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

• 成果类型: Article
• 署名作者: Castiglione, Gianni M.; Chen, Xin; Xu, Zhenhua; Dbouk, Nadir H.; Bose, Anamika A.; Carmona-Berrio, David; Chi, Emiliana E.; Zhou, Lingli; Boronina, Tatiana N.; Cole, Robert N.; Wu, Shirley; Liu, Abby D.; Liu, Thalia D.; Lu, Haining; Kalbfleisch, Ted; Rinker, David; Rokas, Antonis; Ortved, Kyla; Duh, Elia J.
• 署名单位: Vanderbilt University; Vanderbilt University; Johns Hopkins University; Vanderbilt University; Johns Hopkins University; University of Kentucky; University of Pennsylvania
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10906
• DOI: 10.1126/science.adr8589
• 发表日期: 2025-03-28
• 关键词: induced oxidative stress; antioxidant status; skeletal-muscle; nonsense mutations; genome sequence; pulse oximetry; exercise; nrf2; HISTORY; keap1

摘要

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.