Format

Send to

Choose Destination
Cell Metab. 2019 Jul 2;30(1):190-200.e6. doi: 10.1016/j.cmet.2019.04.013. Epub 2019 May 16.

An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna.

Author information

1
Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA.
2
Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
3
Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Boston Children's Hospital, Boston, MA 02115, USA.
5
Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montreal, Canada.
6
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
7
Cartier and Company, LLC, Harwich, MA 02645, USA.
8
Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143, USA.
9
Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA. Electronic address: bruce_spiegelman@dfci.harvard.edu.

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.

KEYWORDS:

5’ untranslated region; PGC1α; bluefin tuna; evolution; ischemic kidney injury; metabolism; mitochondria; oxidative phosphorylation; translational regulation; upstream open reading frame

PMID:
31105043
PMCID:
PMC6620024
[Available on 2020-07-02]
DOI:
10.1016/j.cmet.2019.04.013

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center