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mTOR, Metabolism, and Diseases
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mTOR, Metabolism, and Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Role of Xenobiotics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 23914

Special Issue Editor

Dr. Masahiro Morita

E-Mail Website
Guest Editor
Department of Molecular Medicine, UT Health Science Center San Antonio, San Antonio, TX 78229, USA
Interests: cancer; metabolism; mRNA translation; mRNA degradation; mTOR
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mechanistic target of rapamycin (mTOR) integrates extracellular and intracellular signals (e.g., growth factors, insulin, nutrients, and oxygen) to stimulate anabolism, including protein, lipid, and nucleic acid synthesis, and bolster cellular growth and proliferation while suppressing autophagy. mTOR forms two distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which differ in their composition, downstream targets, regulation, and sensitivity to the naturally occurring allosteric mTOR inhibitor, rapamycin. Hyperactivation of mTOR frequently accompanies diseases characterized by perturbations in energy metabolism and cell growth, such as cancer and metabolic syndrome. The first generation of mTOR inhibitors, rapamycin and its analogs, have been used for the treatment of a few types of cancer with modest therapeutic effects. A new generation of ATP-competitive inhibitors that directly target the mTOR catalytic domain show potent and comprehensive inhibition and are in early clinical trials. Chronic rapamycin significantly increases lifespan in model organisms with better health indicators. The major clinical benefits of mTOR inhibition will likely be in the prevention or management of age-related diseases such as cancer, metabolic syndrome and its associated complications resulting in late life morbidity compression.

This special issue “mTOR, Metabolism, and Diseases” will cover a selection of recent research topics and current review articles in the field of the mTOR signaling pathway.

Dr. Masahiro Morita
Guest Editor

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Keywords

  • mTOR
  • Rapamycin
  • Inhibitor
  • cancer
  • metabolic syndrome
  • aging
  • mRNA translation
  • 4E-BP
  • S6K
  • autophagy

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Published Papers (6 papers)

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Research

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16 pages, 3511 KiB  
Article
Joint Degeneration in a Mouse Model of Pseudoachondroplasia: ER Stress, Inflammation, and Block of Autophagy
by Jacqueline T. Hecht, Alka C. Veerisetty, Mohammad G. Hossain, Debabrata Patra, Frankie Chiu, Francoise Coustry and Karen L. Posey
Int. J. Mol. Sci. 2021, 22(17), 9239; https://doi.org/10.3390/ijms22179239 - 26 Aug 2021
Cited by 10 | Viewed by 2626
Abstract
Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The [...] Read more.
Pseudoachondroplasia (PSACH), a short limb skeletal dysplasia associated with premature joint degeneration, is caused by misfolding mutations in cartilage oligomeric matrix protein (COMP). Here, we define mutant-COMP-induced stress mechanisms that occur in articular chondrocytes of MT-COMP mice, a murine model of PSACH. The accumulation of mutant-COMP in the ER occurred early in MT-COMP articular chondrocytes and stimulated inflammation (TNFα) at 4 weeks, and articular chondrocyte death increased at 8 weeks while ER stress through CHOP was elevated by 12 weeks. Importantly, blockage of autophagy (pS6), the major mechanism that clears the ER, sustained cellular stress in MT-COMP articular chondrocytes. Degeneration of MT-COMP articular cartilage was similar to that observed in PSACH and was associated with increased MMPs, a family of degradative enzymes. Moreover, chronic cellular stresses stimulated senescence. Senescence-associated secretory phenotype (SASP) may play a role in generating and propagating a pro-degradative environment in the MT-COMP murine joint. The loss of CHOP or resveratrol treatment from birth preserved joint health in MT-COMP mice. Taken together, these results indicate that ER stress/CHOP signaling and autophagy blockage are central to mutant-COMP joint degeneration, and MT-COMP mice joint health can be preserved by decreasing articular chondrocyte stress. Future joint sparing therapeutics for PSACH may include resveratrol. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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16 pages, 1772 KiB  
Article
Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin
by Malgorzata Lopatynska-Mazurek, Lukasz Komsta, Ewa Gibula-Tarlowska and Jolanta H. Kotlinska
Int. J. Mol. Sci. 2021, 22(13), 7083; https://doi.org/10.3390/ijms22137083 - 30 Jun 2021
Cited by 11 | Viewed by 2857
Abstract
Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces [...] Read more.
Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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13 pages, 9093 KiB  
Article
New Insights into Red Blood Cell Microcytosis upon mTOR Inhibitor Administration
by Justyna Jakubowska, Bartłomiej Pawlik, Krystyna Wyka, Małgorzata Stolarska, Katarzyna Kotulska, Sergiusz Jóźwiak, Wojciech Młynarski and Joanna Trelińska
Int. J. Mol. Sci. 2021, 22(13), 6802; https://doi.org/10.3390/ijms22136802 - 24 Jun 2021
Cited by 3 | Viewed by 2693
Abstract
The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell [...] Read more.
The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 μM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 μM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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22 pages, 7151 KiB  
Article
Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells
by Paola Lenzi, Rosangela Ferese, Francesca Biagioni, Federica Fulceri, Carla L. Busceti, Alessandra Falleni, Stefano Gambardella, Alessandro Frati and Francesco Fornai
Int. J. Mol. Sci. 2021, 22(10), 5379; https://doi.org/10.3390/ijms22105379 - 20 May 2021
Cited by 28 | Viewed by 4029
Abstract
Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of [...] Read more.
Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (PINK1, PARKIN, ULK1, AMBRA1) and mitochondrial fission (FIS1, DRP1). This occurs along with over-expression of VPS34, an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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35 pages, 15174 KiB  
Article
Quantitative Ultrastructural Morphometry and Gene Expression of mTOR-Related Mitochondriogenesis within Glioblastoma Cells
by Rosangela Ferese, Paola Lenzi, Federica Fulceri, Francesca Biagioni, Cinzia Fabrizi, Stefano Gambardella, Pietro Familiari, Alessandro Frati, Fiona Limanaqi and Francesco Fornai
Int. J. Mol. Sci. 2020, 21(13), 4570; https://doi.org/10.3390/ijms21134570 - 27 Jun 2020
Cited by 16 | Viewed by 3103
Abstract
In glioblastoma (GBM) cells, an impairment of mitochondrial activity along with autophagy suppression occurs. Autophagy suppression in GBM promotes stemness, invasion, and poor prognosis. The autophagy deficit seems to be due, at least in part, to an abnormal up-regulation of the mammalian target [...] Read more.
In glioblastoma (GBM) cells, an impairment of mitochondrial activity along with autophagy suppression occurs. Autophagy suppression in GBM promotes stemness, invasion, and poor prognosis. The autophagy deficit seems to be due, at least in part, to an abnormal up-regulation of the mammalian target of rapamycin (mTOR), which may be counteracted by pharmacological mTORC1 inhibition. Since autophagy activation is tightly bound to increased mitochondriogenesis, a defect in the synthesis of novel mitochondria is expected to occur in GBM cells. In an effort to measure a baseline deficit in mitochondria and promote mitochondriogenesis, the present study used two different GBM cell lines, both featuring mTOR hyperactivity. mTORC1 inhibition increases the expression of genes and proteins related to autophagy, mitophagy, and mitochondriogenesis. Autophagy activation was counted by RT-PCR of autophagy genes, LC3- immune-fluorescent puncta and immune-gold, as well as specific mitophagy-dependent BNIP3 stoichiometric increase in situ, within mitochondria. The activation of autophagy-related molecules and organelles after rapamycin exposure occurs concomitantly with progression of autophagosomes towards lysosomes. Remarkably, mitochondrial biogenesis and plasticity (increased mitochondrial number, integrity, and density as well as decreased mitochondrial area) was long- lasting for weeks following rapamycin withdrawal. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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Review

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16 pages, 983 KiB  
Review
mTOR Activity and Autophagy in Senescent Cells, a Complex Partnership
by Angel Cayo, Raúl Segovia, Whitney Venturini, Rodrigo Moore-Carrasco, Claudio Valenzuela and Nelson Brown
Int. J. Mol. Sci. 2021, 22(15), 8149; https://doi.org/10.3390/ijms22158149 - 29 Jul 2021
Cited by 41 | Viewed by 7510
Abstract
Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and [...] Read more.
Cellular senescence is a form of proliferative arrest triggered in response to a wide variety of stimuli and characterized by unique changes in cell morphology and function. Although unable to divide, senescent cells remain metabolically active and acquire the ability to produce and secrete bioactive molecules, some of which have recognized pro-inflammatory and/or pro-tumorigenic actions. As expected, this “senescence-associated secretory phenotype (SASP)” accounts for most of the non-cell-autonomous effects of senescent cells, which can be beneficial or detrimental for tissue homeostasis, depending on the context. It is now evident that many features linked to cellular senescence, including the SASP, reflect complex changes in the activities of mTOR and other metabolic pathways. Indeed, the available evidence indicates that mTOR-dependent signaling is required for the maintenance or implementation of different aspects of cellular senescence. Thus, depending on the cell type and biological context, inhibiting mTOR in cells undergoing senescence can reverse senescence, induce quiescence or cell death, or exacerbate some features of senescent cells while inhibiting others. Interestingly, autophagy—a highly regulated catabolic process—is also commonly upregulated in senescent cells. As mTOR activation leads to repression of autophagy in non-senescent cells (mTOR as an upstream regulator of autophagy), the upregulation of autophagy observed in senescent cells must take place in an mTOR-independent manner. Notably, there is evidence that autophagy provides free amino acids that feed the mTOR complex 1 (mTORC1), which in turn is required to initiate the synthesis of SASP components. Therefore, mTOR activation can follow the induction of autophagy in senescent cells (mTOR as a downstream effector of autophagy). These functional connections suggest the existence of autophagy regulatory pathways in senescent cells that differ from those activated in non-senescence contexts. We envision that untangling these functional connections will be key for the generation of combinatorial anti-cancer therapies involving pro-senescence drugs, mTOR inhibitors, and/or autophagy inhibitors. Full article
(This article belongs to the Special Issue mTOR, Metabolism, and Diseases)
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