Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis.
Heme biosynthesis consists of a series of eight enzymatic reactions that originate in mitochondria and continue in the cytosol before returning to mitochondria. Although these core enzymes are well studied, additional mitochondrial transporters and regulatory factors are predicted to be required. To discover such unknown components, we utilized a large-scale computational screen to identify mitochondrial proteins whose transcripts consistently coexpress with the core machinery of heme biosynthesis. We identified SLC25A39, SLC22A4, and TMEM14C, which are putative mitochondrial transporters, as well as C1orf69 and ISCA1, which are iron-sulfur cluster proteins. Targeted knockdowns of all five genes in zebrafish resulted in profound anemia without impacting erythroid lineage specification. Moreover, silencing of Slc25a39 in murine erythroleukemia cells impaired iron incorporation into protoporphyrin IX, and vertebrate Slc25a39 complemented an iron homeostasis defect in the orthologous yeast mtm1Delta deletion mutant. Our results advance the molecular understanding of heme biosynthesis and offer promising candidate genes for inherited anemias.
Nilsson
Roland
R
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Schultz
Iman J
IJ
Pierce
Eric L
EL
Soltis
Kathleen A
KA
Naranuntarat
Amornrat
A
Ward
Diane M
DM
Baughman
Joshua M
JM
Paradkar
Prasad N
PN
Kingsley
Paul D
PD
Culotta
Valeria C
VC
Kaplan
Jerry
J
Palis
James
J
Paw
Barry H
BH
Mootha
Vamsi K
VK
D000740:Anemia / Q000235:genetics; D000818:Animals; D004625:Embryo, Nonmammalian / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006418:Heme / Q000096:biosynthesis* / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
D007506:Iron-Sulfur Proteins; D033681:Mitochondrial Membrane Transport Proteins; D034741:RNA, Small Interfering; D006418:Heme