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Cellular metabolism, Nutrient sensing, mTOR, AMPK, SIRTuins, Glycolysis, Oxidative phosphorylation, Lipogenesis, Autophagy, Metabolic disorders

Introduction

Cellular metabolism is the set of biochemical reactions that occur within a cell to sustain life, providing energy and building blocks for cellular functions. It is tightly regulated to meet the dynamic demands of the cell in response to nutrient availability, energy requirements, and environmental stresses [1]. Nutrient-sensing pathways act as molecular sensors that detect changes in nutrient levels and coordinate metabolic responses accordingly. This review aims to elucidate how these pathways regulate cellular metabolism and their implications in health and disease.

Overview of nutrient-sensing pathways

Nutrient-sensing pathways encompass a network of signaling cascades that monitor the availability of nutrients such as glucose, amino acids, and lipids [2].

mTOR (mechanistic target of rapamycin): Integrates signals from growth factors, amino acids, and energy status to regulate processes like protein synthesis, autophagy, and lipid metabolism.

AMPK (AMP-activated protein kinase): Activated in response to low cellular energy levels (high AMP/ADP ratio) to stimulate catabolic pathways (e.g., fatty acid oxidation) and inhibit anabolic processes (e.g., lipogenesis).

SIRTuins: NAD+-dependent deacetylases that link cellular metabolism and energy status to gene expression, mitochondrial function, and longevity [3,4].

Regulation of glycolysis and oxidative phosphorylation

Glycolysis and oxidative phosphorylation are central metabolic pathways that generate ATP to meet cellular energy demands. Nutrientsensing pathways modulate these pathways through:

mTOR: Promotes glycolysis and inhibits mitochondrial biogenesis under nutrient-rich conditions.

AMPK: Suppresses glycolysis and enhances mitochondrial biogenesis and oxidative phosphorylation to restore cellular energy levels during energy stress.

SIRTuins: Regulate mitochondrial function and energy metabolism by deacetylating key proteins involved in oxidative phosphorylation [5].

Control of lipid metabolism

Lipid metabolism is crucial for energy storage, membrane structure, and signaling molecules. Nutrient-sensing pathways regulate lipid metabolism through

mTOR: Stimulates lipogenesis in response to nutrient abundance.

AMPK: Inhibits lipogenesis and promotes fatty acid oxidation during energy deficit.

SIRTuins: Modulate lipid metabolism by deacetylating transcription factors and enzymes involved in lipid synthesis and oxidation.

Role in autophagy and cellular stress responses

Autophagy is a cellular process that degrades damaged organelles and proteins to maintain cellular homeostasis and adapt to stress conditions [6,7]. Nutrient-sensing pathways regulate autophagy through.

mTOR: Inhibits autophagy under nutrient-rich conditions; autophagy is activated upon mTOR inhibition during nutrient deprivation.

AMPK: Activates autophagy to provide alternative energy sources and maintain cellular function during metabolic stress.

SIRTuins: Promote autophagy through deacetylation of autophagy-related proteins and transcription factors.

Implications for health and disease

Dysregulation of nutrient-sensing pathways is implicated in various metabolic disorders, including obesity, type 2 diabetes, and cancer [8,9]. Therapeutic strategies targeting these pathways show promise for treating metabolic diseases and enhancing longevity. Future research directions include elucidating crosstalk between nutrient-sensing pathways, exploring their tissue-specific roles, and developing selective pharmacological agents to modulate these pathways.

Discussion

The regulation of cellular metabolism by nutrient-sensing pathways is a complex and dynamic process essential for maintaining cellular homeostasis and adapting to environmental changes. This review has highlighted the pivotal roles of mTOR, AMPK, and SIRTuins in governing metabolic pathways such as glycolysis, oxidative phosphorylation, lipogenesis, and autophagy.

Integration of nutrient-sensing pathways

Nutrient-sensing pathways, including mTOR, AMPK, and SIRTuins, integrate signals from various sources such as glucose levels, amino acids, and cellular energy status to orchestrate metabolic responses. These pathways act as molecular switches that fine-tune metabolic pathways according to nutrient availability and cellular energy demands. For instance, mTORC1 promotes anabolic processes like protein synthesis and lipogenesis under nutrient-rich conditions, whereas AMPK is activated during energy stress to inhibit anabolic pathways and stimulate catabolic processes such as fatty acid oxidation and autophagy. SIRTuins, on the other hand, link cellular metabolism to energy status through NAD+-dependent deacetylation, influencing mitochondrial function and longevity.

Regulation of glycolysis and oxidative phosphorylation

Glycolysis and oxidative phosphorylation are essential for ATP production and cellular energy balance. Nutrient-sensing pathways play crucial roles in modulating these pathways to meet cellular energy demands. Under nutrient-rich conditions, mTOR promotes glycolysis by enhancing the expression of glycolytic enzymes and inhibiting mitochondrial biogenesis through mechanisms involving PGC-1α. Conversely, AMPK activation during energy stress inhibits glycolysis to preserve glucose and stimulates mitochondrial biogenesis and oxidative phosphorylation to enhance ATP production [10]. SIRTuins contribute to mitochondrial function by deacetylating proteins involved in oxidative phosphorylation, thereby influencing cellular energy production and metabolic efficiency.

Control of lipid metabolism

Lipid metabolism is tightly regulated by nutrient-sensing pathways to balance energy storage and utilization. mTOR activation promotes lipogenesis in response to nutrient abundance, whereas AMPK inhibits lipogenesis and promotes fatty acid oxidation during energy deficit. SIRTuins regulate lipid metabolism through deacetylation of transcription factors and enzymes involved in lipid synthesis and oxidation, influencing lipid storage and utilization in response to nutrient availability and energy status.

Role in autophagy and cellular stress responses

Autophagy is a critical cellular process for maintaining cellular homeostasis and adapting to stress conditions such as nutrient deprivation and oxidative stress. Nutrient-sensing pathways regulate autophagy to provide alternative energy sources and remove damaged organelles and proteins. mTORC1 is a potent inhibitor of autophagy under nutrient-rich conditions, while its inhibition during nutrient deprivation induces autophagy to recycle cellular components and sustain cellular function. AMPK activation stimulates autophagy as a survival mechanism to maintain cellular energy levels and promote cell viability under metabolic stress conditions. SIRTuins also play a role in autophagy regulation through deacetylation of autophagy-related proteins and transcription factors, linking nutrient availability to cellular stress responses.

Implications for health and disease

Dysregulation of nutrient-sensing pathways is associated with various metabolic disorders, including obesity, type 2 diabetes, and cancer. Understanding the mechanisms by which these pathways contribute to metabolic diseases provides insights into potential therapeutic strategies. Targeting nutrient-sensing pathways with pharmacological agents or dietary interventions holds promise for treating metabolic disorders and improving health outcomes. Future research should focus on elucidating the crosstalk between nutrient-sensing pathways, investigating their tissue-specific roles, and developing targeted therapies to restore metabolic balance and promote overall health.

Conclusion

In conclusion, nutrient-sensing pathways are central regulators of cellular metabolism, coordinating metabolic processes in response to nutrient availability, energy status, and environmental cues. This review has underscored the critical roles of mTOR, AMPK, and SIRTuins in governing glycolysis, oxidative phosphorylation, lipid metabolism, and autophagy. Continued research into these pathways promises to uncover new insights into metabolic regulation, with implications for therapeutic interventions in metabolic disorders and aging-related diseases.

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