PUBLICATION
ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging
- Authors
- Snieckute, G., Ryder, L., Vind, A.C., Wu, Z., Arendrup, F.S., Stoneley, M., Chamois, S., Martinez-Val, A., Leleu, M., Dreos, R., Russell, A., Gay, D.M., Genzor, A.V., Choi, B.S., Basse, A.L., Sass, F., Dall, M., Dollet, L.C.M., Blasius, M., Willis, A.E., Lund, A.H., Treebak, J.T., Olsen, J.V., Poulsen, S.S., Pownall, M.E., Jensen, B.A.H., Clemmensen, C., Gerhart-Hines, Z., Gatfield, D., Bekker-Jensen, S.
- ID
- ZDB-PUB-231208-7
- Date
- 2023
- Source
- Science (New York, N.Y.) 382: eadf3208eadf3208 (Journal)
- Registered Authors
- Pownall, Betsy
- Keywords
- none
- MeSH Terms
-
- Mice, Knockout
- Mice
- Aging*/metabolism
- Stress, Physiological*
- Protein Biosynthesis
- Zebrafish
- Obesity*/metabolism
- Animals
- Reactive Oxygen Species*/metabolism
- Ribosomes*/metabolism
- MAP Kinase Kinase Kinase 3*/genetics
- MAP Kinase Kinase Kinase 3*/metabolism
- PubMed
- 38060659 Full text @ Science
Citation
Snieckute, G., Ryder, L., Vind, A.C., Wu, Z., Arendrup, F.S., Stoneley, M., Chamois, S., Martinez-Val, A., Leleu, M., Dreos, R., Russell, A., Gay, D.M., Genzor, A.V., Choi, B.S., Basse, A.L., Sass, F., Dall, M., Dollet, L.C.M., Blasius, M., Willis, A.E., Lund, A.H., Treebak, J.T., Olsen, J.V., Poulsen, S.S., Pownall, M.E., Jensen, B.A.H., Clemmensen, C., Gerhart-Hines, Z., Gatfield, D., Bekker-Jensen, S. (2023) ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging. Science (New York, N.Y.). 382:eadf3208eadf3208.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping