Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly

Campbell, Courtney J.; Pall, Ashley E.; Naik, Akshata R.; Thompson, Lindsey; Stemmler, Timothy L.

doi:10.3390/ijms22116006

Cited by 12 publications

(6 citation statements)

References 91 publications

(188 reference statements)

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“…Unfortunately, a high-resolution structure of the human mature FXN 81–210 oligomer is still lacking. Many studies reported iron-binding properties of monomeric frataxin proteins ( Campbell et al, 2021 ). A total of twelve aspartate and glutamate residues along the conserved acidic ridge were found to bind iron but no structurally defined iron-binding site could be identified.…”

Section: Iron Storage Functionmentioning

confidence: 99%

“…First, the number of iron bound to frataxin varied between studies (from one to seven), with Fe 2+ and Fe 3+ binding with similar affinities. The proposed iron-binding site involves several glutamate and aspartate residues from the conserved acidic ridge ( Campbell et al, 2021 ). However, the structure of the complex between FXN and the NFS1-ISD11-ACP-ISCU complex ( Fox et al, 2019 ) revealed that most of these amino acids are either directly involved in the interaction with NFS1 or in the internal structure of the protein ( Figure 3 ).…”

Section: Specialized Role Of Frataxin In Iron-sulfur Cluster Biosynth...mentioning

confidence: 99%

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Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

et al. 2022

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Friedreich’s ataxia (FRDA) is the most prevalent autosomic recessive ataxia and is associated with a severe cardiac hypertrophy and less frequently diabetes. It is caused by mutations in the gene encoding frataxin (FXN), a small mitochondrial protein. The primary consequence is a defective expression of FXN, with basal protein levels decreased by 70–98%, which foremost affects the cerebellum, dorsal root ganglia, heart and liver. FXN is a mitochondrial protein involved in iron metabolism but its exact function has remained elusive and highly debated since its discovery. At the cellular level, FRDA is characterized by a general deficit in the biosynthesis of iron-sulfur (Fe-S) clusters and heme, iron accumulation and deposition in mitochondria, and sensitivity to oxidative stress. Based on these phenotypes and the proposed ability of FXN to bind iron, a role as an iron storage protein providing iron for Fe-S cluster and heme biosynthesis was initially proposed. However, this model was challenged by several other studies and it is now widely accepted that FXN functions primarily in Fe-S cluster biosynthesis, with iron accumulation, heme deficiency and oxidative stress sensitivity appearing later on as secondary defects. Nonetheless, the biochemical function of FXN in Fe-S cluster biosynthesis is still debated. Several roles have been proposed for FXN: iron chaperone, gate-keeper of detrimental Fe-S cluster biosynthesis, sulfide production stimulator and sulfur transfer accelerator. A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.

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Section: Iron Storage Functionmentioning

confidence: 99%

Section: Specialized Role Of Frataxin In Iron-sulfur Cluster Biosynth...mentioning

confidence: 99%

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

et al. 2022

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“…A set of additional proteins ensures the proper functioning of SDH. These proteins encompass those involved in the assembly of iron-sulfur clusters, such as Frataxin [ 58 ]. The deficiency of Frataxin is known to cause Friedreich’s ataxia.…”

Section: The Succinate Crossroad: Enzymes and Metabolites Stakeholdersmentioning

confidence: 99%

Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad

et al. 2022

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Research focused on succinate dehydrogenase (SDH) and its substrate, succinate, culminated in the 1950s accompanying the rapid development of research dedicated to bioenergetics and intermediary metabolism. This allowed researchers to uncover the implication of SDH in both the mitochondrial respiratory chain and the Krebs cycle. Nowadays, this theme is experiencing a real revival following the discovery of the role of SDH and succinate in a subset of tumors and cancers in humans. The aim of this review is to enlighten the many questions yet unanswered, ranging from fundamental to clinically oriented aspects, up to the danger of the current use of SDH as a target for a subclass of pesticides.

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“…The activity of a set of additional proteins ensures the proper functioning of SDH. These proteins encompass those involved in the assembly of iron-sulfur clusters, such as Frataxin [58]. The deficiency of Frataxin is known to cause Friedreich's ataxia.…”

Section: Figure 1 the Succinate Dehydrogenase (A) And Some Of Its Inh...mentioning

confidence: 99%

Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad

Bénit¹,

Goncalves²,

El-Khoury³

et al. 2022

Preprint

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Research focused on succinate dehydrogenase (SDH) and its substrate, succinate, culminated in the 50’s accompanying the rapid development of research dedicated to bioenergetics and intermediary metabolism. This allowed to uncover the implication of the SDH in both the mitochondrial respiratory chain and the Krebs cycle. Nowadays this theme is experiencing a real revival following the discovery of the role of SDH and succinate in a subset of tumors and cancers in human. The aim of this review is to enlighten the many questions yet unanswered, ranging from fundamental to clinically oriented aspects, up to the danger of the current use of SDH as a target for a sub class of pesticides.

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Molecular Details of the Frataxin–Scaffold Interaction during Mitochondrial Fe–S Cluster Assembly

Cited by 12 publications

References 91 publications

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad

Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad

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