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Organelle dynamics

(P)TEN-ding to mitochondria

Nature Reviews Molecular Cell Biology volume 15, pages 366–367 (2014)Cite this article

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Using molecular and genetic analyses and mass spectrometry in human cells and in mouse models, the authors found that PTENα is translated by an eIF2α (eukaryotic translation initiation factor 2α)-dependent mechanism that is initiated from an upstream, in-frame CUG initiation codon and results in a protein that is 173 amino acids larger than PTEN. A palindromic sequence that encompasses the initiation site has a crucial role in recognizing the CUG codon. Although PTENα is the first mammalian protein reported to be translated by such a mechanism, CUG-dependent translation may represent a prevailing mechanism for translating protein isoforms and generating protein diversity.

Microscopy and subcellular fractionation revealed that PTENα localizes to the cytoplasm and to mitochondria. The authors examined whether PTENα functions in the electron transport chain by measuring its effect on the activity of oxidative phosphorylation complexes. In mouse tissues, PTENα expression levels correlated with COX activity levels. Pten-null mouse cells showed a >75% decrease in COX activity compared to their wild-type counterparts; this deficiency was fully restored by the ectopic expression of PTENα but was only partially restored by PTEN expression. In human cells, overexpression of PTENα increased COX activity. Additionally, data suggested that the phosphatase activity of PTENα is important for COX activation and that PTENα may physically associate with COX. Thus, PTENα has a role in regulating mitochondrial metabolism, potentially by maintaining COX in a hypophosphorylated state.

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References

  1. Liang, H. et al. PTENα, a PTEN isoform translated through alternative initiation, regulates mitochondrial function and energy metabolism. Cell Metab. http://dx.doi.org/10.1016/j.cmet.2014.03.023 (2014)

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  1. Eytan Zlotorynski
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Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol. 13, 283–296 (2012)

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Zlotorynski, E. (P)TEN-ding to mitochondria. Nat Rev Mol Cell Biol 15, 366–367 (2014). https://doi.org/10.1038/nrm3808

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