PUBLICATION
An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna
- Authors
- Dumesic, P.A., Egan, D.F., Gut, P., Tran, M.T., Parisi, A., Chatterjee, N., Jedrychowski, M., Paschini, M., Kazak, L., Wilensky, S.E., Dou, F., Bogoslavski, D., Cartier, J.A., Perrimon, N., Kajimura, S., Parikh, S.M., Spiegelman, B.M.
- ID
- ZDB-PUB-200901-11
- Date
- 2019
- Source
- Cell Metabolism 30: 190-200.e6 (Journal)
- Registered Authors
- Gut, Philipp, Parisi, Alice
- Keywords
- 5’ untranslated region, PGC1α, bluefin tuna, evolution, ischemic kidney injury, metabolism, mitochondria, oxidative phosphorylation, translational regulation, upstream open reading frame
- MeSH Terms
-
- 5' Untranslated Regions/genetics*
- Animals
- Diptera
- Female
- HEK293 Cells
- Humans
- Immunoprecipitation
- Male
- Mice
- Mutation/genetics
- Open Reading Frames/genetics*
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism*
- Phylogeny
- Protein Processing, Post-Translational/genetics
- Tuna
- Zebrafish
- PubMed
- 31105043 Full text @ Cell Metab.
Citation
Dumesic, P.A., Egan, D.F., Gut, P., Tran, M.T., Parisi, A., Chatterjee, N., Jedrychowski, M., Paschini, M., Kazak, L., Wilensky, S.E., Dou, F., Bogoslavski, D., Cartier, J.A., Perrimon, N., Kajimura, S., Parikh, S.M., Spiegelman, B.M. (2019) An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna. Cell Metabolism. 30:190-200.e6.
Abstract
Mitochondrial abundance and function are tightly controlled during metabolic adaptation but dysregulated in pathological states such as diabetes, neurodegeneration, cancer, and kidney disease. We show here that translation of PGC1α, a key governor of mitochondrial biogenesis and oxidative metabolism, is negatively regulated by an upstream open reading frame (uORF) in the 5' untranslated region of its gene (PPARGC1A). We find that uORF-mediated translational repression is a feature of PPARGC1A orthologs from human to fly. Strikingly, whereas multiple inhibitory uORFs are broadly present in fish PPARGC1A orthologs, they are completely absent in the Atlantic bluefin tuna, an animal with exceptionally high mitochondrial content. In mice, an engineered mutation disrupting the PPARGC1A uORF increases PGC1α protein levels and oxidative metabolism and confers protection from acute kidney injury. These studies identify a translational regulatory element governing oxidative metabolism and highlight its potential contribution to the evolution of organismal mitochondrial function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping