Cellular compartmentation and MgATP dominance
At the cellular level, magnesium is the second most abundant cation after potassium, with total concentrations around 15–25 mM, but free cytosolic Mg²⁺ is kept in the low‑millimolar or sub‑millimolar range because most magnesium is bound to nucleotides, especially ATP. The MgATP complex is the actual substrate for the vast majority of ATP-dependent enzymes, including kinases, ion pumps, and many DNA and RNA processing enzymes, so maintenance of MgATP is effectively the primary “priority” for survival. [1
This has several consequences during insufficiency:
Cells buffer declining free Mg²⁺ by shifting binding equilibria and exchanging magnesium between weaker and stronger binding sites, tending to preserve MgATP complexes needed for core metabolism and signaling. [2
High-turnover ATPases (for example, Na⁺/K⁺‑ATPase, Ca²⁺ pumps) and kinases are among the first processes affected as MgATP falls, leading to altered membrane potentials and signaling long before overt cell death. [1
Because ATP itself is tightly regulated in many cells until late in metabolic stress, dynamic modulation of free Mg²⁺ and redistribution between compartments (cytosol vs organelles, nucleus vs cytoplasm) are key levers by which the cell implicitly “decides” what to maintain.[2
Transporters and tissue‑level “triage”
Magnesium entry, exit, and subcellular movement are governed by a family of channels and transporters (TRPM6/7, MagT1, CNNM family, SLC41, mitochondrial MRS2, and others), whose expression and activity differ across tissues. In the kidney and gut, TRPM6 and associated transporters tune whole‑body retention; loss‑of‑function mutations in these molecules cause severe hypomagnesemia with secondary hypocalcemia and neurologic symptoms, illustrating how strongly the system is biased to protect extracellular and neuronal function. [2
Tissue transport kinetics create a functional hierarchy:
Heart, liver, and kidney cells have relatively higher magnesium transport rates, supporting rapid adaptation to fluctuations and preserving function in critical organs. [12]
Skeletal muscle, red cells, and brain exhibit slower exchange; this may stabilize intracellular Mg²⁺ in the short term but also means these tissues can silently accumulate deficits over time without dramatic serum changes. [1
In inherited TRPM6/MagT1 defects, immune cells and excitable tissues are particularly vulnerable, highlighting priority given to growth, immunity, and excitability pathways that depend on fast Mg²⁺ flux. [3
Within cells, mitochondrial MRS2 and cardiolipin-dependent complexes help maintain mitochondrial magnesium, crucial for oxidative phosphorylation and ATP synthesis, and their disruption (for example, in Barth syndrome) destabilizes mitochondrial Mg²⁺ and energy production. This architecture implicitly ensures preferential support of mitochondrial ATP generation when magnesium is limited. [2
Enzymatic networks and DNA/genome maintenance
Magnesium is required for hundreds of enzymes, especially those handling phosphorylated substrates: kinases, phosphatases, adenylate cyclase, phosphodiesterases, and many metabolic dehydrogenase systems. It also binds to nucleic acids and ribosomes, stabilizing RNA structure and ribosome assembly, making it fundamental to protein synthesis. [1
For genomic maintenance, magnesium sits at the center of:
DNA polymerases and ligases required for replication and repair, which use Mg²⁺ as an essential cofactor for catalysis and fidelity. [16
Nucleotide excision repair, base excision repair, and mismatch repair enzymes, which require Mg²⁺ and MgATP to recognize lesions, incise DNA, and resynthesize correct sequences. [11
Chromatin structural stability, where magnesium screens negative charges on phosphate backbones and contributes to chromatin compaction. [16
In low-magnesium environments, in vitro and cell culture work shows slowed DNA synthesis, impaired repair, and increased chromosomal instability and micronucleus formation, consistent with a shift away from high-fidelity genome maintenance when Mg²⁺ is scarce. But because catastrophic DNA damage is incompatible with survival, cells often respond by growth arrest (G0/G1 accumulation) rather than proceeding through replication with inadequate Mg²⁺, effectively prioritizing genome integrity by halting proliferation. [10
Neuron and muscle stability under hypomagnesemia
In excitable tissues, magnesium plays a dual role: stabilizing membranes and modulating calcium-dependent signaling. At synapses and neuromuscular junctions, Mg²⁺ competes with calcium at presynaptic terminals and NMDA receptors, reducing spontaneous neurotransmitter release and limiting excitotoxicity; depletion lowers firing thresholds, increases nerve conduction velocity, and predisposes to hyperexcitability, tremors, and seizures. [12
During deficiency:
Intracellular Mg²⁺ falls, removing its inhibitory effect on certain potassium channels (for example, ROMK in kidney, analogous mechanisms in excitable tissues), altering resting potentials and repolarization dynamics. [21
Mg²⁺ loss in cardiac myocytes disrupts control of intracellular calcium and action potential duration, favoring arrhythmias, especially when combined with hypokalemia and structural heart disease. [12
Clinically, this is reflected in the “priority” of excitable tissue protection: even mild to moderate hypomagnesemia is associated with arrhythmias, seizures, and muscle cramps, which often prompt clinical intervention well before structural tissues show obvious signs, indicating that failure of neuronal and cardiac stability is among the earliest clear endpoints of magnesium triage failure. [7
Bone, muscle, and connective tissue as sacrificial buffers
Bone and skeletal muscle constitute large, semi-labile reservoirs that can buffer magnesium over weeks to months. During chronic low intake, bone surface magnesium can be released in parallel with calcium via parathyroid hormone (PTH)–mediated resorption, and renal conservation further slows net loss from the system. [4
However, sustained mobilization and impaired replacement have consequences:
Bone: magnesium deficiency impairs 1α‑hydroxylase activity involved in 1,25‑dihydroxyvitamin D formation and can reduce bone extracellular fluid pH via reduced Mg-dependent proton pumps in periosteum and endosteum, contributing to demineralization and osteoporosis. [12
Muscle: experimental magnesium-deficient diets in mice alter expression of magnesium transport/homeostasis genes, modify fiber characteristics, and disturb pathways regulating muscle metabolism and contractility, even with relatively modest changes in serum magnesium. [26]
Connective tissue: low magnesium has been implicated in connective tissue dysplasia and impaired elastin/collagen integrity, consistent with its role in matrix metalloproteinases and cross-linking enzymes. [27]
From a systems perspective, bone and muscle are “deprioritized” under deficiency: they surrender magnesium to protect extracellular and critical organ pools, at the cost of gradual structural and functional decline. [6
Endocrine and metabolic cross‑talk in deficiency
Magnesium interacts tightly with hormonal networks that themselves reshape distribution and prioritization:
PTH and vitamin D: low Mg²⁺ stimulates PTH, which promotes bone resorption and renal reabsorption of both calcium and magnesium, but severe hypomagnesemia paradoxically impairs PTH secretion and action, leading to hypocalcemia and further neuromuscular instability. [8
Insulin: magnesium is a cofactor for the insulin receptor tyrosine kinase and many downstream kinases; deficiency promotes insulin resistance and alters glucose homeostasis, especially in adipose and muscle tissues. [15
RAAS and catecholamines: magnesium deficiency activates the renin–angiotensin–aldosterone system and stress hormones, further affecting vascular tone, cardiac workload, and renal electrolyte handling. [15
In adipose tissue, magnesium deficiency increases oxidative stress, mitochondrial dysfunction, and low‑grade inflammation, contributing to systemic metabolic dysfunction and potentially drawing magnesium into inflammatory and repair processes at the expense of long-term anabolic and storage functions. [15