{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T11:50:08Z","timestamp":1779882608440,"version":"3.53.1"},"reference-count":51,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Education of Shanxi Province","award":["J201911301, J202111303, 2020L0158, SXYBKY201713"],"award-info":[{"award-number":["J201911301, J202111303, 2020L0158, SXYBKY201713"]}]},{"DOI":"10.13039\/501100013318","name":"Department of Science and Technology of Shanxi Province","doi-asserted-by":"publisher","award":["20210302124494"],"award-info":[{"award-number":["20210302124494"]}],"id":[{"id":"10.13039\/501100013318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013805","name":"Shanxi Agricultural University","doi-asserted-by":"publisher","award":["2017YJ05"],"award-info":[{"award-number":["2017YJ05"]}],"id":[{"id":"10.13039\/501100013805","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Animals"],"abstract":"<jats:p>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-1\u03b1 paralogs (Hif-1\u03b1a and Hif-1\u03b1b), resulting from the teleost-specific genome duplication (TGD), whereas most euteleosts possess only a single Hif-1\u03b1a 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-1\u03b1a 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 stability of Hif-1\u03b1a. We also investigated the expression profiles of hif-1\u03b1 and downstream genes in four fish species (two otomorphs and two euteleosts). In otomorphs, the hif-1\u03b1a genes were highly expressed specifically in the heart; concomitantly, two critical downstream genes, ldha and mct4, exhibited relatively high expression levels in vital tissues such as the heart, brain, and muscle. This coordinated expression pattern promotes a heightened glycolytic capacity and facilitates lactate shuttling in these tissues, thereby ensuring energy supply during hypoxic stress. Our integrated computational analyses indicate that otomorphs achieve enhanced hypoxia tolerance through the subfunctionalization of Hif-1\u03b1 paralogs.<\/jats:p>","DOI":"10.3390\/ani16010119","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:08:11Z","timestamp":1767190091000},"page":"119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mutated Hif-1\u03b1a Proteins with Increased Stability Under Normoxic Conditions Enhance Hypoxia Tolerance of Otomorphs by Promoting Glycolysis and Lactate Shuttle"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6775-0995","authenticated-orcid":false,"given":"Xianzong","family":"Wang","sequence":"first","affiliation":[{"name":"College of Animal Science, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"},{"name":"Shanxi Key Laboratory of Animal Genetics Resource Utilization and Breeding, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4674-4343","authenticated-orcid":false,"given":"Junli","family":"Yan","sequence":"additional","affiliation":[{"name":"College of Urban and Rural Construction, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9768-1660","authenticated-orcid":false,"given":"Huili","family":"Zhai","sequence":"additional","affiliation":[{"name":"College of Animal Science, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Guo","sequence":"additional","affiliation":[{"name":"College of Animal Science, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyi","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Animal Science, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5200-9240","authenticated-orcid":false,"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Animal Science, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"},{"name":"Shanxi Key Laboratory of Animal Genetics Resource Utilization and Breeding, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1027-7009","authenticated-orcid":false,"given":"Shaozhen","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Animal Science, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"},{"name":"Shanxi Key Laboratory of Animal Genetics Resource Utilization and Breeding, Shanxi Agricultural University, Taigu District, Jinzhong 030801, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Ding, J., Liu, C., Luo, S., Gao, X., Wu, Y., Wang, J., Wang, X., Wu, X., and Shen, W. 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