Leucine biosynthesis regulates cytoplasmic iron-sulfur enzyme biogenesis in an Atm1p-independent manner

Tibor Bedekovics, Hongqiao Li, Gabriella B. Gajdos, Grazia Isaya

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Fe-S clusters (ISCs) are versatile cofactors utilized by many mitochondrial, cytoplasmic, and nuclear enzymes. Whereas mitochondria can independently initiate and complete ISC synthesis, other cellular compartments are believed to assemble ISCs from putative precursors exported from the mitochondria via an ATP binding cassette (ABC) transporter conserved from yeast (Atm1p) to humans (ABCB7). However, the regulatory interactions between mitochondrial and extramitochondrial ISC synthesis are largely unknown. In yeast, we found that mitochondrial ISC synthesis is regulated by the leucine biosynthetic pathway, which among other proteins involves an abundant cytoplasmic [4Fe-4S] enzyme, Leu1p. Enzymatic blocks in the pathway (i.e. leu1Δ or leu2Δ gene deletion mutations) induced post-transcriptional up-regulation of core components of mitochondrial ISC biosynthesis (i.e. the sulfur donor Nfs1p, the iron donor Yfh1p, and the ISC scaffold Isu1p). In leu2Δ cells, transcriptional mechanisms also led to dramatic up-regulation of Leu1p with concomitant down-regulation of mitochondrial aconitase (Aco1p), a [4Fe-4S] enzyme in the tricarboxylic acid cycle. Accordingly, the leu2Δ deletion mutation exacerbated Aco1p inactivation in cells with mutations in Yfh1p. These data indicate that defects in leucine biosynthesis promote the biogenesis of enzymatically active Leu1p at the expense of Aco1p activity. Surprisingly, this effect is independent of Atm1p; previous reports linking the loss of Leu1p activity to Atm1p depletion were confounded by the fact that LEU2 was used as a selectable marker to create Atm1p-depleted cells, whereas a leu2Δallele was present in Atm1p-repleted controls. Thus, still largely unknown transcriptional and post-transcriptional mechanisms control ISC distribution between mitochondria and other cellular compartments.

Original languageEnglish (US)
Pages (from-to)40878-40888
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number47
DOIs
StatePublished - Nov 25 2011

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Mitochondria
Biosynthesis
Sulfur
Leucine
Iron
Sequence Deletion
Yeast
Up-Regulation
Enzymes
Yeasts
Aconitate Hydratase
ATP-Binding Cassette Transporters
Citric Acid Cycle
Biosynthetic Pathways
Gene Deletion
Scaffolds
Down-Regulation
Genes
Defects
Mutation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Leucine biosynthesis regulates cytoplasmic iron-sulfur enzyme biogenesis in an Atm1p-independent manner. / Bedekovics, Tibor; Li, Hongqiao; Gajdos, Gabriella B.; Isaya, Grazia.

In: Journal of Biological Chemistry, Vol. 286, No. 47, 25.11.2011, p. 40878-40888.

Research output: Contribution to journalArticle

Bedekovics, Tibor ; Li, Hongqiao ; Gajdos, Gabriella B. ; Isaya, Grazia. / Leucine biosynthesis regulates cytoplasmic iron-sulfur enzyme biogenesis in an Atm1p-independent manner. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 47. pp. 40878-40888.
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