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. CampagnaCarlo 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

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


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
Issue number7425
StatePublished - Nov 22 2012

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts'. Together they form a unique fingerprint.

Cite this