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 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.
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Hui
H
Liang
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Shiming
S
He
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Jingyi
J
Yang
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China; Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
Xinying
X
Jia
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Pan
P
Wang
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Xi
X
Chen
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China; Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
Zhong
Z
Zhang
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Xiajuan
X
Zou
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China.
Michael A
MA
McNutt
Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA. Electronic address: wes2007@med.cornell.edu.
Wen Hong
WH
Shen
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Center for Age-Related Diseases, Peking University Health Science Center, Beijing 100191, P.R. China. Electronic address: yinyuxin@hsc.pku.edu.cn.
Yuxin
Y
Yin
D000255:Adenosine Triphosphate / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004579:Electron Transport / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000235:genetics*; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D014176:Protein Biosynthesis / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D051059:PTEN Phosphohydrolase; D020033:Protein Isoforms; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C487757:Pten protein, mouse