Zebrafish pkm activates the Hif-1α signaling pathway and promotes metabolic reprogramming

Metabolic regulation and hypoxia adaptation are tightly coordinated biological processes that rely on precise control of glycolytic flux. As rate-limiting enzymes in the glycolysis pathway, PKM1 and PKM2 isoenzymes play important roles in cellular energy production, hypoxia response, and maintenance of hematopoietic homeostasis. Despite these important cellular functions, the physiological roles of PKM orthologs at the whole organism level are not well characterized. Here, we demonstrate that the zebrafish pkma and pkmb genes, two orthologs of PKM, are essential for embryonic development and adaptation to hypoxia. Loss of pkma resulted in embryonic lethality, whereas pkmb deficiency led to impaired erythropoiesis and myelopoiesis. Notably, both mutants exhibited reprogramming of glycolysis and tricarboxylic acid cycle (TCA) metabolism, accompanied by decreased tolerance to hypoxia. We also found that pkma and pkmb enhance Hif-1α signaling in vivo. Together, these findings identify pkma and pkmb as dual metabolic and hypoxia regulatory factors, underscoring their critical roles in oxygen homeostasis.