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

Significance In addition to their well-documented roles in energy metabolism and heme biogenesis, mitochondria also play an important role in intracellular signaling, which is important for tissue and organ development. We previously showed that a cytosolic siderophore facilitates mitochondrial iron import in eukaryotes. Depletion of the siderophore by inactivating 3-hydroxy butyrate dehydrogenase 2 ( bdh 2), whose gene product is necessary for siderophore biogenesis, results in heme deficiency and delays erythroid maturation in developing zebrafish embryo. Here we show that inactivation of bdh 2 results in mitochondrial dysfunction, triggers their degradation by mitophagy, and hampers erythroid maturation. Reestablishment of bdh 2 restores mitochondrial function, prevents premature mitochondrial degradation, and promotes erythroid maturation. Our results demonstrate that mitochondrial communication with the nucleus is critical for erythroid development.