Ironing out mechanisms of iron homeostasis and disorders of iron deficiency

Koleini, Navid; Shapiro, Jason S.; Geier, Justin; Ardehali, Hossein

doi:10.1172/jci148671

Cited by 83 publications

(64 citation statements)

References 141 publications

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“…Iron is critical for normal cell function, but its excess can lead to cellular damage due to oxidative stress. Thus, the levels of cellular iron, particularly in the mitochondria, are tightly regulated ( Koleini et al, 2021 ). Iron has been implicated in the development of some neurodegenerative diseases that are associated with aging, including Alzheimer’s and Parkinson’s diseases ( Xu et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

“…Iron can donate and accept electrons from various substrates due to its unique oxidation-reduction properties, making it an important cofactor in mammalian cells. Iron is also essential for heme and Fe-S clusters and exerts other biological effects through its role in processes such as demethylation, dehydrogenation, and reduction of sulfur ( Koleini et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Aging is associated with increased brain iron through cortex-derived hepcidin expression

Sato

Shapiro

Chang

et al. 2022

eLife

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Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrated that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain cortex exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, ferroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aging is associated with increased brain iron through cortex-derived hepcidin expression

Sato

Shapiro

Chang

et al. 2022

eLife

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Section: Molecular and Metabolic Drivers Of Ferroptosismentioning

confidence: 99%

“…The cellular uptake of iron is mediated by the binding of iron-bound transferrin (which contains two ferric iron molecules) to its receptor (transferrin receptor protein 1 (TFR1)), which triggers clathrin-dependent endocytosis of the entire holo-complex 19 . The endosome is then acidified by vacuolar ATPase, leading to the reduction of ferric iron to ferrous iron by the STEAP (six-transmembrane epithelial antigen of prostate) family of metalloreductases 19 . Ferrous iron is then released from the endosome into the cytoplasm via natural resistance-associated macrophage protein 2 (NRAMP2; also known as DMT1), and apo-transferrin and TFR1 are shuttled back to the cell surface to be reused by the cell 20 .…”

Section: Molecular and Metabolic Drivers Of Ferroptosismentioning

confidence: 99%

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

et al. 2022

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The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia–reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets.

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“…The aforementioned causes considered ID as extra-cardiac comorbidity that has an impact on patients with HF. However, mounting evidence indicates differences in mechanisms leading to cellular and systemic ID [ 175 , 176 , 177 ]. In HF, it is was found that myocardial ID (MID) is poorly related to systemic iron homoeostasis biomarkers [ 68 , 70 ], suggesting that MID may be caused by other mechanisms other than reduced systemic iron availability [ 178 , 179 ].…”

Section: Causes Of Iron Deficiency In Heart Failurementioning

confidence: 99%

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

Alnuwaysir

Hoes

Veldhuisen

et al. 2021

JCM

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Iron is an essential micronutrient for a myriad of physiological processes in the body beyond erythropoiesis. Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF), with a prevalence reaching up to 59% even in non-anaemic patients. ID impairs exercise capacity, reduces the quality of life, increases hospitalisation rate and mortality risk regardless of anaemia. Intravenously correcting ID has emerged as a promising treatment in HF as it has been shown to alleviate symptoms, improve quality of life and exercise capacity and reduce hospitalisations. However, the pathophysiology of ID in HF remains poorly characterised. Recognition of ID in HF triggered more research with the aim to explain how correcting ID improves HF status as well as the underlying causes of ID in the first place. In the past few years, significant progress has been made in understanding iron homeostasis by characterising the role of the iron-regulating hormone hepcidin, the effects of ID on skeletal and cardiac myocytes, kidneys and the immune system. In this review, we summarise the current knowledge and recent advances in the pathophysiology of ID in heart failure, the deleterious systemic and cellular consequences of ID.

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Ironing out mechanisms of iron homeostasis and disorders of iron deficiency

Cited by 83 publications

References 141 publications

Aging is associated with increased brain iron through cortex-derived hepcidin expression

Aging is associated with increased brain iron through cortex-derived hepcidin expression

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology

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