Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin

Gervason, Sylvain; Larkem, Djabir; Mansour, Amir Ben; Botzanowski, Thomas; Müller, Christina S.; Pecqueur, Ludovic; Pavec, Gwenaëlle Le; Delaunay‐Moisan, Agnès; Brun, Omar; Agramunt, Jordi; Grandas, Anna; Fontecave, Marc; Schünemann, Volker; Cianférani, Sarah; Sizun, Christina; Toledano, Michel B.; D’Autréaux, Benoît

doi:10.1038/s41467-019-11470-9

Cited by 129 publications

(240 citation statements)

References 58 publications

(135 reference statements)

Supporting

Mentioning

221

Contrasting

Order By: Relevance

“…It is known that hysteresis has physiological importance to buffer radical changes in the concentration of metabolites in biological systems [ 53 ]. The interaction between AtNFS1 and AtISD11 would be crucial since in the absence of the latter it was observed that AtNFS1 shows very low cysteine desulfurase activity, as was recently reported in humans [ 27 , 39 ]. Moreover, AtFH directly stimulates the cysteine desulfurase activity.…”

Section: Discussionmentioning

confidence: 73%

“…Frataxin is a protein that has been widely conserved through evolution in bacteria, yeasts, mammals, and plants without major structural changes [ 19 , 20 ]. Several functions were proposed in which frataxin would be involved, including iron homeostasis and respiration [ 21 ], heme metabolism [ 22 ], assembly of Fe-S centers [ 23 , 24 ], oxidative phosphorylation and oxidative stress [ 25 ], storage of Fe in mitochondria in a water-soluble and non-toxic form [ 21 , 26 ], and recently, its involvement in persulfide transfer [ 27 ]. Previously, we described the presence of frataxin from Arabidopsis [ 24 , 28 ] and maize [ 29 , 30 ] and the results indicate that it is an essential protein in plants, required for optimal activity of Fe-S proteins and it is also involved in protection against oxidative damage [ 24 , 28 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Iron-Sulfur Cluster Complex Assembly in the Mitochondria of Arabidopsis thaliana

Armas

Balparda

Terenzi

et al. 2020

Plants

View full text Add to dashboard Cite

In plants, the cysteine desulfurase (AtNFS1) and frataxin (AtFH) are involved in the formation of Fe-S groups in mitochondria, specifically, in Fe and sulfur loading onto scaffold proteins, and the subsequent formation of the mature Fe-S cluster. We found that the small mitochondrial chaperone, AtISD11, and AtFH are positive regulators for AtNFS1 activity in Arabidopsis. Moreover, when the three proteins were incubated together, a stronger attenuation of the Fenton reaction was observed compared to that observed with AtFH alone. Using pull-down assays, we found that these three proteins physically interact, and sequence alignment and docking studies showed that several amino acid residues reported as critical for the interaction of their human homologous are conserved. Our results suggest that AtFH, AtNFS1 and AtISD11 form a multiprotein complex that could be involved in different stages of the iron–sulfur cluster (ISC) pathway in plant mitochondria.

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Iron-Sulfur Cluster Complex Assembly in the Mitochondria of Arabidopsis thaliana

Armas

Balparda

Terenzi

et al. 2020

Plants

View full text Add to dashboard Cite

show abstract

“…The role of these metals in the FRDA pathology is completely unknown and therefore, the impact of a therapy focused on controlling cellular levels of these metals has not been addressed with the exception of a work using the fruit fly [225]. Among these metals, zinc might be of special relevance due to its ability to impair ISC assembly [15].…”

Section: Future Directions and Prospectsmentioning

confidence: 99%

“…Although the function of frataxin remains unclear, early studies observed a deficient activity of the iron-sulphur clusters (ISC) containing enzymes of the mitochondrial respiratory chain and Krebs cycle in heart homogenates, mitochondria from skeletal muscles, fibroblasts and lymphoblasts derived from patients [11,12]. In this line, several reports have detailed the function of frataxin as stimulator of ISC biogenesis by facilitating the persulfide transfer [13][14][15]. ISC are prosthetic cofactors, responsible for the activity of different enzymes which are involved in energy metabolism, iron metabolism, purine synthesis and DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Therapies and Oxidative Stress in Friedreich’s Ataxia: The Right Path or Just a Diversion?

et al. 2020

View full text Add to dashboard Cite

Friedreich’s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those “antioxidant” drugs that went beyond the disease’s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.

show abstract

“…The prokaryotic cysteine desulfurase is a modestly active enzyme; whereas, the eukaryotic complex is a low activity system that requires FXN activation to meet cellular Fe-S cluster biosynthetic demands (5,18,(35)(36)(37). There is strong evidence that FXN has a role in stimulating the cysteine desulfurase and sulfur transfer chemistry for Fe-S cluster assembly (18)(19)(20)(23)(24)(25)(26)38).…”

Section: Substitutions Have Varied Effects On the Dimeric Binding Conmentioning

confidence: 99%

Recapitulating the frataxin activation mechanism in an engineered bacterial cysteine desulfurase supports the architectural switch model

Patra

Lin

Ghosh

et al. 2020

Preprint

View full text Add to dashboard Cite

Iron-sulfur (Fe-S) clusters have a key role in many biochemical processes and are essential for most life forms. Despite recent mechanistic advances in understanding the Fe-S cluster biosynthetic pathway, critical questions remain unresolved. Although human NFS1 and E. coli IscS share ∼60% sequence identity, NFS1 exhibits low activity and requires activation by the Friedreich’s ataxia protein frataxin (FXN) for in vivo function. Surprisingly, structures of the human complex reveal three distinct quaternary structures with one form exhibiting the same subunit interactions as IscS. An architectural switch model has been proposed in which evolutionarily lost interactions between NFS1 subunits results in the formation of low-activity architectures; FXN binding compensates for these lost interactions and facilitates a subunit rearrangement to activate the complex. Here, we used a structure and evolution-guided approach to identify three conserved residues proposed to weaken interactions between NFS1 subunits and transplanted these amino acids into IscS. Compared to native IscS, the engineered variant had a 4000-fold weaker dimer interface and diminished activity that correlated with the absence of the second catalytic subunit. Remarkably, the addition of the FXN homolog to the engineered variant stimulated the decay of the Cys-quinonoid pyridoxal 5’-phosphate intermediate, shifted IscS from the monomeric to dimeric form, and increased the cysteine desulfurase activity, reproducing results from the human system and supporting the architectural switch model. Overall, these studies indicate a weakening of the homodimeric interface was a key development during the evolution of the eukaryotic system and provide new insights into the role of FXN.

show abstract

Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin

Cited by 129 publications

References 58 publications

Iron-Sulfur Cluster Complex Assembly in the Mitochondria of Arabidopsis thaliana

Iron-Sulfur Cluster Complex Assembly in the Mitochondria of Arabidopsis thaliana

Antioxidant Therapies and Oxidative Stress in Friedreich’s Ataxia: The Right Path or Just a Diversion?

Recapitulating the frataxin activation mechanism in an engineered bacterial cysteine desulfurase supports the architectural switch model

Contact Info

Product

Resources

About