PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism

Cell Metab. 2014 May 6;19(5):836-48. doi: 10.1016/j.cmet.2014.03.023. Epub 2014 Apr 24.


PTEN is one of the most frequently mutated genes in human cancer. It is known that PTEN has a wide range of biological functions beyond tumor suppression. Here, we report that PTENα, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTENα is initiated from a CUG codon upstream of and in-frame with the coding region of canonical PTEN. Eukaryotic translation initiation factor 2A (eIF2A) controls PTENα translation, which requires a CUG-centered palindromic motif. We show that PTENα induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTENα impairs mitochondrial respiratory chain function. PTENα interacts with canonical PTEN to increase PINK1 protein levels and promote energy production. Our studies demonstrate the importance of eIF2A-mediated alternative translation for generation of protein diversity in eukaryotic systems and provide insights into the mechanism by which the PTEN family is involved in multiple cellular processes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / genetics
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Electron Transport / genetics
  • Electron Transport Complex IV / genetics
  • Energy Metabolism / genetics*
  • Mice
  • Mitochondria / genetics*
  • Molecular Sequence Data
  • PTEN Phosphohydrolase / genetics*
  • Protein Biosynthesis / genetics*
  • Protein Isoforms / genetics*
  • Protein Kinases / genetics


  • Protein Isoforms
  • Adenosine Triphosphate
  • Electron Transport Complex IV
  • Protein Kinases
  • PTEN-induced putative kinase
  • PTEN Phosphohydrolase
  • Pten protein, mouse