The mTOR-Autophagy Axis and the Control of Metabolism.

Nerea Deleyto-Seldas,Alejo Efeyan

doi:10.3389/fcell.2021.655731

Abstract

The mechanistic target of rapamycin (mTOR), master regulator of cellular metabolism, exists in two distinct complexes: mTOR complex 1 and mTOR complex 2 (mTORC1 and 2). MTORC1 is a master switch for most energetically onerous processes in the cell, driving cell growth and building cellular biomass in instances of nutrient sufficiency, and conversely, allowing autophagic recycling of cellular components upon nutrient limitation. The means by which the mTOR kinase blocks autophagy include direct inhibition of the early steps of the process, and the control of the lysosomal degradative capacity of the cell by inhibiting the transactivation of genes encoding structural, regulatory, and catalytic factors. Upon inhibition of mTOR, autophagic recycling of cellular components results in the reactivation of mTORC1; thus, autophagy lies both downstream and upstream of mTOR. The functional relationship between the mTOR pathway and autophagy involves complex regulatory loops that are significantly deciphered at the cellular level, but incompletely understood at the physiological level. Nevertheless, genetic evidence stemming from the use of engineered strains of mice has provided significant insight into the overlapping and complementary metabolic effects that physiological autophagy and the control of mTOR activity exert during fasting and nutrient overload.

Highlights

Reviewed by: Yoana Rabanal, University of Castilla-La Mancha, Spain Gustavo J
The signal transduction cascade from hormones/growth factors that activates the mechanistic target of rapamycin (mTOR) kinase starts with the activation of a receptor tyrosine kinase at the plasma membrane that switches on mTOR and Autophagy the PI3K–Akt axis, which results in the inhibition of the tuberous sclerosis complex (TSC)
Rheb is anchored at the outer surface of the lysosome, and it can only interact with and activate mTORC1 if mTORC1 is tethered to the outer lysosomal surface, a re-localization process that occurs in a cellular nutrient-dependent manner (Sancak et al, 2008; Figure 1)

Summary

Introduction

Reviewed by: Yoana Rabanal, University of Castilla-La Mancha, Spain Gustavo J. The increased demand for energy and building blocks for macromolecule synthesis upon mTORC1 activation, together with the block in autophagy, results in a biosynthetic burden that the cell alleviates with the execution of parallel programs that reinforce nutrient uptake (Park et al, 2017; Torrence et al, 2020) and synthesis (Robitaille et al, 2013; Ben-Sahra et al, 2016; Valvezan et al, 2017), and enables the catabolic capacity of the cells through the proteasomal degradation of proteins (Zhang et al, 2014) to remove unwanted cellular material and to boost the pool of free amino acids available for protein synthesis.

Results

Conclusion