Cellular metabolism and lysosomal mTOR signaling

Nnah, Israel C.; Khayati, Khoosheh; Dobrowolski, Radoslaw

doi:10.1515/cdth-2015-0001

Cited by 7 publications

(8 citation statements)

References 109 publications

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“…Under normal cellular conditions, mTORC1 regulates clearance of misfolded protein aggregates and mTORC1 activity has been directly associated with sporadic AD (22). mTORC1 is regulated by multiple external trophic ligands through the tuberous sclerosis complex and by amino acids through the Rag small GTPase (39, 40). Heterodimeric RagA/B and RagC/D complexes are responsible for regulating tethering of mTORC1 to lysosomal membranes in response to increasing intracellular amino acid levels; lysosomal localization of the mTORC1 kinase directly correlates with its activation through Rheb (40).…”

Section: Discussionmentioning

confidence: 99%

The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice

et al. 2016

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The molecular mechanisms leading to and responsible for age-related, sporadic Alzheimer's disease (AD) remain largely unknown. It is well documented that aging patients with elevated levels of the amino acid metabolite homocysteine (Hcy) are at high risk of developing AD. We investigated the impact of Hcy on molecular clearance pathways in mammalian cells, including in vitro cultured induced pluripotent stem cell-derived forebrain neurons and in vivo neurons in mouse brains. Exposure to Hcy resulted in up-regulation of the mechanistic target of rapamycin complex 1 (mTORC1) activity, one of the major kinases in cells that is tightly linked to anabolic and catabolic pathways. Hcy is sensed by a constitutive protein complex composed of leucyl-tRNA-synthetase and folliculin, which regulates mTOR tethering to lysosomal membranes. In hyperhomocysteinemic human cells and cystathionine β-synthase-deficient mouse brains, we find an acute and chronic inhibition of the molecular clearance of protein products resulting in a buildup of abnormal proteins, including β-amyloid and phospho-Tau. Formation of these protein aggregates leads to AD-like neurodegeneration. This pathology can be prevented by inhibition of mTORC1 or by induction of autophagy. We conclude that an increase of intracellular Hcy levels predisposes neurons to develop abnormal protein aggregates, which are hallmarks of AD and its associated onset and pathophysiology with age.-Khayati, K., Antikainen, H., Bonder, E. M., Weber, G. F., Kruger, W. D., Jakubowski, H., Dobrowolski, R. The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice.

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Section: Discussionmentioning

confidence: 99%

The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice

et al. 2016

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“…So far, no specific allosteric inhibitors are known and both complexes are susceptible to mTOR inhibitors such as Rapamycin or Torin (Hara et al ., ; Sarbassov et al ., ). Functionally, mTORC1 has been shown to predominantly tether to lysosomal membranes where it senses the levels of amino acids and growth factors to regulate cellular metabolic processes including protein and lipid synthesis, lysosomal biogenesis, and autophagy (Cafferkey et al ., ; Kunz et al ., ; Wullschleger et al ., ; Laplante & Sabatini, ; Nnah et al ., ). Whether mTORC1 can be activated or localized elsewhere, possibly by differing sets of environmental cues, remains to be determined.…”

Section: Mtor Kinase Complexes and Their Regulationmentioning

confidence: 97%

TOR‐mediated regulation of metabolism in aging

et al. 2017

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SummaryCellular metabolism is regulated by the mTOR kinase, a key component of the molecular nutrient sensor pathway that plays a central role in cellular survival and aging. The mTOR pathway promotes protein and lipid synthesis and inhibits autophagy, a process known for its contribution to longevity in several model organisms. The nutrient‐sensing pathway is regulated at the lysosomal membrane by a number of proteins for which deficiency triggers widespread aging phenotypes in tested animal models. In response to environmental cues, this recently discovered lysosomal nutrient‐sensing complex regulates autophagy transcriptionally through conserved factors, such as the transcription factors TFEB and FOXO, associated with lifespan extension. This key metabolic pathway strongly depends on nucleocytoplasmic compartmentalization, a cellular phenomenon gradually lost during aging. In this review, we discuss the current progress in understanding the contribution of mTOR‐regulating factors to autophagy and longevity. Furthermore, we review research on the regulation of metabolism conducted in multiple aging models, including Caenorhabditis elegans, Drosophila and mouse, and human iPSCs. We suggest that conserved molecular pathways have the strongest potential for the development of new avenues for treatment of age‐related diseases.

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“…is an evolutionarily conserved serine/threonine kinase that controls organismal growth, and has been found to be deregulated in several devastating human diseases including cancer and neurodegeneration [1,2]. MTORC1 integrates major intracellular and extracellular signaling pathways including growth factor signaling, amino acid sensing, energy status, and cellular stress [1,3].…”

Section: Mtorc1 (Mechanistic Target Of Rapamycin Kinase Complex 1)mentioning

confidence: 99%

“…MTORC1 integrates major intracellular and extracellular signaling pathways including growth factor signaling, amino acid sensing, energy status, and cellular stress [1,3]. Such MTORC1-mediated signal integration allows for well-controlled regulation of anabolic and catabolic processes such as protein and lipid synthesis, autophagy, lysosomal biogenesis, and energy metabolism that together regulate cellular growth and homeostasis [2,4]. The MTORC1 complex is localized to endolysosomal membranes through an amino acid-dependent mechanism that involves the heterodimeric RRAGA/B-RRAGC/D GTPases.…”

Section: Mtorc1 (Mechanistic Target Of Rapamycin Kinase Complex 1)mentioning

confidence: 99%

“…When positioned on endolysosomal membranes, MTORC1 kinase activity is stimulated by RHEB, a membrane-tethered RAS homolog. Therefore, 2 key sequential events are required for MTORC1 activation: translocation of the complex to endolysosomal membranes, and stimulation of its kinase activity by the GTP-bound RHEB, which is differentially regulated by growth factor signaling [1,2].…”

Section: Mtorc1 (Mechanistic Target Of Rapamycin Kinase Complex 1)mentioning

confidence: 99%

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TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy

et al. 2018

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The mechanistic target of rapamycin kinase complex 1 (MTORC1) is a central cellular kinase that integrates major signaling pathways, allowing for regulation of anabolic and catabolic processes including macroautophagy/autophagy and lysosomal biogenesis. Essential to these processes is the regulatory activity of TFEB (transcription factor EB). In a regulatory feedback loop modulating transcriptional levels of RRAG/Rag GTPases, TFEB controls MTORC1 tethering to membranes and induction of anabolic processes upon nutrient replenishment. We now show that TFEB promotes expression of endocytic genes and increases rates of cellular endocytosis during homeostatic baseline and starvation conditions. TFEB-mediated endocytosis drives assembly of the MTORC1-containing nutrient sensing complex through the formation of endosomes that carry the associated proteins RRAGD, the amino acid transporter SLC38A9, and activate AKT/protein kinase B (AKT p-T308). TFEB-induced signaling endosomes en route to lysosomes are induced by amino acid starvation and are required to dissociate TSC2, re-tether and activate MTORC1 on endolysosomal membranes. This study characterizes TFEB-mediated endocytosis as a critical process leading to activation of MTORC1 and autophagic function, thus identifying the importance of the dynamic endolysosomal system in cellular clearance. Abbreviations: CAD: central adrenergic tyrosine hydroxylase-expressing-a-differentiated; ChIP-seq: chromosome immunoprecipitation sequencing; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; EEA1: early endosomal antigen 1; EGF: epidermal growth factor; FBS: fetal bovine serum; GFP: green fluorescent protein; GTPase: guanosine triphosphatase; HEK293T: human embryonic kidney 293 cells expressing a temperature-sensitive mutant of the SV40 large T antigen; LAMP: lysosomal-associated membrane protein; LYNUS: lysosomal nutrient-sensing complex; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha/beta; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin kinase complex; OE: overexpression; PH: pleckstrin homology; PtdIns(3,4,5)P: phosphatidylinositol 3,4,5-trisphosphate; RRAGD: Ras related GTPase binding D; RHEB: Ras homolog enriched in brain; SLC38A9: solute carrier family 38 member 9; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TSC2: tuberous sclerosis 2; TMR: tetramethylrhodamine; ULK1: unc-51 like kinase 1; WT: wild type.

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Cellular metabolism and lysosomal mTOR signaling

Cited by 7 publications

References 109 publications

The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice

The amino acid metabolite homocysteine activates mTORC1 to inhibit autophagy and form abnormal proteins in human neurons and mice

TOR‐mediated regulation of metabolism in aging

TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy

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