ArticleThe Journal of biological chemistry2015
Mapping Key Residues of ISD11 Critical for NFS1-ISD11 Subcomplex Stability: IMPLICATIONS IN THE DEVELOPMENT OF MITOCHONDRIAL DISORDER, COXPD19.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 58 citations in OpenAlex.
- Nanobodies as tools for studying human frataxin biology.Communications biology · 2026Article
- NFS1 Plays a Critical Role in Regulating Ferroptosis Homeostasis.Biomolecules · 2025Review
- Frataxin: from the sequence to the biological role.Biophysical reviews · 2025Review
- Roles of conserved active site residues in the IscS cysteine desulfurase reaction.Frontiers in microbiology · 2023Article
- Structural and Functional Characterization of CreFH1, the Frataxin Homolog fromPlants (Basel, Switzerland) · 2022Article
- During FeS cluster biogenesis, ferredoxin and frataxin use overlapping binding sites on yeast cysteine desulfurase Nfs1.The Journal of biological chemistry · 2022Article
- Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma.Cancer cell international · 2021Article
- Iron-Sulfur Cluster Complex Assembly in the Mitochondria ofPlants (Basel, Switzerland) · 2020Article
- Redox-dependent regulation of mitochondrial dynamics by DJ-1 paralogs in Saccharomyces cerevisiae.Redox biology · 2020Article
- Iron-sulfur cluster ISD11 deficiency (JIMD reports · 2019Article
- Expression of soluble native protein inBiotechnology reports (Amsterdam, Netherlands) · 2018Article
- Iron-sulfur cluster biosynthesis and trafficking - impact on human disease conditions.Metallomics : integrated biometal science · 2018Review
- Iron-sulfur cluster biogenesis and trafficking in mitochondria.The Journal of biological chemistry · 2017Review
- Structure of human Fe-S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP-ISD11 interactions.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery.The Journal of biological chemistry · 2016Article
- The Eukaryotic-Specific ISD11 Is a Complex-Orphan Protein with Ability to Bind the Prokaryotic IscS.PloS one · 2016Article
- Structural and Functional Perspectives on Mitochondrial LYR-Domain Proteins in Plants.Physiologia plantarumArticle
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5 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Biogenesis of the iron-sulfur (Fe-S) cluster is an indispensable process in living cells. In mammalian mitochondria, the initial step of the Fe-S cluster assembly process is assisted by the NFS1-ISD11 complex, which delivers sulfur to scaffold protein ISCU during Fe-S cluster synthesis. Although ISD11 is an essential protein, its cellular role in Fe-S cluster biogenesis is still not defined. Our study maps the important ISD11 amino acid residues belonging to putative helix 1 (Phe-40), helix 3 (Leu-63, Arg-68, Gln-69, Ile-72, Tyr-76), and C-terminal segment (Leu-81, Glu-84) are critical for in vivo Fe-S cluster biogenesis. Importantly, mutation of these conserved ISD11 residues into alanine leads to its compromised interaction with NFS1, resulting in reduced stability and enhanced aggregation of NFS1 in the mitochondria. Due to altered interaction with ISD11 mutants, the levels of NFS1 and Isu1 were significantly depleted, which affects Fe-S cluster biosynthesis, leading to reduced electron transport chain complex (ETC) activity and mitochondrial respiration. In humans, a clinically relevant ISD11 mutation (R68L) has been associated in the development of a mitochondrial genetic disorder, COXPD19. Our findings highlight that the ISD11 R68A/R68L mutation display reduced affinity to form a stable subcomplex with NFS1, and thereby fails to prevent NFS1 aggregation resulting in impairment of the Fe-S cluster biogenesis. The prime affected machinery is the ETC complex, which showed compromised redox properties, causing diminished mitochondrial respiration. Furthermore, the R68L ISD11 mutant displayed accumulation of mitochondrial iron and reactive oxygen species, leading to mitochondrial dysfunction, which correlates with the phenotype observed in COXPD19 patients.
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