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Title: PTEN/Akt Signaling Controls Mitochondrial Respiratory Capacity through 4E-BP1
Authors: Goo, C.K.
Lim, H.Y.
Ho, Q.S.
Too, H.-P.
Clement, M.-V. 
Wong, K.P.
Issue Date: 26-Sep-2012
Citation: Goo, C.K., Lim, H.Y., Ho, Q.S., Too, H.-P., Clement, M.-V., Wong, K.P. (2012-09-26). PTEN/Akt Signaling Controls Mitochondrial Respiratory Capacity through 4E-BP1. PLoS ONE 7 (9) : -. ScholarBank@NUS Repository.
Abstract: Akt, a serine/threonine kinase has been shown to stimulate glycolysis in cancer cells but its role in mitochondrial respiration is unknown. Using PTEN-knockout mouse embryonic fibroblasts (MEFPTEN-/-) with hyper-activated Akt as a cell model, we observed a higher respiratory capacity in MEFPTEN-/- compared to the wildtype (MEFWT). The respiratory phenotype observed in MEFPTEN-/- was reproduced in MEFWT by gene silencing of PTEN which substantiated its role in regulating mitochondrial function. The increased activities of the respiratory complexes (RCs) I, III and IV were retained in the same relative proportions as those present in MEFWT, alluding to a possible co-ordinated regulation by PTEN/Akt. Using LY294002 (a PI3K inhibitor) and Akt inhibitor IV, we showed that the regulation of enzyme activities and protein expressions of the RCs was dependent on PI3K/Akt. There was insignificant difference in the protein expressions of mitochondrial transcription factor: peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and its downstream targets, the nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (mtTFA) between MEFPTEN-/- and MEFWT. Similarly, mRNA levels of the same subunits of the RCs detected in Western blots were not significantly different between MEFPTEN-/- and MEFWT suggesting that the regulation by Akt on mitochondrial function was probably not via gene transcription. On the other hand, a decrease of total 4E-BP1 with a higher expression of its phosphorylated form relative to total 4E-BP1 was found in MEFPTEN-/-, which inferred that the regulation of mitochondrial respiratory activities by Akt was in part through this protein translation pathway. Notably, gene silencing of 4E-BP1 up-regulated the protein expressions of all RCs and the action of 4E-BP1 appeared to be specific to these mitochondrial proteins. In conclusion, PTEN inactivation bestowed a bioenergetic advantage to the cells by up-regulating mitochondrial respiratory capacity through the 4E-BP1-mediated protein translation pathway. © 2012 Goo et al.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0045806
Appears in Collections:Staff Publications

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