| 2010 |
FDX2 (Fdx2), but not FDX1 (Fdx1/adrenodoxin), is essential for heme A and Fe/S protein biosynthesis in human mitochondria. FDX2 deficiency impairs Fe/S protein biogenesis, leading to increased cellular iron uptake and iron accumulation in mitochondria. Conversely, FDX2 is unable to efficiently reduce mitochondrial cytochromes P450 or convert steroids, functions specific to FDX1. |
RNAi-mediated depletion of FDX1 or FDX2 in human cells, with biochemical readouts for heme A, Fe/S cluster assembly, steroid conversion, and iron homeostasis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
20547883
|
| 2017 |
Both FDX1 and FDX2 bind the cysteine desulfurase complex (NFS1/ISD11/Acp) via residues near their Fe-S clusters, but FDX2 binds the complex more tightly than FDX1 (by isothermal titration calorimetry). In vitro, reduced FDX2 supports Fe-S cluster assembly on ISCU at a faster rate than FDX1. FDX2 donates electrons to the cysteine desulfurase complex, resulting in conversion of L-cysteine to L-alanine and sulfide generation. |
NMR spectroscopy (protein-protein interaction mapping), isothermal titration calorimetry, in vitro Fe-S cluster assembly assay on ISCU |
Biochemistry |
High |
28001042
|
| 2020 |
FDX2, together with its reductase FDXR (NADPH-coupled), provides electrons required for reductive [2Fe-2S] cluster fusion on ISCA1-ISCA2 in an IBA57-dependent manner, enabling maturation of mitochondrial [4Fe-4S] proteins. This electron transfer step is distinct from FDX2's earlier role in [2Fe-2S] cluster synthesis on ISCU2. FDX1 and other cellular reducing systems cannot substitute for FDX2 in this step. |
In vitro reconstitution of [4Fe-4S] aconitase maturation without artificial reductants, using purified components; Mössbauer spectroscopy; biochemical complementation assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
32817474
|
| 2022 |
FDX2, but not FDX1, is required for Fe-S protein maturation; FDX1 is specific for steroidogenesis, heme a biosynthesis, and lipoyl cofactor biosynthesis (providing electrons to lipoyl synthase). The distinct substrate specificity of each ferredoxin is determined by small conserved sequence motifs; swapping these motifs exchanges their target specificities. |
RNAi depletion in human cells, in vitro biochemical assays, domain-swap mutagenesis, functional assays for steroidogenesis/lipoylation/Fe-S assembly |
Nature chemical biology |
High |
36280795
|
| 2013 |
A homozygous loss-of-function mutation in FDX1L (FDX2; c.1A>T disrupting the ATG initiation codon) causes severe reduction of Fdx2 protein in patient muscle and fibroblast mitochondria, resulting in severely impaired activities of Fe-S-dependent respiratory chain complexes I, II, III and mitochondrial aconitase, establishing FDX2 as the second component of the Fe-S cluster biogenesis machinery in human muscle. |
Exome sequencing + homozygosity mapping; enzyme activity assays in patient skeletal muscle; western blot of patient mitochondria |
European journal of human genetics : EJHG |
Medium |
24281368
|
| 2018 |
A homozygous missense mutation in FDX2 (c.431C>T, p.P144L) causes severely reduced FDX2 protein expression (normal mRNA, reduced protein by western blot) in patient muscle, with an unusual pattern of succinate dehydrogenase and cytochrome c oxidase deficiency and iron accumulation on muscle biopsy, confirming FDX2's essential role in Fe-S cluster biogenesis in vivo. |
Genetic mapping + whole exome sequencing; RT-PCR; western blot of patient muscle; muscle biopsy with histochemical and iron staining |
Brain : a journal of neurology |
Medium |
30010796
|
| 2024 |
The pathogenic P144L mutation of FDX2 negatively affects the FDXR-dependent electron transfer pathway from NADPH to FDX2 by altering the protein-protein recognition between FDX2 and its physiological electron donor FDXR, thereby reducing FDX2's capacity to assemble both [2Fe-2S] and [4Fe-4S] clusters. The C-terminal tail of FDX2 plays a functional role in electron transfer between FDX2 and FDXR. |
Structural characterization (NMR, EPR), redox potentiometry, in vitro electron transfer assays comparing WT and P144L FDX2 with FDXR, protein-protein interaction mapping |
Protein science : a publication of the Protein Society |
High |
39467201
|
| 2025 |
Dominant gain-of-function mutations at the FDX2-NFS1 binding interface (identified in C. elegans and validated biochemically) suppress frataxin deficiency by boosting iron-sulfur cluster levels. Excess wild-type FDX2 inhibits frataxin-stimulated NFS1 (cysteine desulfurase) activity in vitro and blocks Fe-S cluster synthesis in mammalian cell culture, indicating that frataxin and FDX2 compete for the same binding site on NFS1. Partial knockdown of FDX2 (loss of one gene copy) ameliorates the growth defect in frataxin-mutant C. elegans and the ataxia phenotype in a mouse model of Friedreich's ataxia. |
Genome-scale forward genetic screen in C. elegans; in vitro NFS1 activity assays with excess FDX2; mammalian cell culture Fe-S cluster synthesis assay; mouse model rescue experiment |
Nature |
High |
41372402
|
| 2024 |
FDX2 loss in ovarian cancer cells causes global downregulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, driving senescence. In p53-deficient cells, FDX2 loss leads to apoptosis rather than senescence. FDX2 loss also sensitizes cells to ferroptosis via compromised redox homeostasis of membrane phospholipids. |
Conditional knockout of FDX2 in ovarian cancer cell line; proteomics; DNA damage assays; ferroptosis sensitivity assays; p53 pathway analysis |
The Journal of biological chemistry |
Medium |
39151727
|
| 2025 |
Paramagnetic NMR combined with DFT calculations of the [Fe2S2]2+ cluster of human FDX2 reveals that the two Fe(III) centers are inequivalent due to electron spin density transfer between cluster inorganic sulfide ions and aliphatic carbon atoms via C-H---S-Fe3+ interactions. The magnetic exchange coupling constant between the two Fe3+ ions is estimated at ~386 cm-1. |
Paramagnetic NMR spectroscopy; density functional theory quantum chemical calculations |
Inorganic chemistry |
Medium |
40121555
|
| 2025 |
A novel FDX2 splicing mutation (c.200+4 A>G) generates a mutant protein with 21 replacement N-terminal residues (replacing exon-2-encoded residues) that likely retains structural integrity (no significant backbone dynamic differences vs WT by NMR), but patient cells with low FDX2 levels show impaired mitochondrial respiration, defects in Fe-S proteins, enhanced mitochondrial iron accumulation, and significantly diminished mitochondrial SOD2 levels. |
RNA splicing analysis; NMR structural comparison of mutant vs WT FDX2; mitochondrial respiration assay; Fe-S protein activity assays; mitochondrial iron measurement; western blot for SOD2 |
Cell death & disease |
Medium |
41372147
|