PUBLICATION

Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis

Authors
Kardon, J.R., Yien, Y.Y., Huston, N.C., Branco, D.S., Hildick-Smith, G.J., Rhee, K.Y., Paw, B.H., Baker, T.A.
ID
ZDB-PUB-150511-1
Date
2015
Source
Cell   161: 858-867 (Journal)
Registered Authors
Paw, Barry
Keywords
none
MeSH Terms
  • Saccharomyces cerevisiae/cytology
  • Saccharomyces cerevisiae/metabolism
  • Humans
  • Eukaryota/genetics
  • Eukaryota/metabolism*
  • Heme/biosynthesis*
  • Saccharomyces cerevisiae Proteins/metabolism
  • Animals
  • Sequence Alignment
  • Biological Evolution
  • Aminolevulinic Acid/metabolism
  • Mitochondria/metabolism
  • Mitochondrial Proteins/metabolism
  • Zebrafish/metabolism
  • 5-Aminolevulinate Synthetase/metabolism
  • Erythropoiesis*
  • Molecular Sequence Data
  • Endopeptidase Clp/chemistry
  • Endopeptidase Clp/genetics
  • Endopeptidase Clp/metabolism*
  • Molecular Chaperones/metabolism
  • Amino Acid Sequence
(all 22)
PubMed
25957689 Full text @ Cell
Abstract
The mitochondrion maintains and regulates its proteome with chaperones primarily inherited from its bacterial endosymbiont ancestor. Among these chaperones is the AAA+ unfoldase ClpX, an important regulator of prokaryotic physiology with poorly defined function in the eukaryotic mitochondrion. We observed phenotypic similarity in S. cerevisiae genetic interaction data between mitochondrial ClpX (mtClpX) and genes contributing to heme biosynthesis, an essential mitochondrial function. Metabolomic analysis revealed that 5-aminolevulinic acid (ALA), the first heme precursor, is 5-fold reduced in yeast lacking mtClpX activity and that total heme is reduced by half. mtClpX directly stimulates ALA synthase in vitro by catalyzing incorporation of its cofactor, pyridoxal phosphate. This activity is conserved in mammalian homologs; additionally, mtClpX depletion impairs vertebrate erythropoiesis, which requires massive upregulation of heme biosynthesis to supply hemoglobin. mtClpX, therefore, is a widely conserved stimulator of an essential biosynthetic pathway and uses a previously unrecognized mechanism for AAA+ unfoldases.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cz3325TgTransgenic Insertion
    la781TgTransgenic Insertion
      tb223
        Point Mutation
        tq223
          Point Mutation
          tt250
            Point Mutation
            1 - 5 of 5
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            Human Disease / Model
            No data available
            Sequence Targeting Reagents
            Target Reagent Reagent Type
            clpxaMO1-clpxaMRPHLNO
            clpxaMO2-clpxaMRPHLNO
            clpxbMO1-clpxbMRPHLNO
            clpxbMO2-clpxbMRPHLNO
            1 - 4 of 4
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            Fish
            Antibodies
            No data available
            Orthology
            Gene Orthology
            clpxa
            1 - 1 of 1
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            Engineered Foreign Genes
            Marker Marker Type Name
            EGFPEFGEGFP
            GFPEFGGFP
            1 - 2 of 2
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            Mapping
            No data available