Series 23 August 2023

Metabolic signalling

Metabolic regulation lies at the intersection of many research fields, including biochemistry, molecular and cell biology, physiology and the study of disease pathogenesis. Numerous advances have been made in our understanding of how metabolic pathways can be dynamically regulated by cellular events to meet the energy needs of the cell and maintain cell and organismal homeostasis. Dysregulation of these pathways, which influence signal transduction and gene expression, is linked to metabolic diseases such as obesity and type 2 diabetes, as well as to cancer and ageing.

This series features Review articles that discuss various aspects of the regulation of metabolic signalling, the interface between metabolic regulators and cellular processes and the implications of their deregulation for human diseases.

Reviews

Mechanisms controlling cellular and systemic iron homeostasis

Iron homeostasis in animals is tightly controlled, and numerous cellular pathways regulate iron uptake, storage, metabolism and secretion. Recent findings provide new insights into the sensory systems that fine-tune iron homeostasis and explain how cellular and systemic iron fluxes intersect.
- Bruno Galy
- Marcus Conrad
- Martina Muckenthaler
Review Article2 Oct 2023 Nature Reviews Molecular Cell Biology
The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease

Mechanistic target of rapamycin mTOR complex 1 (mTORC1) is a central regulator of cellular metabolism. Recent studies of the molecular architecture of mTORC1 shed new light on its physiological functions and on the consequences of their dysregulation in cancer, type 2 diabetes and neurodegeneration.
- Claire Goul
- Roberta Peruzzo
- Roberto Zoncu
Review Article23 Aug 2023 Nature Reviews Molecular Cell Biology
Metabolites as signalling molecules

Metabolites are generally viewed as intermediates or products of metabolism. However, many metabolites are also signalling molecules that regulate metabolic reactions and other processes in development, homeostasis and disease. As such, metabolites can confer adaptive responses to environmental changes.
- Steven Andrew Baker
- Jared Rutter
Review Article12 Jan 2023 Nature Reviews Molecular Cell Biology
Signalling mechanisms and cellular functions of SUMO

Sumoylation regulates thousands of proteins, many of which are nuclear. Recent studies have implicated sumoylation in liquid–liquid phase separation and assembly of nuclear bodies, and have uncovered its roles in immunity and pluripotency and links to disease, thereby opening new therapeutic avenues.
- Alfred C. O. Vertegaal
Review Article24 Jun 2022 Nature Reviews Molecular Cell Biology
The cellular and functional complexity of thermogenic fat

Brown and beige adipocytes are mammalian thermogenic fat cells that regulate whole-body energy metabolism. Notably, brown/beige adipocytes are heterogeneous and their functions extend beyond thermogenesis, encompassing roles as metabolite sinks, as secretory cells and as regulators of adipose tissue homeostasis. Thus, induction of brown/beige fat activity correlates with improved metabolic health.
- Paul Cohen
- Shingo Kajimura
Review Article23 Mar 2021 Nature Reviews Molecular Cell Biology
MicroRNA-mediated regulation of glucose and lipid metabolism

MicroRNAs widely regulate systemic metabolism, prominently that of glucose and lipids. Consequently, microRNA misexpression can lead to metabolic diseases such as diabetes and atherosclerosis. MicroRNAs are therefore emerging as potential therapeutic targets to control metabolism and, owing to their secretion in extracellular vesicles, as metabolic biomarkers.
- Pamela Agbu
- Richard W. Carthew
Review Article26 Mar 2021 Nature Reviews Molecular Cell Biology
NAD⁺ metabolism and its roles in cellular processes during ageing

Nicotinamide adenine dinucleotide (NAD⁺) is a central redox factor and enzymatic cofactor that functions in a plethora of cellular processes, including metabolic pathways and DNA metabolism, and affects cell fate and function. NAD⁺ levels gradually decline with age, and therapeutic elevation of NAD⁺ levels is being trialled for extending human healthspan and lifespan.
- Anthony J. Covarrubias
- Rosalba Perrone
- Eric Verdin
Review Article22 Dec 2020 Nature Reviews Molecular Cell Biology
Crosstalk between mechanotransduction and metabolism

Mechanical forces are important regulators of cell function and behaviour. This role is partly achieved through the modulation of cell metabolism, which, reciprocally, affects tissue mechanics. Unravelling the mechanisms of this crosstalk will increase our understanding of how cells interact with their microenvironment.
- Patrizia Romani
- Lorea Valcarcel-Jimenez
- Sirio Dupont
Review Article13 Nov 2020 Nature Reviews Molecular Cell Biology
Reactive oxygen species (ROS) as pleiotropic physiological signalling agents

Reactive oxygen species (ROS) were originally associated with cellular damage and disease. However, ROS, notably hydrogen peroxide, at low physiological levels also engage in physiological signalling, supporting cellular responses and adaptation to changing environments and stress. Accordingly, controlling specific ROS-mediated signalling pathways offers new perspectives for a more refined redox medicine.
- Helmut Sies
- Dean P. Jones
Review Article30 Mar 2020 Nature Reviews Molecular Cell Biology
Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

The transcriptional response to hypoxia and the role of hypoxia inducible factors have been extensively studied. Yet, hypoxic cells also adapt to hypoxia by modulating protein synthesis, metabolism and nutrient uptake. Understanding these processes could shed light on pathologies associated with hypoxia, including cardiovascular diseases and cancer, and disease mechanisms, such as inflammation and wound repair.
- Pearl Lee
- Navdeep S. Chandel
- M. Celeste Simon
Review Article6 Mar 2020 Nature Reviews Molecular Cell Biology
mTOR at the nexus of nutrition, growth, ageing and disease

The mTOR pathway integrates diverse environmental cues to control biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing, and is thus a promising target for pharmacological intervention.
- Grace Y. Liu
- David M. Sabatini
Review Article14 Jan 2020 Nature Reviews Molecular Cell Biology
Mechanisms and regulation of cholesterol homeostasis

Cholesterol is an important structural component of all animal cell membranes that functions in various processes, including membrane dynamics and cell signalling, and is also a precursor of other molecules. Deregulation of cholesterol metabolism — biosynthesis, dietary absorption and cellular uptake, storage and efflux — is linked to many diseases, including cardiovascular and genetic diseases, and cancer. A better understanding of cholesterol metabolism offers the possibility to control systemic cholesterol levels to improve human health.
- Jie Luo
- Hongyuan Yang
- Bao-Liang Song
Review Article17 Dec 2019 Nature Reviews Molecular Cell Biology
Lysosomes as dynamic regulators of cell and organismal homeostasis

Lysosomes are mainly associated with cellular waste disposal. But it has recently been discovered that by integrating various environmental cues, they have a broader role as regulatory hubs for cellular and organismal homeostasis. The modulation of lysosome function could thus be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.
- Andrea Ballabio
- Juan S. Bonifacino
Review Article25 Nov 2019 Nature Reviews Molecular Cell Biology
Metabolic regulation of cell growth and proliferation

Cellular metabolism is rewired in proliferating cells to support their increased need for macromolecule biosynthesis. A better understanding of how cells utilize nutrients for biosynthetic pathways and how they overcome the metabolic challenges associated with high proliferation rates can lead to better control of cell proliferation and improved cancer treatments.
- Jiajun Zhu
- Craig B. Thompson
Review Article11 Apr 2019 Nature Reviews Molecular Cell Biology
Crosstalk between metabolism and circadian clocks

Circadian rhythms align organismal functions with phases of rest and activity. Accordingly, circadian oscillations occur in many physiological processes, including various metabolic functions. In turn, metabolic cues are emerging as regulators of the circadian clock. This crosstalk between metabolism and circadian rhythms has important implications for human health.
- Hans Reinke
- Gad Asher
Review Article11 Jan 2019 Nature Reviews Molecular Cell Biology
Adipogenesis and metabolic health

An increase in white adipose tissue is associated with obesity and reduced metabolic function. Interestingly, however, adipose tissue expansion through the generation of new adipocytes (adipogenesis), rather than through increasing adipocyte size, can prevent this metabolic decline. Thus, a better understanding of adipogenesis can inform new strategies to increase metabolic health in humans.
- Alexandra L. Ghaben
- Philipp E. Scherer
Review Article4 Jan 2019 Nature Reviews Molecular Cell Biology
Metabolites as regulators of insulin sensitivity and metabolism

Metabolomics and lipidomics have enabled the identification of metabolites (such as lipids, amino acids and bile acids) and metabolic pathways that modulate insulin sensitivity both directly and indirectly. Understanding the metabolic adaptations involved in insulin resistance may lead to novel approaches for preventing and treating T2DM.
- Qin Yang
- Archana Vijayakumar
- Barbara B. Kahn
Review Article13 Aug 2018 Nature Reviews Molecular Cell Biology
Regulation of chromatin and gene expression by metabolic enzymes and metabolites

Metabolism feeds into gene regulation, allowing adaptation of gene expression to satisfy cellular needs, including in pathological scenarios such as cancer. Metabolism modulates gene expression through metabolites, which serve as cofactors for DNA and histone modifiers, and through metabolic enzymes, which locally regulate chromatin and transcription in the nucleus.
- Xinjian Li
- Gabor Egervari
- Zhimin Lu
Review Article21 Jun 2018 Nature Reviews Molecular Cell Biology
Biochemical and cellular properties of insulin receptor signalling

Research over the past few decades has elucidated the biochemical mechanisms underlying insulin receptor signalling. Recent insights into the complexity of its temporal and tissue-specific regulation, which involves various combinations of signalling modules in different cell types, are shedding light on the pleiotropic effects of insulin action and the pathogenesis of insulin resistance.
- Rebecca A. Haeusler
- Timothy E. McGraw
- Domenico Accili
Review Article4 Oct 2017 Nature Reviews Molecular Cell Biology
AMPK: guardian of metabolism and mitochondrial homeostasis

AMP-activated protein kinase (AMPK) senses cellular energy levels and phosphorylates a variety of cellular substrates to inhibit or stimulate anabolic and catabolic processes, adjusting metabolism to energy needs. Recent studies have uncovered a crucial role of AMPK in the regulation of mitochondrial dynamics and mitophagy, further expanding its role in the control of cellular metabolism.
- Sébastien Herzig
- Reuben J. Shaw
Review Article4 Oct 2017 Nature Reviews Molecular Cell Biology
Cytosolic lipolysis and lipophagy: two sides of the same coin

Lipolysis degrades triacylglycerols to supply cells with free fatty acids, which are essential components of membrane lipids and substrates for energy production. Recent discoveries transformed our understanding of the functions of and crosstalk between 'neutral' lipolysis, which occurs in the cytosol, and lipophagy and 'acid' lipolysis, which occur in lysosomes, and how dysfunction in these processes contributes to metabolic diseases.
- Rudolf Zechner
- Frank Madeo
- Dagmar Kratky
Review Article30 Aug 2017 Nature Reviews Molecular Cell Biology
Slowing ageing by design: the rise of NAD⁺ and sirtuin-activating compounds

Sirtuins are NAD⁺-dependent protein deacylases that can reverse various aspects of ageing in model organisms. Trials in non-human primates and humans indicate that sirtuin-activating compounds (STACs) and NAD⁺precursors are safe and effective in treating inflammatory and metabolic disorders, thereby holding great potential to treat various diseases and to extend lifespan in humans.
- Michael S. Bonkowski
- David A. Sinclair
Review Article24 Aug 2016 Nature Reviews Molecular Cell Biology
Mitonuclear communication in homeostasis and stress

As most mitochondrial proteins are encoded in the nucleus, mitochondrial activity requires efficient communication between the nuclear and mitochondrial genomes. This is mediated by nucleus-to-mitochondria (anterograde), mitochondria-to-nucleus (retrograde) and mitonuclear feedback signalling, as well as the integrated stress response and extracellular communication, which regulate homeostasis and, consequently, healthspan and lifespan.
- Pedro M. Quirós
- Adrienne Mottis
- Johan Auwerx
Review Article9 Mar 2016 Nature Reviews Molecular Cell Biology
The aetiology and molecular landscape of insulin resistance

Insulin resistance is one of the earliest manifestations of several human diseases, including type 2 diabetes and cardiovascular disease. This Review discusses the causes of insulin resistance and recent insights into the underlying mechanisms, providing directions for the development of novel therapeutic strategies
- David E. James
- Jacqueline Stöckli
- Morris J. Birnbaum
Review Article20 Jul 2021 Nature Reviews Molecular Cell Biology

Metabolic signalling

Reviews

Mechanisms controlling cellular and systemic iron homeostasis

The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease

Metabolites as signalling molecules

Signalling mechanisms and cellular functions of SUMO

The cellular and functional complexity of thermogenic fat

MicroRNA-mediated regulation of glucose and lipid metabolism

NAD⁺ metabolism and its roles in cellular processes during ageing

Crosstalk between mechanotransduction and metabolism

Reactive oxygen species (ROS) as pleiotropic physiological signalling agents

Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

mTOR at the nexus of nutrition, growth, ageing and disease

Mechanisms and regulation of cholesterol homeostasis

Lysosomes as dynamic regulators of cell and organismal homeostasis

Metabolic regulation of cell growth and proliferation

Crosstalk between metabolism and circadian clocks

Adipogenesis and metabolic health

Metabolites as regulators of insulin sensitivity and metabolism

Regulation of chromatin and gene expression by metabolic enzymes and metabolites

Biochemical and cellular properties of insulin receptor signalling

AMPK: guardian of metabolism and mitochondrial homeostasis

Cytosolic lipolysis and lipophagy: two sides of the same coin

Slowing ageing by design: the rise of NAD⁺ and sirtuin-activating compounds

Mitonuclear communication in homeostasis and stress

The aetiology and molecular landscape of insulin resistance

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