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ZFIN ID: ZDB-PUB-150511-1
Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis
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.
Date: 2015
Source: Cell 161: 858-867 (Journal)
Registered Authors: Paw, Barry
Keywords: none
MeSH Terms:
  • 5-Aminolevulinate Synthetase/metabolism
  • Amino Acid Sequence
  • Aminolevulinic Acid/metabolism
  • Animals
  • Biological Evolution
  • Endopeptidase Clp/chemistry
  • Endopeptidase Clp/genetics
  • Endopeptidase Clp/metabolism*
  • Erythropoiesis*
  • Eukaryota/genetics
  • Eukaryota/metabolism*
  • Heme/biosynthesis*
  • Humans
  • Mitochondria/metabolism
  • Mitochondrial Proteins/metabolism
  • Molecular Chaperones/metabolism
  • Molecular Sequence Data
  • Saccharomyces cerevisiae/cytology
  • Saccharomyces cerevisiae/metabolism
  • Saccharomyces cerevisiae Proteins/metabolism
  • Sequence Alignment
  • Zebrafish/metabolism
PubMed: 25957689 Full text @ Cell
FIGURES
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.
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