The central moTOR of metabolism

Abstract

The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.

Keywords: amino acids; lipids; mTOR; mTORC1; mTORC2; metabolism; protein; rapamycin.

Figure 1:. Regulation of mTORC1 Activity by Amino Acids and Growth Factors.

mTORC1 is activated by interacting with Rheb-GTP at the lysosome. Recruitment of mTORC1 to the lysosome is mediated by the RagGTPases; heterodimers of Rags recruit mTORC1 by binding to the mTORC1 subunit Raptor when RagA/RagB is bound to GTP and RagC/RagD is bound to GDP. The GTP/GDP loading status of the Rags is mediated by Ragulator and GATOR1, as well as other GAPs and GEFs. Specific sensors for the amino acids Methionine (SAMTOR), Leucine (Sestrin2), and Arginine (CASTOR1/2) have been identified; when levels of the sensed amino acids are low, these proteins inhibit GATOR1 or GATOR2 activity to modulate the GAP activity of GATOR1 towards RagA and RagB. Amino acids also stimulate the GEF activity of Ragulator/SLC38A9/v-ATPase complex towards RagA/B and the GAP activity of FLCN towards RagC/D. Glucose levels are sensed indirectly via DHAP levels, which controls GATOR2 activity via an as-yet undescribed mechanism. The GEF activity of Ragulator is modulated by multiple amino acids via the v-ATPase and SLC38A9; cholesterol also activates mTORC1 signaling via SLC38A9. NPC1 (Niemann-Pick C1), the major lysosomal cholesterol transporter, interacts with SLC38A9 and inhibits the activation of mTORC1 by cholesterol. Protein-derived amino acids stimulate lysosomal mTORC1 activity via a HOPS-dependent pathway that has not yet been fully described, but which is antagonized by the RagGTPases. The availability of Rheb-GTP is limited by the activity of the TSC complex, which is a GAP for Rheb; TSC activity is inhibited by insulin/IGF-1 signaling via AKT, which phosphorylates TSC2. Purine nucleotides are sensed via TSC2 as well, inhibiting TSC activity, although the precise sensor has not yet been identified. Figure adapted from (Green et al., 2022a) and used with permission from Springer Nature.

Figure 2:. Regulation of mTORC2 activity by Growth Factors.

mTORC2 is activated by insulin, IGF-1, and leptin via activation of PI3K signaling. mTORC2 is activated by binding of mSIN1 to PIP₃; substrates of mTORC2 include the S473 and T450 residues of AKT as well as specific sites on SGK, multiple PKC isoforms, and SIRT6 (reviewed in (Kennedy and Lamming, 2016)).

Figure 3:. Control of cellular metabolism and other processes by mTORC1 and mTORC2.

mTORC1 regulates processes required for cell proliferation including the pentose phosphate pathway, protein translation, lipolysis, lipogenesis, and mitochondrial biogenesis. Most of this regulation is mediated downstream of S6K1 and the 4E-BPs. In contrast mTORC2 regulates the pentose phosphate pathway through phosphorylation of transketolase, hexosamine biosynthesis through the phosphorylation of GFAT1 (glutamine:fructose-6-phosphate amidotransferase 1), and controls lipid metabolism through SREBP1, HIF1α, FOXO1 mediated transcriptional regulation. These pathways cumulatively control essential building blocks for cell proliferation, division, and maintenance.