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Mitochondrial Atpif1 Regulates Haem Synthesis in Developing Erythroblasts

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Mitochondrial Atpif1 Regulates Haem Synthesis in Developing Erythroblasts LETTER doi:10.1038/nature11536 Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts Dhvanit I. Shah1, Naoko Takahashi-Makise2, Jeffrey D. Cooney1{, Liangtao Li2, Iman J. Schultz1{, Eric L. Pierce1{, Anupama Narla1,3, Alexandra Seguin2, Shilpa M. Hattangadi3,4{, Amy E. Medlock5, Nathaniel B. Langer1{, Tamara A. Dailey5, Slater N. Hurst1, Danilo Faccenda6, Jessica M. Wiwczar7{, Spencer K. Heggers1, Guillaume Vogin1{, Wen Chen1{, Caiyong Chen1, Dean R. Campagna8, Carlo Brugnara9,YiZhou3, Benjamin L. Ebert1, Nika N. Danial7, Mark D. Fleming8, Diane M. Ward2, Michelangelo Campanella6, Harry A. Dailey5, Jerry Kaplan2 & Barry H. Paw1,3 Defects in the availability of haem substrates or the catalytic activ- and band-3 (data not shown). On the basis of red cell indices, the ity of the terminal enzyme in haem biosynthesis, ferrochelatase erythrocytes from pnt embryos that survive to adult stage exhibited (Fech), impair haem synthesis and thus cause human congenital hypochromic, microcytic anaemia (Supplementary Fig. 1a). Histolo- anaemias1,2. The interdependent functions of regulators of mito- gical analysis of adult pnt haematopoietic tissues showed no gross chondrial homeostasis and enzymes responsible for haem synthesis morphological defects (Supplementary Fig. 1b). are largely unknown. To investigate this we used zebrafish genetic To identify a candidate gene for the pnt locus we carried out posi- screens and cloned mitochondrial ATPase inhibitory factor 1 tional cloning and chromosomal walk, which identified the most (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt tq209). Here we describe a direct mechanism establishing that a b Atpif1 regulates the catalytic efficiency of vertebrate Fech to syn- z42828bz15222 z160 z67416 z13215 thesize haem. The loss of Atpif1 impairs haemoglobin synthesis Telomere Chr. 19 in zebrafish, mouse and human haematopoietic models as a con- WT sequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, Recombinants per 15 16 39 40 42 redox potential, [2Fe–2S] clusters and Fech activity, we used gen- 3,824 meiosis etic complementation studies of Fech constructs with or without pnt atpif1a [2Fe–2S] clusters in pnt, as well as pharmacological agents modu- pnt miRNA dnajc8 bai1 lating mitochondrial pH and redox potential. The presence of hnrpr [2Fe–2S] cluster renders vertebrate Fech vulnerable to perturba- c d Dr atpif1a tions in Atpif1-regulated mitochondrial pH and redox potential. WT pnt Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Dr atpif1b Fech to synthesize haem, resulting in anaemia. The identification 1 of mitochondrial Atpif1 as a regulator of haem synthesis advances Mm Atpif1 our understanding of the mechanisms regulating mitochondrial Hs ATPIF1 * mRNA level (relative value) (relative 0 haem homeostasis and red blood cell development. An ATPIF1 atpif1a atpif1b deficiency may contribute to important human diseases, such as tq209 congenital sideroblastic anaemias and mitochondriopathies. Figure 1 | Disruption of atpif1 in pinotage (pnt ) produces A deficiency in haem, which is used in a wide variety of metabolic hypochromic anaemia. a, pnt embryos are severely anaemic. Wild-type (WT) and regulatory pathways in cells3, results in pathological conditions embryo at 72 h post-fertilization exhibits o-dianisidine-stained (brown) 4 haemoglobinized cells. Original magnification 35. b, The positional cloning of that range from mild anaemia to early in utero death . As an essential the pnt locus on zebrafish chromosome 19. A positional cloning approach using component of haemoglobin, the individual enzymes and substrates of 1,912 diploid pnt embryos identified the closest linked genetic marker as haem biosynthesis have been well studied2; however, key gaps remain z42828b. A chromosomal walk was initiated at a distance of ,0.01 centimorgan in our knowledge of genes that regulate intracellular iron and haem (cM) from the pnt locus. The bacterial artifical chromosome clone, transport and homeostasis. This incomplete understanding prevents encompassing the pnt locus, is shown below, along with the annotated genes researchers from developing targeted therapies for a broad range of within the critical physical contig. c, Phylogenetic dendrogram showing the disorders, including congenital anaemias and porphyrias, as well as amino acid homology between the various atpif1 genes. D. rerio (Dr) atpif1a metabolic and neurological disorders. aligns with its related paralogue, atpif1b, on zebrafish chromosome 17. Both atpif1a and atpif1b are shown clustering with their functional mammalian We recovered pnt, a zebrafish (Danio rerio) non-lethal recessive orthologues from mouse (Mm) and human (Hs). d, qRT–PCR analysis of 5 mutant, fromanunbiased ethyl nitrosourea (ENU) mutagenesis screen atpif1a and atpif1b mRNA in pnt and wild-type embryos, showing reduced for defects in circulating erythroid cells6. pnt embryos were anaemic atpif1a and normal atpif1b mRNA level in pnt. *P , 0.05 (t-test, n 5 3, error (Fig. 1a) despite normal expression of the erythroid cell markers b-globin bars indicate standard error of the mean, s.e.m.). 1Department of Medicine, Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 2Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312, USA. 3Department of Medicine, Division of Hematology-Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 4Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. 5Biomedical and Health Sciences Institute, Departments of Microbiology, Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA. 6Royal Veterinary College, University of London and University College London Consortium for Mitochondrial Research, London NW1 0TU, UK. 7Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. 8Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 9Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. {Present addresses: University of Texas Health Science Center, San Antonio, Texas 78229, USA (J.D.C.); InteRNA Technologies, 3584 CH Utrecht, The Netherlands (I.J.S.); Georgia Institute of Technology, Atlanta, Georgia 30332, USA (E.L.P.); Yale University, New Haven, Connecticut 06510, USA (S.M.H. and J.M.W.); Columbia University, New York, New York 10032, USA (N.B.L.); Alexis Vautrin Cancer Centre, 54511 Vandoeuvre-Les-Nancy Cedex, France (G.V.); and Texas A&M Health Science Center, Temple, Texas 76504, USA (W.C.). 608 | NATURE | VOL 491 | 22 NOVEMBER 2012 ©2012 Macmillan Publishers Limited. All rights reserved LETTER RESEARCH probable candidate gene to be mitochondrial ATPase inhibitory factor ab 1 (zgc:162207; which we refer to hereafter as atpif1a) (Fig. 1b). Phylogenetic analysis showed that an ATPase inhibitory factor 1-like 1 protein (zgc: 153321; which we refer to hereafter as atpif1b) on chro- WT mosome 17 is 71% similar to atpif1a at the amino acid level (Fig. 1c), and is probably the result of gene duplication in teleosts7. Peptide mRNA level (relative value) (relative * alignments further displayed human (ATPIF1, chromosome 1) and 0 mouse (Atpif1, chromosome 4) orthologues for atpif1a and atpif1b atpif1a WT MOatpif1a (Fig. 1c). Quantitative reverse-transcriptase polymerase chain reaction MOatpif1a (qRT–PCR) showed reduced levels of atpif1a messenger RNA in pnt pnt pnt pnt embryos (Fig. 1d) and pnt adult kidney marrow compared to their WT pnt + atpif1a + atpif1a(E26A) + atpif1b c respective wild-type controls (Supplementary Fig. 1c). The levels of atpif1b mRNA were, however, unchanged in pnt embryos (Fig. 1d) and elevated two to threefold in pnt adult kidney marrow (Supplementary Fig. 1c). Thus, atpif1a is probably the gene disrupted in the pnt locus. Previous studies have shown that mitochondrial Atpif1 regulates the proton motive force via mitochondrial influx of H1 ions, mitochon- drial structure, and ATP synthesis, indicating that Atpif1 is required in 8 a wide range of metabolically active tissues . The broad requirement % Rescue: 80 0 78 for Atpif1 is reinforced by the ubiquitous expression of both atpif1a d f and atpif1b in zebrafish embryos (Supplementary Fig. 1d) and Atpif1 ORF 3′ UTR in various mouse adult and fetal organs (Supplementary Fig. 1e). WT AAAAAA 1 To verify the loss-of-function phenotype for atpif1a, we injected two AC atpif1a antisense splice-blocking (Fig. 2a) and translational-blocking pnt AAAAAA morpholinos (data not shown) to knock down atpif1a expression in mRNA level * zebrafish embryos. The atpif1a-silenced embryos (morphants) lacked e +/+ +/pnt pnt/pnt value) (relative 0 haemoglobinized cells, as detected by o-dianisidine staining, thereby atpif1a WT Mut Vector phenocopying the anaemia in pnt embryos (Fig. 2a). The anaemic 1 2345 6 phenotype in the morphant embryos correlates with a reduction of atpif1a mRNA levels, verifying that the splice-blocking morpholinos Figure 2 | Functional characterization of the atpif1a gene. a, Splice blocking morpholino (MO) knockdown of atpif1a phenocopies the anaemia observed in accurately targeted atpif1a (Fig. 2b, Supplementary Discussion 1 and pnt embryos. Original
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