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.
and:
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?
References
- 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.
- Zid, Brian M., et al. "4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila." Cell 139.1 (2009): 149-160.
- Goo, Chong Kiat, et al. "PTEN/Akt signaling controls mitochondrial respiratory capacity through 4E-BP1." (2012): e45806.
- Morita, Masahiro, et al. "mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation." Cell metabolism 18.5 (2013): 698-711.
- 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.
