Mutations in the mitochondrial co-chaperone jaclp induce a sideroblastic phenotype in s. cerevisiae

Roy Kim, Sandeep Saxena, Debkumar Pain, Andrew Dancis

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Acquired idiopathic sideroblastic anemia is a disorder characterized by ineffective erythropoiesis with deficient heme biosynthesis and hyperaccumulation of iron in the mitochondria of erythroid precursors. The molecular basis of these disturbances in iron metabolism is unknown. S. cerevisiae JAC1 is an essential gene predicted to encode a member of the J-family of molecular co-chaperones which interact with HspVO proteins. Using a selection scheme for mutants with dysregulated iron homeostasis, we isolated two mutants, jacl-6 and jacl-30. The phenotype of the mutants suggest that the Jacl protein plays a role in cellular iron metabolism. These mutants are predicted to carry truncated Jacl proteins and exhibit increased levels of surface ferric reductase activity, cellular ferrous iron uptake, and mitochondrial iron concentrations. On the other hand, heme and iron-sulfur protein levels are significantly decreased. Immunoblotting studies show that Jaclp is localized to the mitochondrial matrix, the site of the first and last two steps of heme biosynthesis in 5. cerevisiae. Using the same selection scheme, we isolated mutants of SSQ1 that displayed phenotypes similar to the jacl-6 and jacl-30 mutants. Given that SSQ1 encodes a mitochondrial Hsp70-type chaperone, it may be the partner of Jaclp. The findings suggest that Jaclp is a co-chaperone protein which is likely to interact with Ssqlp as part of a mitochondrial chaperone complex involved in control of iron trafficking and heme levels. Such a chaperone complex is likely to be present in human mitochondria as well. BLAST analysis of the NCBI human protein database reveals two proteins homologous to Jaclp with features of mitochondrial J-type cochaperones. These candidate human homologs of Jaclp may contribute to the pathophysiology of acquired idiopathic sideroblastic anemia.

Original languageEnglish (US)
Pages (from-to)227a
Issue number11 PART I
StatePublished - 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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