Manganese is an essential trace element that is the cofactor for the mitochondrial superoxide dismutase (MnSOD, SOD2), for the glutamine synthetase enzyme in the brain, and for the glycosyltransferases that are involved in the synthesis of the proteoglycans and of the glycoproteins that are the structural components of the bone, the cartilage, and the connective tissues. MnSOD is the only enzyme that disarms the superoxide radical (O2-) at the source — in the mitochondrial matrix, where the superoxide is generated as a byproduct of the electron transport chain activity — and without adequate manganese and MnSOD activity, the superoxide accumulates, the mitochondrial DNA is damaged, the mitochondrial membranes are peroxidised, and the cellular energy metabolism collapses. This manganese-dependent vulnerability of the mitochondrial antioxidant defence is one of the most important mechanisms of the oxidative stress that underlies the neurodegenerative diseases, the metabolic syndrome, and the bone loss that are the clinical manifestations of the manganese deficiency. The manganese deficiency is rare in the general population because manganese is widely distributed in plant-based foods (whole grains, nuts, seeds, green leafy vegetables), but it can occur in people who consume a highly processed diet, in people with the chronic malabsorption syndromes, and in people with the genetic disorders of manganese metabolism.
MnSOD and the Mitochondrial Antioxidant Defence
The superoxide radical (O2-) is the primary reactive oxygen species (ROS) that is generated in the mitochondria — it is produced at complexes I and III of the electron transport chain as a byproduct of the electron leakage to the oxygen. The superoxide is not the most reactive of the ROS (the hydroxyl radical is more reactive), but it is the most abundant and it is the parent of the other ROS — it is spontaneously or enzymatically dismutated to hydrogen peroxide (H2O2), which is then reduced to water by the glutathione peroxidase and by the catalase. If the superoxide is not dismutated, it reacts with the iron-sulfur clusters in the mitochondrial enzymes (including the aconitase and the complexes I and II), releasing the iron and producing the highly reactive hydroxyl radical (OH*) through the Fenton reaction. The hydroxyl radical is the most reactive of all the ROS and it attacks the mitochondrial DNA, the mitochondrial proteins, and the mitochondrial lipids, causing the mitochondrial dysfunction that is the hallmark of the oxidative stress and of the ageing process.
MnSOD is the only enzyme that disarms the superoxide radical in the mitochondrial matrix — it catalyses the dismutation of the superoxide to hydrogen peroxide at a rate that is 10,000 times faster than the spontaneous dismutation. MnSOD is a homotetramer of four identical subunits, each of which contains one manganese atom at the active site, and it is encoded by the SOD2 gene on chromosome 6. The regulation of the MnSOD expression is primarily at the transcriptional level — it is induced by the oxidative stress (through the NF-kappaB and the AP-1 transcription factors), by the inflammatory cytokines (IL-1, TNF-alpha), by the radiation, and by the exercise. The induction of MnSOD by the oxidative stress is one of the most important adaptive responses of the cell to the oxidative challenge — it allows the cell to increase its capacity to dispose of the superoxide before it can cause the damage to the mitochondrial DNA, the proteins, and the lipids.
Manganese and the Bone Health
Manganese is also an essential cofactor for the glycosyltransferases that are involved in the synthesis of the proteoglycans and of the glycoproteins that are the structural components of the bone, the cartilage, and the connective tissues. The proteoglycans (including the aggrecan, the decorin, and the biglycan) are the large, heavily glycosylated proteins that are responsible for the resilience and the compressive strength of the cartilage and of the bone matrix, and their synthesis requires the manganese-dependent glycosyltransferases. The glycoproteins (including the osteocalcin and the matrix Gla protein) are the vitamin K-dependent proteins that are involved in the regulation of the bone mineralisation, and their synthesis also requires the manganese-dependent glycosyltransferases for the addition of the carbohydrate side chains. Without adequate manganese, the synthesis of these proteoglycans and glycoproteins is impaired, the bone matrix is defective, and the bone mineralisation is compromised — producing the osteoporosis and the increased fracture risk that are the clinical manifestations of the manganese deficiency in the skeletal system.
Practical Application
For general manganese supplementation, the evidence-based approach is to supplement with 2-5mg of manganese daily (as manganese gluconate, manganese citrate, or manganese amino acid chelate — the forms that are well absorbed and well tolerated). The RDA of manganese is 2.3mg daily for men and 1.8mg daily for women, and the tolerable upper intake level is 11mg daily for adults (above which the manganese can produce the neurological symptoms that are characteristic of the manganism — the Parkinson-like syndrome that is associated with the chronic manganese exposure in miners and in workers who are exposed to manganese-containing dusts and fumes). The manganese should be taken in the separate dose from the calcium and from the iron supplements (by at least 2 hours) because these minerals compete for the absorption in the gut. For comprehensive antioxidant and bone health support, manganese pairs well with the copper (which is required for the cytosolic Cu,ZnSOD in the cytoplasm), with the zinc (which is required for the Cu,ZnSOD and for the alkaline phosphatase enzyme in the bone), with the vitamin K2 (which is required for the activation of the osteocalcin and the matrix Gla protein), and with the calcium and the vitamin D (which are the primary minerals and the primary hormone for the bone mineralisation).
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