Running a genetic stop sign accelerates oxygen metabolism and energy production in horses, 2025, Castiglione et al

Science. (Accepted): Running a genetic stop sign accelerates oxygen metabolism and energy production in horses
Castiglione, GM, Chen, X., Xu, Z., Dbouk, N.H., Bose, A., Carmona-Berrio, D., Chi, E.E., Zhou, L., Boronina, T.N., Cole, R.N., Wu, S., Liu, A., Liu, T., Lu, H., Kalbfleisch, T., Rinker, D., Rokas, A., Ortved, K., and Duh, E.J.

INTRODUCTION
Horses are famous examples of evolutionary novelty, with the fossil record chronicling their ascent from dog-sized ancestors into physiological powerhouses, long before domestication. In modern thoroughbred racehorses, mass-adjusted oxygen consumption is more than double that of elite human athletes, fueling the voracious energy production demands of equine skeletal muscle. Genomes of modern and ancient equids have revealed mutations in olfactory receptors, keratins, and myosin-related genes that are absent from humans and cows, yet none of these are directly involved in aerobic metabolism and energy production. How Equus ancestors met the energy demands associated with their remarkable morphological innovations is therefore unknown.

RATIONALE
To study the molecular underpinnings of equine aerobic metabolism, we focused on a clinically important pathway that can enhance mitochondrial bioenergetics while simultaneously mitigating the tissue-damaging oxidative stress caused by exercise or disease. The NRF2/KEAP1 pathway is a major area of focus in exercise science and clinical translational efforts, including chronic diseases such as emphysema. Diminished KEAP1 inhibitory activity leads to increased NRF2 activity, thereby enhancing antioxidant production and mitochondrial respiration. KEAP1 mutations have occurred at least twice in evolution: initially to facilitate the vertebrate transition from aquatic to terrestrial life by protecting against ultraviolet light–induced oxidative stress, and more recently during the evolution of birds to counterbalance the oxidative stress imposed by energetically demanding flapping flight.

RESULTS
We reveal that horses, donkeys, and zebras (Equus) possess a relic of the ancient Equidae radiation—a premature stop codon in KEAP1 (R15X) that evolved in a common Equus ancestor. Using mass spectrometry, we demonstrate that this de novo opal stop codon (UGA) does not truncate the protein and is instead recoded into a cysteine in horse KEAP1 (C15). Using biochemistry and structural biology, we show that opal recoding is facilitated by a set of Equus-specific mutations at the mRNA and protein levels that coevolved with R15X, ultimately enhancing opal recoding relative to human orthologs. Through cellular assays, we show that the evolution of R15C KEAP1 increases sensitivity to electrophiles and reactive oxygen species, leading to increased NRF2 activity and lower oxidative stress. Using comparative metabolomics of myotubes derived from thoroughbred quadriceps and CRISPR-Cas9–generated cell models, we provide evidence that this genetic recoding also accelerates adenosine 5′-triphosphate (ATP) production–coupled mitochondrial oxygen consumption rates. These processes provide an elegant solution to the dual problem of enhancing aerobic energy production while mitigating oxidative stress, likely explaining why R15X/C evolved in a common Equus ancestor under selection for improved locomotory bioenergetics.

CONCLUSION
We discovered coordinated biochemical adaptations from the distant past not captured by the fossil record, illustrating how recoding of a de novo stop codon can facilitate adaptation in vertebrates, a strategy previously thought restricted to viruses. These ancient evolutionary innovations can enlighten contemporary clinical efforts seeking to augment NRF2 function and also to promote read-through of disease-associated premature stop codons.

https://www.science.org/doi/10.1126/science.adr8589

 

There’s also an article about this
https://www.vanderbilt.edu/evolutio...-ignoring-an-ancient-mutation-that-says-stop/

And it was discussed on this week’s Science in Action in the BBC World Service https://www.bbc.co.uk/sounds/play/w3ct5vfb

 

It was a generally interesting science story but the added elements of genetics and evolution ‘finding a way’ and doing unexpected things along with the metabolic and possibly future links with disease mechanisms made me think others here would be interested.

 

Fascinating, thanks for posting @hotblack!