| First Author | Dumesic PA | Year | 2019 |
| Journal | Cell Metab | Volume | 30 |
| Issue | 1 | Pages | 190-200.e6 |
| PubMed ID | 31105043 | Mgi Jnum | J:278393 |
| Mgi Id | MGI:6323469 | Doi | 10.1016/j.cmet.2019.04.013 |
| Citation | Dumesic PA, et al. (2019) An Evolutionarily Conserved uORF Regulates PGC1alpha and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna. Cell Metab 30(1):190-200.e6 |
| abstractText | 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 PGC1alpha, 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 PGC1alpha 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. |
