Researchers have revealed a secret behind horses' exceptional endurance – a mutation in the KEAP1 gene that boosts energy production while protecting against cellular oxidative stress. The findings – which shed light on a unique evolutionary adaptation that has shaped one of nature's most powerful athletes – hold potential implications for human medicine. They also highlight how the recoding of a de novo stop codon – a strategy thought restricted to viruses – can facilitate adaptation in vertebrates. Long prized for their speed and endurance, horses possess remarkable physiological adaptations that make them exceptional endurance runners, particularly given their large size. Their ability to take in, transport, and utilize oxygen is widely recognized as extraordinary, with maximal oxygen consumption (VO2max) more than twice that of elite human athletes. Although the dense concentration of mitochondria in horse skeletal muscle enhances energy production to enable these feats, it also drives the production of reactive oxygen species (ROS), which can result in significant tissue damage and cellular dysfunction. The molecular mechanisms horses have evolved to manage the oxidative stress caused by their exceptional mitochondrial activity remain unknown.
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). Castiglione et al. 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. 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.
