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Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.

Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated. [Display omitted] • Mitophagy participate in maintaining mitochondrial and cellular functionality. • Mitophagy dysregulation is deeply associated with serious pathogenesis. • Iron homeostasis and mitophagy regulation are deeply interconnected. • Decrease in free cellular/mitochondrial iron level can induce mitophagy. • Mitophagy normalization is one of the therapeutic effects of iron chelators. [ABSTRACT FROM AUTHOR]

Iron is an essential trace element in the metabolism of almost all living organisms. Iron overload can disrupt bone homeostasis by significant inhibition of osteogenic differentiation and stimulation of osteoclastogenesis, consequently leading to osteoporosis. Iron accumulation is also involved in the osteoporosis induced by multiple factors, such as estrogen deficiency, ionizing radiation, and mechanical unloading. Iron chelators are first developed for treating iron overloaded disorders. However, growing evidence suggests that iron chelators can be potentially used for the treatment of bone loss. In this review, we focus on the therapeutic effects of iron chelators on bone loss. Iron chelators have therapeutic effects not only on iron overload induced osteoporosis, but also on osteoporosis induced by estrogen deficiency, ionizing radiation, and mechanical unloading, and in Alzheimer’s disease-associated osteoporotic deficits. Iron chelators differently affect the cellular behaviors of bone cells. For osteoblast lineage cells (bone mesenchymal stem cells and osteoblasts), iron chelation stimulates osteogenic differentiation. Conversely, iron chelation significantly inhibits osteoclast differentiation. These different responses may be associated with the different needs of iron during differentiation. Fibroblast growth factor 23, angiogenesis, and antioxidant capability are also involved in the osteoprotective effects of iron chelators.

Iron is an essential trace element in the metabolism of almost all living organisms. Iron overload can disrupt bone homeostasis by significant inhibition of osteogenic differentiation and stimulation of osteoclastogenesis, consequently leading to osteoporosis. Iron accumulation is also involved in the osteoporosis induced by multiple factors, such as estrogen deficiency, ionizing radiation, and mechanical unloading. Iron chelators are first developed for treating iron overloaded disorders. However, growing evidence suggests that iron chelators can be potentially used for the treatment of bone loss. In this review, we focus on the therapeutic effects of iron chelators on bone loss. Iron chelators have therapeutic effects not only on iron overload induced osteoporosis, but also on osteoporosis induced by estrogen deficiency, ionizing radiation, and mechanical unloading, and in Alzheimer's disease-associated osteoporotic deficits. Iron chelators differently affect the cellular behaviors of bone cells. For osteoblast lineage cells (bone mesenchymal stem cells and osteoblasts), iron chelation stimulates osteogenic differentiation. Conversely, iron chelation significantly inhibits osteoclast differentiation. These different responses may be associated with the different needs of iron during differentiation. Fibroblast growth factor 23, angiogenesis, and antioxidant capability are also involved in the osteoprotective effects of iron chelators. • Iron overload induces osteoporosis. • Iron accumulation is involved in multiple osteoporosis models. • Iron chelators have osteoprotective effects on bone loss. • Iron chelators stimulate osteogenic differentiation, and inhibit osteoclast differentiation. [ABSTRACT FROM AUTHOR]

• Free unbound iron possibly contributes to the hypercoagulation and inflammation found in severe COVID-19. • The nonapoptotic and immunogenic cell death "ferroptosis" may be a potential contributor to the pathogenesis of COVID-19. • The bioactive compound lactoferrin and other iron chelators may provide a high therapeutic value in the treatment of COVID-19. • The relatively lower risk for COVID-19 found in individuals with blood group O may be linked to a lower serum iron status in these individuals. Iron overload is increasingly implicated as a contributor to the pathogenesis of COVID-19. Indeed, several of the manifestations of COVID-19, such as inflammation, hypercoagulation, hyperferritinemia, and immune dysfunction are also reminiscent of iron overload. Although iron is essential for all living cells, free unbound iron, resulting from iron dysregulation and overload, is very reactive and potentially toxic due to its role in the generation of reactive oxygen species (ROS). ROS react with and damage cellular lipids, nucleic acids, and proteins, with consequent activation of either acute or chronic inflammatory processes implicated in multiple clinical conditions. Moreover, iron-catalyzed lipid damage exerts a direct causative effect on the newly discovered nonapoptotic cell death known as ferroptosis. Unlike apoptosis, ferroptosis is immunogenic and not only leads to amplified cell death but also promotes a series of reactions associated with inflammation. Iron chelators are generally safe and are proven to protect patients in clinical conditions characterized by iron overload. There is also an abundance of evidence that iron chelators possess antiviral activities. Furthermore, the naturally occurring iron chelator lactoferrin (Lf) exerts immunomodulatory as well as anti-inflammatory effects and can bind to several receptors used by coronaviruses thereby blocking their entry into host cells. Iron chelators may consequently be of high therapeutic value during the present COVID-19 pandemic. [ABSTRACT FROM AUTHOR]