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

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1460-9. doi: 10.1073/pnas.1600077113. Epub 2016 Feb 29.


Mitochondria are the site of iron utilization, wherein imported iron is incorporated into heme or iron-sulfur clusters. Previously, we showed that a cytosolic siderophore, which resembles a bacterial siderophore, facilitates mitochondrial iron import in eukaryotes, including zebrafish. An evolutionarily conserved 3-hydroxy butyrate dehydrogenase, 3-hydroxy butyrate dehydrogenase 2 (Bdh2), catalyzes a rate-limiting step in the biogenesis of the eukaryotic siderophore. We found that inactivation of bdh2 in developing zebrafish embryo results in heme deficiency and delays erythroid maturation. The basis for this erythroid maturation defect is not known. Here we show that bdh2 inactivation results in mitochondrial dysfunction and triggers their degradation by mitophagy. Thus, mitochondria are prematurely lost in bdh2-inactivated erythrocytes. Interestingly, bdh2-inactivated erythroid cells also exhibit genomic alterations as indicated by transcriptome analysis. Reestablishment of bdh2 restores mitochondrial function, prevents premature mitochondrial degradation, promotes erythroid development, and reverses altered gene expression. Thus, mitochondrial communication with the nucleus is critical for erythroid development.

Keywords: 2,5-DHBA; bdh2; erythroid maturation; mitophagy; retrograde signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology
  • Embryo, Nonmammalian / cytology
  • Erythrocytes / cytology*
  • Erythrocytes / physiology
  • Gene Expression Regulation, Developmental
  • Gene Silencing
  • Hydroxybutyrate Dehydrogenase / genetics
  • Hydroxybutyrate Dehydrogenase / metabolism*
  • Mitochondria / physiology
  • Mitochondria / ultrastructure
  • Mitophagy / physiology*
  • Oxygen / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*


  • Zebrafish Proteins
  • Bdh2 protein, zebrafish
  • Hydroxybutyrate Dehydrogenase
  • Oxygen