Regulation and metabolic functions of mTORC1 and mTORC2

2021 ◽  
Author(s):  
Angelia Szwed ◽  
Eugene Kim ◽  
Estela Jacinto
Keyword(s):  
Protein Complexes ◽  
Cellular Tissue ◽  
Metabolic Reprogramming ◽  
Cellular Functions ◽  
Environmental Signals ◽  
Metabolic Functions ◽  
Cancer Models ◽  
Intracellular Metabolism ◽  
Uptake Of Nutrients

Cells metabolize nutrients for biosynthetic and bioenergetic needs to fuel growth and proliferation. The uptake of nutrients from the environment and their intracellular metabolism is a highly controlled process that involves crosstalk between growth signaling and metabolic pathways. Despite constant fluctuations in nutrient availability and environmental signals, normal cells restore metabolic homeostasis to maintain cellular functions and prevent disease. A central signaling molecule that integrates growth with metabolism is the mechanistic target of rapamycin (mTOR). mTOR is a protein kinase that responds to levels of nutrients and growth signals. mTOR forms two protein complexes, mTORC1, which is sensitive to rapamycin and mTORC2, which is not directly inhibited by this drug. Rapamycin has facilitated the discovery of the various functions of mTORC1 in metabolism. Genetic models that disrupt either mTORC1 or mTORC2 have expanded our knowledge on their cellular, tissue as well as systemic functions in metabolism. Nevertheless, our knowledge on the regulation and functions of mTORC2, particularly in metabolism, has lagged behind. Since mTOR is an important target for cancer, aging and other metabolism-related pathologies, understanding the distinct and overlapping regulation and functions of the two mTOR complexes is vital for the development of more effective therapeutic strategies. This review will discuss the key discoveries and recent findings on the regulation and metabolic functions of the mTOR complexes. We highlight findings from cancer models, but also discuss other examples of the mTOR-mediated metabolic reprogramming occurring in stem and immune cells, type 2 diabetes/obesity, neurodegenerative disorders and aging.

scholarly journals Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy

2019 ◽  
Vol 57 (3) ◽  
pp. 1748-1767 ◽  
Author(s):  
Michael Naidoo ◽  
Karen Anthony
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Protein Complexes ◽  
Neuropsychiatric Symptoms ◽  
Cellular Tissue ◽  
Protein Product ◽  
The Body ◽  
Brain Targeting ◽  
Cellular Functions ◽  
The Brain

AbstractDuchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and mutations affecting its expression are associated with the DMD neuropsychiatric syndrome. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. However, unlike in skeletal muscle; in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. We then review the gene expression, RNA processing and functions of Dp71. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. The literature suggests changes observed in the DMD brain are neurodevelopmental in origin and that their risk and severity is associated with a cumulative loss of distal DMD gene products such as Dp71. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. Unravelling the function and pathophysiological significance of dystrophin in the brain has become a high research priority to inform the development of brain-targeting treatments for Duchenne.

scholarly journals Metabolic reprogramming during the Trypanosoma brucei life cycle

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 683 ◽  
Author(s):  
Terry K. Smith ◽  
Frédéric Bringaud ◽  
Derek P. Nolan ◽  
Luisa M. Figueiredo
Keyword(s):  
Life Cycle ◽  
Trypanosoma Brucei ◽  
Model Organism ◽  
Protozoan Parasite ◽  
Tsetse Fly ◽  
Metabolic Reprogramming ◽  
Mammalian Host ◽  
Insect Vector ◽  
Environmental Signals ◽  
Cellular Metabolic Activity

Cellular metabolic activity is a highly complex, dynamic, regulated process that is influenced by numerous factors, including extracellular environmental signals, nutrient availability and the physiological and developmental status of the cell. The causative agent of sleeping sickness, Trypanosoma brucei, is an exclusively extracellular protozoan parasite that encounters very different extracellular environments during its life cycle within the mammalian host and tsetse fly insect vector. In order to meet these challenges, there are significant alterations in the major energetic and metabolic pathways of these highly adaptable parasites. This review highlights some of these metabolic changes in this early divergent eukaryotic model organism.

Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

2020 ◽  
Vol 13 (663) ◽  
pp. eabd8379
Author(s):  
Heba Ali ◽  
Lena Marth ◽  
Dilja Krueger-Burg
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inhibitory Synapses ◽  
Molecular Architecture ◽  
Cellular Functions ◽  
Altered Expression ◽  
Health And Disease ◽  
Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

scholarly journals The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models

2015 ◽  
Vol 46 (6) ◽  
pp. 2335-2345 ◽  
Author(s):  
JUAN GARONA ◽  
MARINA PIFANO ◽  
ULISES D. ORLANDO ◽  
MARIA B. PASTRIAN ◽  
NANCY B. IANNUCCI ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumour Growth ◽  
The Novel ◽  
Cancer Models

scholarly journals NEUROPROTECTIVE ROLE OF ASCORBIC ACID: ANTIOXIDANT AND NON-ANTIOXIDANT FUNCTIONS

2018 ◽  
Vol 11 (10) ◽  
pp. 30 ◽  
Author(s):  
Arun Kumar ◽  
Reena V Saini ◽  
Adesh K Saini
Keyword(s):  
Ascorbic Acid ◽  
Vitamin C ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glutamate Toxicity ◽  
Cellular Functions ◽  
Dietary Antioxidant ◽  
The Central Nervous System

Ascorbic acid (AA) or Vitamin C is an important antioxidant which participates in numerous cellular functions. Although in human plasma its concentration is in micromolars but it reaches millimolar concentrations in most of the human tissues. The high ascorbate cellular concentrations are generated and maintained by a specific sodium-dependent Vitamin C transporter type 2 (SVCT2, member of Slc23 family). Metabolic processes recycle Vitamin C from its oxidized forms (ascorbate) inside the cells. AA concentration is highest in the neurons of the central nervous system (CNS) of mammals, and deletion of its transporter affects mice brain and overall survival. In the CNS, intracellular ascorbate serves several functions including antioxidant protection, peptide amidation, myelin formation, synaptic potentiation, and protection against glutamate toxicity. SVCT2 maintains neuronal ascorbate content in CNS which has relevance for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. As ascorbate supplements decrease infarct size in ischemia-reperfusion injury and protect neurons from oxidative damage, it is a vital dietary antioxidant. The aim of this review is to assess the role of the SVCT2 in regulating neuronal ascorbate homeostasis in CNS and the extent to which ascorbate affects brain function as an antioxidant.

scholarly journals Zsírsavtúltengés – inzulinrezisztencia és β-sejt-halál

2016 ◽  
Vol 157 (19) ◽  
pp. 733-739 ◽  
Author(s):  
Miklós Csala
Keyword(s):  
Fatty Acids ◽  
Insulin Signaling ◽  
Cell Damage ◽  
Local Inflammation ◽  
Cellular Functions ◽  
Β Cell ◽  
The Metabolic Syndrome ◽  
Rapid Spread ◽  
New Strategies

The increasing prevalence of type 2 diabetes correlates with the rapid spread of obesity worldwide. Adipocytes are strained by the demand of excessive storage, and the local inflammation accelerates triglyceride turnover, which elevates the plasma levels of free fatty acids. Sustained hyper-free fatty acidemia leads to disturbances in cellular functions (lipotoxicity) or even to programmed cell death. Activated stress kinases interfere with insulin signaling, and often facilitate apoptosis. Hyper-free fatty acidemia, therefore, links obesity to diabetes through insulin resistance and β-cell damage. Lipotoxicity research – including the comparison of the effects exerted by saturated, unsaturated and trans fatty acids – provides explanations for long-known phenomena. Our widening knowledge in the field offers new strategies for prevention and treatment of the metabolic syndrome and diabetes. Orv. Hetil., 2016, 157(19), 733–739.

scholarly journals Intracellular metabolism of neutrophils and risk for development of type 2 diabetes mellitus in patients with metabolic syndrome

2012 ◽  
Vol 15 (2) ◽  
pp. 13-16 ◽  
Author(s):  
Andrey Evgen'evich Kratnov ◽  
Elena Nikolaevna Lopatnikova ◽  
Alexander Andreevich Kratnov
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Type 2 Diabetes Mellitus ◽  
Activity Level ◽  
Myeloperoxidase Activity ◽  
Increased Risk ◽  
Male Patients ◽  
Intracellular Metabolism

77 male patients (mean age 47?7.4 years) without ischaemic heart disease were tested for metabolic syndrome factors, risk for developmentof type 2 diabetes mellitus (T2DM) according to FINDRISK questionnaire, following with assessment of intracellularmetabolism parameters of neutrophils. Increased risk for T2DM positively correlated in these patients with myeloperoxidase activity,level of hydrogen peroxide within neutrophils and BMI. We observed elevation of oxygen-dependent metabolism in neutrophils formpatients with morbid obesity, accompanied with decrease in antioxidant factors, which is suggestive of oxidative stress.

Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications

2022 ◽  
Vol 23 ◽  
Author(s):  
Lin Yang ◽  
Zhixin Zhang ◽  
Doudou Wang ◽  
Yu Jiang ◽  
Ying Liu
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Protein Complexes ◽  
Cell Metabolism ◽  
Critical Role ◽  
Mtor Inhibitors ◽  
Mtor Signaling

Abstract: The mechanistic target of rapamycin (mTOR) is a pivotal regulator of cell metabolism and growth. In the form of two different multi-protein complexes, mTORC1 and mTORC2, mTOR integrates cellular energy, nutrient and hormonal signals to regulate cellular metabolic homeostasis. In type 2 diabetes mellitus (T2DM) aberrant mTOR signaling underlies its pathological conditions and end-organ complications. Substantial evidence suggests that two mTOR-mediated signaling schemes, mTORC1-p70S6 kinase 1 (S6K1) and mTORC2-protein kinase B (AKT), play a critical role in insulin sensitivity and that their dysfunction contributes to development of T2DM. This review summaries our current understanding of the role of mTOR signaling in T2DM and its associated complications, as well as the potential use of mTOR inhibitors in treatment of T2DM.

scholarly journals Lessons from equilibrium statistical physics regarding the assembly of protein complexes

2019 ◽  
Vol 117 (1) ◽  
pp. 114-120 ◽  
Author(s):  
Pablo Sartori ◽  
Stanislas Leibler
Keyword(s):  
Self Assembly ◽  
Statistical Physics ◽  
Liquid Mixture ◽  
Protein Complexes ◽  
Biological Evolution ◽  
Cellular Protein ◽  
Cellular Functions ◽  
Physical Constraints ◽  
Polypeptide Chains ◽  
Protein Complex Assembly

Cellular functions are established through biological evolution, but are constrained by the laws of physics. For instance, the physics of protein folding limits the lengths of cellular polypeptide chains. Consequently, many cellular functions are carried out not by long, isolated proteins, but rather by multiprotein complexes. Protein complexes themselves do not escape physical constraints, one of the most important being the difficulty of assembling reliably in the presence of cellular noise. In order to lay the foundation for a theory of reliable protein complex assembly, we study here an equilibrium thermodynamic model of self-assembly that exhibits 4 distinct assembly behaviors: diluted protein solution, liquid mixture, “chimeric assembly,” and “multifarious assembly.” In the latter regime, different protein complexes can coexist without forming erroneous chimeric structures. We show that 2 conditions have to be fulfilled to attain this regime: 1) The composition of the complexes needs to be sufficiently heterogeneous, and 2) the use of the set of components by the complexes has to be sparse. Our analysis of publicly available databases of protein complexes indicates that cellular protein systems might have indeed evolved so as to satisfy both of these conditions.

AMP-activated protein kinase: new regulation, new roles?

2012 ◽  
Vol 445 (1) ◽  
pp. 11-27 ◽  
Author(s):  
David Carling ◽  
Claire Thornton ◽  
Angela Woods ◽  
Matthew J. Sanders
Keyword(s):  
Protein Kinase ◽  
Living Cells ◽  
Cellular Functions ◽  
Disease States ◽  
Kinase Cascade ◽  
Amp Activated Protein Kinase ◽  
Obesity And Cancer ◽  
Hydrolysis Of ◽  
Protein Kinase Cascade

The hydrolysis of ATP drives virtually all of the energy-requiring processes in living cells. A prerequisite of living cells is that the concentration of ATP needs to be maintained at sufficiently high levels to sustain essential cellular functions. In eukaryotic cells, the AMPK (AMP-activated protein kinase) cascade is one of the systems that have evolved to ensure that energy homoeostasis is maintained. AMPK is activated in response to a fall in ATP, and recent studies have suggested that ADP plays an important role in regulating AMPK. Once activated, AMPK phosphorylates a broad range of downstream targets, resulting in the overall effect of increasing ATP-producing pathways whilst decreasing ATP-utilizing pathways. Disturbances in energy homoeostasis underlie a number of disease states in humans, e.g. Type 2 diabetes, obesity and cancer. Reflecting its key role in energy metabolism, AMPK has emerged as a potential therapeutic target. In the present review we examine the recent progress aimed at understanding the regulation of AMPK and discuss some of the latest developments that have emerged in key areas of human physiology where AMPK is thought to play an important role.

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