Isocitrate Dehydrogenases Idh1 and Idh2 Regulate Pronephric Morphogenesis in Xenopus laevis.

Abstract

Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), generating NADPH to maintain cellular redox balance. Among the three isoforms, cytosolic Idh1 and mitochondrial Idh2 are NADP⁺-dependent enzymes that are essential for metabolic homeostasis. Although Idh1 and Idh2 have been extensively studied in cancer and other metabolic disorders, their roles in vertebrate development remain understudied. To address this gap, this study investigated the roles of Idh1 and Idh2 in kidney development in Xenopus laevis. Both genes were expressed in the pronephric region, and morpholino-mediated knockdown caused pronephric defects, which were more severe in idh1-depleted embryos. Wild-type idh1* mRNA restored pronephric marker expression, confirming specificity. Notably, the oncogenic idh1*R132H variant also rescued the pronephric defects induced by idh1 knockdown, indicating that its neomorphic activity is absent under embryonic metabolic conditions. These findings identify Idh1 and Idh2 as key regulators of pronephric morphogenesis and reveal a developmental function of Idh1 that is distinct from its canonical catalytic role.