Mammalian iron–sulfur cluster biogenesis: Recent insights into the roles of frataxin, acyl carrier protein and ATPase-mediated transfer to recipient proteins

Maio, Nunziata; Jain, Anshika; Rouault, Tracey A.

doi:10.1016/j.cbpa.2019.11.014

Cited by 59 publications

(45 citation statements)

References 74 publications

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“…FXN has been proposed to have several physiological roles: allosteric regulator of ISC biogenesis [ 21 , 45 ], the iron source for building ISC clusters [ 24 ], regulator of iron homeostasis [ 25 ] and ferroptosis [ 26 ]. All the above roles involve iron ions; therefore, it is of key importance to understand the effects of ferrous and ferric iron on the structure and function of FXN.…”

Section: Discussionmentioning

confidence: 99%

“…The proposed role of FXN as an allosteric regulator of the biosynthetic iron-sulphur cluster (ISC) machinery has recently found further confirmations [ 16 , 17 , 18 , 19 ]. The ISC biosynthetic pathway takes place in the mitochondria and is a multi-step process involving several proteins [ 19 , 20 , 21 ]: the early cluster assembly requires a yet-unidentified iron source and is performed by a pentameric quaternary protein complex. The complex is formed by FXN, the cysteine desulfurase NFS1 (extracting the sulphide from free cysteine), ISD11 (an accessory protein), ACP (an acyl-carrier protein), and ISCU (the scaffold protein on which the clusters are assembled).…”

Section: Introductionmentioning

confidence: 99%

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Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Doni

Passerini

Audran

et al. 2020

IJMS

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Frataxin is a highly conserved protein whose deficiency results in the neurodegenerative disease Friederich’s ataxia. Frataxin’s actual physiological function has been debated for a long time without reaching a general agreement; however, it is commonly accepted that the protein is involved in the biosynthetic iron-sulphur cluster (ISC) machinery, and several authors have pointed out that it also participates in iron homeostasis. In this work, we use site-directed spin labeling coupled to electron paramagnetic resonance (SDSL EPR) to add new information on the effects of ferric and ferrous iron binding on the properties of human frataxin in vitro. Using SDSL EPR and relating the results to fluorescence experiments commonly performed to study iron binding to FXN, we produced evidence that ferric iron causes reversible aggregation without preferred interfaces in a concentration-dependent fashion, starting at relatively low concentrations (micromolar range), whereas ferrous iron binds without inducing aggregation. Moreover, our experiments show that the ferrous binding does not lead to changes of protein conformation. The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Doni

Passerini

Audran

et al. 2020

IJMS

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“… 4 FXN is a highly conserved mitochondrial protein regulating the biosynthesis of iron sulfur clusters (Fe-S) through an interaction with the de novo Fe-S complex assembly machinery. 5 Fe-S are prosthetic groups crucial for many biological functions, including the mitochondrial respiratory chain; heme, lipoid acid, and molybdenum biosynthesis; tRNA thiolation; and iron metabolism. 6 , 7 , 8 , 9 Frataxin deficiency leads to impaired Fe-S biogenesis, impairment of Fe-S enzymes, mitochondrial dysfunction, iron metabolism dysregulation, and eventually cellular dysfunction and death.…”

Section: Introductionmentioning

confidence: 99%

High Levels of Frataxin Overexpression Lead to Mitochondrial and Cardiac Toxicity in Mouse Models

Belbellaa

Reutenauer

Messaddeq

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Friedreich ataxia (FA) is currently an incurable inherited mitochondrial disease caused by reduced levels of frataxin (FXN). Cardiac dysfunction is the main cause of premature death in FA. Adeno-associated virus (AAV)-mediated gene therapy constitutes a promising approach for FA, as demonstrated in cardiac and neurological mouse models. While the minimal therapeutic level of FXN protein to be restored and biodistribution have recently been defined for the heart, it is unclear if FXN overexpression could be harmful. Indeed, depending on the vector delivery route and dose administered, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or off-target organs such as the liver. The present study demonstrates safety of FXN cardiac overexpression up to 9-fold the normal endogenous level but significant toxicity to the mitochondria and heart above 20-fold. We show gradual severity with increasing FXN overexpression, ranging from subclinical cardiotoxicity to left ventricle dysfunction. This appears to be driven by impairment of the mitochondria respiratory chain and ultrastructure, which leads to cardiomyocyte subcellular disorganization, cell death, and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriate vector expression level, long-term safety, and biomarkers to monitor such events.

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“…Zinc and various hormones, enzymes, and nutrients in breastmilk are important for protein and nucleic acid homeostasis [ 8 ]. Iron is required not only for hemopoiesis, but also for Fe-S cluster synthesis, which is especially important for respiration and DNA replication [ 9 ]. Calcium is the main component of animal bones and teeth, and calcium ions are involved in regulatory functions [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Relationship between Selected Trace Elements in Human Milk and Psychosocial Characteristics in Korean Early Postpartum Women

Noh

Lee

2021

IJERPH

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This study aimed to identify the relationship between selected trace elements in human milk and depression, breastfeeding self-efficacy, sleep satisfaction, and the demographic and obstetric characteristics of lactating mothers. Forty lactating mothers recovering after birth in two postpartum care centers located in Changwon, South Korea, were studied. Calcium, sodium, iron, and selenium concentrations in human milk were analyzed using inductively coupled plasma mass spectrometry at the analysis center of Kyungnam University. Data were analyzed using descriptive statistics, the Kruskal-Wallis test, the Mann-Whiney U test, and Spearman’s correlation coefficients using an SPSS 23.0 program. There were no significant differences in concentration of selected trace elements (calcium, sodium, iron, and selenium) in human milk according to demographic and obstetric characteristics. Sodium concentration was negatively correlated with breastfeeding self-efficacy (r = −0.51, CI = −0.71 to −0.24). Selenium concentration was negatively correlated with calcium concentration (r = −0.34, CI = −0.58 to 0.38). Postpartum depression was negatively correlated with sleep satisfaction (r = −0.46, CI = −0.67 to −0.17) and with breastfeeding self-efficacy (r = −0.41, CI = −0.64 to −0.11). Breastfeeding self-efficacy was positively correlated with sleep satisfaction (r = 0.48, CI = 0.20 to 0.69). This study suggests that sodium concentration in human milk is associated with breastfeeding self-efficacy.

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Mammalian iron–sulfur cluster biogenesis: Recent insights into the roles of frataxin, acyl carrier protein and ATPase-mediated transfer to recipient proteins

Cited by 59 publications

References 74 publications

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

Effects of Fe2+/Fe3+ Binding to Human Frataxin and Its D122Y Variant, as Revealed by Site-Directed Spin Labeling (SDSL) EPR Complemented by Fluorescence and Circular Dichroism Spectroscopies

High Levels of Frataxin Overexpression Lead to Mitochondrial and Cardiac Toxicity in Mouse Models

Relationship between Selected Trace Elements in Human Milk and Psychosocial Characteristics in Korean Early Postpartum Women

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