scholarly journals mTORC1 as the main gateway to autophagy

2017 ◽  
Vol 61 (6) ◽  
pp. 565-584 ◽  
Author(s):  
Yoana Rabanal-Ruiz ◽  
Elsje G. Otten ◽  
Viktor I. Korolchuk
Keyword(s):  
Amino Acids ◽  
Nutrient Sensing ◽  
Biomedical Sciences ◽  
Energy Sensor ◽  
As Stress ◽  
Amino Acid Sensing ◽  
Amp Activated Protein Kinase ◽  
Cellular Components ◽  
Synthesis And Degradation

Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP-activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review.

scholarly journals Effect of 1,5-Anhydro-D-Fructose on the Inhibition of Adipogenesis in 3T3-L1 Adipocytes

2012 ◽  
Vol 7 (11) ◽  
pp. 1934578X1200701 ◽  
Author(s):  
Akiko Kojima-Yuasa ◽  
Yohei Deguchi ◽  
Yotaro Konishi ◽  
Isao Matsui-Yuasa
Keyword(s):  
Metabolic Diseases ◽  
Physiological Role ◽  
Structural Similarity ◽  
Regulation Of Transcription ◽  
Energy Sensor ◽  
Mammalian Tissues ◽  
Cellular Lipid Accumulation ◽  
Amp Activated Protein Kinase

1,5-Anhydro-D-fructose (1,5-AF) is a monosaccharide that shares a structural similarity to glucose. 1,5-AF is found in fungi, algae, Escherichia coli and rat liver and is produced by the degradation of starch and glycogen, which is catalyzed by the enzyme α-1,4-glucan lyase. However, the physiological role of 1,5-AF in mammalian tissues is not well understood. Here, we investigated the anti-obesity potential of 1,5-AF on adipogenesis in 3T3-L1 adipocytes. 1,5-AF caused a significant decrease in GPDH activity in 3T3-L1 preadipocytes and mature adipocytes without eliciting cytotoxicity, and inhibited cellular lipid accumulation through down-regulation of transcription factors such as PPARγ and C/EBPα. 1,5-AF also induced dose-dependent phosphorylation of AMP-activated protein kinase (AMPK), a cellular energy sensor. However, the total AMPK protein content remained unchanged. Furthermore, 1,5-AF increased the levels of reactive oxygen species, an important upstream signal for AMPK activation in 3T3-L1 adipocytes. Our results show that 1,5-AF exerts anti-obesity action in vitro and suggest that 1,5-AF is potentially a novel preventative agent for obesity and other metabolic diseases.

scholarly journals Calorie Restriction: Is AMPK a Key Sensor and Effector?

Physiology ◽  
2011 ◽  
Vol 26 (4) ◽  
pp. 214-224 ◽  
Author(s):  
Carles Cantó ◽  
Johan Auwerx
Keyword(s):  
Protein Kinase ◽  
Life Span ◽  
Calorie Restriction ◽  
Energy Availability ◽  
Beneficial Effects ◽  
Extend Life Span ◽  
Energy Sensor ◽  
External Cues ◽  
Amp Activated Protein Kinase

Dietary restriction can extend life span in most organisms tested to date, suggesting that mechanisms sensing nutrient and energy availability might regulate longevity. The AMP-activated protein kinase (AMPK) has emerged as a key energy sensor with the ability to transcriptionally reprogram the cell and metabolically adapt to external cues. In this review, we will discuss the possible role of AMPK in the beneficial effects of calorie restriction on health and life span.

scholarly journals Recent Data on Cellular Component Turnover: Focus on Adaptations to Physical Exercise

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 542 ◽  
Author(s):  
Anthony Sanchez ◽  
Robin Candau ◽  
Henri Bernardi
Keyword(s):  
Muscle Protein ◽  
Mammalian Target Of Rapamycin ◽  
Protein Translation ◽  
Muscle Disorders ◽  
Ubiquitin Protein Ligase ◽  
Energy Sensor ◽  
Mitochondrial Turnover ◽  
Foxo Transcription Factors ◽  
Amp Activated Protein Kinase ◽  
Cellular Components

Significant progress has expanded our knowledge of the signaling pathways coordinating muscle protein turnover during various conditions including exercise. In this manuscript, the multiple mechanisms that govern the turnover of cellular components are reviewed, and their overall roles in adaptations to exercise training are discussed. Recent studies have highlighted the central role of the energy sensor (AMP)-activated protein kinase (AMPK), forkhead box class O subfamily protein (FOXO) transcription factors and the kinase mechanistic (or mammalian) target of rapamycin complex (MTOR) in the regulation of autophagy for organelle maintenance during exercise. A new cellular trafficking involving the lysosome was also revealed for full activation of MTOR and protein synthesis during recovery. Other emerging candidates have been found to be relevant in organelle turnover, especially Parkin and the mitochondrial E3 ubiquitin protein ligase (Mul1) pathways for mitochondrial turnover, and the glycerolipids diacylglycerol (DAG) for protein translation and FOXO regulation. Recent experiments with autophagy and mitophagy flux assessment have also provided important insights concerning mitochondrial turnover during ageing and chronic exercise. However, data in humans are often controversial and further investigations are needed to clarify the involvement of autophagy in exercise performed with additional stresses, such as hypoxia, and to understand the influence of exercise modality. Improving our knowledge of these pathways should help develop therapeutic ways to counteract muscle disorders in pathological conditions.

scholarly journals Amino Acid Sensing in Metabolic Homeostasis and Health

2020 ◽  
Author(s):  
Xiaoming Hu ◽  
Feifan Guo
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Regulation ◽  
Metabolic Diseases ◽  
Nutrient Sensing ◽  
The Body ◽  
Bioactive Molecules ◽  
Metabolic Homeostasis ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Abstract Sensing and responding to changes in nutrient levels, including those of glucose, lipids, and amino acids, by the body is necessary for survival. Accordingly, perturbations in nutrient sensing are tightly linked with human pathologies, particularly metabolic diseases such as obesity, type 2 diabetes mellitus, and other complications of metabolic syndromes. The conventional view is that amino acids are fundamental elements for protein and peptide synthesis, while recent studies have revealed that amino acids are also important bioactive molecules that play key roles in signaling pathways and metabolic regulation. Different pathways that sense intracellular and extracellular levels of amino acids are integrated and coordinated at the organismal level, and, together, these pathways maintain whole metabolic homeostasis. In this review, we discuss the studies describing how important sensing signals respond to amino acid availability and how these sensing mechanisms modulate metabolic processes, including energy, glucose, and lipid metabolism. We further discuss whether dysregulation of amino acid sensing signals can be targeted to promote metabolic disorders, and discuss how to translate these mechanisms to treat human diseases. This review will help to enhance our overall understanding of the correlation between amino acid sensing and metabolic homeostasis, which have important implications for human health.

scholarly journals Role of energy- and nutrient-sensing kinases AMP-activated Protein Kinase (AMPK) and Mammalian Target of Rapamycin (mTOR) in Adipocyte Differentiation

IUBMB Life ◽  
2013 ◽  
Vol 65 (7) ◽  
pp. 572-583 ◽  
Author(s):  
Sonia Fernández-Veledo ◽  
Ana Vázquez-Carballo ◽  
Rocio Vila-Bedmar ◽  
Victòria Ceperuelo-Mallafré ◽  
Joan Vendrell
Keyword(s):  
Protein Kinase ◽  
Adipocyte Differentiation ◽  
Mammalian Target Of Rapamycin ◽  
Nutrient Sensing ◽  
Target Of Rapamycin ◽  
Amp Activated Protein Kinase

The role of nutrition in stimulating muscle protein accretion at the molecular level

2007 ◽  
Vol 35 (5) ◽  
pp. 1298-1301 ◽  
Author(s):  
S.R. Kimball
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Mrna Translation ◽  
Regulatory Proteins ◽  
Downstream Effectors ◽  
Regulate Protein ◽  
Protein Synthesis And Degradation ◽  
Synthesis And Degradation

Nutrients act both directly and indirectly to modulate muscle protein accretion through changes in protein synthesis and degradation. For example, glucose, amino acids and fatty acids can all be metabolized to produce energy in the form of ATP that can be utilized for protein synthesis. In addition, amino acids are used directly for the synthesis of new proteins. Nutrients also regulate protein synthesis through activation of a signalling pathway involving the protein kinase, mTOR [mammalian TOR (target of rapamycin)]. Together with several regulatory proteins, mTOR forms a complex referred to as TORC1 (TOR complex 1). Because of its central role in controlling cell growth, TORC1 is an integral component of the mechanism through which nutrients modulate protein synthesis. Herein, the mechanism(s) through which nutrients, and in particular amino acids, regulate signalling through TORC1 will be discussed. In addition, downstream effectors of TORC1 action on mRNA translation will be briefly presented. Finally, a previously unrecognized effector of TORC1 signalling in regulating protein synthesis will be described.

scholarly journals Nutrient Sensing and Redox Balance: GCN2 as a New Integrator in Aging

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Paulina Falcón ◽  
Marcela Escandón ◽  
Álvaro Brito ◽  
Soledad Matus
Keyword(s):  
Stress Responses ◽  
Redox Balance ◽  
Nutritional Stress ◽  
Nutrient Sensing ◽  
Cellular Processes ◽  
Complex Process ◽  
Probability Of Death ◽  
Stress Sensing ◽  
Amino Acid Sensing

Aging is a complex process in which the accumulation of molecular, cellular, and organism dysfunction increases the probability of death. Several pieces of evidence have revealed a contribution of stress responses in aging and in aging-related diseases, in particular, the key role of signaling pathways associated to nutritional stress. Here, we review the possible interplay between amino acid sensing and redox balance maintenance mediated by the nutritional sensor general control nonderepressive 2 (GCN2). We discuss this new dimension of nutritional stress sensing consequences, standing out GCN2 as a central coordinator of key cellular processes that assure healthy homeostasis in the cell, raising GCN2 as a novel interesting target, that when activated, could imply pleiotropic benefits, particularly GCN2 intervention and its new unexplored therapeutic role as a player in the aging process.

scholarly journals The Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging

2021 ◽  
Vol 2 ◽  
Author(s):  
Stephanie A. Fernandes ◽  
Constantinos Demetriades
Keyword(s):  
Amino Acids ◽  
Nutrient Sensing ◽  
Cancer Type ◽  
Growth Factor Signaling ◽  
Cellular Mechanisms ◽  
Comprehensive Overview ◽  
Critical Determinant ◽  
Age Related ◽  
Mtorc1 Signaling

The mechanistic Target of Rapamycin (mTOR) is a growth-related kinase that, in the context of the mTOR complex 1 (mTORC1), touches upon most fundamental cellular processes. Consequently, its activity is a critical determinant for cellular and organismal physiology, while its dysregulation is commonly linked to human aging and age-related disease. Presumably the most important stimulus that regulates mTORC1 activity is nutrient sufficiency, whereby amino acids play a predominant role. In fact, mTORC1 functions as a molecular sensor for amino acids, linking the cellular demand to the nutritional supply. Notably, dietary restriction (DR), a nutritional regimen that has been shown to extend lifespan and improve healthspan in a broad spectrum of organisms, works via limiting nutrient uptake and changes in mTORC1 activity. Furthermore, pharmacological inhibition of mTORC1, using rapamycin or its analogs (rapalogs), can mimic the pro-longevity effects of DR. Conversely, nutritional amino acid overload has been tightly linked to aging and diseases, such as cancer, type 2 diabetes and obesity. Similar effects can also be recapitulated by mutations in upstream mTORC1 regulators, thus establishing a tight connection between mTORC1 signaling and aging. Although the role of growth factor signaling upstream of mTORC1 in aging has been investigated extensively, the involvement of signaling components participating in the nutrient sensing branch is less well understood. In this review, we provide a comprehensive overview of the molecular and cellular mechanisms that signal nutrient availability to mTORC1, and summarize the role that nutrients, nutrient sensors, and other components of the nutrient sensing machinery play in cellular and organismal aging.

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