Endogenous Siderophore 2,5-Dihydroxybenzoic Acid Deficiency Promotes Anemia and Splenic Iron Overload in Mice

Abstract

Eukaryotes produce a siderophore-like molecule via a remarkably conserved biosynthetic pathway. 3-OH butyrate dehydrogenase (BDH2), a member of the short-chain dehydrogenase (SDR) family of reductases, catalyzes a rate-limiting step in the biogenesis of the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). Depletion of the mammalian siderophore by inhibiting expression of bdh2 results in abnormal accumulation of intracellular iron and mitochondrial iron deficiency in cultured mammalian cells, as well as in yeast cells and zebrafish embryos We disrupted murine bdh2 by homologous recombination to analyze the effect of bdh2 deletion on erythropoiesis and iron metabolism. bdh2 null mice developed microcytic anemia and tissue iron overload, especially in the spleen. Exogenous supplementation with 2,5-DHBA alleviates splenic iron overload in bdh2 null mice. Additionally, bdh2 null mice exhibit reduced serum iron. Although BDH2 has been proposed to oxidize ketone bodies, we found that BDH2 deficiency did not alter ketone body metabolism in vivo. In sum, our findings demonstrate a key role for BDH2 in erythropoiesis.

Role of Lipocalin-2 in Brain Injury after Intracerebral Hemorrhage

“…In particular, recent evidence indicates that 2,5-DHBA (2,5-dihydroxy benzoic acid) is an important mammalian siderophore. 31,32 The role of 2,5-DHBA and the enzyme, 3-hydroxybutyrate dehydrogenase-2, involved in 2,5-DHBA biosynthesis needs to be evaluated in ICH.…”

Inactivation of 3- hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy

“…We have previously shown that bdh2 is a critical regulator of the siderophore 2,5-DHBA and that its absence results in complete abrogation of 2,5-DHBA biogenesis in cultured cells, yeast, zebrafish embryo, and mice (18,20). We also found that bdh2 inactivation results in hypohemoglobinization and reduced erythrocyte maturation in zebrafish embryos (18).…”

“…Interestingly, 2,5-DHBA is synthesized by an evolutionarily conserved pathway, and BDH2, a homolog of bacterial EntA, catalyzes a rate-limiting step (18). Knockdown of bdh2 results in siderophore depletion and as a consequence confers heme deficiency, an iron-dependent mitochondrial process, in cultured cells, yeast, zebrafish, and mice (18,20). We also found that bdh2 inactivation increased erythrocyte immaturity in zebrafish embryos.…”

“…Additionally, the genetic machinery responsible for the biosynthesis of the siderophore is evolutionarily conserved (18). Reduction of BDH2, an enzyme critical for catalysis of 2,5-DHBA, the eukaryotic siderophore, results in heme deficiency in cultured cells, yeast, zebrafish, and mice (18,20,29). The relationship between mfn and the cytosolic siderophore is not known.…”

“…Bdh2 is important for biogenesis of the siderophore 2,5-DHBA (18,20). We next asked whether supplementation with exogenous siderophore can also rescue the hemoglobinization defect and erythrocyte maturation in bdh2 morphants.…”