Running a genetic stop sign accelerates oxygen metabolism and energy production in horses

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; Elia J. Duh

doi:10.1126/science.adr8589

Running a genetic stop sign accelerates oxygen metabolism and energy production in horses

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, Elia J. Duh

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1 Scopus citations

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.

Original language	English
Article number	eadr8589
Journal	Science
Volume	387
Issue number	6741
DOIs	https://doi.org/10.1126/science.adr8589
State	Published - Mar 28 2025

Bibliographical note

Publisher Copyright:
Copyright © 2025 the authors, some rights reserved.

Funding

The Agilent Seahorse Extracellular Flux Analyzer is housed and managed within the Vanderbilt High-Throughput Screening Core Facility, an institutionally supported core, and was funded by NIH Shared Instrumentation Grant 1S10OD018015. Funding: National Institutes of Health grant 1R35GM155367 (G.M.C.); Vanderbilt University, Evolutionary Studies Pilot grant (G.M.C.); National Institutes of Health grant EY022383 (E.J.D.); National Institutes of Health grant EY022683 (E.J.D.); Altsheler-Durell Foundation (E.J.D.); Research to Prevent Blindness (E.J.D.); Wilmer Eye Institute, Imaging and Microscopy Core Module P30EY001765. National Institutes of Health grant AI153356 (A.R.), National Science Foundation grant DEB-2110404 (A.R.), and the Burroughs Wellcome Fund (A.R.).

Funders	Funder number
Research to Prevent Blindness
Altsheler-Durell Foundation
Burroughs Wellcome Fund
National Institutes of Health (NIH)	1S10OD018015, 1R35GM155367
National Science Foundation Arctic Social Science Program	DEB-2110404
Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center	EY022683, EY022383
Wilmer Eye Institute	P30EY001765, AI153356

ASJC Scopus subject areas

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Castiglione, G. M., Chen, X., Xu, Z., Dbouk, N. H., Bose, A. A., Carmona-Berrio, D., Chi, E. E., Zhou, L., Boronina, T. N., Cole, R. N., Wu, S., Liu, A. D., Liu, T. D., Lu, H., Kalbfleisch, T., Rinker, D., Rokas, A., Ortved, K., & Duh, E. J. (2025). Running a genetic stop sign accelerates oxygen metabolism and energy production in horses. Science, 387(6741), Article eadr8589. https://doi.org/10.1126/science.adr8589

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title = "Running a genetic stop sign accelerates oxygen metabolism and energy production in horses",

abstract = "Horses are among nature{\textquoteright}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.",

author = "Castiglione, \{Gianni M.\} and Xin Chen and Zhenhua Xu and Dbouk, \{Nadir H.\} and Bose, \{Anamika A.\} and David Carmona-Berrio and Chi, \{Emiliana E.\} and Lingli Zhou and Boronina, \{Tatiana N.\} and Cole, \{Robert N.\} and Shirley Wu and Liu, \{Abby D.\} and Liu, \{Thalia D.\} and Haining Lu and Ted Kalbfleisch and David Rinker and Antonis Rokas and Kyla Ortved and Duh, \{Elia J.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 the authors, some rights reserved.",

year = "2025",

month = mar,

day = "28",

doi = "10.1126/science.adr8589",

language = "English",

volume = "387",

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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, vol. 387, no. 6741, eadr8589. https://doi.org/10.1126/science.adr8589

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AU - Castiglione, Gianni M.

AU - Chen, Xin

AU - Xu, Zhenhua

AU - Dbouk, Nadir H.

AU - Bose, Anamika A.

AU - Carmona-Berrio, David

AU - Chi, Emiliana E.

AU - Zhou, Lingli

AU - Boronina, Tatiana N.

AU - Cole, Robert N.

AU - Wu, Shirley

AU - Liu, Abby D.

AU - Liu, Thalia D.

AU - Lu, Haining

AU - Kalbfleisch, Ted

AU - Rinker, David

AU - Rokas, Antonis

AU - Ortved, Kyla

AU - Duh, Elia J.

PY - 2025/3/28

Y1 - 2025/3/28

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AB - 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.

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Running a genetic stop sign accelerates oxygen metabolism and energy production in horses

Abstract

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