Manganese metabolism in humans

Abstract

Manganese (Mn) is an essential nutrient for intracellular activities; it functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and Mn superoxide dismutase (Mn-SOD). Through these metalloproteins, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. Mn deficiency is rare. In contrast Mn poisoning may be encountered upon overexposure to this metal. Excessive Mn tends to accumulate in the liver, pancreas, bone, kidney and brain, with the latter being the major target of Mn intoxication. Hepatic cirrhosis, polycythemia, hypermanganesemia, dystonia and Parkinsonism-like symptoms have been reported in patients with Mn poisoning. In recent years, Mn has come to the forefront of environmental concerns due to its neurotoxicity. Molecular mechanisms of Mn toxicity include oxidative stress, mitochondrial dysfunction, protein misfolding, endoplasmic reticulum (ER) stress, autophagy dysregulation, apoptosis, and disruption of other metal homeostasis. The mechanisms of Mn homeostasis are not fully understood. Here, we will address recent progress in Mn absorption, distribution and elimination across different tissues, as well as the intracellular regulation of Mn homeostasis in cells. We will conclude with recommendations for future research areas on Mn metabolism.

Dietary Manganese Exposure in the Adult Population in Germany—What Does it Mean in Relation to Health Risks?

“…This information is primarily based on data from human studies. However, at some points data from animal and in vitro studies are also described to underline certain toxicokinetic aspects …”

“…The elevated retention rate, however, might result from a higher absorption rate but also from an immature capacity to eliminate manganese from the body, or age‐dependent alterations in the intake of competing metals, such as iron . It may further reflect a physiologically higher demand of manganese during development …”

“…Although not understood in every detail, it is known that, on the cellular level, several transport proteins facilitate manganese distribution from blood to tissues. A number of transport proteins have been identified to be involved in the cellular import of manganese; including DMT1, zinc transporters, calcium channels, the magnesium transporter HIP14, and most likely the dopamine transporter and citrate transporters to name a few . The transporters mentioned above mediate the import of divalent manganese into cells.…”

“…Two possible routes for manganese to enter the brain from the blood stream are currently being discussed: (1) directly via the blood brain barrier (BBB) and (2) via the brain cerebrospinal fluid (CSF) barrier, followed by translocation to the brain. According to some authors, the latter route might be of particular importance, at least at elevated manganese plasma concentrations . It is assumed that the transport from the blood into the brain is mediated inter alia by the transferrin/transferrin receptor‐mediated endocytosis pathway.…”

Caenorhabditis elegans and its applicability to studies on restless legs syndrome

“…Among these metals, Mn is the most similar one of Fe, given their biochemical property, metabolism and physiological functions in human. For example, Fe and Mn use the divalent metals transporter 1 (DMT1) and transferrin/transferrin receptor as the primary route of influx, and use ferroportin as the major efflux route (Chen, Bornhorst, & Aschner, 2018; Chen, Bornhorst, Diana Neely, & Avila, 2018; Chen, Parmalee, & Aschner, 2014). Low levels of Fe in the brain may activate expression of influx transporters in order to compensate for Fe deficiency, however, this also brings the risk of transporting more Mn in the brain.…”