels, and metabolic signals (3R35GM145294-03S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/11095144. Licensed CC0.

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