Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling

Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera

Between recognition and the struggle for survival : Lemkos at the beginning of the twenty-first century

During Poland's communist period, Lemkos-Ruthenian highlanders whose indigenous territory is in the Carpathians - were officially considered to be ethnic Ukrainians. The process of political transformation at the beginning of the 1990s revealed the emancipatory aspirations of certain Lemko leaders. It allowed the institutionalization of identity divisions in the group, wherein some members considered themselves part of the Ukrainian nation, while others saw themselves as a separate ethnic group. The Polish authorities, having accepted the Lemko bid for emancipation, financed cultural activities and education. The group gained formal recognition in 2005 with the adoption of the law on minorities, which names the Lemkos as one of four ethnic minorities (Ustawa… 2005). This success, however, has not ended identity disputes within the group, and its separateness is still called into question. What determines the contemporary condition of the Lemko community is its small numbers and territorial dispersion resulting from post-WWII forced displacement. In this chapter, I present the challenges that active Lemko leaders have faced since their legal recognition. On the one hand, they benefit from the protection of minorities now guaranteed by Polish law and take measures to maintain and preserve Lemko culture. However, they must also deal with both intragroup and external opponents who contest emancipatory aspirations