Iron-sulfur cluster biogenesis in mammalian cells: New insights into the molecular mechanisms of cluster delivery

Biochim Biophys Acta. 2015 Jun;1853(6):1493-512. doi: 10.1016/j.bbamcr.2014.09.009. Epub 2014 Sep 19.


Iron-sulfur (Fe-S) clusters are ancient, ubiquitous cofactors composed of iron and inorganic sulfur. The combination of the chemical reactivity of iron and sulfur, together with many variations of cluster composition, oxidation states and protein environments, enables Fe-S clusters to participate in numerous biological processes. Fe-S clusters are essential to redox catalysis in nitrogen fixation, mitochondrial respiration and photosynthesis, to regulatory sensing in key metabolic pathways (i.e. cellular iron homeostasis and oxidative stress response), and to the replication and maintenance of the nuclear genome. Fe-S cluster biogenesis is a multistep process that involves a complex sequence of catalyzed protein-protein interactions and coupled conformational changes between the components of several dedicated multimeric complexes. Intensive studies of the assembly process have clarified key points in the biogenesis of Fe-S proteins. However several critical questions still remain, such as: what is the role of frataxin? Why do some defects of Fe-S cluster biogenesis cause mitochondrial iron overload? How are specific Fe-S recipient proteins recognized in the process of Fe-S transfer? This review focuses on the basic steps of Fe-S cluster biogenesis, drawing attention to recent advances achieved on the identification of molecular features that guide selection of specific subsets of nascent Fe-S recipients by the cochaperone HSC20. Additionally, it outlines the distinctive phenotypes of human diseases due to mutations in the components of the basic pathway. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.

Keywords: HSC20; HSPA9; ISCU; LYR motif protein; Mammalian Fe-S cluster assembly; SDHB.

Publication types

  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Amino Acid Sequence
  • Biosynthetic Pathways*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Iron / metabolism*
  • Iron-Sulfur Proteins / biosynthesis*
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Molecular Sequence Data
  • Sequence Homology, Amino Acid
  • Sulfur / metabolism*


  • HSP70 Heat-Shock Proteins
  • HSPA9 protein, human
  • Iron-Sulfur Proteins
  • Mitochondrial Proteins
  • Sulfur
  • Iron