Functions of mitochondrial ISCU and cytosolic ISCU in mammalian iron-sulfur cluster biogenesis and iron homeostasis
Open accessAbstract
Iron-sulfur (Fe-S) clusters are required for the functions of mitochondrial aconitase, mammalian iron regulatory protein 1, and many other proteins in multiple subcellular compartments. Recent studies in Saccharomyces cerevisiae indicated that Fe-S cluster biogenesis also has an important role in mitochondrial iron homeostasis. Here we report the functional analysis of the mitochondrial and cytosolic isoforms of the human Fe-S cluster scaffold protein, ISCU. Suppression of human ISCU by RNAi not only inactivated mitochondrial and cytosolic aconitases in a compartment-specific manner but also inappropriately activated the iron regulatory proteins and disrupted intracellular iron homeostasis. Furthermore, endogenous ISCU levels were suppressed by iron deprivation. These results provide evidence for a coordinated response to iron deficiency that includes activation of iron uptake, redistribution of intracellular iron, and decreased utilization of iron in Fe-S proteins.
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Mitochondrial and cytosolic aconitase rely on iron-sulfur clusters for their metabolic function.
“which both rely on ISCs for their metabolic function (33)”
From Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction (2022) · cites this paper as [33]
ISCU levels are suppressed by iron deprivation, to decrease iron utilization by curtailing iron-sulfur cluster biogenesis.
“Additionally, ISCU levels are suppressed by iron deprivation, to decrease iron utilization by curtailing iron-sulfur cluster biogenesis [90].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [90]
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References 65 · Cited by 294
- Authors
- Tong, W.-H., & Rouault, T. A.
- Affiliations
- National Institutes of Health (US)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (US)
- Corresponding author
- Rouault, Tracey A.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 3
- Issue
- 3
- Pages
- 199-210
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2110649328
- Cited by
- 294
- References
- 65
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 13 · 2023: 10 · 2022: 12 · 2021: 12 · 2020: 19 · 2019: 23 · 2018: 14 · 2017: 14 · 2016: 11 · 2015: 9 · 2014: 19 · 2013: 24 · 2012: 12
- FWCI
- 13.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Child Health and Human Development
- Topics
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- iron-sulfur cluster assembly, IscU, mitochondrial iron homeostasis, aconitase, iron regulatory protein 1, iron deficiency, iron absorption, iron redistribution, RNAi knockdown
- MeSH terms
- Aconitate Hydratase, Cells, Cultured, Cytosol, Gene Expression Regulation, HeLa Cells, Homeostasis, Humans, Iron, Iron-Sulfur Proteins, Mitochondria, Models, Biological, Protein Binding, Protein Isoforms, Response Elements, Gene Silencing, RNA, Small Interfering, Iron Regulatory Protein 1, Iron Regulatory Protein 2
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