Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis

Cai, Kai; Tonelli, Marco; Frederick, Ronnie O.; Markley, John L.

doi:10.1021/acs.biochem.6b00447

Cited by 107 publications

(103 citation statements)

References 38 publications

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“…Despite the spectral overlap of the signals from oxidized FDX2 and the Fe-S cluster, the increase at 456 nm can be used as a means to assess the cluster assembly rates. This was earlier verified by separating [2Fe-2S]-ISCU from oxidized FDX2 prior to collecting the spectrum at 456 nm [14]. …”

Section: Methodsmentioning

confidence: 94%

“…In the next stage, FXN and oxidized ferredoxin are released. Ferredoxin is reduced by ferredoxin reductase (FDXR), which binds to the same surface of ferredoxin that binds NFS1 [14,67], and Fe 2+ -FXN is regenerated with Fe 2+ from a yet to be identified mitochondrial iron protein. Then reduced ferredoxin and Fe 2+ -FXN bind back to the (NIAU) 2 complex, and the cycle is repeated to complete the assembly of a [2Fe-2S] cluster.…”

Section: Discussionmentioning

confidence: 99%

“…Samples of unlabeled ISCU, (NIA) 2 , FDX2 and unlabeled and [U- 15 N]-FXN 81–210 were produced and purified as described previously [8,13,14]. …”

Section: Methodsmentioning

confidence: 99%

“…The desulfurase complex produced by co-expressing human ISD11 and NFS1 in E. coli cells contains the covalently-bound 4′-phosphopantetheine form of E. coli acyl carrier protein (Acp) [13]. Because this chimeric complex has been found to exhibit cysteine desulfurase activity and to support Fe-S cluster assembly in vitro [14], E. coli Acp appears to substitute for the human mitochondrial ACP. We determined the stoichiometry of the cysteine desulfurase complex as [NFS1] 2 :[ISD11] 2 :[Acp] 2 [13], hence-forth abbreviated as “(NIA) 2 ”.…”

mentioning

confidence: 99%

“…Human mitochondria contain two ferredoxins (FDX1 and FDX2), whose roles in Fe-S cluster assembly have been subject to debate [19,21,22]. It was shown recently that both FDX1 and FDX2 can interact with (NIA) 2 and donate electrons for Fe-S cluster assembly in vitro , although FDX2 binds more tightly and promotes more rapid cluster assembly than FDX1 [14]. …”

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confidence: 99%

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Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly

Cai

Frederick

Tonelli

et al. 2018

Journal of Inorganic Biochemistry

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Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry and multinuclear NMR spectroscopy to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. Our results show that FXN tightly binds a single Fe2+ but not Fe3+. While FXN (with or without bound Fe2+) does not bind the scaffold protein ISCU directly, the two proteins interact mutually when each is bound to the cysteine desulfurase complex ([NFS1]2:[ISD11]2:[Acp]2), abbreviated as (NIA)2, where “N” represents the cysteine desulfurase (NFS1), “I” represents the accessory protein (ISD11), and “A” represents acyl carrier protein (Acp). FXN binds (NIA)2 weakly in the absence of ISCU but more strongly in its presence. Fe2+-FXN binds to the (NIA)2-ISCU2 complex without release of iron. However, upon the addition of both L-cysteine and a reductant (either reduced FDX2 or DTT), Fe2+ is released from FXN as consistent with Fe2+-FXN being the proximal source of iron for Fe-S cluster assembly.

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Section: Methodsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

“…Samples of unlabeled ISCU, (NIA) 2 , FDX2 and unlabeled and [U- 15 N]-FXN 81–210 were produced and purified as described previously [8,13,14]. …”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly

Cai

Frederick

Tonelli

et al. 2018

Journal of Inorganic Biochemistry

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Mitochondrial [2Fe‐2S] ferredoxins: new functions for old dogs

et al. 2022

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Ferredoxins (FDXs) comprise a large family of iron–sulfur proteins that shuttle electrons from NADPH and FDX reductases into diverse biological processes. This review focuses on the structure, function and specificity of mitochondrial [2Fe‐2S] FDXs that are related to bacterial FDXs due to their endosymbiotic inheritance. Their classical function in cytochrome P450‐dependent steroid transformations was identified around 1960, and is exemplified by mammalian FDX1 (aka adrenodoxin). Thirty years later the essential function in cellular Fe/S protein biogenesis was discovered for the yeast mitochondrial FDX Yah1 that is additionally crucial for the formation of haem a and ubiquinone CoQ6. In mammals, Fe/S protein biogenesis is exclusively performed by the FDX1 paralog FDX2, despite the high structural similarity of both proteins. Recently, additional and specific roles of human FDX1 in haem a and lipoyl cofactor biosyntheses were described. For lipoyl synthesis, FDX1 transfers electrons to the radical S‐adenosyl methionine‐dependent lipoyl synthase to kickstart its radical chain reaction. The high target specificity of the two mammalian FDXs is contained within small conserved sequence motifs, that upon swapping change the target selection of these electron donors.

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Rare presentation of FDX2‐related disorder and untargeted global metabolomics findings

Aggarwal

Pillai

Billington

et al. 2021

American J of Med Genetics Pt A

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We present the case of a 20-year-old male with a history of myopathy and multiple episodes of rhabdomyolysis, and lactic acidosis. He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years). Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I). The FDX2 gene encodes a mitochondrial protein, ferredoxin 2, that is involved in the biogenesis of Fe-S clusters. Biallelic pathogenic variants in FDX2 have previously been associated with episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy. Only two cases with FDX2-related rhabdomyolysis as a predominant feature have been reported in medical literature. Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis. He does not have optic atrophy or leukoencephalopathy. This is the oldest patient reported with FDX2-related disorder and he has significantly elevated CK during episodes of rhabdomyolysis. In addition, we describe untargeted global metabolomic findings during an episode of metabolic decompensation, shedding light on the biochemical pathway perturbation associated with this ultra-rare genetic disorder.

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Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis

Cited by 107 publications

References 38 publications

Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly

Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly

Mitochondrial [2Fe‐2S] ferredoxins: new functions for old dogs

Rare presentation of FDX2‐related disorder and untargeted global metabolomics findings

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