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Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
Abstract: 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.
Publication Date: 2025-03-28 PubMed ID: 40146832DOI: 10.1126/science.adr8589Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research article explores how a unique mutation found in all horses allows them to have more efficient energy production and resistance against cellular damage. This adaptation is explained through the exploration of the NRF2/KEAP1 pathway and a stop codon mutation in KEAP1.
Background and Purpose
- The researchers aimed to understand the molecular adaptations in horses that fulfill their high energy demands due to their athletic nature.
- NRF2/KEAP1 pathway, a significant pathway regulating redox and metabolic homeostasis, was the focus of this study.
Findings
- They found an ancient mutation present in all existing horses which amplifies the metabolic process while reducing oxidative stress that can potentially damage tissues.
- This mutation is a premature opal stop codon in KEAP1, de novo by nature, which instead of stopping translation, is recoded into a cysteine. This unknown mechanism results in an R15C mutation in KEAP1 that shows increased sensitivity towards electrophiles and reactive oxygen species.
Implications and Consequences
- This recoding causes increased NRF2 activity, resulting in heightened mitochondrial adenosine 5′-triphosphate production – the primary source of energy for cellular activities – and improved cellular resistance towards oxidative damage.
- In essence, the study shows that a premature stop codon, which was previously known to occur only in viruses, can also occur and facilitate adaptation in vertebrates. This contributes to our understanding of genetic adaptation and the role of seemingly minor genetic changes in shaping species-specific traits.
Study Significance
- This study sheds light on the molecular adaptations that allow horses to be high-performance athletes, thus paving the way for more detailed studies of specific energy production adaptations in different species.
- It also opens doors for further examination of the function of stop codons and their potential purposeful recoding, which may lead to significant impacts in genetic and medical research. This could possibly revolutionize our understanding of gene translation and coding mechanisms.
Cite This Article
APA
Castiglione GM, Chen X, Xu Z, Dbouk NH, Bose AA, Carmona-Berrio D, Chi EE, Zhou L, Boronina TN, Cole RN, Wu S, Liu AD, Liu TD, Lu H, Kalbfleisch T, Rinker D, Rokas A, Ortved K, Duh EJ.
(2025).
Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
Science, 387(6741), eadr8589.
https://doi.org/10.1126/science.adr8589 Publication
Researcher Affiliations
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, TN, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, TN, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, TN, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Mass Spectrometry and Proteomics Facility, Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Veterinary Science, Gluck Equine Research Center, University of Kentucky, Lexington, KY, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, TN, USA.
- Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
- Evolutionary Studies Initiative, Vanderbilt University, Nashville, TN, USA.
- Department of Clinical Studies, New Bolton Center, University of Pennsylvania, Kennett Square, PA, USA.
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
MeSH Terms
- Animals
- Horses / genetics
- Energy Metabolism
- Mitochondria / metabolism
- Mitochondria / genetics
- Kelch-Like ECH-Associated Protein 1 / metabolism
- Kelch-Like ECH-Associated Protein 1 / genetics
- NF-E2-Related Factor 2 / metabolism
- NF-E2-Related Factor 2 / genetics
- Oxidative Stress
- Codon, Terminator
- Mutation
- Oxygen / metabolism
- Adenosine Triphosphate / metabolism
- Reactive Oxygen Species / metabolism
- Oxidation-Reduction
Citations
This article has been cited 2 times.- Sharma M, Singh A, Kumar V, Olla N, Arora R, Sharma R, Mohan NH, Ahlawat S. Advances in Equine Genomics: Decoding the Genetic Architecture of Morphology, Performance, Behavior, and Adaptation. Mol Biotechnol 2025 Dec 19;.
- Zhang X, Liu Y, Ma W, Li L, Bai D, Dugarjaviin M. Integrated Transcriptomic and Proteomic Analysis Reveals Differential Gene and Protein Expression and Signaling Pathways During a 20 Km Endurance Exercise and Recovery in Mongolian Horses. Animals (Basel) 2025 Jul 5;15(13).
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