Metabolic Signature of Dietary Iron Overload in a Mouse Model

Volani, Chiara; Paglia, Giuseppe; Smarason, Sigurdur; Pramstaller, Peter P.; Demetz, Egon; Pfeifhofer-Obermair, Christa; Weiss, Günter

doi:10.3390/cells7120264

Cited by 34 publications

(37 citation statements)

References 50 publications

(73 reference statements)

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“…Alterations of iron homeostasis in the setting of sepsis are driven by cytokines and acute phase proteins along with their effects on erythropoiesis and erythrocyte damage. While these subtle alterations are considered as a defense strategy of the body against invading microbes, alterations of iron homeostasis may negatively impact on metabolic processes of cells including mitochondrial respiration, immune function, or tissue oxygen supply [27,28].…”

Section: Discussionmentioning

confidence: 99%

Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study

et al. 2020

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Background Sepsis, a dysregulated host response following infection, is associated with massive immune activation and high mortality rates. There is still a need to define further risk factors and laboratory parameters predicting the clinical course. Iron metabolism is regulated by both, the body’s iron status and the immune response. Iron itself is required for erythropoiesis but also for many cellular and metabolic functions. Moreover, iron availability is a critical determinant in infections because it is an essential nutrient for most microbes but also impacts on immune function and intravascular oxidative stress. Herein, we used a prospective study design to investigate the putative impact of serum iron parameters on the outcome of sepsis. Methods Serum markers of iron metabolism were measured in a prospective cohort of 61 patients (37 males, 24 females) with sepsis defined by Sepsis-3 criteria in a medical intensive care unit (ICU) and compared between survivors and non-survivors. Regulation of iron parameters in patients stratified by focus of infection and co-medication as well as association of the markers with sepsis severity scores and survival were investigated with linear and logistic regression corrected for sex and age effects. Results Positive correlations of increased serum iron and ferritin concentrations upon ICU admission with the severity of organ failure (SOFA score) and with mortality were observed. Moreover, high TF-Sat, elevated ferritin and serum iron levels and low transferrin concentrations were associated with reduced survival. A logistic regression model consisting of SOFA and transferrin saturation (SOFA–TF-Sat) had the best predictive power for survival in septic ICU patients. Of note, administration of blood transfusions prior to ICU admission resulted in increased TF-Sat and reduced survival of septic patients. Conclusions Our study could show an important impact of serum iron parameters on the outcome of sepsis. Furthermore, we identified transferrin saturation as a stand-alone predictor of sepsis survival and as a parameter of iron metabolism which may in a combined model improve the prediction power of the SOFA score. Trial registration The study was carried out in accordance with the recommendations of the Declaration of Helsinki on biomedical research. The study was approved by the institutional ethics review board of the Medical University Innsbruck (study AN2013-0006).

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Section: Discussionmentioning

confidence: 99%

Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study

et al. 2020

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“…Selectively after iron overload, which is known to trigger mitochondrial reprogramming and oxidative/nitrosative stress [165], Pink1-ablation was observed to induce expression upregulations of several cytosolic iron homeostasis factors. A genotype-dependent trend towards upregulation was observed for Hmox1 as a factor that protects against heme cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Systematic Surveys of Iron Homeostasis Mechanisms reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

Key

Sen

Arsovic

et al. 2020

Preprint

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Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson’s disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

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“…Iron is a crucial micronutrient as it is involved in several metabolic processes, such as DNA synthesis, oxygen transport, cellular metabolism, and mitochondrial respiration [5,6]. On the other hand, environmental sources of iron and other particles can disrupt and interfere with local iron-homeostasis in the lung [7].…”

Section: Introductionmentioning

confidence: 99%

The Significance of iron deficiency and anemia in a real-life COPD cohort

Pizzini¹,

Aichner²,

Sonnweber³

et al. 2020

Int. J. Med. Sci.

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Background: Current evidence suggests an increased prevalence of iron deficiency (ID) and anemia in chronic obstructive pulmonary disease (COPD). ID and subsequent anemia can be due to iron losses via bleeding resulting in absolute ID or inflammation-driven retention of iron within macrophages resulting in functional ID and anemia of inflammation. Methods: This is a retrospective analysis of 204 non-exacerbated COPD patients in outpatient care. Current definitions of absolute and functional ID were applied to determine the prevalence of ID and to analyze associations to disease severity in terms of lung function parameters and clinical symptoms. Results: The studied cohort of COPD patients demonstrated a high prevalence of ID, ranging from 30 to 40% during the observation time. At the initial presentation, absolute or functional ID was found in 9.3% to 12.3% of COPD individuals, whereas combined forms of absolute and functional ID were most prevalent (25.9% of all individuals). The prevalence of ID increased during longitudinal follow-up (37 ± 15 months), and especially combined forms of ID were significantly related to anemia. Anemia prevalence ranged between 14.2% and 20.8% during the observation period and anemia was associated with lower FEV1, DLCOc, and CRP elevation. Accordingly, ID was associated with decreased FEV1, DLCOc, and an elevation in CRP. Conclusion: ID is common in COPD patients, but a uniform definition for accurate diagnosis does not exist. Prevalence of functional ID and anemia increased during follow-up. The associations of ID and anemia with reduced functional lung capacity and elevated inflammation may reflect a more severe COPD phenotype.

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Metabolic Signature of Dietary Iron Overload in a Mouse Model

Cited by 34 publications

References 50 publications

Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study

Linkage of alterations in systemic iron homeostasis to patients’ outcome in sepsis: a prospective study

Systematic Surveys of Iron Homeostasis Mechanisms reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence

The Significance of iron deficiency and anemia in a real-life COPD cohort

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