Manganese is a transition metal that is the essential cofactor of the manganese superoxide dismutase (MnSOD, SOD2) enzyme — the primary antioxidant enzyme in the mitochondrial matrix and the primary defence against the superoxide radicals that are generated by the mitochondrial electron transport chain. Manganese is also the cofactor of the glutamine synthetase enzyme (which is the primary enzyme for the synthesis of glutamine in astrocytes and which is critical for the nitrogen homeostasis in the brain), of the pyruvate carboxylase enzyme (which is essential for gluconeogenesis and for the synthesis of the neurotransmitters glutamate and GABA), and of the arginase enzyme (which is required for the urea cycle and for the synthesis of the polyamines that regulate cell growth and proliferation). This broad range of manganese-dependent enzymes makes manganese critical for mitochondrial function, for brain nitrogen metabolism, for gluconeogenesis, and for the urea cycle, and its deficiency is associated with a correspondingly broad range of clinical manifestations including epilepsy, impaired gluconeogenesis, and the connective tissue abnormalities that are associated with impaired proteoglycan synthesis.
Manganese Superoxide Dismutase
MnSOD (SOD2) is the primary antioxidant enzyme in the mitochondrial matrix — it is the enzyme that dismutates the superoxide radical (O2-) that is generated as a byproduct of the mitochondrial electron transport chain into hydrogen peroxide (H2O2) and oxygen. The superoxide radical is the primary ROS that is generated by the mitochondria (primarily from the semi-ubiquinone radical that is formed during electron transfer in Complex I and Complex III), and it is the precursor of the more damaging ROS that are generated downstream — including the hydroxyl radical (from the Fenton reaction) and the peroxynitrite radical (from the reaction of superoxide with nitric oxide). MnSOD is the primary defence against this mitochondrial superoxide accumulation, and without adequate manganese for MnSOD, the superoxide that is generated by the electron transport chain accumulates to levels that damage the mitochondria, produce the mitochondrial dysfunction that is one of the primary hallmarks of the cellular ageing process, and trigger the cell death pathways that lead to apoptosis and to the loss of cells that characterise the age-related degenerative diseases.
The clinical importance of MnSOD for mitochondrial function is underscored by the MnSOD knockout mouse — a mouse that is genetically engineered to lack the MnSOD gene and that is characterised by severe mitochondrial oxidative stress, mitochondrial dysfunction, and early death from oxidative stress damage to the heart and the brain. The MnSOD knockout mouse is one of the most dramatic demonstrations of the essential role of MnSOD in mitochondrial protection, and it illustrates how critical the superoxide-scavenging activity of MnSOD is for the survival of the cell. The heterozygous MnSOD knockout mouse (which has reduced MnSOD activity) shows a more modest mitochondrial dysfunction and has a normal lifespan but is more susceptible to oxidative stress damage and to the degenerative diseases that are associated with oxidative stress, including neurodegeneration, cardiomyopathy, and the metabolic dysfunction that is associated with ageing.
Manganese and Glutamine Synthetase in the Brain
Manganese is also the cofactor of the glutamine synthetase enzyme — the astrocyte-specific enzyme that synthesises glutamine from glutamate and ammonia and that is the primary mechanism by which the brain disposes of the ammonia that is generated by the deamination of amino acids and by the metabolism of the neurotransmitters glutamate and GABA. Glutamine synthetase is one of the most important enzymes in the brain for the maintenance of nitrogen homeostasis and for the regulation of the glutamate-glutamine cycle — the cycle by which glutamate is released from neurons, taken up by astrocytes, converted to glutamine by glutamine synthetase, and returned to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is the primary mechanism by which the synaptic concentration of glutamate is maintained at levels that are safe for the neuron — when glutamine synthetase activity is impaired (as in manganese deficiency, which is rare but which can develop in people with conditions that impair manganese absorption), the ammonia that is generated by glutamate metabolism accumulates in astrocytes, the glutamate-glutamine cycle is impaired, and the synaptic concentration of glutamate rises to excitotoxic levels. The epilepsy that is associated with manganese deficiency is thought to be the direct result of this glutamate-mediated excitotoxicity in the brain.
Practical Application
For general manganese supplementation, the evidence-based dose is 2-5mg of manganese daily (as manganese gluconate or manganese citrate, the commonly used forms), taken with a meal for optimal absorption. The RDA for manganese is 2.3mg daily for adult men and 1.8mg daily for adult women, and most people in the developed world achieve this from a varied diet that includes whole grains, nuts, seeds, leafy green vegetables, and tea. Manganese should be taken separately from calcium and from iron supplements (which compete with manganese for absorption) and from the zinc supplements that are used at high doses (which induce the manganese-absorbing protein metallothionein in the enterocyte, reducing manganese absorption). Manganese is generally well-tolerated with no significant adverse effects at therapeutic doses, though chronic supplementation above 10mg daily should be avoided because manganese is a transition metal that can accumulate to toxic levels in the brain (producing the manganism that is characterised by parkinsonism, psychiatric symptoms, and cognitive impairment, and that is similar to the Parkinson disease that results from MPTP or from manganese exposure in mine workers).
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