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PTEN/Akt Signaling Controls Mitochondrial Respiratory Capacity through 4E-BP1

Figure 7

A proposed model of crosstalk between Akt/mTOR/4E-BP1 signaling pathway and mitochondria.

PTEN knockout in mouse embryonic fibroblasts (MEFPTEN−/−) results in an accumulation of PIP3 produced by PI3K at the plasma membrane. The recruitment of Akt and phosphoinositide-dependent protein kinase 1 (PDK1) by PIP3 is mediated via their pleckstrin homology (PH) domains. The phosphorylation at Ser473 by mTORC2 and that at Thr308 by PDK1 leads to a fully activated Akt [39] which then phosphorylates mTORC1. 4E-BP1, the downstream target of mTORC1, on phosphorylation becomes inactive as a repressor of protein translation as it is not able to bind to eIF4E [11]. This leads to the initiation of protein translation of RC components as shown in this study, contributing to enhanced OXPHOS in MEFPTEN−/−. Likewise, knockdown of PTEN in MEFWT or of 4E-BP1 in MEFWT and MEFPTEN−/− by RNA silencing also increased RC expressions. Conversely, attenuation of the hyper-activated Akt in MEFPTEN−/− by LY294002 or Akt inhibitor IV leads to lower RC activities and expressions. Together, the data presented supports our hypothesis of a link between Akt/mTOR/4E-BP1 and mitochondrial respiratory function.

Figure 7

doi: https://doi.org/10.1371/journal.pone.0045806.g007