ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

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The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging.

Original languageEnglish
Article numbereadf3208
JournalScience (New York, N.Y.)
Volume382
Issue number6675
Number of pages14
ISSN0036-8075
DOIs
Publication statusPublished - 2023

    Research areas

  • Mice, Animals, Reactive Oxygen Species/metabolism, Zebrafish, Ribosomes/metabolism, Aging, Obesity/genetics

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