title: Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.
abstract: Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.
authors.affiliation: Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Dhvanit I
authors.initials: DI
authors.lastname: Shah
authors.forename: Naoko
authors.initials: N
authors.lastname: Takahashi-Makise
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Cooney
authors.forename: Liangtao
authors.initials: L
authors.lastname: Li
authors.forename: Iman J
authors.initials: IJ
authors.lastname: Schultz
authors.forename: Eric L
authors.initials: EL
authors.lastname: Pierce
authors.forename: Anupama
authors.initials: A
authors.lastname: Narla
authors.forename: Alexandra
authors.initials: A
authors.lastname: Seguin
authors.forename: Shilpa M
authors.initials: SM
authors.lastname: Hattangadi
authors.forename: Amy E
authors.initials: AE
authors.lastname: Medlock
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Langer
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Dailey
authors.forename: Slater N
authors.initials: SN
authors.lastname: Hurst
authors.forename: Danilo
authors.initials: D
authors.lastname: Faccenda
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Wiwczar
authors.forename: Spencer K
authors.initials: SK
authors.lastname: Heggers
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vogin
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Caiyong
authors.initials: C
authors.lastname: Chen
authors.forename: Dean R
authors.initials: DR
authors.lastname: Campagna
authors.forename: Carlo
authors.initials: C
authors.lastname: Brugnara
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.forename: Nika N
authors.initials: NN
authors.lastname: Danial
authors.forename: Mark D
authors.initials: MD
authors.lastname: Fleming
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ward
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Campanella
authors.forename: Harry A
authors.initials: HA
authors.lastname: Dailey
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
authors.forename: Barry H
authors.initials: BH
authors.lastname: Paw
mesh_terms: D000756:Anemia, Sideroblastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis; D005294:Ferrochelatase / Q000378:metabolism; D005816:Genetic Complementation Test; D006418:Heme / Q000096:biosynthesis*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
chemical_list: D005294:Ferrochelatase; D006418:Heme; D024101:Mitochondrial Proteins; D011506:Proteins; D000097795:ATPase Inhibitory Protein