Scientists have discovered that horses owe their legendary stamina to a unique genetic mutation.
This mutation supercharges energy production in muscle cells while cleverly keeping oxidative stress in check – a remarkable evolutionary hack that helps explain horses’ unmatched endurance. Even more fascinating, this adaptation involves recoding a genetic “stop” signal into an active part of the gene, a trick previously only seen in viruses.
KEAP1 Mutation Boosts Horse Endurance
Scientists have uncovered a key reason behind horses’ remarkable endurance: a mutation in the KEAP1 gene that boosts energy production while helping protect cells from oxidative stress. This discovery reveals a unique evolutionary adaptation that has contributed to the horse’s status as one of nature’s most powerful athletes, and could also offer insights relevant to human health.
Notably, the adaptation involves the recoding of a stop codon, normally a signal to end protein production, into a functional amino acid. This genetic recoding, previously thought to occur only in viruses, shows how a rare mechanism can support adaptation in vertebrates.
Physiological Power of Equine Athletes
Horses have long been admired for their speed and stamina, especially given their large body size. They possess extraordinary physiological traits, including an exceptional ability to take in, circulate, and use oxygen. Their maximum oxygen consumption (VO2max) is more than double that of elite human athletes.
Oxidative Stress: The Hidden Cost of Performance
Part of this performance comes from their muscle cells, which are packed with mitochondria to fuel energy production. However, this high mitochondrial activity also generates large amounts of reactive oxygen species (ROS), molecules that can damage cells and tissues. Until now, the specific biological systems that allow horses to balance this energy output with protection against oxidative damage had remained unclear.
Investigating KEAP1 Across Mammals
To address this knowledge gap, Gianni Casiglione and colleagues conducted an evolutionary analysis of the KEAP1 gene – a key regulator of redox balance and mitochondrial energy production – across 196 mammalian species. KEAP1 is recognized as an important target in exercise science and has been implicated in multiple human diseases, such as lung cancer and chronic obstructive pulmonary disease (COPD).
The Mutation That Rewrites the Rules
The researchers found that modern horses, as well as donkeys and zebra, have evolved a unique genetic adaptation involving a premature stop codon (UGA) in the KEAP1 gene. Using phylogenomic, proteomic, and metabolomic analyses, along with live tissue studies, the authors discovered that rather than truncating the protein, this stop codon is efficiently recoded into a cysteine (C15) in horses, enhancing the gene’s functionality.
A Balanced Boost for Energy and Protection
According to the findings, this single-point mutation reduces the repression of NRF2, a protein that mitigates oxidative stress, resulting in increased mitochondrial respiration and ATP production. While excessive NRF2 activity can be harmful in other mammals, this adaptation appears to provide horses with a balanced solution – enhancing mitochondrial energy production while controlling oxidative stress.
Reference: “Running a genetic stop sign accelerates oxygen metabolism and energy production in horses” by Gianni M. Castiglione, Xin Chen, Zhenhua Xu, Nadir H. Dbouk, Anamika A. Bose, David Carmona-Berrio, Emiliana E. Chi, Lingli Zhou, Tatiana N. Boronina, Robert N. Cole, Shirley Wu, Abby D. Liu, Thalia D. Liu, Haining Lu, Ted Kalbfleisch, David Rinker, Antonis Rokas, Kyla Ortved and Elia J. Duh, 28 March 2025, Science.
DOI: 10.1126/science.adr8589
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.