Mammalian frataxin directly enhances sulfur transfer of NFS1 persulfide to both ISCU and free thiols

Aubérie Parent, Xavier Elduque, David Cornu, Laura Belot, Jean-Pierre Le Caer, Anna Grandas, Michel B. Toledano and Benoit D’Autréaux ()
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Aubérie Parent: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique
Xavier Elduque: Departament de Química Orgànica i IBUB, Facultat de Química, Universitat de Barcelona
David Cornu: Plateforme IMAGIF, Centre de Recherche de Gif, Centre National de la Recherche Scientifique
Laura Belot: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique
Jean-Pierre Le Caer: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique
Anna Grandas: Departament de Química Orgànica i IBUB, Facultat de Química, Universitat de Barcelona
Michel B. Toledano: Laboratoire Stress Oxydant et Cancer, Service de Biologie Intégrative et de Génétique Moléculaire, Institut de Biologie et de Technologie de Saclay, Commissariat à l’Energie Atomique et aux Energies Alternatives
Benoit D’Autréaux: Institut de Chimie des Substances Naturelles, UPR2301, Centre de Recherche de Gif, Centre National de la Recherche Scientifique

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Friedreich’s ataxia is a severe neurodegenerative disease caused by the decreased expression of frataxin, a mitochondrial protein that stimulates iron–sulfur (Fe-S) cluster biogenesis. In mammals, the primary steps of Fe-S cluster assembly are performed by the NFS1–ISD11–ISCU complex via the formation of a persulfide intermediate on NFS1. Here we show that frataxin modulates the reactivity of NFS1 persulfide with thiols. We use maleimide-peptide compounds along with mass spectrometry to probe cysteine-persulfide in NFS1 and ISCU. Our data reveal that in the presence of ISCU, frataxin enhances the rate of two similar reactions on NFS1 persulfide: sulfur transfer to ISCU leading to the accumulation of a persulfide on the cysteine C104 of ISCU, and sulfur transfer to small thiols such as DTT, L-cysteine and GSH leading to persulfuration of these thiols and ultimately sulfide release. These data raise important questions on the physiological mechanism of Fe-S cluster assembly and point to a unique function of frataxin as an enhancer of sulfur transfer within the NFS1–ISD11–ISCU complex.

Date: 2015
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DOI: 10.1038/ncomms6686

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