Atpif1, a mitochondrial ATPase inhibitor, was identified as a zebrafish anemic mutant, pinotage, providing an important link in our understanding of the relationship between mitochondrial homeostasis and haem synthesis and identifying a gene that may have a role in human iron, haem and mitochondrial diseases. Defects in haem biosynthesis in erythrocytes cause anaemia. Many of the enzymes and substrates involved in this important process are known, but it is still unclear how iron transport is regulated in the mitochondria and coordinated with haem homeostasis. Here, Barry Paw and colleagues report the cloning of mitochondrial ATPase inhibitor factor 1 (atpif1) from a zebrafish genetic screen. Atpif1 regulates ferrochelatase, the terminal enzyme in haem biosynthesis, through alteration of mitochondrial pH and redox potential in the presence of a [2Fe–2S] cluster as the iron supply. The authors show that the human orthologue of Atpif1 is vital for normal red-blood-cell differentiation, suggesting that its deficiency may contribute to human diseases such as congenital sideroblastic anaemias and other mitochondriopathies. 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.

Introduction: Radionecrosis (RN) represents the main complication of stereotactic radiotherapy (SRT) for brain metastases. It may be observed in up to 34% of cases at 24 months after treatment and associated with significant morbidity in 10-17%. Areas covered: Our aim is to discuss the results of original studies on RN related to SRT for brain metastases. Expert commentary: Although the development of RN is unpredictable, larger volume of the lesion, prior whole brain irradiation, and higher dose of radiation represent the major risk factors. RN appears on MRI as contrast-enhancing necrotic lesions, surrounded by edema, occurring at least 3 months after SRT, localized within fields of irradiation. No firm criteria are established. Surgery can provide symptomatic relief but is associated with a risk of complications. Corticosteroids are considered the standard of care treatment, despite limited efficacy and many adverse effects. Bevacizumab represents another interesting option that needs to be validated.

Purpose: By extending to other animal models the experiments on irradiated rabbit testes performed by the German Albers-Schönberg and Frieben and inspired by the preliminary observations of Regaud on spermatogenesis after irradiation, Bergonié and Tribondeau established a link between radiosensitivity and proliferation as a ‘law’ in 1906. Although it is still popular and taken as one of the founding laws of radiation oncology, it was early considered as a ‘first approximation’. Conclusions: More than 100 years later, one tribute paid to these pioneers should be to at least avoid mixing notions like radiosensitivity, proliferation, differentiation, stem cells that they deeply contributed to define and to re-read their works in their original version in order to better understand what the technological and conceptual advances really are today.