Mitochondrial Atpif1 regulates heme synthesis in developing erythroblasts
| Autor: | Anupama Narla, Jeffrey D. Cooney, Nika N. Danial, Carlo Brugnara, Guillaume Vogin, Tamara A. Dailey, Diane M. Ward, Shilpa M. Hattangadi, Barry H. Paw, Slater N. Hurst, Danilo Faccenda, Jessica Wiwczar, Naoko Takahashi-Makise, Caiyong Chen, Dean R. Campagna, Yi Zhou, Amy E. Medlock, Jerry Kaplan, Harry A. Dailey, Benjamin L. Ebert, Liangtao Li, Nathaniel B. Langer, Eric L. Pierce, Dhvanit I. Shah, Iman J. Schultz, Michelangelo Campanella, Mark D. Fleming, Spencer K. Heggers, Wen Chen, Alexandra Seguin |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Settore BIO/06
Erythroblasts Mutant Sideroblastic Heme Biology Mitochondrion Article Mitochondrial Proteins chemistry.chemical_compound Mice Animals Humans Erythropoiesis Zebrafish chemistry.chemical_classification Multidisciplinary Animal digestive oral and skin physiology Genetic Complementation Test Proteins Anemia Ferrochelatase Hydrogen-Ion Concentration biology.organism_classification Anemia Sideroblastic Mitochondria Disease Models Animal Enzyme Biochemistry chemistry Disease Models biology.protein Oxidation-Reduction Homeostasis Genetic screen |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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 anaemias1,2. 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. |
| Databáze: | OpenAIRE |
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