Magnesium Deficiency: A Cause of Heterogenous Disease in Humans

MAGNESIUM IS THE most prevalent intracellular divalent cation and the second most prevalent cation in the body. The normal adult body content is ;25 g and its distribution is approximately equally divided between the skeleton and soft tissues. A large proportion (about onethird) of skeletal magnesium (Mg) resides on the surface of bone. Because this fraction is surface exchangeable and because the skeletal Mg level falls during Mg depletion, it is hypothesized that this component serves as a reservoir to maintain the extracellular Mg concentration. Extracellular Mg accounts for only 1% of total body Mg. In the plasma, 55% of Mg is ionized, or free, 15% is complexed to anions, and the rest (;30%) is bound to protein (chiefly albumin). Mg is contained within all intracellular compartments. It is principally bound to ATP (80–90%) and other negatively charged molecules. Total cellular Mg ranges from 5–20 mM; the greater the metabolic activity of a cell, the greater the Mg content. Intracellular free Mg accounts for about 1–5% of total cellular Mg (0.2–1.0 mM). Mg is actively transported into and out of cells and is influenced by various hormonal and pharmacological factors which perhaps regulate the intracellular Mg concentration and hence activity of Mg-sensitive enzymes. For example, insulin has been shown to increase intracellular Mg in a number of tissues including skeletal and cardiac muscle, uterine smooth muscle, red blood cells, platelets, and lymphocytes (for review see Refs. 9 and 10). The physiological role of Mg is principally related to enzyme activity (Table 1); over 300 enzyme systems are dependent on the presence of this cation. All enzyme utilizing ATP requires Mg for substrate formation. Intracellular free Mg also acts as an allosteric activator of enzyme action including critical enzyme systems such as adenylate cyclase, phospholipase C, and Na/K-ATPase. Transport of other ions such as potassium and calcium across the plasma membrane may also require the presence of Mg. Mg has been termed “nature’s physiologic calcium channel blocker.” During Mg depletion, intracellular potassium decreases while calcium and sodium increase. Mg is therefore critical for a number of cellular functions, including oxidative phosphorylation, glycolysis, DNA transcription, and protein synthesis. The clinical complications of Mg depletion no doubt are, at least in part, due to perturbation of Mg-requiring enzyme systems.