Skip to main content Skip to main navigation menu Skip to site footer
Review
Published: 11-23-2022

The role of leucine in the activation of cellular metabolism: a large integrative review

USP - University of São Paulo, São Paulo, Brazil
FACERES – Faculty of Medicine of São José do Rio Preto, São Paulo, Brazil
Leucine Cell metabolism Signaling Tissue regeneration

Abstract

This review addressed the signaling of cellular activation by leucine, discussed the risks of excessive signaling by proteins in the Western diet, and explored the potential of leucine stimulation in tissue regeneration. As result, amino acids are, in addition to building blocks of macromolecules, cellular activation signals. Essential amino acids are not produced by animals and leucine appears to be the main signaling amino acid. Mammals adjusted the cell activation and growth rate of their young by the leucine concentration of the milk produced. Several studies demonstrate the benefits of leucine supplementation in preventing sarcopenia, improving muscle and liver performance, as well as a possible neuroprotective role in head trauma and dementia. However, its excess, so common in the Western diet, is related to obesity, type II diabetes, neurodegenerative diseases, and cancer. The mTORC1 kinase integrates cellular activation stimuli from macro protein synthesis to epigenetic regulation. Controlling mTORC1 activity by consuming leucine can prevent, treat, or cause disease. A greater understanding of the regulatory effects of leucine and mTOR in unstable tissues such as tumors or fragile tissues such as the CNS are areas of great relevance and with extensive fields still to be explored.

Metrics

Metrics Loading ...

References

  1. Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 133-139, 2013.
  2. Zheng L, Zhang W, Zhou Y et al. (2016) Recent advances in understanding amino acid sensing mechanisms that regulate mTORC1. Int J Mol Sci. doi:10.3390/ijms17101636
  3. Zhang S, Zeng X, Ren M et al. Novel metabolic and physiological functions of branched chain amino acids: a review. J Animal Sci Biotechnol, (2017) doi: 10.1186/s40104-016-0139-z
  4. Siddik MAB, Shin AC. Recent progress on branched-chain amino acids in obesity, diabetes, and beyond. Endocrinol Metab):234-246, 2019.
  5. Sivanand S, Vander Heiden MG. Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell. 2020:147-156.
  6. Wei Z, Liu X, Cheng C, Yu W, Yi P. Metabolism of amino acids in cancer. Front Cell Dev Biol. (2021). doi: 10.3389/fcell.2020.603837
  7. Peyrollier K, Hajduch E, Blair AS et al: L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport. Biochem J. 2000, 361-368.
  8. Krause U, Bertrand L, Maisin L et al: Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur J Biochem. 2002, 3742-3750.
  9. Lynch CJ, Halle B, Fujii H et al. Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003, 854-863.
  10. Bolster DR, Vary TC, Kimball SR, Jefferson LS: Leucine regulates translation initiation in rat skeletal muscle via enhanced eIF4G phosphorylation. J Nutr. 2004, 1704-1710.
  11. Vianna D, Teodoro GFR, Torres-Leal, FL, Tirapegui J. Protein synthesis regulation by leucine. Braz. J. Pharm. Sci., 2010, 29-36.
  12. Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab, 2012, 1329-342.
  13. Bröer S, BröerA. Amino acid homeostasis and signalling in mammalian cells and organisms. Biochem, 2017, J 1935–1963.
  14. Melnik, BC. Excessive leucine-mtorc1-signalling of cow milk-based infant formula: the missing link to understand early childhood obesity. Journ Obes. (2012) doi: 197653. 10.1155/2012/197653
  15. Melnik BC: Milk—A nutrient system of mammalian evolution promoting mtorc1-dependent translation. Int. J. Mol. Sci., 2015, 7048-17087.
  16. Melick CH, Jewell JL. Regulation of mTORC1 by upstream stimuli. Genes (2020). doi:10.3390/genes11090989
  17. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010, 310-322.
  18. Sabatini DM. Twenty-five years obsessing over mTOR. PNAS, 2017, 1181811825.
  19. Melnik BC. Lifetime impact of cow's milk on overactivation of mTORC1: from fetal to childhood overgrowth, acne, diabetes, cancers and neurodegeneration. Biomolecules. (2021). doi:10.3390/biom11030404.
  20. Vezina C, Kudelski A, Sehgal S N. Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 1975, 721–726.
  21. Martel R R, Klicius J, Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J. Physiol. Pharmacol. 1977, 48–51.
  22. Eng CP, Sehgal SN, Vezina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J. Antibiot. 1984, 1231–1237.
  23. Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991, 905-909.
  24. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011, 21-35.
  25. Qian J, Su S, Liu P. Experimental approaches in delineating mTOR signaling. Genes. (2020). doi: 10.3390/genes11070738.
  26. Wullschleger S, Loewith R, Hall MN.TOR signaling in growth and metabolism. Cell, 2006, 471-484.
  27. Sancak Y, Peterson TR, Shaul YD et al: The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008, 1496– 1501.
  28. Tan VP, Miyamoto S. Nutrient-sensing mTORC1: integration of metabolic and autophagic signals. J. Mol. Cell Cardiol. 2016, 31–41.
  29. Dunlop EA; Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev. 2014, 121–129.
  30. Aylett CH, Sauer E, Imseng S et al: Architecture of human mTOR complex. Science. 2016, 48-52.
  31. Efeyan A, Zoncu R, Sabatini DM. Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med. 2012, 524-533.
  32. Efeyan, A.; Sabatini, D.M. Nutrients and growth factors in mTORC1 activation. Biochem. Soc. Trans. 902–905, 2013.
  33. Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 960-976, 2017.
  34. Kim J, Guan KL. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 63-71, 2019.
  35. Jhanwar-Uniyal M, Wainwright JV, Mohan AL et al: Diverse signaling mechanisms of mTOR complexes: mTORC1 and mTORC2 in forming a formidable relationship. Adv Biol Regul. 51-62, 2019.
  36. Proud CG. A new link in the chain from amino acids to mTORC1 activation. Molecular Cell.7–8, 2011.
  37. Kim J, Guan KL: Amino acid signaling in TOR activation. Annu Rev Biochem., 2011, 1001-32.
  38. Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol :555-556, 2013.
  39. Chantranupong L, Wolfson RL, Sabatini DM: Nutrient-sensing mechanisms across evolution. Cell. 2015, 67-83.
  40. Biswas D, Duffley L, Pulinilkunnil T. Role of branched chain amino acid– catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis. FASEB J. 2019, 8711–8731.
  41. Takahara T, Amemiya Y, Sugiyama R et al. Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. J Biomed Sci. (2020); doi: 10.1186/s 12929-020-00679-2.
  42. Han JM, Jeong SJ, Park MC et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell. 410–424, 2012.
  43. Bar-Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014, 400–406.
  44. Jewell JL, Kim YC, Russell RC et al: Differential regulation of mTORC1 by leucine and glutamine. Science. 2015, 194–198.
  45. Wolfson RL, Sabatini DM. The Dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 2017, 301–309.
  46. Son SM, Park SJ, Lee H et al. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab. 2019, 192–201.
  47. Son SM, Park SJ, Stamatakou E et al. Leucine regulates autophagy via acetylation of the mTORC1 component raptor. Nat Commun. (2020). doi: 10.1038/s41467020-16886.
  48. Luo Y, Xu W, Li G, Cui W. Weighing in on mTOR complex 2 signaling: the expanding role in cell metabolismo. Oxidative Medicine and Cellular Longevity (2018) doi.org/10.1155/2018/7838647.
  49. Smith SF, Collins SE, Charest PG. Ras, PI3K and mTORC2 - three's a crowd? J Cell Sci. (2020). doi: 10.1242/jcs.234930.
  50. Fu W, Hall MN. Regulation of mTORC2 signaling. Genes (Basel). 2020 doi: 10.3390/genes11091045.
  51. Baddour JA, Sousounis K, Tsonis PA. Organ repair and regeneration: An overview. Birth Defects Res. C Embryo Todday, 1–29, 2012.
  52. Cruz, B., Oliveira, A., Ventrucci, G et al. A leucine-rich diet modulates the mTOR cell signalling pathway in the gastrocnemius muscle under different Walker-256 tumour growth conditions. BMC Cancer. (2019).doi.org/10.1186/s12885-0195448-0
  53. Wei X, Luo L, Chen J. Roles of mTOR signaling in tissue regeneration. Cells. (2019). doi:10.3390/cells8091075
  54. Choi YJ, Di Nardo A, Kramvis I et al. Tuberous sclerosis complex proteins control axon formation. Genes Dev. 2008;22(18):2485-2495. doi:10.1101/gad.1685008.
  55. 55. Han JM, Sahi M. TSC1/TSC2 signaling in the CNS. FEBBS Letters, 973-980, 2011.
  56. Ohtake Y, Hayat U, Li S. PTEN inhibition and axon regeneration and neural repair. Neural Regen Res. 1363-1368, 2015.
  57. Zhang J, Yang D, Huang H et al: Coordination of necessary and permissive signals by PTEN inhibition for CNS axon regeneration. Front Neurosci (2018). doi.org/10.3389/fnins.2018.00558.
  58. Philips AM, Khan N. Amino acid sensing pathway: A major check point in the pathogenesis of obesity and COVID-19. Obes Rev. (2021) doi:10.1111/obr.13221.
  59. Wang CH, Chung FT, Lin SM et al. Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit Care Med. 313 321, 2014.
  60. Siddik MAB, Shin AC. Recent progress on branched-chain amino acids in obesity, diabetes, and beyond. Endocrinol Metab 234-246, 2019.
  61. Leenders M, van Loon LJ. Leucine as a pharmaconutrient to prevent and treat sarcopenia and type 2 diabetes. Nutrition Reviews, 675-689, 2011.
  62. Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab. 1329-1342, 2012.
  63. Martínez-Arnau FM, Fonfría-Vivas R, Cauli O. Beneficial effects of leucine supplementation on criteria for sarcopenia: A systematic review. Nutrients. (2019). doi: 10.3390/nu11102504.
  64. Yoshimura Y, Bise T, Shimazu S et al. Effects of a leucine-enriched amino acid supplement on muscle mass, muscle strength, and physical function in post-stroke patients with sarcopenia: A randomized controlled trial. Nutrition. 1-6, 2019.
  65. Akan B. Influence of sarcopenia focused on critically ill patients. Acute Crit Care.2021, 15-21.
  66. Zhang Y, Guo K, LeBlanc RE et al: Increasing dietary leucine intake reduces dietinduced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes.1647-1654, 2007.
  67. Binder E, Bermúdez-Silva FJ, André C et al: Leucine supplementation protects from insulin resistance by regulating adiposity levels. (2013). doi.org/10.1371/journal.pone.0074705.
  68. Bloomgarden Z. Diabetes and branched-chain amino acids: What is the link? J Diabetes. (2018). doi: 10.1111/1753-0407.12645.
  69. Almeida AP, Fortes FS, Silveira BKS et al. (2020). Branched-Chain amino acids intake is negatively related to body adiposity in individuals at cardiometabolic risk. Revista de Nutrição,doi.org/10.1590/1678-9865202033e190208.
  70. Ye Z, Wang S, Zhang C, Zhao Y. Coordinated modulation of energy metabolism and inflammation by branched-chain amino acids and fatty acids. Front Endocrinol. 2020. doi: 10.3389/fendo.2020.00617.
  71. Duan Y, Li F, Li Y et al: The role of leucine and its metabolites in protein and energy metabolism. Amino Acids. (2016). doi: 10.1007/s00726-015-2067-1
  72. Harris RA, Joshi M, Jeoung NH, Obayashi M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. The Journal of nutrition. 2005:1527-30.
  73. Rogero MM, Tirapegui J. Aspectos atuais sobre aminoácidos de cadeia ramificada e exercício físico. Rev Bras Cienc Farm. 563-575, 2008.
  74. Soares JD, Howell SL, Teixeira FJ, Pimentel GD. Dietary amino acids and immunonutrition supplementation in cancer-induced skeletal muscle mass depletion: A mini-review. Curr Pharm Des. 970-978, 2020.
  75. Maltais ML, Perreault K, Courchesne-Loyer A et al. Effect of resistance training and various sources of protein supplementation on body fat mass and metabolic profile in sarcopenic overweight older adult men: a pilot study. Int J Sport Nutr Exerc Metab. 71–77, 2016.
  76. Nabuco HCG, Tomeleri CM, Fernandes RR et al. Effect of whey protein supplementation combined with resistance training on body composition, muscular strength, functional capacity, and plasma-metabolism biomarkers in older women with sarcopenic obesity: a randomized, double-blind, placebocontrolled trial. Clin Nutr ESPEN. 88–95, 2019.
  77. Mirzoev TM. Skeletal muscle recovery from disuse atrophy: protein turnover signaling and strategies for accelerating muscle regrowth. Int J Mol Sci. (2020). doi: 10.3390/ijms21217940.
  78. Bennett BT, Mohamed JS, Alway SE. The effects of calcium-β-hydroxy-βmethylbutyrate on aging-associated apoptotic signaling and muscle mass and function in unloaded but nonatrophied extensor digitorum longus muscles of aged rats. Oxid Med Cell Longev. (2020). doi: 10.1155/2020/3938672.
  79. Jakubowski JS, Nunes EA, Teixeira FJ et al: Supplementation with the leucine metabolite β-hydroxy-β-methylbutyrate (hmb) does not improve resistance exercise-induced changes in body composition or strength in young subjects: a systematic review and meta-analysis. Nutrients. (2020). doi: 10.3390/nu12051523.
  80. Gran P, Cameron-Smith D. The actions of exogenous leucine on mTOR signalling and amino acid transporters in human myotubes. BMC physiology.2011 – Published online 10.1186/1472-6793-11-10.
  81. Liu H, Liu R, Xiong Y et al. Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: involving mTORC1 and mTORC2. Amino Acids. 2014, 1971-1979.
  82. Deldique L, Sanchez-Canedo C, Horman S et al: Antagonistic effects of leucine and glutamine on the mTOR pathway in myogenic C2C12 cells. Amino Acids. 147-155, 2008.
  83. Atherton PJ, Smith K, Etheridge T et al: Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells. Amino Acids. 2010, 1533-1539.
  84. Meijer A, Baquet A, Gustafson L et al. Mechanism of activation of liver glycogen synthase by swelling. J. Biol. Chem. 5823–5828, 1992.
  85. Vary T C, Jefferson S, Kimball SR: Amino acid-induced stimulation of translation initiation in rat skeletal muscle.Am. J. Physiol, 1077-1086, 1999.
  86. Bolster DR, Vary TC, Kimball SR, Jefferson LS. Leucine regulates translation initiation in rat skeletal muscle via enhanced eIF4G phosphorylation. J Nutr. 1704-1710, 2004.
  87. Anthony JC, Anthony TG, Kimball SR et al: Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J. Nutr. 2000, 139-145.
  88. Proud C. mTOR-mediated regulation of translation factors by amino acids. Biochem Biophys Res Commun 2004, 429–436.
  89. Stipanuk MH: Leucine and protein synthesis: mTOR and beyond. Nutr. Rev. 122129, 2007.
  90. Peyrollier K, Hajduch E, Blair AS et al: L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport. Biochem J. 361-368, 2000.
  91. Guo CY, Yu MX, Dai JM et al: Roles of mitogen-activating protein kinase kinase kinase kinase-3 (MAP4k3) in preterm skeletal muscle satellite cell myogenesis and mammalian target of rapamycin complex 1 (mTORC1) activation regulation. Med Sci Monit. 3562-3570. 2017.
  92. Antunes D, Chowdhury A, Aich A et al. Overexpression of branched-chain amino acid aminotransferases rescues the growth defects of cells lacking the Barth syndrome-related gene TAZ1. J Mol Med (2019). doi: 10.1007/s00109-018-1728-4.
  93. D'Antona G, Ragni M, Cardile A et al. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. (2010). doi: 10.1016/j.cmet.2010.08.016.
  94. Tedesco L, Rossi F, Ragni M et al. A special amino-acid formula tailored to boosting cell respiration prevents mitochondrial dysfunction and oxidative stress caused by doxorubicin in mouse cardiomyocytes. Nutrients. (2020). doi: 10.3390/nu12020282.
  95. Duan Y, Li F, Liu H et al. Nutritional and regulatory roles of leucine in muscle growth and fat reduction. Front Biosci :796-813, 2015.
  96. Duan Y, Li F, Li Y et al. The role of leucine and its metabolites in protein and energy metabolism. Amino Acids. 41-51, 2016.
  97. Kamei Y, Hatazawa Y, Uchitomi R et al: S. Regulation of skeletal muscle function by amino acids. Nutrients. (2020) doi: 10.3390/nu12010261.
  98. Zhang Y, Guo K, LeBlanc RE et al: Increasing dietary leucine intake reduces dietinduced obesity and improves glucose and cholesterol metabolism in mice via multimechanisms. Diabetes.1647-1654, 2007.
  99. Valerio A, D'Antona G, Nisoli E. Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective. Aging. 464-478, 2011.
  100. Binder E, Bermúdez-Silva FJ, André C et al: Leucine supplementation protects from insulin resistance by regulating adiposity levels. (2013). doi.org/10.1371/journal.pone.0074705
  101. Liu R, Li H, Fan W et al. Leucine supplementation differently modulates branched-chain amino acid catabolism, mitochondrial function and metabolic profiles at the different stage of insulin resistance in rats on high-fat diet. Nutrients. (2017). doi: 10.3390/nu9060565.
  102. Bloomgarden Z. Diabetes and branched-chain amino acids: What is the link? J Diabetes. (2018). doi: 10.1111/1753-0407.12645.
  103. Zhang L Li F, Guo Q et al: Leucine supplementation: a novel strategy for modulating lipid metabolism and energy homeostasis. Nutrients. (2020). doi: 10.3390/nu1205129
  104. Ye Z, Wang S, Zhang C, Zhao Y. Coordinated modulation of energy metabolism and inflammation by branched-chain amino acids and fatty acids. Front Endocrinol. 2020. doi: 10.3389/fendo.2020.00617.
  105. Valerio T. Mitochondrial biogenesis: pharmacological approaches. Curr Pharm Des. (2014). doi: 10.2174/13816128203514091114211.
  106. Stancliffe RA: Role of beta-hydroxy-beta-methylbutyrate (hmb) in leucine stimulation of mitochondrial biogenesis and fatty acid oxidation. Masters Theses University of Tennessee, 2012.
  107. Liang C, Curry BJ, Brown PL, Zemel MB. Leucine Modulates Mitochondrial Biogenesis and SIRT1-AMPK Signaling in C2C12 Myotubes. J Nutr Metab. (2014). doi: 10.1155/2014/239750.
  108. Sergi D, Naumovski N, Heilbronn LK et al. Mitochondrial (dys)function and insulin resistance: from pathophysiological molecular mechanisms to the impact of diet. Front Physiol. (2019).doi: 10.3389/fphys.2019.00532.
  109. Yu SB, Pekkurnaz G. Mechanisms orchestrating mitochondrial dynamics for energy homeostasis. J Mol Biol. 3922-3941, 2018.
  110. Tubbs E, Chanon S, Robert M et al. Disruption of mitochondria-associated endoplasmic reticulum membrane (mam) integrity contributes to muscle insulin resistance in mice and humans. Diabetes. 636-650, 2018.
  111. Giacomello M, Pyakurel A, Glytsou C. et al. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol, 204–224, 2020.
  112. Baker M J, Frazier A E, Gulbis J M, Ryan M T. Mitochondrial proteinimport machinery: Correlating structure with function. Trends in Cell Biology , 456-464, 2007.
  113. Wenz LS, Opaliński L, Wiedemann L, Becker T. Cooperation of protein machineries in mitochondrial protein sorting. Molecular Cell Research 11191129, 2015.
  114. Sun X, Zemel MB. Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes. Nutr Metab (2009). doi.org/10.1186/1743-7075-6-26.
  115. Craig DM, Ashcroft SP, Belew MY et al. Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis. Front Physiol. 2015 doi: 10.3389/fphys.2015.00296.
  116. Skinner DM. The effect of leucine supplementation on mitochondrial biogenesis and mitochondrial protein synthesis in rats fed a high-fat diet. Honors Theses. University of Arkansas, 2015.
  117. Almeida AP, Fortes FS, Silveira BKS et al. (2020). Branched-Chain amino acids intake is negatively related to body adiposity in individuals at cardiometabolic risk. Revista de Nutrição,doi.org/10.1590/16789865202033e190208.
  118. Myers MJ, Shepherd DL, Durr AJ et al. The role of SIRT1 in skeletal muscle function and repair of older mice. J Cachexia Sarcopenia Muscle.929-949, 2019.
  119. Dam G, Aamann L, Vistrup H, Gluud LL. The role of Branched Chain Amino Acids in the treatment of hepatic Encephalopathy. J Clin Exp Hepatol:448-451, 2018.
  120. Muting D, Wortmann V. Amino acid metabolism in liver diseases. Dtsch Med Wochenschr. 1853–1856,1956;
  121. Fischer J.E., Rosen H.M., Ebeid A.M. The effect of normalization of plasma amino acids on hepatic encephalopathy in man. Surgery. 77–91,1976.
  122. Román E, Torrades MT, Nadal MJ et al. Randomized pilot study: effects of an exercise programme and leucine supplementation in patients with cirrhosis. Digestive Diseases and Sciences. 1966-1975, 2014.
  123. Gluud L, Dam G, Les I et al: Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017 18;5:CD001939
  124. Yang YJ, Kim DJ. An overview of the molecular mechanisms contributing to musculoskeletal disorders in chronic liver disease: osteoporosis, sarcopenia, and osteoporotic sarcopenia. International Journal of Molecular Sciences. (2021). DOI: 10.3390/ijms22052604
  125. Holecek M, Kandar R, Sispera L, Kovarik M. Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle. Amino Acids. 575– 584, 2011.
  126. Tedesco L, Corsetti G, Ruocco C et al. A specific amino acid formula prevents alcoholic liver disease in rodents. Am J Physiol Gastrointest Liver Physiol. (2018). doi: 10.1152/ajpgi.00231.2017.
  127. Wei X, Luo L, Chen J. Roles of mTOR signaling in tissue regeneration. Cells. (2019). doi:10.3390/cells8091075
  128. Jefferson LS, Korner A: A direct effect of growth hormone on the incorporation of precursors into proteins and nucleic acids of perfused rat live Biochem. J. 1967, 826-832.
  129. Krause U, Bertrand L, Maisin L et al: Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur J Biochem. 2002, 3742-3750.
  130. Dennis MD, Baum JI, Kimball SR, Jefferson LS: Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids. J Biol Chem. 2011, 8287-8296.
  131. Prins ML. Glucose metabolism in pediatric traumatic brain injury. Childs Nerv Syst. 2017, 1711-1718.
  132. Bowman CE, Scafidi J, Scafidi S. Metabolic perturbations after pediatric TBI: It's not just about glucose. Exp Neurol, 2019, 74-84.
  133. Bernini A, Masoodi M, Solari D et al. Modulation of cerebral ketone metabolism following traumatic brain injury in humans. J Cereb Blood Flow Metab. 2020, 177-186.
  134. Hewton KG, Johal AS, Parker SJ. Transporters at the Interface between cytosolic and mitochondrial amino acid metabolism. Metabolites. (2021) doi:10.3390/metabo11020112.
  135. Rogero MM, Tirapegui J. Current aspects of branched chain amino acid and exercise. Revista Brasileira De Ciências Farmacêuticas, 563-575, 2008.
  136. Sperringer JE, Addington A, Hutson SM. Branched-chain amino acids and brain metabolism. Neurochem. 2017, 1697–1709.
  137. Spinelli JB, Haigis MC. The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol. 2018, 745-754.
  138. Niklison-Chirou MV, Agostini M, Amelio I, Melino G. Regulation of adult neurogenesis in mammalian brain. Int J Mol Sci. (2020). doi: 10.3390/ijms21144869.
  139. Aquilani R, Iadarola P, Contardi A et al. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil. 1729-1735, 2005.
  140. Sharma B, Lawrence DW, Hutchison MG. Branched chain amino acids (bcaas) and traumatic brain injury: a systematic review. J Head Trauma Rehabil. 33-45, 2018.
  141. Bowman CE, Scafidi J, Scafidi S. Metabolic perturbations after pediatric TBI: It's not just about glucose. Experimental Neurology, 74-84, 2019.
  142. Jeter CB, Hergenroeder GW, Ward NH et al. Human mild traumatic brain injury decreases circulating branched-chain amino acids and their metabolite levels. J Neurotrauma. 671-629, 2013.
  143. Vespa P, Bergneider M, Hattori N et al. Metabolic crisis without brain ischemia is common after traumatic brain injury: a combined microdialysis and positron emission tomography study. J Cereb Blood Flow Metab. 763–774, 2005.
  144. Carre E, Ogier M, Boret H et al. Metabolic crisis in severely head-injured patients: is ischemia just the tip of the iceberg? Front Neurol. (2013). doi: 10.3389/fneur.2013.00146.
  145. Agostini M, Romeo F, Inoue S et al. Metabolic reprogramming during neuronal differentiation. Cell Death Differ, 1502–1514, 2016.
  146. Koppel SJ, Swerdlow RH. Neuroketotherapeutics: A modern review of a century-old therapy. Neurochem Int. 114-125, 2018.
  147. Maffezzini C, Calvo-Garrido J, Wredenberg A, Freyer C. Metabolic regulation of neurodifferentiation in the adult brain. Cell Mol Life Sci. 2020, 2483-2496.
  148. Guzmán M, Blázquez C. Ketone body synthesis in the brain: possible neuroprotective effects. Prostaglandins Leukot Essent Fatty Acids. 287-92, 2004.
  149. White H, Venkatesh B. Clinical review: Ketones and brain injury. Crit Care (2011). doi.org/10.1186/cc10020.
  150. Barber CN, Raben DM. Lipid metabolism crosstalk in the brain: glia and neurons. Front Cell Neurosci. (2019). doi:10.3389/fncel.2019.00212.
  151. Smith QR, Takasato Y, Sweeney DJ, Rapoport SI: Regional cerebrovascular transport of leucine as measured by the in situ brain perfusion technique, J Cereb Blood Flow Metab. 1985, 300-311.
  152. Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood-brain barrier. J. Neurochem. 1987, 1651–165.
  153. Smith QR (1991). The blood-brain barrier and the regulation of amino acid uptake and availability to brain. Adv. Exp. Med. Biol.414–416, 1991
  154. Zaragoza R. Transport of amino acids across the blood-brain barrier. Front Physiol. (2020). doi:10.3389/fphys.2020.00973
  155. Martinez-Hernandez A, Bell KP, Norenberg MD. Glutamine synthetase: glial localization in brain. Science. 1977, 1356-1358.
  156. Yudkoff M. Brain metabolism of branched-chain amino acids. Glia. 1997, 92–98.
  157. Hutson SM, Lieth E, LaNoue KF. Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr. 2001, 846-850.
  158. Yudkoff M, Daikhin Y, Nissim I et al. Brain amino acid requirements and toxicity: the example of leucine. J Nutr.1531-1538, 2005.
  159. Nissim I, States B, Yudkoff M, Segal S. Characterization of amino acid metabolism by cultured rat kidney cells: study with 15N. Am J Physiol. 1987, 1243-1252.
  160. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord. 2003, 369–378.
  161. Park E, Alexander A. Velumian AA, Fehlings MG: The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. Journal of Neurotrauma. 754-774, 2004.
  162. Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases—what is the evidence? Front Cell Neurosci. (2015). Doi 10.3389/fnins.2015.00469
  163. Kirdajova DB, Kriska J, TureckovaJ, Anderova Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front Cell Neurosc (2020). doi.org/10.3389/fncel.2020.00051.
  164. Shambaugh GE 3rd, Koehler RA. Fetal fuels VI. Metabolism of alphaketoisocaproic acid in fetal rat brain. Metabolism. 421-427, 1983.
  165. Yudkoff M. Interactions in the metabolism of glutamate and the branchedchain amino acids and ketoacids in the CNS. Neurochem Res. 10-18, 2017.
  166. Yudkoff M, Daikhin Y, Nelson D et al: Neuronal metabolism of branchedchain amino acids: flux through the aminotransferase pathway in synaptosomes. J Neurochem. 2136–2145, 1996.
  167. Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 208-215, 1999.
  168. Syková E. Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neurosci 861–876, 2004.
  169. Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci , 626–640, 2005.
  170. Schafer DP, Lehrman EK, Stevens B. The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS. Glia. 24-36, 2013.
  171. Cabral A, Portela R, Tasso T e col: Doenças dos aminoácidos de cadeia ramificada. Acta Med Port. 659-665, 1998.
  172. Soldin SJ, Brugnara C, Wong EC: Pediatric Reference Intervals. 5ª ed. Washington.AACC Press, 2005.
  173. Chuang DT, Chuang JL, Wynn RM. Lessons from genetic disorders of branched-chain amino acid metabolism. J Nutr. 243-249, 2006.
  174. Hoffmann B, Helbling C, Schadewaldt P et al. Impact of longitudinal plasma leucine levels on the intellectual outcome in patients with classic MSUD. Pediatr Res 17–20, 2006.
  175. Valadares ER. Leucinose: Doença do xarope de bordo. In: Martins AM, organizador. Protocolo brasileiro de dietas: erros inatos do metabolismo. São Paulo: Segmento Farma, 53-58, 2007.
  176. Zinnanti WJ, Lazovic J: Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy. J Inherit Metab Dis. 71-79, 2012.
  177. Manoli I, Venditti CP. Disorders of branched chain amino acid metabolism. Transl Sci Rare Dis. 91-110, 2016.
  178. Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. EMBO J. 1474-1492, 2017.
  179. Jensen NJ, Wodschow HZ, Nilsson M, Rungby J. Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. Int J Mol Sci. (2020). doi: 10.3390/ijms21228767.
  180. Polis B, Samson AO. Role of the metabolism of branched-chain amino acids in the development of Alzheimer's disease and other metabolic disorders. Neural Regen Res. 1460-1470, 2020.
  181. Socha E, Kośliński P, Koba M et al. Serum amino acid profiles in patients with mild cognitive impairment and in patients with mild dementia or moderate dementia. Amino Acids. 97-109, 2021.
  182. Shang X, Hill E, Li Y, He M. Energy and macronutrient intakes at breakfast and cognitive declines in community-dwelling older adults: a 9-year follow-up cohort study. Am J Clin Nutr. (2021). doi: 10.1093/ajcn/nqaa403.
  183. Sato H, Takado Y, Toyoda S et al: Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model. (2021). Science Advances. doi/abs/10.1126/sciadv.abd5046
  184. Oddo S.The role of mTOR signaling in Alzheimer disease. Front Biosci. 941-952, 2012.
  185. Tramutola A, Triplett JC, Di Domenico F, Alteration of mTOR signaling occurs early in the progression of Alzheimer disease (AD): analysis of brain from subjects with pre-clinical AD, amnestic mild cognitive impairment and late-stage AD.J Neurochem. 739-749, 2015.
  186. Crino PB. The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol. 379-392, 2016.
  187. Li H, Ye D, Xie W et al: Defect of branched-chain amino acid metabolism promotes the development of Alzheimer's disease by targeting the mTOR signaling. Biosci Rep. (2018). doi: 10.1042/BSR20180127.
  188. Norwitz NG, Querfurth H. mTOR mysteries: nuances and questions about the mechanistic target of rapamycin in neurodegeneration. Front Neurosci. (2020). doi: 10.3389/fnins.2020.00775
  189. Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 963-966, 2008
  190. Liu K, Lu Y, Lee JK et al: PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 1075-1081, 2010.
  191. Suzuki H, Yamashiro D, Ogawa S et al: Intake of seven essential amino acids improves cognitive function and psychological and social function in middle-aged and older adults: a double-blind, randomized, placebo-controlled trial. Front Nutr. (2020). doi: 10.3389/fnut.2020.586166.
  192. Tynkkynen J, Chouraki V, van der Lee SJ et al: Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts. Alzheimers Dement. (2018). doi: 10.1016/j.jalz.2018.01.003
  193. Fernando WMADB, Rainey-Smith SR, Gardener SL et al: Associations of dietary protein and fiber intake with brain and blood amyloid-β. J Alzheimers Dis. (2018) doi: 10.3233/JAD-170742.
  194. Hanger DP, Byers HL, Wray S, et al. Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem. (2007). doi: 10.1074/jbc.M703269200.
  195. Croft CL, Kurbatskaya K, Hanger DP, Noble W. Inhibition of glycogen synthase kinase-3 by BTA-EG4 reduces tau abnormalities in an organotypic brain slice culture model of Alzheimer's disease. Sci Rep. (2017). doi: 10.1038/s41598017-07906-
  196. Yang L, Wang H, Liu L, Xie A. The role of insulin/IGF-1/PI3K/Akt/GSK3beta signaling in Parkinson’s disease dementia. Front Neurosci. (2018). DOI=10.3389/fnins.2018.00073
  197. Xu F, NaL, Li Y. et al. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci (2020). doi.org/10.1186/s13578-020-00416-0.
  198. Caccamo A, Magrì A, Medina DX et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell. 370-80, 2013.
  199. Kitagishi Y, Nakanishi A, Ogura Y, Matsuda S. Dietary regulation of PI3K/AKT/GSK-3beta pathway in Alzheimer’s disease. Alzheimers Res Ther (2014) doi: 10.1186/alzrt265
  200. Episcopo F, Drouin-Ouellet J, Tirolo C et al: GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte-neuron interactions. Cell Death Dis. (2016). doi: 10.1038/cddis.2016.104.
  201. Duda P, Wiśniewski J, Wójtowicz T e col. Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging. Expert Opin Ther Targets. 833-848, 2018.
  202. Hosios AM, Hecht VC, Danai LV et al. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev Cell.540-549, 2016.
  203. Brandhorst S, Longo VD. Fasting and caloric restriction in cancer prevention and treatment. Recent Results Cancer Res. 241-266, 2016.
  204. Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care.64-70, 2018.
  205. Brandhorst S, Longo VD. Protein quantity and source, fasting-mimicking diets, and longevity. Adv Nutr. 340-350, 2019.
  206. Martin SB, Reiche WS, Fifelski NA et al: Leucine and branched-chain amino acid metabolism contribute to the growth of bone sarcomas by regulating AMPK and mTORC1 signaling. Biochem J. 1579-1599, 2020.
  207. Bröer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev. 249–286, 2008.
  208. Taylor PM. Role of amino acid transporters in amino acid sensing. Am J Clin Nutr. 223-230, 2014.
  209. Bröer S, Fairweather SJ. Amino Acid Transport Across the Mammalian Intestine. Compr Physiol, 343-373, 2018.
  210. Nicklin P, Bergman P, Zhang B. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 2009 521-534, 2009.
  211. Palm W, Park Y, Wright K et al. The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell. 259-270, 2015.
  212. Chen R, Zou Y, Mao D et al. The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation. J Cell Biol.173-182, 2014.
  213. Bhutia YD, Babu E, Ramachandran S, Ganapathy V. Amino acid transporters in cancer and their relevance to “glutamine addiction”: novel targets for the design of a new class of anticancer drugs. Cancer Res. 1782–1788, 2015.
  214. Cormerais Y, Vučetić M, Parks SK, Pouyssegur J. Amino acid transporters are a vital focal point in the control of mTORC1 signaling and cancer. Int J Mol Sci. (2020). doi:10.3390/ijms22010023.
  215. Errasti-Murugarren E, Palacín M. Heteromeric Amino Acid Transporters in Brain: from Physiology to Pathology. Neurochem Res (2021) doi: 10.1007/s11064-021-03261-w.
  216. Wang Q, Holst J. The L-type amino acid transporter family serves as an important route for EAA entry into cells and consists of four members (LAT1–4). L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. J Cancer Res. 1281-94, 2015.
  217. Bhutia YD, Ganapathy V. Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochim Biophys Acta. 2531-2539, 2016.
  218. Lukey MJ, Katt WP, Cerione RA. Targeting amino acid metabolism for cancer therapy. Drug Discov Today. 796-804, 2017.
  219. Zhang J, Xu Y, Li D et al. Review of the correlation of LAT1 with diseases: mechanism and treatment. Front Chem. (2020) doi:10.3389/fchem.2020.564809.
  220. Jewell JL, Kim YC, Russell RC et al. Differential regulation of mTORC1 by leucine and glutamine. Science. 194-198, 2015.
  221. Drummond MJ, Glynn EL, Fry CS et al: An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle. Am J Physiol Endocrinol Metab. 1011-1018, 2010.
  222. Hayashi K, Jutabha P, Endou H et al. LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells. J Immunol. (2013). doi: 10.4049/jimmunol. 1300923
  223. Salisbury TB, Arthur S. The regulation and function of the L-type amino acid transporter 1 (LAT1) in cancer. Int J Mol Sci. (2018). doi: 10.3390/ijms19082373
  224. Tărlungeanu DC, Deliu E, Dotter CP et al. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell. 1481-1494, 2016.
  225. Suzuki A, Iwata J. Amino acid metabolism and autophagy in skeletal development and homeostasis. Bone. (2021). doi: 10.1016/j.bone.2021.
  226. Ozaki K, Yamada T, Horie T et al. The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway. Sci Signal. (2019). doi:10.1126/scisignal.aaw3921.
  227. Wang Q, Tiffen J, Bailey CG et al: Targeting amino acid transport in metastatic castration-resistant prostate cancer: effects on cell cycle, cell growth, and tumor development. Journal of the National Cancer Institute. 9-21, 2013.
  228. Marshall AD, van Geldermalsen M, Otte N J et al: LAT1 is a putative therapeutic target in endometrioid endometrial carcinoma. Int. J. Cancer, 2529– 2539, 2016.
  229. Cormerais Y, Pagnuzzi-Boncompagni M, Schrötter S et al: Inhibition of the amino-acid transporter LAT1 demonstrates anti-neoplastic activity in medulloblastoma. J Cell Mol Med. 2711–2718, 2019.
  230. Häfliger P, Charles RP. The L-Type Amino Acid Transporter LAT1-An emerging target in cancer. Int J Mol Sci. (2019). doi:10.3390/ijms20102428.
  231. Sato K, Miyamoto M, Takano M et al: Significant relationship between the LAT1 expression pattern and chemoresistance in ovarian clear cell carcinoma. Virchows Arch 701–710, 2019.
  232. Kaira K, Kawashima O, Endoh H et al. Expression of amino acid transporter (LAT1 and 4F2hc) in pulmonary pleomorphic carcinoma. Hum. Pathol. 2142–149, 2019.
  233. Lu JJ, Li P, Yang Y et al: Prognostic value of LAT-1 status in solid cancer: A systematic review and meta-analysis. PLoS One. (2020). doi: 10.1371/journal.pone.0233629.
  234. Sinclair LV, Rolf J, Emslie E et al: Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013, 500-508.
  235. Ananieva EA, Patel CH, Drake CH et al. Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J Biol Chem. 18793-18804, 2014.
  236. Wang Q, Holst J. L-type amino acid transport and cancer: targeting the mTORC1 pathway to inhibit neoplasia. J Cancer Res. 1281-1294, 2015.
  237. Ananieva EA, Powell JD, Hutson SM. Leucine metabolism in T cell activation: mTOR signaling and beyond. Adv Nutr. 798-805, 2016.
  238. Häfliger P, Charles RP. The L-type amino acid transporter LAT1: An emerging target in câncer. (2019). Int J Mol Sci. doi: 10.3390/ijms20102428.
  239. Danay Cibrian D, Castillo-Gonzalez R, Fernandez-Gallego N et al: Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation. J Allergy Clin Immunol (2020) doi.org/10.1016/j.jaci.2019.09.025
  240. Puris E, Gynther M, Auriola S. et al. L-Type amino acid transporter 1 as a target for drug delivery. Pharm Res (2020). https://doi.org/10.1007/s11095-02002826-8.
  241. Hayashi K, Kaminuma O, Nishimura T et al: LAT1-specific inhibitor is effective against T cell-mediated allergic skin inflammation. Allergy. 463–467, 2020.
  242. Kaminuma O, Nishimura T, Saeki M et al: (2020). L-type amino acid transporter 1 (LAT1) specific inhibitor is effective against T cell-mediated nasal hyperresponsiveness. Allergology International. DOI: 69. 10.1016/j.alit.2019.12.006.
  243. Ito D, Miura K, Saeki M et al: L-type amino acid transporter 1 inhibitor suppresses murine Th2 cell-mediated bronchial hyperresponsiveness independently of eosinophil accumulation. Asia Pac Allergy. (2021). doi: 10.5415/apallergy.2021.11.e33
  244. Hayashi K, Anza N: L-type amino acid transporter 1 as a target for inflammatory disease and cancer immunotherapy, Journal of Pharmacological Sciences, 2021,1347-8613.
  245. Yoshida S, Pacitto R, Inoki K, Swanson J. Macropinocytosis, mTORC1 and cellular growth control. Cell Mol Life Sci. 1227-1239, 2018.
  246. Hoeller O, Bolourani P, Clark J, et al. Two distinct functions for PI3kinases in macropinocytosis. J Cell Sci. 4296-4307, 2013.
  247. Kay RR, Williams TD, Paschke P. Amplification of PIP3 signalling by macropinocytic cups. Biochem J. 643-648. 2018.
  248. Salloum G, Jakubik CT, Erami Z et al: PI3Kβ is selectively required for growth factor-stimulated macropinocytosis. Journal of Cell Science (2019). doi: 10.1242/jcs.231639
  249. Swanson JA, Watts C Macropinocytosis.Trends Cell Biol. 424-428,1995.
  250. Swanson JA. Shaping cups into phagosomes and macropinosomes. Nat Rev Mol Cell Biol. 639-649, 2008.
  251. Yoshida S, Hoppe AD, Araki N, Swanson JA. Sequential signaling in plasma-membrane domains during macropinosome formation in macrophages. J Cell Sci. 3250-3561, 2009.
  252. Commisso C, Davidson SM, Soydaner-Azeloglu RG et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. (2013) Nature. doi: 10.1038/nature12138.
  253. Palm W, Park Y, Wright K et al: The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell , 259–270, 2015.
  254. Palm W. Metabolic functions of macropinocytosis. Philos Trans R Soc Lond B Biol Sci. (2019). doi: 10.1098/rstb.2018.0285.
  255. Shaojuan S, Yanan Z, Tingting D et al: The dual role of macropinocytosis in cancers: promoting growth and inducing methuosis to participate in anticancer therapies as targets (2021). Frontiers in Oncology. doi. 10.3389/fonc.2020.570108.
  256. Shibutani S, Okazaki H, Iwata H. Dynamin-dependent amino acid endocytosis activates mechanistic target of rapamycin complex 1 (mTORC1). J Biol Chem. 18052-18061, 2017.
  257. Swanson JA, Yirinec B, Burke E et al. Effect of alterations in the size of the vacuolar compartment on pinocytosis in J774.2 macrophages. J. Cell. Physiol. 195–201, 1986.
  258. Swanson JA, Burke E, Silverstein SC. Tubular lysosomes accompany stimulated pinocytosis in macrophages. J. Cell Biol. 1217–1222, 1987.
  259. Swanson JA, Yoshida S. Macropinosomes as units of signal transduction. Philos Trans R Soc Lond B Biol Sci. (2019). doi:10.1098/rstb.2018.015.
  260. Shaw RJ, Cantley LC. Ras, PI3K and mTOR signalling controls tumour cell growth. Nature. 424–430, 2006.
  261. Yoshida S, Pacitto R, Yao Y et al: Growth factor signaling to mTORC1 by amino acid-laden macropinosomes. J Cell Biol. 159-172, 2015.
  262. Lewis WH. Pinocytosis. Johns Hopkins Hosp Bull, 17–26, 1931.
  263. Bridges D, Fisher K, Zolov SN et al: Rab5 proteins regulate activation and localization of target of rapamycin complex 1. J. Biol. Chem. 20913–20921, 2012.
  264. Nagano M, Toshima JY, Siekhaus DE et al. Rab5-mediated endosome formation is regulated at the trans-Golgi network. Commun Biol (2019). Doi. 10.1038/s42003-019-0670-5.
  265. Tang W, Tam JH, Seah C et al: Arf6 controls beta-amyloid production by regulating macropinocytosis of the amyloid precursor protein to lysosomes. (2015). Mol Brain. doi: 10.1186/s13041-015-0129-7.
  266. Zeineddine R, Yerbury JJ. The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases. (2015). Front Physiol. doi: 10.3389/fphys.2015.00277.
  267. Kabayama H, Nakamura T, Takeuchi M et al: Ca2+ induces macropinocytosis via F-actin depolymerization during growth cone colapse. (2009) Mol. Cell Neurosci. doi: 10.1016/j.mcn.2008.08.009.
  268. Fitzner D, Schnaars M, van Rossum D et al. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011:447458, 2011.
  269. Lin XP, Mintern JD, Gleeson PA. Macropinocytosis in different cell types: similarities and differences. Membranes (Basel). (2020) doi:10.3390/membranes10080177.
  270. Petrova V, Nieuwenhuis B, Fawcett JW, Eva R. Axonal organelles as molecular platforms for axon growth and regeneration after injury. Int J Mol Sci. (2021). doi: 10.3390/ijms22041798.
  271. DeBerardinis RJ, Mancuso A, Daikhin E et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. 19345-19350, 2007.
  272. Filipp FV, Ratnikov B, De Ingeniis J, et al: Glutamine-fueled mitochondrial metabolism is decoupled from glycolysis in melanoma. Pigment Cell Melanoma Res. 732-739, 2012.
  273. Sun H, Chen L, Cao S et al: Warburg effects in cancer and normal proliferating cells: two tales of the same name. Genomics, Proteomics & Bioinformatics, 273-286, 2019.
  274. Birkeland ES, Koch LM, Dechant R. Another consequence of the warburg effect? metabolic regulation of na+/h+ exchangers may link aerobic glycolysis to cell growth. Front Oncol. (2020). doi: 10.3389/fonc.2020.01561.
  275. DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 127–129, 2020.
  276. Lieu EL, Nguyen T, Rhyne S, Kim J. Amino acids in cancer. Exp Mol Med. 15-30, 2020.
  277. Keenan MM, Chi JT. Alternative fuels for cancer cells. Cancer J. 49-55, 2015.
  278. Sivanand S, Vander Heiden MG. Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell.147-156, 2020.
  279. Ananieva EA, Wilkinson AC. Branched-chain amino acid metabolism in cancer. Curr Opin Clin Nutr Metab Care. 64-70, 2018.
  280. Peng H, Wang Y, Luo W. Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene. 6747-6756, 2020.
  281. Wei Z, Liu X, Cheng C, Yu W, Yi P. Metabolism of amino acids in cancer. Front Cell Dev Biol. (2021) doi: 10.3389/fcell.2020.603837.
  282. Hattori A, Tsunoda M, Konuma T et al: Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature. 500-504, 2017.
  283. Charpentier JC, Chen D, Lapinski PE et al: Macropinocytosis drives T cell growth by sustaining the activation of mTORC1. Nat Commun. (2020). doi: 10.1038/s41467-019-13997-3.
  284. Zheng YH, Hu WJ, Chen BC et al: BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver Int, 1836-1847, 2016.
  285. Song Y, Zhao B, Xu Y et al: Prognostic significance of branched-chain amino acid transferase 1 and CD133 in triple-negative breast cancer. BMC Cancer. (2020). doi: 10.1186/s12885-020-07070-2
  286. Luo L, Sun W, Zhu W et al: BCAT1 decreases the sensitivity of cancer cells to cisplatin by regulating mTOR-mediated autophagy via branched-chain amino acid metabolism. Cell Death Dis. (2021) doi: 10.1038/s41419-021-03456-7.
  287. Zhang L, Han J. Branched-chain amino acid transaminase 1 (BCAT1) promotes the growth of breast cancer cells through improving mTOR-mediated mitochondrial biogenesis and function. Biochem Biophys Res Commun. 224-231, 2017.
  288. Tabe Y, Lorenzi PL, Konopleva M. Amino acid metabolism in hematologic malignancies and the era of targeted therapy. Blood. 1014-1023, 2019.
  289. Manning BD, Cantley LC. Rheb fills a gap between TSC and TOR. Trends Biochem Sci. 573–576, 2003.
  290. Wullschleger S, Loewith R, Hall MN.TOR signaling in growth and metabolism. Cell,471-484, 2006.
  291. Avruch J, Long X, Ortiz-Vega S et al: Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab. (2009). doi: 10.1152/ajpendo.90645.2008.
  292. Dodd KM, Tee AR. Leucine and mTORC1: a complex relationship. Am J Physiol Endocrinol Metab. 1329-1342, 2012.
  293. Dibble CC, Manning BD: Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol, 555–564, 2013.
  294. Dunlop EA, Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin. Cell Dev. Biol. 121–129, 2014.
  295. Ben-Sahra I, Manning BD. mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol. 72-82, 2017.
  296. Blenis J. TOR, the gateway to cellular metabolism, cell growth, and disease. Cell. 10-13, 2017.
  297. Kim J, Guan KL. mTOR as a central hub of nutrient signalling and cell growth. Nat Cell Biol. 63-71, 2019.
  298. Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease.Nat Rev Mol Cell Biol. 183-203, 2020.
  299. Thoreen CC, Chantranupong L, Keys HR et al: A unifying model for mTORC1-mediated regulation of mRNA translation. Nature.109-113, 2012.
  300. Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol, 133–139, 2013.
  301. Chantranupong L, Wolfson RL, Sabatini DM. Nutrient-sensing mechanisms across evolution. Cell. 67-83, 2015.
  302. Tan VP, Miyamoto, S. Nutrient-sensing mTORC1: integration of metabolic and autophagic signals. J. Mol. Cell Cardiol, 31–41, 2016.
  303. Li XZ, Yan XH. Sensors for the mTORC1 pathway regulated by amino acids. J Zhejiang Univ Sci B. 699-712, 2019.
  304. Szwed A, Kim E, Jacinto E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol Rev. 1371-1426, 2021.
  305. Sancak Y, Peterson TR, Shaul YD e col. Rag GTPases bind RAPTOR and mediate amino acid signaling to mTORC1. Science. 1496-1501, 2008.
  306. Li SC, Kane PM. The yeast lysosome-like vacuole: endpoint and crossroads. Biochim. Biophys. Acta, 650–663, 2009.
  307. Sancak Y, Bar-Peled L, Zoncu R et al: Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell: 290-303, 2010.
  308. Efeyan A, Zoncu R, Sabatini DM. Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med. 524-533, 2012.
  309. Groenewoud MJ, Zwartkruis FJ. Rheb and Rags come together at the lysosome to activate mTORC1. Biochem Soc Trans. 951-955, 2013.
  310. Zhu M, Wang X, Regulation of mTORC1 by small GTPases in response to nutrients, J Nutr, 1004–1011, 2020.
  311. Bar-Peled L, Sabatini DM. Regulation of mTORC1 by amino acids. Trends Cell Biol. 400-406, 2014.
  312. Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 545-555, 2015.
  313. Abraham RT. Making sense of amino acid sensing. Science. 128-129, 2015.
  314. Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 960-976, 2017.
  315. Zhuang Y, Wang XX, He J et al: Recent advances in understanding of amino acid signaling to mTORC1 activation. Front Biosci. 971-982, 2019.
  316. Meng D, Yang Q, Wang H, et al. Glutamine and asparagine activate mTORC1 independently of Rag GTPases. J Biol Chem. 2890-2899, 2020.
  317. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 274-293, 2012.
  318. Zheng L, Zhang W, Zhou Y et al (2016). Recent advances in understanding amino acid sensing mechanisms that regulate mTORC1. Int J Mol Sci.doi:10.3390/ijms17101636.
  319. Takahara T, Amemiya Y, Sugiyama R. et al. Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes. J Biomed Sci (2020). doi.org/10.1186/s12929-020-00679-2.
  320. Nicklin P, Bergman P, Zhang B et al: Bidirectional transport of amino acids regulates mTOR and autophagy. Cell. 521-34, 2009.
  321. Jewell JL, Kim YC, Russell RC, Yu FX. Differential regulation of mTORC1 by leucine and glutamine.Science. 194-198, 2015.
  322. Li XZ, Yan XH. Sensors for the mTORC1 pathway regulated by amino acids. J Zhejiang Univ Sci B. 699-712, 2019.
  323. Han JM, Jeong SJ, Park MC, et a. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell. 410-424, 2012.
  324. Durán RV, Hall MN. Leucyl-tRNA synthetase: double duty in amino acid sensing. Cell Res. 1207-1209, 2012.
  325. Segev N, Hay N. Hijacking leucyl-tRNA synthetase for amino aciddependent regulation of TORC1. Mol Cell. 4-6, 2012.
  326. Yoon MS, Son K, Arauz E et al. Leucyl-tRNA synthetase activates vps34 in amino acid-sensing mtorc1 signaling. Cell Rep. 1510-1517, 2016.
  327. Yu YC, Han JM, Kim S. Aminoacyl-tRNA synthetases and amino acid signaling. Biochim Biophys Acta Mol Cell Res (2021). doi: 10.1016/j.bbamcr.2020.118889.
  328. Melick C, Jewell JL. Regulation of mTORC1 by upstream stimuli. Genes (2020). doi:10.3390/genes11090989.
  329. Wolfson RL, Chantranupong L, Saxton RA et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 43-48, 2016.
  330. Chantranupong L, Wolfson RL, Orozco JM et al: The sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep. 1-8, 2014.
  331. Kimball SR, Gordon BS, Moyer JE et al. Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation. Cell. Signal. 896– 906, 2016
  332. Wolfson RL, Sabatini DM. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 301-309, 2017.
  333. Wang S, Tsun ZY, Wolfson RL et al. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science. 188-194, 2015.
  334. Chantranupong L, Scaria SM, Saxton RA et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164, 2016.
  335. Ho A, Cho CS, Namkoong S et al. Biochemical basis of sestrin physiological activities. Trends Biochem Sci. 41, 621–632, 2016.
  336. Lee JH, Cho US, Karin M. Sestrin regulation of TORC1: is sestrin a leucine sensor? Sci. Signal. (2016). doi:10.1126/scisignal.aaf2885
  337. Gu X, Orozco JM, Saxton RA et al: SAMTOR is na S-adenosylmethionine sensor for the mTORC1 pathway. Science. 813–818, 2017.
  338. Gulati P, Gaspers LD, Dann SG et al: Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34.Cell Metab.456-65, 2008.
  339. Mercan F, Lee H, Kolli S, Bennett AM. Novel role for SHP-2 in nutrientresponsive control of S6 kinase 1 signaling. Mol Cell Biol. 293-306, 2013.
  340. Son SM, Park SJ, Lee H et al. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab. 192-201, 2019.
  341. Weckhuysen S, Marsan E, Lambrecq V et al; Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia. 994-1003, 2006.
  342. Baldassari S, Licchetta L, Tinuper P, Bisulli F, Pippucci T. GATOR1 complex: the common genetic actor in focal epilepsies. J Med Genet. 503-510, 2016.
  343. Baldassari S, Picard F, Verbeek NE et al: The landscape of epilepsyrelated GATOR1 variants. Genet Med.:398-408, 2019.
  344. Dawson RE, Nieto Guil AF, Robertson LJ et al. Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy. Neurobiol Dis. (2020). doi: 10.1016/j.nbd.2019.104640.
  345. Iffland PH 2nd, Carson V, Bordey A, Crino PB. GATORopathies: The role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia. 2163-2173, 2019.
  346. Specchio N, Pepi C, De Palma L et al: Neuroimaging and genetic characteristics of malformation of cortical development due to mTOR pathway dysregulation: clues for the epileptogenic lesions and indications for epilepsy surgery. Expert Rev Neurother. 1333-1345, 2021.
  347. Lee WS, Baldassari S, Stephenson SEM et al: Cortical Dysplasia and the mTOR pathway: How the study of human brain tissue has led to insights into epileptogenesis. Int J Mol Sci. (2022) doi: 10.3390/ijms23031344.
  348. Griffith JL, Wong M. The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol. 49-58, 2018.
  349. Karalis V, Bateup HS. Current approaches and future directions for the treatment of mTORopathies. Dev Neurosci. 143-158, 2021.
  350. Moloney PB, Cavalleri GL, Delanty N. Epilepsy in the mTORopathies: opportunities for precision medicine. Brain Commun. (2021). doi: 10.1093/braincomms/fcab222.
  351. Nguyen LH, Bordey A. Convergent and divergent mechanisms of epileptogenesis in mTORopathies. Front Neuroanat. (2021) doi: 10.3389/fnana.2021.664695.
  352. Buerger C, DeVries B, Stambolic V. Localization of Rheb to the endomembrane is critical for its signaling function. Biochem Biophys Res Commun. 869-880, 2006.
  353. Dennis MD, Baum JI, Kimball SR, Jefferson LS. Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids. J Biol Chem. 8287-8296, 2011.
  354. Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 21-35, 2011.
  355. Hao F, Kondo K, Itoh T et al; Rheb localized on the Golgi membrane activates lysosome-localized mTORC1 at the Golgi-lysosome contact site. J Cell Sci. (2018). doi: 10.1242/jcs.208017.
  356. Angarola B, Ferguson SM. Coordination of Rheb lysosomal membrane interactions with mTORC1 activation. (2020) Faculty Rev. doi:10.12688/f1000research.22367.1
  357. Makhoul C, Gleeson PA. Regulation of mTORC1 activity by the Golgi apparatus. Faculty Rev (2021) DOI: 10.12703/r/10-50. PMID: 34195689; PMCID: PMC8204759.
  358. Demetriades C, Doumpas N, Teleman AA. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell, 786799, 2014.
  359. Menon S, Dibble CC, Talbott G et al: Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 771– 785, 2014.
  360. Demetriades C, Plescher M, Teleman AA. Lysosomal recruitment of TSC2 is a universal response to cellular stress. Nat Commun. (2016) doi:10.1038/ncomms10662.
  361. Carroll B, Maetzel D, Maddocks OD et al. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. Elife (2016). doi:10.7554/eLife.11058
  362. Orlova KA, Crino PB. The tuberous sclerosis complex. Ann NY Acad Sci. 87-105, 2010.
  363. Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia. 27-36, 2010.
  364. Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. The Lancet. Neurology. 2733-745, 2015.
  365. Leclezio L, de Vries PJ. Advances in the treatment of tuberous sclerosis complex. Curr Opin Psychiatry. 113-120, 2015.
  366. Specchio N, Pietrafusa N, Trivisano M et al. Autism and epilepsy in patients with tuberous sclerosis complex. Frontiers in Neurology. (2020). DOI: 10.3389/fneur.2020.00639.
  367. Wong M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed J. 40-50, 2013.
  368. Liu J, Reeves C, Michalak Z et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun. (2014). doi: 10.1186/2051-5960-2-71.
  369. Zhong S, Zhao Z, Xie W et al: GABAergic interneuron and neurotransmission are mTOR-dependently disturbed in experimental focal cortical dysplasia. Mol Neurobiol. 156-169, 2021.
  370. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer, Cancer Cell, 9-22, 2007.
  371. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 274–293, 2012.
  372. Krueger DA, Wilfong AA, Holland-Bouley K et al: Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol. 679-687, 2013.
  373. Benjamin D, Hall MN. mTORC1: turning off is just as important as turning on.Cell. 627-628, 2014.
  374. Liu J, Reeves C, Michalak Z et al. Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies. Acta Neuropathol Commun (2014). doi: 10.1186/2051-5960-2-71.
  375. Crino PB. The mTOR signalling cascade: paving new roads to cure neurological disease. Nat Rev Neurol. 379-92, 2016.
  376. Blenis J. TOR, the gateway to cellular metabolism, cell growth, and disease. Cell. 10-13, 2017.
  377. Wang F, Chen F, Wang G et al. Rapamycin provides anti-epileptogenic effect in a rat model of post-traumatic epilepsy via deactivation of mTOR signaling pathway. Exp Ther Med. 4763-4770, 2018.
  378. Hillmann P, Fabbro D. PI3K/mTOR pathway inhibition: opportunities in oncology and rare genetic diseases. Int J Mol Sci. (2019) doi:10.3390/ijms20225792.
  379. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci.1886-918, 2012.
  380. Hosios AM, Hecht VC, Danai LV et al: Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev Cell. 540-549, 2016.
  381. Gao X, Zhang Y, Arrazola P et al. TSC tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol. 699-704, 2002.
  382. Guba M, von Breitenbuch P, Steinbauer M et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 128-35, 2002.
  383. Rupertus K, Dahlem C, Menger MD et al. Rapamycin inhibits hepatectomy-induced stimulation of metastatic tumor growth by reduction of angiogenesis, microvascular blood perfusion, and tumor cell proliferation. Ann Surg Oncol. 2629-2637, 2009.
  384. Álvarez-García O,García-Lopez E, Loredo V et al. Rapamycin induces growth retardation by disrupting angiogenesis in the growth plate. Kidney International, 561 – 568, 2010.
  385. Roy D, Sin SH, Lucas A et al. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Res. 2235-2246, 2013.
  386. Faes S, Demartines N, Dormond O. Mechanistic target of rapamycin inhibitors in renal cell carcinoma: potential, limitations, and perspectives. Front Cell Dev Biol. (2021) doi: 10.3389/fcell.2021.636037
  387. Witzig TE, Geyer SM, Ghobrial I et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 53475356, 2005.
  388. Hess G. Temsirolimus for the treatment of mantle cell lymphoma. Expert Rev Hematol. 631-40, 2009.
  389. Lee JS, Vo TT, Fruman DA. Targeting mTOR for the treatment of B cell malignancies. Br J Clin Pharmacol. 1213-1228, 2016.
  390. Hess G, Wagner K, Keller U, et al. Final results of a phaseII/IIIi trial of the combination bendamustine and rituximab with temsirolimus (bert) in relapsed mantle cell lymphoma and follicular lymphoma. Hemasphere. (2020) doi:10.1097/HS9.0000000000000398.
  391. Martelli AM, Evangelisti C, Chiarini F, McCubrey JA. The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. Oncotarget, 89-103, 2010.
  392. Barrett D, Brown VI, Grupp SA, Teachey DT. Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 299-316, 2012.
  393. Renner C, Zinzani P L, Gressin R et al: Swiss SAKK and French GOELAMS group from European Mantle Cell Lymphoma Network (2012). A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica /doi.org/10.3324/haematol.2011.053173
  394. Ghosh J, Kapur R: Role of mTORC1–S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leucemia. Experimental Hematology 13–21, 2017.
  395. Tabe Y, Tafuri A, Sekihara K et al. Inhibition of mTOR kinase as a therapeutic target for acute myeloid leukemia. Expert Opin Ther Targets. 705714, 2017.
  396. Feng Y, Chen X, Cassady K et al. The role of mtor inhibitors in hematologic disease: from bench to bedside. Front Oncol. (2021) doi:10.3389/fonc.2020.611690.
  397. Mekki M, Bridson JM, Sharma A, Halawa A. mTOR inhibitors in kidney transplantation: A comprehensive review J Kidney, (2017) doi: 10.4172/24721220.1000146.
  398. Franz DN, Leonard J, Tudor C et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol. 490–498, 2006.
  399. Li XY, Zhang LQ, Zhang XG et al. Association between AKT/mTOR signalling pathway and malignancy grade of human gliomas. J Neurooncol. 453458, 2011.
  400. Duzgun Z, Eroglu Z, Biray C. Role of mTOR in glioblastoma. Gene. 187190, 2016.
  401. Ryskalin L, Lazzeri G, Flaibani M et al: mTOR-Dependent cell proliferation in the brain. Biomed Res Int. (2017). doi: 10.1155/2017/7082696.
  402. Waetzig R, Matthes M, Leister J et al. Comparing mTOR inhibitor rapamycin with Torin-2 within the RIST molecular-targeted regimen in neuroblastoma cells. Int J Med Sci. 137-149, 2021.
  403. Lenzi P, Ferese R, Biagioni F et al: Rapamycin ameliorates defects in mitochondrial fission and mitophagy in glioblastoma cells. Int J Mol Sci. (2021) doi: 10.3390/ijms22105379.
  404. Mukhopadhyay S, Frias MA, Chatterjee A et al: the enigma of rapamycin dosage. Mol Cancer Ther 347–353, 2016.
  405. Xie J, Wang X, Proud CG. mTOR inhibitors in c

How to Cite

Gebrin, A. S., & Zotarelli-Filho, I. J. (2022). The role of leucine in the activation of cellular metabolism: a large integrative review. International Journal of Nutrology, 15(7). https://doi.org/10.54448/ijn22S201