Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts

Dhvanit I. Shah, Naoko Takahashi-Makise, Jeffrey D. Cooney, Liangtao Li, Iman J. Schultz, Eric L. Pierce, Anupama Narla, Alexandra Seguin, Shilpa M. Hattangadi, Amy Elizabeth Medlock, Nathaniel B. Langer, Tamara A. Dailey, Slater N. Hurst, Danilo Faccenda, Jessica M. Wiwczar, Spencer K. Heggers, Guillaume Vogin, Wen Chen, Caiyong Chen, Dean R. Campagna & 10 others Carlo Brugnara, Yi Zhou, Benjamin L. Ebert, Nika N. Danial, Mark D. Fleming, Diane M. Ward, Michelangelo Campanella, Harry A. Dailey, Jerry Kaplan, Barry H. Paw

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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.

Original languageEnglish (US)
Pages (from-to)608-612
Number of pages5
JournalNature
Volume491
Issue number7425
DOIs
StatePublished - Nov 22 2012

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Ferrochelatase
Erythroblasts
Heme
Zebrafish
Oxidation-Reduction
Vertebrates
Anemia
Homeostasis
Enzymes
Adenosine Triphosphatases
Hemoglobins
Erythrocytes
Pharmacology

ASJC Scopus subject areas

  • General

Cite this

Shah, D. I., Takahashi-Makise, N., Cooney, J. D., Li, L., Schultz, I. J., Pierce, E. L., ... Paw, B. H. (2012). Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature, 491(7425), 608-612. https://doi.org/10.1038/nature11536

Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. / 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 Elizabeth; 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.

In: Nature, Vol. 491, No. 7425, 22.11.2012, p. 608-612.

Research output: Contribution to journalArticle

Shah, DI, Takahashi-Makise, N, Cooney, JD, Li, L, Schultz, IJ, Pierce, EL, Narla, A, Seguin, A, Hattangadi, SM, Medlock, AE, Langer, NB, Dailey, TA, Hurst, SN, Faccenda, D, Wiwczar, JM, Heggers, SK, Vogin, G, Chen, W, Chen, C, Campagna, DR, Brugnara, C, Zhou, Y, Ebert, BL, Danial, NN, Fleming, MD, Ward, DM, Campanella, M, Dailey, HA, Kaplan, J & Paw, BH 2012, 'Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts', Nature, vol. 491, no. 7425, pp. 608-612. https://doi.org/10.1038/nature11536
Shah DI, Takahashi-Makise N, Cooney JD, Li L, Schultz IJ, Pierce EL et al. Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature. 2012 Nov 22;491(7425):608-612. https://doi.org/10.1038/nature11536
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 Elizabeth ; 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. / Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. In: Nature. 2012 ; Vol. 491, No. 7425. pp. 608-612.
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AU - Shah, Dhvanit I.

AU - Takahashi-Makise, Naoko

AU - Cooney, Jeffrey D.

AU - Li, Liangtao

AU - Schultz, Iman J.

AU - Pierce, Eric L.

AU - Narla, Anupama

AU - Seguin, Alexandra

AU - Hattangadi, Shilpa M.

AU - Medlock, Amy Elizabeth

AU - Langer, Nathaniel B.

AU - Dailey, Tamara A.

AU - Hurst, Slater N.

AU - Faccenda, Danilo

AU - Wiwczar, Jessica M.

AU - Heggers, Spencer K.

AU - Vogin, Guillaume

AU - Chen, Wen

AU - Chen, Caiyong

AU - Campagna, Dean R.

AU - Brugnara, Carlo

AU - Zhou, Yi

AU - Ebert, Benjamin L.

AU - Danial, Nika N.

AU - Fleming, Mark D.

AU - Ward, Diane M.

AU - Campanella, Michelangelo

AU - Dailey, Harry A.

AU - Kaplan, Jerry

AU - Paw, Barry H.

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