Manganese is an essential trace mineral that is the cofactor for the manganese superoxide dismutase (MnSOD, SOD2) — the enzyme that is the primary line of defence against the superoxide radical in the mitochondrial matrix. The MnSOD is a homotetrameric enzyme that contains one manganese atom per subunit, and it catalyses the dismutation of the superoxide radical (O2-) to hydrogen peroxide (H2O2) and oxygen (O2) in the mitochondrial matrix — protecting the mitochondria from the oxidative damage that is generated by the electron transport chain activity. The mitochondria are the primary site of the superoxide production in the cell (because of the electron leakage from the electron transport chain complexes I and III), and the MnSOD is the only enzyme that specifically disarms the superoxide radical in the mitochondrial matrix. Without adequate manganese and functional MnSOD, the superoxide accumulates in the mitochondria, the mitochondrial membranes are damaged (by lipid peroxidation), the mitochondrial DNA is damaged (by oxidative modification), and the mitochondrial ATP production is impaired — producing the oxidative stress, the mitochondrial dysfunction, and the cell death that are the hallmarks of the manganese deficiency. The typical dietary manganese intake is 2-5mg daily (from whole grains, nuts, seeds, tea, and leafy green vegetables), and the estimated safe and adequate intake is 2-5mg daily for adults — the manganese deficiency is rare in the general population (because manganese is present in a wide variety of plant-based foods), but it can occur in people with the severe malnutrition, with the chronic alcoholism, and with the genetic disorders of the manganese metabolism.
MnSOD and the Mitochondrial Antioxidant Defence
The mitochondrial matrix is the primary site of the superoxide production in the cell — the electron transport chain complexes I (NADH dehydrogenase) and III (cytochrome bc1 complex) leak electrons to the molecular oxygen, forming the superoxide radical (O2-). This superoxide production is an inevitable byproduct of the normal oxidative phosphorylation — even in the healthy mitochondria, approximately 0.2-2% of the oxygen that is consumed by the electron transport chain is partially reduced to superoxide. The MnSOD is the primary defence against this mitochondrial superoxide — it is present in the mitochondrial matrix at concentrations of approximately 1-5 microM and it provides the first line of defence against the superoxide that is generated by the electron transport chain. Without the MnSOD and the manganese cofactor, the superoxide accumulates in the mitochondrial matrix, the mitochondrial membranes are damaged by lipid peroxidation (because the superoxide reacts with the polyunsaturated fatty acids of the mitochondrial membranes to form the lipid peroxyl radicals and the malondialdehyde), the mitochondrial DNA is damaged by oxidative modification (the mtDNA lacks the histones and the robust DNA repair systems of the nuclear DNA), and the mitochondrial ATP production is impaired — producing the mitochondrial dysfunction and the cell death that are the hallmark of the oxidative stress and of the age-related diseases.
The clinical importance of manganese for the MnSOD function is underscored by the observation that the manganese deficiency reduces the MnSOD activity in all tissues and increases the mitochondrial oxidative stress — and that the manganese supplementation restores the MnSOD activity and reduces the mitochondrial oxidative stress in manganese-deficient individuals. A study in 30 patients with the epilepsy found that the manganese supplementation (at 10mg daily, as manganese gluconate) for 6 months significantly reduced the seizure frequency (by 40%) and improved the antioxidant status (as measured by the MnSOD activity in the erythrocytes and by the malondialdehyde levels in the serum) — suggesting that the manganese deficiency may be a modifiable risk factor for the epilepsy in some patients.
Manganese and the Bone Health
Manganese is also required for the synthesis of the proteoglycans and of the glycosaminoglycans (GAGs) that are the essential components of the bone matrix — the proteoglycans (particularly the chondroitin sulfate and the keratan sulfate) provide the structural framework of the bone and regulate the bone mineralisation by binding the calcium and the phosphate ions. Without adequate manganese, the proteoglycan synthesis is impaired, the bone matrix is weakened, and the osteoporosis develops — particularly in postmenopausal women who are already at increased risk of osteoporosis due to the oestrogen deficiency. The manganese deficiency is therefore one of the nutritional risk factors for the osteoporosis, and the manganese supplementation (as part of a comprehensive bone support formula that includes calcium, vitamin D, vitamin K, magnesium, and boron) may help to reduce the risk of the osteoporosis and of the fragility fractures in older adults.
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 aspartate — the forms that are well absorbed and well tolerated). Most people achieve adequate manganese from a varied diet — manganese is found in whole grains, nuts, seeds, tea, and leafy green vegetables. 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 interfere with the iron absorption and produce the neurological symptoms of the manganese toxicity). For comprehensive antioxidant and bone health support, manganese pairs well with the calcium (which is the primary mineral component of the bone), with the vitamin D (which promotes the calcium absorption and the bone mineralisation), with the vitamin K (which activates the osteocalcin and the matrix Gla protein, the two proteins that are essential for the bone mineralisation), with the magnesium (which is a cofactor for many of the enzymes of the bone matrix synthesis), and with the zinc (which is required for the collagen synthesis and for the alkaline phosphatase activity in the osteoblasts).
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