mTORC1 beyond anabolic metabolism: Regulation of cell death

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1), a multi-subunit protein kinase complex, interrogates growth factor signaling with cellular nutrient and energy status to control metabolic homeostasis. Activation of mTORC1 promotes biosynthesis of macromolecules, including proteins, lipids, and nucleic acids, and simultaneously suppresses catabolic processes such as lysosomal degradation of self-constituents and extracellular components. Metabolic regulation has emerged as a critical determinant of various cellular death programs, including apoptosis, pyroptosis, and ferroptosis. In this article, we review the expanding knowledge on how mTORC1 coordinates metabolic pathways to impinge on cell death regulation. We focus on the current understanding on how nutrient status and cellular signaling pathways connect mTORC1 activity with ferroptosis, an iron-dependent cell death program that has been implicated in a plethora of human diseases. In-depth understanding of the principles governing the interaction between mTORC1 and cell death pathways can ultimately guide the development of novel therapies for the treatment of relevant pathological conditions.

Figure 1.

Metabolites that coordinate mTORC1 activity with ferroptosis regulation. mTORC1 interrogates growth factor signaling and cellular nutrient status to regulate anabolic metabolism including protein translation, fatty acid biosynthesis, and nucleotide biosynthesis. mTORC1 senses the availability of leucine, arginine, and SAM (indicative of methionine abundance) through the Sestrin2 and SAR1B, CASTOR1, and SAMTOR sensor proteins, respectively. Intracellular cysteine contributes to ferroptosis resistance by supporting both glutathione biosynthesis and GPX4 protein synthesis. By contrast, intracellular glutamine utilization by glutaminolysis sensitizes ferroptosis. Production of MUFA leads to ferroptosis resistance, whereas PUFA generation promotes ferroptosis. Pyrimidine synthesis is coupled to the cellular energy status through DHODH that functions at the electron transport chain (ETC). DHODH mediates orotate production while depositing electrons to the ETC for generation of ubiquinol, which acts as a suppressor of ferroptosis. Transferrin receptor-mediated iron uptake and subsequent iron release from the lysosome promote ferroptosis execution. RTK, receptor tyrosine kinase. PI3K, phosphoinositide 3-kinase. TSC, tuberous sclerosis complex. MUFA, monounsaturated fatty acid. PUFA, polyunsaturated fatty acid. DHODH, dihydroorotate dehydrogenase. QH₂, ubiquinol. Tfn, transferrin.

Figure 2.

Signaling pathways that connect mTORC1 activity with ferroptosis regulation. mTORC1 is activated by growth factor signaling through the RTK-PI3K-Akt axis, of which one downstream outcome is the elevated MUFA production mediated by SREBP1 and SCD1. Growth factor signaling also promotes glucose uptake, which antagonizes AMPK activity. AMPK increases, while mTORC1 decreases, ULK1 activity that is required for autophagy initiation. Autophagic degradation of ferritin, a process termed ferrotinophagy, promotes ferroptosis by releasing iron from the intracellular iron store. The p53 tumor suppressor promotes expression of Sestrin2 that inhibits mTORC1 activity. On the other hand, p53 represses the expression of SLC7A11 required by the system x_c⁻ plasma membrane antiporter, thereby promoting ferroptosis. Both these anti-mTORC1 and pro-ferroptosis roles are key components of the p53-mediated tumor suppressive function. mTORC1 promotes NRF2 activation by increasing KEAP1 degradation. NRF2 acts as a transcription factor that promotes the expression of enzymes involved in glutathione biosynthesis for ferroptosis suppression. Besides mTORC1, the Hippo pathway is another mechanism of cell size and growth regulation. The Hippo pathway effector proteins YAP and TAZ promote ferroptosis partly by increasing the expression of transferrin receptor and the acyl-CoA synthetase long chain family member 4 (ACSL4). Intercellular contact mediated by cadherin proteins led to NF2 activation and subsequently nuclear exclusion of YAP, thereby inhibiting ferroptosis. RTK, receptor tyrosine kinase. PI3K, phosphoinositide 3-kinase. PTEN, phosphatase and tensin homolog. GLUT1, glucose transporter 1 (encoded by SLC2A1). AMPK, AMP-activated protein kinase. ULK1, unc-51 like autophagy activating kinase 1. KEAP1, kelch-like ECH-associated protein 1. NRF2, nuclear factor E2-related factor 2. SREBP1, sterol regulatory element binding protein 1. SCD1, stearoyl-CoA desaturase 1. MUFA, monounsaturated fatty acid. NF2, also known as MERLIN. LATS1/2, large tumor suppressor kinase 1/2. YAP, Yes1 associated transcriptional regulator. TAZ, also known as WWTR1, WW domain containing transcription regulator 1.

Figure 3.

mTORC1 in apoptosis and pyroptosis. (A) mTORC1 in apoptosis regulation. Intracellular metabolic and bioenergetic homeostasis is maintained through coordinated actions of multiple metabolic processes, including nutrient uptake, glycolysis, pentose phosphate pathway, TCA cycle, and mitochondrial respiration. mTORC1 participates in the regulation of a variety of these metabolic pathways. Disruption of metabolic homeostasis can promote the intrinsic mitochondrial apoptotic pathway, where activation of BAX and BAK facilitates the release of cytochrome c from mitochondria into the cytosol. Cytochrome c then forms apoptosome with Apaf-1, which in turn activates downstream caspases to promote apoptosis. RTK, receptor tyrosine kinase. PI3K, phosphoinositide 3-kinase. Apaf-1, apoptotic peptidase activating factor 1. BAX, BCL2 associated X, apoptosis regulator. BAK, also known as BAK1, BCL2 antagonist/killer 1. (B) mTORC1 in pyroptosis regulation. Inflammasome assembly stimulated by a variety of pathogen-associated molecular patterns (PAMPs) recruits caspase 1, which in turn proteolytically activates IL-1β and IL-18. Activated caspase 1 also leads to GSDMD cleavage required for pyroptosis. Components of the Ragulator-Rag-mTORC1 pathway are required for GSDMD oligomerization and plasma membrane pore formation during pyroptosis, in a manner dependent on the production of mitochondrial ROS. Independent of mTORC1, Ragulator-Rag also promotes caspase 8-dependent GSDMD cleavage to facilitate pyroptosis in the presence of the pathogenic bacteria Yersinia. ROS, reactive oxygen species. GSDMD, gasdermin D. NT-GSDMD, N-terminus of gasdermin D. ASC, also known as PYCARD, PYD and CARD domain containing.