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

Phillip A. Dumesic, Daniel F. Egan, Philipp Gut, Mei T. Tran, Alice Parisi, Nirmalya Chatterjee, Mark Jedrychowski, Margherita Paschini, Lawrence Kazak, Sarah E. Wilensky, Florence Dou, Dina Bogoslavski, Jeffrey A. Cartier, Norbert Perrimon, Shingo Kajimura, Samir M. Parikh, Bruce M. Spiegelman

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)190-200.e6
JournalCell Metabolism
Volume30
Issue number1
DOIs
StatePublished - Jul 2 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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