Mechanisms controlling cellular and systemic iron homeostasis

Galy, Bruno; Conrad, Marcus; Muckenthaler, Martina

doi:10.1038/s41580-023-00648-1

Cited by 186 publications

(86 citation statements)

References 303 publications

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“…Other cellular processes that require heme include regulation of transcription, translation, microRNA processing, mitochondrial protein import, protein stability, and differentiation. [1][2][3][5][6][7] The Biosynthesis of Heme Heme biosynthesis is an evolutionarily conserved pathway found in both prokaryotes and eukaryotes. In eukaryotes, the biosynthesis of heme occurs in the cytosol and mitochondria through eight sequential enzymatic steps discussed below (►Table 2; ►Fig.…”

Section: Lay Summarymentioning

confidence: 99%

“…90 Interestingly, autophagy, which is also an important process in heme homeostasis and mobilization of iron, is mediated by HO-1 in the liver during injury and protects against hepatocyte death, suggesting a mechanism by which autophagy could be enhanced during porphyria. 6,91,92 Fluorescent porphyrins possess distinctive properties to cause organelle-selective protein aggregation through a mechanism called the "porphyrination-deporphyrination cycle." 90,93 PP-IX is central to this cycle; this metabolite undergoes "porphyrination" by binding to target proteins, consequently inducing localized unfolding and conformational change.…”

Section: Cellular Consequences Of Porphyrin Accumulationmentioning

confidence: 99%

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The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease

Balogun,

Nejak-Bowen

2023

Semin Liver Dis

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The porphyrias are a group of metabolic disorders that are caused by defects in heme biosynthesis pathway enzymes. The result is accumulation of heme precursors, which can cause neurovisceral and/or cutaneous photosensitivity. Liver is commonly either a source or target of excess porphyrins, and porphyria-associated hepatic dysfunction ranges from minor abnormalities to liver failure. In this review, the first of a three-part series, we describe the defects commonly found in each of the eight enzymes involved in heme biosynthesis. We also discuss the pathophysiology of the hepatic porphyrias in detail, covering epidemiology, histopathology, diagnosis, and complications. Cellular consequences of porphyrin accumulation are discussed, with an emphasis on oxidative stress, protein aggregation, hepatocellular cancer, and endothelial dysfunction. Finally, we review current therapies to treat and manage symptoms of hepatic porphyria.

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Section: Lay Summarymentioning

confidence: 99%

Section: Cellular Consequences Of Porphyrin Accumulationmentioning

confidence: 99%

The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease

Balogun,

Nejak-Bowen

2023

Semin Liver Dis

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“…The latter are also attractive since endogenous metal ions' homeostasis and signaling contribute importantly to health and disease states, and their modulation or disturbance may lead to translational opportunities to leverage disease vulnerabilities. Without going into great detail, the cases of cuproplasia 33 and ferroptosis 34 are worth highlighting. The former is defined as copper-dependent cell growth and proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…Instead, concerning ferroptosis, its hallmark is the iron-dependent lipid peroxidation, a phenomenon associated with cell and tissue demise, thus constituting a nonapoptotic form of cell death. 34 Many studies have provided evidence that ferroptosis can inhibit tumor growth. Therefore, substances that regulate iron ions, such as chelators and regulators of related proteins or organelles, can control cancer progression via modulation of ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

“…As such, cuproplasia can be pharmacologically targeted either via copper-selective chelators or copper ionophores, in addition to genetical or pharmacological disturbance of proteins involved in copper homeostasis. Instead, concerning ferroptosis, its hallmark is the iron-dependent lipid peroxidation, a phenomenon associated with cell and tissue demise, thus constituting a nonapoptotic form of cell death . Many studies have provided evidence that ferroptosis can inhibit tumor growth.…”

Section: Introductionmentioning

confidence: 99%

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Metals in Cancer Research: Beyond Platinum Metallodrugs

Casini,

Pöthig

2024

ACS Cent. Sci.

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The discovery of the medicinal properties of platinum complexes has fueled the design and synthesis of new anticancer metallodrugs endowed with unique modes of action (MoA). Among the various families of experimental antiproliferative agents, organometallics have emerged as ideal platforms to control the compounds' reactivity and stability in a physiological environment. This is advantageous to efficiently deliver novel prodrug activation strategies, as well as to design metallodrugs acting only via noncovalent interactions with their pharmacological targets. Noteworthy, another justification for the advance of organometallic compounds for therapy stems from their ability to catalyze bioorthogonal reactions in cancer cells.When not yet ideal as drug leads, such compounds can be used as selective chemical tools that benefit from the advantages of catalytic amplification to either label the target of interest (e.g., proteins) or boost the output of biochemical signals. Examples of metallodrugs for the so-called "catalysis in cells" are considered in this Outlook together with other organometallic drug candidates. The selected case studies are discussed in the frame of more general challenges in the field of medicinal inorganic chemistry.

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A Hemoglobin Bionics‐Based System for Combating Antibiotic Resistance in Chronic Diabetic Wounds via Iron Homeostasis Regulation

Sun,

Liu,

Sun

et al. 2024

Advanced Materials

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Owing to the increased tissue iron accumulation in patients with diabetes, microorganisms may activate high expression of iron‐involved metabolic pathways, leading to the exacerbation of bacterial infections and disruption of systemic glucose metabolism. Therefore, an on‐demand transdermal dosing approach that utilizes iron homeostasis regulation to combat antimicrobial resistance is a promising strategy to address the challenges associated with low administration bioavailability and high antibiotic resistance in treating infected diabetic wounds. Here, we aim to propose an effective therapy based on hemoglobin bionics to induce disturbances in bacterial iron homeostasis. The preferred “iron cargo” was synthesized by protoporphyrin IX chelated with dopamine and gallium (PDGa), and was delivered via a glucose/pH‐responsive microneedle bandage (PDGa@GMB). The PDGa@GMB down‐regulated the expression levels of the iron uptake regulator (Fur) and the peroxide response regulator (perR) in Staphylococcus aureus, leading to iron nutrient starvation and oxidative stress, ultimately suppressing iron‐dependent bacterial activities. Consequently, PDGa@GMB demonstrated insusceptibility to genetic resistance while maintaining sustainable antimicrobial effects (> 90%) against resistant strains of both S. aureus and E. coli, and accelerated tissue recovery (< 20 d). Overall, PDGa@GMB not only counteracts antibiotic resistance but also holds tremendous potential in mediating microbial‐host crosstalk, synergistically attenuating pathogen virulence and pathogenicity.This article is protected by copyright. All rights reserved

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Mechanisms controlling cellular and systemic iron homeostasis

Cited by 186 publications

References 303 publications

The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease

The Hepatic Porphyrias: Revealing the Complexities of a Rare Disease

Metals in Cancer Research: Beyond Platinum Metallodrugs

A Hemoglobin Bionics‐Based System for Combating Antibiotic Resistance in Chronic Diabetic Wounds via Iron Homeostasis Regulation

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