Mechanisms of iron regulation and oxidative stress in sarcopenia and neurodegenerative diseases

Iron (Fe) is a trace metal that is essential for several life-sustaining functions, such as oxygen binding, mitochondrial electron transport and oxidative/reductive transformations. Because Fe can be toxic to cells, specific proteins tightly regulate the uptake, transport, efflux, and storage of the metal. Fe is normally stored in the protein ferritin as non-reactive non-heme iron (Fe3+). In recent years, there is a renewed interest in Fe because of recent findings of non-heme Fe (i.e., Fe binding proteins such as ferritin, hemosiderin, lipofuscin, neuromelanin and Fe–biogenic magnetite) accumulation in muscle and nervous system tissues with age. This age-related accumulation of a labile Fe pool in tissues increases the potential for free redox-active Fe (reduced ferrous iron, Fe2+), which may represent one of the major contributors to the extensive amounts of oxidative stress observed with age. Cellular systems produce oxidants such as hydrogen peroxide and superoxide anion, but metals are required to produce the highly damaging hydroxyl radical. Several studies have investigated the role of Fe in neurodegeneration, but very few reports are available on the role played by Fe accumulation in age-related loss of muscle mass, strength and function, a condition known as sarcopenia. The accumulation of Fe in post-mitotic tissues with age and disease suggests that pharmacological interventions to control excess labile iron could be beneficial. This review will also discuss specific mechanisms of Fe transport, including divalent metal transporter 1 (DMT1), mitoferrin, and Zip14, a transmembrane protein belonging to the ZIP family of metal-ion transporters. Furthermore, the potential for hydrophilic and lipophilic Fe chelators as a strategy to prevent oxidant-induced stress in pre-clinical and clinical studies will be discussed.