Mutated Hif-1αa Proteins with Increased Stability Under Normoxic Conditions Enhance Hypoxia Tolerance of Otomorphs by Promoting Glycolysis and Lactate Shuttle.

ABSTRACT: Fishes are frequently exposed to hypoxic stress, yet their tolerance to hypoxia varies significantly among species. The association between this variation and alterations in the hypoxia-inducible factor (HIF) pathway remains unclear. We discovered that otomorphs generally retain two Hif-1α paralogs (Hif-1αa and Hif-1αb), resulting from the teleost-specific genome duplication (TGD), whereas most euteleosts possess only a single Hif-1αa copy. In otomorphs, key mutations disrupt one conserved Leu-X-X-Leu-Ala-Pro (LXXLAP) motif in the oxygen-dependent degradation (ODD) domain of the Hif-1αa proteins. Molecular dynamics simulations revealed that these mutations impede the recognition of the critical proline residue by prolyl hydroxylase domain protein 2 (PHD2), suggesting enhanced normoxic stab

SUBMITTER: Wang X 

PROVIDER: S-EPMC12784922 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature