A 2020 review paper about mTOR (ref. 1) says:

because biomass accumulation demands vast reserves of energetic currency, mTORC1 enhances translation of nuclear-encoded mitochondrial transcripts through 4E-BP1 to expand the ATP production capacity of the cell

The above quote cites a 2009 paper (ref. 2) that says:

Upon DR mitochondrial protein density increased 25% in control flies, while in d4E-BP null mutant flies there was no change

(DR stands for "dietary restriction", which is known to inhibit TOR, which is an inhibitor of d4E-BP, if I understand correctly.)

These two really confuse me, as it seems to me that ref. 1 cites ref. 2 but says the opposite.
To spell it out: It seems that everyone agrees that active (i.e., non-phosphorylated) 4E-BPs inhibit translation, but ref. 1 claims that the inhibition is strongest for nuclear-encoded mitochondrial transcripts, while ref. 2 claims the inhibition is weakest for these transcripts.

As far as I can tell, the claim by ref. 1 is also supported by two other papers: A 2012 paper (ref. 3) that says:

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.

And a 2013 paper (ref. 4) that says:

Whereas 4E-BP1/2 depletion did not affect polysome distribution of β-actin mRNA (Figure 6B, upper), it prevented the Ink1341-induced shift of TFAM and ATP5O mRNAs toward lighter polysomes (Figure 6B, lower). Therefore, 4E-BPs act as major mediators of mTORC1 on translation of TFAM and ATP5O mRNAs. Accordingly, asTORi decreased ATP5O and TFAM protein levels in control, but not in 4E-BP1/2-depleted cells

Finally, I found a 2017 paper (ref. 5) that seems to make a claim similar to the one ref. 2 makes. It says:

cold inhibits translation in general, but the synthesis of proteins destined to the mitochondria is selectively preserved, resulting in a cellular enrichment of these molecules.


4E-BP can be phosphorylated at multiple sites but phosphorylation of Thr37/Thr46 by the mammalian target of rapamycin (mTOR) acts as a priming event required for further phosphorylation. Cold exposure increased the proportion of nonphosphorylated protein, largely at the expense of the primed fraction [...] Taken collectively, our observations suggest that reduced ambient temperature induces a physiological state comprising posttranslational modification of 4E-BP—resulting in a lower proportion of the phosphorylated isoform primed for inactivation—and a switch from global protein translation toward mitochondrial metabolism and efficiency.

So my question is:
Is it really that refs 1,3,4 say one thing, and refs 2,5 say the opposite?
If yes: Has anyone offered an explanation to resolve the seemingly contradicting results?


  1. Liu, Grace Y., and David M. Sabatini. "mTOR at the nexus of nutrition, growth, ageing and disease." Nature Reviews Molecular Cell Biology 21.4 (2020): 183-203.
  2. Zid, Brian M., et al. "4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila." Cell 139.1 (2009): 149-160.
  3. Goo, Chong Kiat, et al. "PTEN/Akt signaling controls mitochondrial respiratory capacity through 4E-BP1." (2012): e45806.
  4. Morita, Masahiro, et al. "mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation." Cell metabolism 18.5 (2013): 698-711.
  5. Carvalho, Gil B., et al. "The 4E-BP growth pathway regulates the effect of ambient temperature on Drosophila metabolism and lifespan." Proceedings of the National Academy of Sciences 114.36 (2017): 9737-9742.


You must log in to answer this question.

Browse other questions tagged .