Magnesium is the second most abundant intracellular cation in the human body (after potassium) and it is the essential cofactor for all ATP-dependent reactions — every reaction in the body that uses ATP as an energy source requires magnesium as a cofactor because ATP exists in the cell primarily as the MgATP2- complex, and it is this complex that is the true substrate for the ATPases and the other ATP-dependent enzymes. Magnesium is therefore involved in virtually every metabolic process in the body — it is required for the function of the Na+/K+ ATPase (which maintains the resting membrane potential), for the function of the Ca2+-ATPase (which pumps calcium out of the cell and into the sarcoplasmic reticulum), for the function of the mitochondrial oxidative phosphorylation enzymes (which generate the ATP that powers the cell), for the function of the protein synthesis machinery (which requires ATP for the aminoacyl-tRNA charging and for the peptide bond formation), and for the function of the DNA and RNA polymerases (which are required for the replication and the transcription of the genetic material). Without adequate magnesium, all of these ATP-dependent processes are impaired, and the cellular energy metabolism collapses — producing the fatigue, the muscle weakness, the cramps, the tetany, the cardiac arrhythmias, and the seizures that are the clinical manifestations of severe hypomagnesaemia.
Magnesium and the Mitochondrial ATP Generation
The mitochondria are the cellular power plants that generate ATP through the oxidative phosphorylation pathway — a series of enzymatic reactions in the inner mitochondrial membrane that couple the oxidation of NADH and FADH2 to the pumping of protons across the inner membrane and to the synthesis of ATP by the ATP synthase enzyme. Magnesium is required at multiple steps in this pathway — it is a cofactor for the kinases that generate the ADP and the substrate-level phosphorylation intermediates, it is a cofactor for the mitochondrial dehydrogenases (including the pyruvate dehydrogenase and the isocitrate dehydrogenase that generate the NADH), and it is a cofactor for the ATP synthase enzyme itself (which requires magnesium for the catalytic site where the ATP is synthesised). The mitochondrial magnesium content is approximately 20mM (which is similar to the ATP concentration), and this magnesium is dynamically regulated by the mitochondrial magnesium transporter (Mrs2p), which allows magnesium to enter and leave the mitochondrial matrix in response to the cellular energy demand. When magnesium is deficient, the mitochondrial ATP generation is impaired, the cellular energy charge falls, and the cell cannot perform the metabolic functions that are essential for its survival — this is the primary mechanism of the cellular dysfunction and the tissue injury that characterise severe hypomagnesaemia.
The clinical importance of magnesium for mitochondrial function is underscored by the observation that many of the symptoms of magnesium deficiency (including the fatigue, the muscle weakness, and the cardiac arrhythmias) are the direct result of the impaired mitochondrial ATP generation. The cardiac muscle is particularly dependent on a continuous supply of ATP from the mitochondria (it consumes approximately 6-8kg of ATP per day in the resting adult), and when the mitochondrial ATP generation is impaired by magnesium deficiency, the cardiac contractile function is compromised and the cardiac arrhythmias are triggered. The neurological symptoms of magnesium deficiency (including the tetany, the paraesthesias, and the seizures) are also the result of the impaired ATP generation in the neurons — the Na+/K+ ATPase is particularly sensitive to ATP depletion, and when it fails, the resting membrane potential collapses, the neurons become hyperexcitable, and the seizures are triggered.
Magnesium and the Calcium Channel Regulation
Magnesium is the natural antagonist of the calcium channels — it competes with calcium for the binding sites on the voltage-gated calcium channels and on the NMDA receptor channels, and it thereby regulates the calcium influx into the cells and modulates the calcium-dependent signalling pathways. This calcium channel antagonism by magnesium is one of the most important mechanisms by which magnesium exerts its physiological effects — it reduces the calcium influx into the vascular smooth muscle cells (producing vasodilation), it reduces the calcium influx into the neurons (producing the neuronal inhibition that is protective against seizures and against the excitotoxic neuronal death), and it reduces the calcium influx into the cardiac myocytes (modulating the cardiac contractility and protecting against the arrhythmias that are triggered by the calcium-dependent early afterdepolarisations). The calcium channel antagonism of magnesium is also the basis for its use in the management of the pre-eclampsia and the eclampsia of pregnancy — the magnesium sulphate infusion that is the first-line treatment for these conditions works by suppressing the calcium-dependent release of the vasoconstrictor neurotransmitters and by reducing the calcium-induced vasoconstriction in the cerebral vasculature.
Practical Application
For general magnesium supplementation, the evidence-based approach is to supplement with 200-400mg of magnesium daily (as magnesium citrate, magnesium glycinate, or magnesium malate — the forms that are best absorbed and best tolerated). The RDA of magnesium is 310-420mg daily for adults, but the majority of the adult population does not achieve this intake from food sources alone (because the processing of the food supply has removed the magnesium that is present in the whole grain and in the leafy green vegetables). For the treatment of the symptoms of magnesium deficiency (including the muscle cramps, the fatigue, and the cardiac arrhythmias), higher doses of 400-800mg daily may be required, and the treatment should be supervised by a physician because of the risk of the diarrhoea and of the hypermagnesaemia that are associated with the high-dose supplementation. For comprehensive electrolyte and metabolic support, magnesium pairs well with potassium (which is the most closely related intracellular cation and whose deficiency often coexists with magnesium deficiency), with calcium (which is the extracellular cation whose absorption and metabolism are regulated by magnesium), and with vitamin B6 (which is required for the renal reabsorption of magnesium and whose deficiency impairs the magnesium conservation).
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