Publication Date:
2012-11-09
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Dhvanit I -- Takahashi-Makise, Naoko -- Cooney, Jeffrey D -- Li, Liangtao -- Schultz, Iman J -- Pierce, Eric L -- Narla, Anupama -- Seguin, Alexandra -- Hattangadi, Shilpa M -- Medlock, Amy E -- Langer, Nathaniel B -- Dailey, Tamara A -- Hurst, Slater N -- Faccenda, Danilo -- Wiwczar, Jessica M -- Heggers, Spencer K -- Vogin, Guillaume -- Chen, Wen -- Chen, Caiyong -- Campagna, Dean R -- Brugnara, Carlo -- Zhou, Yi -- Ebert, Benjamin L -- Danial, Nika N -- Fleming, Mark D -- Ward, Diane M -- Campanella, Michelangelo -- Dailey, Harry A -- Kaplan, Jerry -- Paw, Barry H -- K01 DK085217/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- P30 DK072437/DK/NIDDK NIH HHS/ -- R01 DK052380/DK/NIDDK NIH HHS/ -- R01 DK070838/DK/NIDDK NIH HHS/ -- R01 DK096051/DK/NIDDK NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):608-12. doi: 10.1038/nature11536. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135403" target="_blank"〉PubMed〈/a〉
Keywords:
Anemia, Sideroblastic/genetics/metabolism/pathology
;
Animals
;
Disease Models, Animal
;
Erythroblasts/cytology/*metabolism
;
*Erythropoiesis
;
Ferrochelatase/metabolism
;
Genetic Complementation Test
;
Heme/*biosynthesis
;
Humans
;
Hydrogen-Ion Concentration
;
Mice
;
Mitochondria/*metabolism/pathology
;
Mitochondrial Proteins/deficiency/genetics/*metabolism
;
Oxidation-Reduction
;
Proteins/genetics/*metabolism
;
Zebrafish/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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