The mTOR-Autophagy Axis and the Control of Metabolism

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.

Keywords: autophagy; lysosome; mechanistic target of rapamycin; metabolism; nutrients.

FIGURE 1

The mTOR–autophagy axis. MTORC1 blocks the early steps in autophagy by phosphorylation-dependent inhibition of Atg13 and ULK1 and also restrains the degradative capacity of the cell by inhibiting the activity of TFEB family members. Several autophagy-related proteins and other lysosomal factors are encoded by genes that harbor a CLEAR sequence in their promoter region, and are bound and transactivated by active TFEB family members. Thus, inhibition of mTORC1 enables autophagic degradation and degradative capacity of the cell, while also suppressing anabolism and, thus, lowering the demand for energy and nutrients. In turn, lysosome-derived amino acids (leucine and arginine) and also other nutrients (glucose-DHAP, cholesterol, SAM) can partially reactivate Rag GTPase – nutrient signaling upstream of mTORC1. MTORC2 and the AGC kinases Akt and SGK1 also limit the autophagic flux and lysosomal capacity via transcription-dependent and -independent processes. The cytoplasmic sequestration of the FoxO transcription factors indirectly limits autophagic degradation, as several FoxO targets encode proteins that directly participate in different steps of autophagy and lysosomal catabolism.