Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis
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nihms-685684.pdf
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Author(s)
Yien, Yvette Y.
Huston, Nicholas C.
Branco, Diana S.
Hildick-Smith, Gordon J.
Rhee, Kyu Y.
Paw, Barry H.
Kardon, Julia R.
Baker, Tania
Date Issued
May 2015
Journal
Cell
Publisher
Elsevier BV
Citation
Kardon, Julia R. et al. “Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis.” Cell 161, 4 (May 2015): 858–867 © 2015 Elsevier Inc
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CELL.2015.04.017
