Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Mackenzie, Elizabeth L.; Iwasaki, Kouta; Tsuji, Yoshiaki

doi:10.1089/ars.2007.1893

Cited by 450 publications

(411 citation statements)

References 344 publications

(451 reference statements)

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“…12,19 Serum ferritin levels have been thought to reflect the body iron stores; however, it is also a secreted by-product of intracellular ferritin synthesis. 20 This last process is increased in some inflammation states as chronic diseases. It would be possible that the high serum ferritin levels found in our study reflected both situations.…”

Section: Discussionmentioning

confidence: 99%

Low bone mineral density is associated with insulin resistance in bone marrow transplant subjects

Faulhaber

Premaor

Filho

et al. 2009

Bone Marrow Transplant

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Post-BMT subjects have an increased bone fracture risk. Additionally, several factors were associated with osteopenia and osteoporosis in these individuals. We aimed to identify other factors associated with osteopenia and osteoporosis in allogeneic post-BMT subjects. We conducted a cross-sectional study with 47 allogeneic post-BMT subjects. Serum 25-hydroxyvitamin D (25(OH)D), parathyroid hormone, ferritin, vitamin B 12 , insulin, glucose, cholesterol and triglyceride levels were measured. Insulin resistance and secretion were estimated through the homeostatic model assessment for insulin resistance (HOMA-IR) and homeostatic model assessment for b-cell function (HOMA-B), respectively. A bone densitometry (BMD) was also obtained. The median time after BMT was 47.7 (12-115) months. Osteoporosis was identified in 17.0% of the subjects and osteopenia in 19.7%. The mean serum ferritin (P ¼ 0.002), insulin (Po0.0001), glucose (P ¼ 0.003) and triglyceride (P ¼ 0.018) levels were higher in individuals with osteopenia/osteoporosis. HOMA-IR (Po0.0001) and HOMA-B (Po0.0001) were increased in post-BMT subjects with osteopenia/osteoporosis. There was no other factor associated with the outcome. After adjustments ferritin, serum 25(OH)D and HOMA-IR remained independently associated with osteopenia/osteoporosis; however triglycerides no longer were. In conclusion, in the present study, low serum 25(OH)D levels, high serum ferritin levels and insulin resistance were associated with osteopenia/osteoporosis in post-BMT subjects.

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Section: Discussionmentioning

confidence: 99%

Low bone mineral density is associated with insulin resistance in bone marrow transplant subjects

Faulhaber

Premaor

Filho

et al. 2009

Bone Marrow Transplant

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“…Chemically, the Tet oxidation activity could be efficiently regulated by changing the level of the known cofactor iron(II), but which may induce severe deleterious effects if not tightly controlled in mammals. 30 Here, we hypothesize that AA may enhance Tet-mediated oxidation of 5mC and provide unique capacity of regulating the dynamics of DNA methylation. To test our hypothesis, we systematically investigated the effects of AA on the catalytic activity of Tet proteins, 5mC oxidation, and DNA demethylation and the underlying mechanisms.…”

Section: ■ Introductionmentioning

confidence: 95%

“…We reexamined the reactions by the use of Fe 2+ at physiologically relevant concentration (10 μM). 30 Excess dithiothreitol (1.0 mM) was also included in all tested reaction solutions. Under such conditions, we observed the formation of 5hmC and 5fC in the presence of the purified Tet2 CD but without AA ( Figure 1A and the Supporting Information, Figure S1B).…”

Section: ■ Introductionmentioning

confidence: 99%

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

et al. 2013

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DNA hydroxymethylation and its mediated DNA demethylation are critical for multiple cellular processes, for example, nuclear reprogramming, embryonic development, and many diseases. Here, we demonstrate that a vital nutrient ascorbic acid (AA), or vitamin C (Vc), can directly enhance the catalytic activity of Tet dioxygenases for the oxidation of 5-methylcytosine (5mC). As evidenced by changes in intrinsic fluorescence and catalytic activity of Tet2 protein caused by AA and its oxidation-resistant derivatives, we further show that AA can uniquely interact with the C-terminal catalytic domain of Tet enzymes, which probably promotes their folding and/or recycling of the cofactor Fe 2+ . Other strong reducing chemicals do not have a similar effect. These results suggest that AA also acts as a cofactor of Tet enzymes. In mouse embryonic stem cells, AA significantly increases the levels of all 5mC oxidation products, particularly 5-formylcytosine and 5-carboxylcytosine (by more than an order of magnitude), leading to a global loss of 5mC (∼40%). In cells deleted of the Tet1 and Tet2 genes, AA alters neither 5mC oxidation nor the overall level of 5mC. The AA effects are however restored when Tet2 is re-expressed in the Tet-deficient cells. The enhancing effects of AA on 5mC oxidation and DNA demethylation are also observed in a mouse model deficient in AA synthesis. Our data establish a direct link among AA, Tet, and DNA methylation, thus revealing a role of AA in the regulation of DNA modifications. ■ INTRODUCTIONDNA demethylation remarkably contributes to the dynamics of the epigenetic marker 5-methylcytosine (5mC) in mammals and is critical for multiple biological processes, including animal cloning, 1 nuclear reprogramming, 2,3 development, 4−8 and highly locus-specific regulation of gene activities. 9−11 DNA demethylation can be initiated by the oxidation of 5mC and the formation of 5-hydroxymethylcytosine (5hmC), which are catalyzed by ten eleven translocation (Tet) family dioxygenases. 12−15 The formed 5hmC can be diluted by DNA replication, suggesting a passive DNA demethylation pathway. 16 Moreover, the 5hmC can be further oxidized by Tet proteins to form 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be excised by thymine DNA glycosylase (TDG) followed by the reintroduction of unmethylated cytosine through the base-excision repair (BER) pathway. 14,15 This important pathway for active DNA demethylation has been thought to be involved in a number of prominent biological processes. 5,6,10,11 Early and recent studies suggested that active and replication-independent DNA demethylation might be a rapid process. 10,11 The radically altered methylation, as observed in replication-independent demethylation of the paternal genome in zygotes, may complete within hours. 5,6,17−19 However, the observed levels of the active DNA demethylation intermediates, 5fC and 5caC in the cultured cells, were 100-fold less than the primary product 5hmC. 13−15,20−22 Biochemically, the Tet-mediated DNA dem...

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“…Iron is a vital element mandatory for metabolic processes and the function of many enzymes, including cytochrome P450s and ribonucleotide reductase, however, a surplus of free iron leads to the formation of reactive oxygen species (ROS) via the Fenton reaction, which is potentially harmful to the cells [1,2]. Iron is also involved in the catalysis of oxidation of important cellular proteins, lipids, and DNA.…”

Section: Introductionmentioning

confidence: 99%

“…In vertebrates, there are two ferritin subunits, heavy and light, which coassemble in 24 subunit bundles forming a channel that encloses iron [7]. The heavy, or H, subunit is catalytically active, and induces oxidation of ferrous iron Fe(II) to ferric iron Fe(III) and aggregation of the oxidized iron inside the core, while the light (L) subunit does not have ferroxidase activity but may serve a structural function [2,8]. In this manner, ferritin functions to protect cells against iron-mediated toxicity [9,10].…”

Section: Introductionmentioning

confidence: 99%

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

Mackenzie

Ray

Tsuji

2008

Free Radical Biology and Medicine

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Tight regulation of intracellular iron levels in response to mitochondrial dysfunction is an important mechanism that prevents oxidative stress, thereby limiting cellular damage. Here, we describe a cytoprotective response involving transcriptional activation of the ferritin H gene in response to the mitochondrial complex I inhibitor and neurotoxic compound, rotenone. Rotenone exposure increased ferritin H mRNA and protein synthesis in NIH3T3 fibroblasts and SH-SY5Y neuroblastoma cells. Transient transfection of a ferritin H promoter-luciferase reporter into NIH3T3 cells showed that ferritin H was transcriptionally activated by rotenone through an antioxidant responsive element (ARE). Chromatin immunoprecipitation assays showed that rotenone treatment enhanced binding of Nrf2 and JunD transcription factors to the ARE. In addition, rotenone induced production of reactive oxygen species (ROS), and pretreatment with N-acetylcysteine abrogated ferritin H mRNA induction by rotenone, suggesting that this response is oxidative stress-mediated. Furthermore, reduced ferritin H expression by siRNA sensitized cells to rotenone-induced apoptosis with enhanced ROS production and annexin V positive cells. Taken together, these results suggest that ferritin H transcription is activated by rotenone via an oxidative stress-mediated pathway leading to ARE activation, and may be critically important to protect cells from mitochondrial dysfunction and oxidative stress.

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Intracellular Iron Transport and Storage: From Molecular Mechanisms to Health Implications

Cited by 450 publications

References 344 publications

Low bone mineral density is associated with insulin resistance in bone marrow transplant subjects

Low bone mineral density is associated with insulin resistance in bone marrow transplant subjects

Ascorbic Acid Enhances Tet-Mediated 5-Methylcytosine Oxidation and Promotes DNA Demethylation in Mammals

Role and regulation of ferritin H in rotenone-mediated mitochondrial oxidative stress

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