2. Academic Validation
  3. Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis

Mitochondrial ClpX Activates a Key Enzyme for Heme Biosynthesis and Erythropoiesis

  • Cell. 2015 May 7;161(4):858-67. doi: 10.1016/j.cell.2015.04.017.
Julia R Kardon 1,  Yvette Y Yien 2,  Nicholas C Huston 2,  Diana S Branco 2,  Gordon J Hildick-Smith 2,  Kyu Y Rhee 3,  Barry H Paw 4,  Tania A Baker 5
Affiliations

Affiliations

  • 1 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 2 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10065, USA; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
  • 4 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Hematology-Oncology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 5 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: tabaker@mit.edu.
PMID: 25957689 DOI: 10.1016/j.cell.2015.04.017
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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