Can protein breaks provoke too much autophagy?

Reader Arash raised the interesting question whether the intermittent dietary protein restriction used in protein breaks could cause excessive autophagy.   This is important because too much autophagy can kill cells in certain settings, like oxygen deprivation in the brain (cerebral ischemia).

Excess autophagy apparently does not occur with intermittent protein restriction, because autophagy is self-limiting in this circumstance.  Restricting dietary protein, which is made of amino acids, deactivates mammalian target of rapamycin complex 1 (mTORC1), leading to protein degradation in cells by autophagy, which frees up amino acids, leading to reactivation of mTORC1 and consequent inhibition of autophagy again.

Laing explains:

[I]ncreased intracellular free amino acids produced during autophagic degradation can reactivate the mTORC1 signaling and thus downregulate autophagy, serving as a self-limiting feedback loop in autophagy regulation. …

[I]t has been shown that mTORC1 can sense small increases in intracellular amino acids such as leucine, which leads to increased phosphorylation of both p70S6 kinase and its downstream target, ribosomal protein S6. Notably, such effects of amino acids on mTORC1 can be independent of stimulation by insulin or other growth factors, but are dependent on autophagic proteolysis. …

A recent study by Yu et al. also showed that mTOR signaling is reactivated by prolonged starvation, which attenuates autophagy and restores lysosome homeostasis. This negative feedback loop is envisioned to be part of a homeostatic mechanism required to prevent prolonged or overactivation of autophagy.

Liang C. Negative regulation of autophagy. Cell Death Differ. 2010 December; 17(12): 1807.

Also, Yu finds “mTOR signaling is inhibited during autophagy initiation, but reactivated with prolonged starvation. mTOR reactivation is autophagy-dependent, and requires the degradation of autolysosomal products.”

Yu L, et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010;465:942.

See also: Avruch J, et al. Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab. 2009;296.

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