Mitochondrial iron-sulfur protein biogenesis and human disease

Biochimie. 2014 May;100:61-77. doi: 10.1016/j.biochi.2014.01.010. Epub 2014 Jan 23.

Abstract

Work during the past 14 years has shown that mitochondria are the primary site for the biosynthesis of iron-sulfur (Fe/S) clusters. In fact, it is this process that renders mitochondria essential for viability of virtually all eukaryotes, because they participate in the synthesis of the Fe/S clusters of key nuclear and cytosolic proteins such as DNA polymerases, DNA helicases, and ABCE1 (Rli1), an ATPase involved in protein synthesis. As a consequence, mitochondrial function is crucial for nuclear DNA synthesis and repair, ribosomal protein synthesis, and numerous other extra-mitochondrial pathways including nucleotide metabolism and cellular iron regulation. Within mitochondria, the synthesis of Fe/S clusters and their insertion into apoproteins is assisted by 17 proteins forming the ISC (iron-sulfur cluster) assembly machinery. Biogenesis of mitochondrial Fe/S proteins can be dissected into three main steps: First, a Fe/S cluster is generated de novo on a scaffold protein. Second, the Fe/S cluster is dislocated from the scaffold and transiently bound to transfer proteins. Third, the latter components, together with specific ISC targeting factors insert the Fe/S cluster into client apoproteins. Disturbances of the first two steps impair the maturation of extra-mitochondrial Fe/S proteins and affect cellular and systemic iron homeostasis. In line with the essential function of mitochondria, genetic mutations in a number of ISC genes lead to severe neurological, hematological and metabolic diseases, often with a fatal outcome in early childhood. In this review we briefly summarize our current functional knowledge on the ISC assembly machinery, and we present a comprehensive overview of the various Fe/S protein assembly diseases.

Keywords: Genome integrity; Iron regulation; Iron–sulfur cluster; Mitochondrial ISC system.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Gene Expression Regulation
  • Homeostasis
  • Humans
  • Iron / metabolism
  • Iron-Sulfur Proteins / chemistry
  • Iron-Sulfur Proteins / genetics*
  • Iron-Sulfur Proteins / metabolism
  • Mice
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Diseases / genetics*
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism
  • Molecular Chaperones / chemistry
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Mutation
  • Protein Biosynthesis

Substances

  • Iron-Sulfur Proteins
  • Mitochondrial Proteins
  • Molecular Chaperones
  • Iron