title: Inactivation of 3-hydroxybutyrate dehydrogenase 2 delays zebrafish erythroid maturation by conferring premature mitophagy.
abstract: 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.
authors.affiliation: Department of Pathobiology, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44120;
authors.forename: Gangarao
authors.initials: G
authors.lastname: Davuluri
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Zhuoming
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44120;
authors.forename: David
authors.initials: D
authors.lastname: Wald
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44120;
authors.forename: Takuya F
authors.initials: TF
authors.lastname: Sakaguchi
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01604; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01604 michael.green@umassmed.edu lxd259@gmail.com.
authors.forename: Michael R
authors.identifier: http://orcid.org/0000-0003-3017-3298
authors.initials: MR
authors.lastname: Green
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106; michael.green@umassmed.edu lxd259@gmail.com.
authors.forename: L
authors.initials: L
authors.lastname: Devireddy
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D004625:Embryo, Nonmammalian / Q000166:cytology; D004912:Erythrocytes / Q000166:cytology* / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006884:Hydroxybutyrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology / Q000648:ultrastructure; D063306:Mitophagy / Q000502:physiology*; D010100:Oxygen / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; C000609732:Bdh2 protein, zebrafish; D006884:Hydroxybutyrate Dehydrogenase; D010100:Oxygen
keywords: 2,5-DHBA; bdh2; erythroid maturation; mitophagy; retrograde signaling