Running a genetic stop sign accelerates oxygen metabolism and energy production in horses
Horses are among nature's greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation-conserved in all extant equids-that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5'-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.
Authors
- Lingli Zhou (ORCID: https://orcid.org/0000-0002-9321-9348)
- Abby Liu (ORCID: https://orcid.org/0000-0002-0411-1491)
- Robert N. Cole (ORCID: https://orcid.org/0000-0002-3096-4754)
- Elia J. Duh (ORCID: https://orcid.org/0000-0003-1917-373X)
- S.X. Wu
- Tatiana Boronina (ORCID: https://orcid.org/0000-0001-5270-3849)
- Nadir H Dbouk (ORCID: https://orcid.org/0000-0001-8755-0491)
- Gianni M. Castiglione (ORCID: https://orcid.org/0000-0002-0768-4236)
- Antonis Rokas (ORCID: https://orcid.org/0000-0002-7248-6551)
- Ted Kalbfleisch (ORCID: https://orcid.org/0000-0002-2370-8189)
- Zhenhua Xu
- Thalia D. Liu (ORCID: https://orcid.org/0000-0002-8587-0691)
- Kyla F. Ortved (ORCID: https://orcid.org/0000-0003-0398-2444)
- David C. Rinker (ORCID: https://orcid.org/0000-0001-5894-7633)
- Haining Lu (ORCID: https://orcid.org/0000-0001-5209-8669)
- Xin Chen (ORCID: https://orcid.org/0009-0002-2596-7755)
- A. A. Bose (ORCID: https://orcid.org/0009-0008-1237-0320)
- David Carmona-Berrio (ORCID: https://orcid.org/0000-0002-5405-3306)
- E. Emiliana
Institutions
- University of Kentucky (US)
- Johns Hopkins University (US)
- Vanderbilt University (US)
- Johns Hopkins Medicine (US)
- University of Pennsylvania (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Science
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1126/science.adr8589
- Citations
- 3
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.42