PTENα, a PTEN Isoform Translated through Alternative Initiation, Regulates Mitochondrial Function and Energy Metabolism

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 PTEN alpha, an N-terminally extended form of PTEN, functions in mitochondrial metabolism. Translation of PTEN alpha 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 PTEN alpha translation, which requires a CUG-centered palindromic motif. We show that PTEN alpha induces cytochrome c oxidase activity and ATP production in mitochondria. TALEN-mediated somatic deletion of PTEN alpha impairs mitochondrial respiratory chain function. PTEN alpha 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.