Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells.

For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.

Microbiota Metabolites in Health and Disease.

Metabolism is one of the strongest drivers of interkingdom interactions-including those between microorganisms and their multicellular hosts. Traditionally thought to fuel energy requirements and provide building blocks for biosynthetic pathways, metabolism is now appreciated for its role in providing metabolites, small-molecule intermediates generated from metabolic processes, to perform various regulatory functions to mediate symbiotic relationships between microbes and their hosts. Here, we review recent advances in our mechanistic understanding of how microbiota-derived metabolites orchestrate and support physiological responses in the host, including immunity, inflammation, defense against infections, and metabolism. Understanding how microbes metabolically communicate with their hosts will provide us an opportunity to better describe how a host interacts with all microbes-beneficial, pathogenic, and commensal-and an opportunity to discover new ways to treat microbial-driven diseases.

Krebs Cycle Reborn in Macrophage Immunometabolism.

A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle-derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.

Hypoxia and Innate Immunity: Keeping Up with the HIFsters.

Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF.

Complement and the Regulation of T Cell Responses.

The complement system is an evolutionarily ancient key component of innate immunity required for the detection and removal of invading pathogens. It was discovered more than 100 years ago and was originally defined as a liver-derived, blood-circulating sentinel system that classically mediates the opsonization and lytic killing of dangerous microbes and the initiation of the general inflammatory reaction. More recently, complement has also emerged as a critical player in adaptive immunity via its ability to instruct both B and T cell responses. In particular, work on the impact of complement on T cell responses led to the surprising discoveries that the complement system also functions within cells and is involved in regulating basic cellular processes, predominantly those of metabolic nature. Here, we review current knowledge about complement's role in T cell biology, with a focus on the novel intracellular and noncanonical activities of this ancient system.

Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation.

Researchers are intensifying efforts to understand the mechanisms by which changes in metabolic states influence differentiation programs. An emerging objective is to define how fluctuations in metabolites influence the epigenetic states that contribute to differentiation programs. This is because metabolites such as S-adenosylmethionine, acetyl-CoA, α-ketoglutarate, 2-hydroxyglutarate, and butyrate are donors, substrates, cofactors, and antagonists for the activities of epigenetic-modifying complexes and for epigenetic modifications. We discuss this topic from the perspective of specialized CD4+ T cells as well as effector and memory T cell differentiation programs. We also highlight findings from embryonic stem cells that give mechanistic insight into how nutrients processed through pathways such as glycolysis, glutaminolysis, and one-carbon metabolism regulate metabolite levels to influence epigenetic events and discuss similar mechanistic principles in T cells. Finally, we highlight how dysregulated environments, such as the tumor microenvironment, might alter programming events.

Unraveling the Complex Interplay Between T Cell Metabolism and Function.

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.

Inositol Pyrophosphates as Versatile Metabolic Messengers.

Discovered in 1993, inositol pyrophosphates are evolutionarily conserved signaling metabolites whose versatile modes of action are being increasingly appreciated. These include their emerging roles as energy regulators, phosphodonors, steric/allosteric regulators, and G protein-coupled receptor messengers. Through studying enzymes that metabolize inositol pyrophosphates, progress has also been made in elucidating the various cellular and physiological functions of these pyrophosphate-containing, energetic molecules. The two main forms of inositol pyrophosphates, 5-IP7 and IP8, synthesized respectively by inositol-hexakisphosphate kinases (IP6Ks) and diphosphoinositol pentakisphosphate kinases (PPIP5Ks), regulate phosphate homeostasis, ATP synthesis, and several other metabolic processes ranging from insulin secretion to cellular energy utilization. Here, we review the current understanding of the catalytic and regulatory mechanisms of IP6Ks and PPIP5Ks, as well as their counteracting phosphatases. We also highlight the genetic and cellular evidence implicating inositol pyrophosphates as essential mediators of mammalian metabolic homeostasis.

Mitochondria at the crossroads of health and disease.

Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.

Digesting the complex metabolic effects of diet on the host and microbiome.

The past 50 years of interdisciplinary research in humans and model organisms has delivered unprecedented insights into the mechanisms through which diet affects energy balance. However, translating these results to prevent and treat obesity and its associated diseases remains challenging. Given the vast scope of this literature, we focus this Review on recent conceptual advances in molecular nutrition targeting the management of energy balance, including emerging dietary and pharmaceutical interventions and their interactions with the human gut microbiome. Notably, multiple current dietary patterns of interest embrace moderate-to-high fat intake or prioritize the timing of eating over macronutrient intake. Furthermore, the rapid expansion of microbiome research findings has complicated multiple longstanding tenets of nutrition while also providing new opportunities for intervention. Continued progress promises more precise and reliable dietary recommendations that leverage our growing knowledge of the microbiome, the changing landscape of clinical interventions, and our molecular understanding of human biology.

Translational potential of mouse models of human metabolic disease.

Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification of therapeutic targets in the future.

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

SON-light activation of glucose regulation.

Body temperature maintenance is an important regulator of glucose homeostasis. In this issue of Cell, Meng et al. discover a regulatory axis in which light activation of photoreceptive retinal ganglia stimulates the supraoptic nucleus (SON) to inhibit brown adipose tissue (BAT) thermogenesis and impair glucose homeostasis. This could explain the impact of constant light exposure on metabolism.

What is cancer metabolism?

The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While many studies of cell metabolism focus on cancer cells, the principles of metabolism elucidated in cancer cells apply to a wide range of mammalian cells. The goal of this review is to discuss how the field of cancer metabolism provides a framework for revealing principles of cell metabolism and for dissecting the metabolic networks that allow cells to meet their specific demands. Understanding context-specific metabolic preferences and liabilities will unlock new approaches to target cancer cells to improve patient care.

Igniting adipocyte thermogenesis.

Maintenance of body temperature is intimately tied to energy expenditure and body weight regulation. In this issue of Cell, Li, Wang, et al. discovered that localized hyperthermia induces the thermogenic program to increase energy expenditure and decrease body weight in mice and humans.

SnapShot: Regulation and biology of PGC-1α.

The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-1α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes. Expressing specific PGC-1α isoforms in mice can confer protection in different disease models. This SnapShot summarizes how regulation of Ppargc1a transcription, splicing, translation, protein stability, and activity underlies its multifaceted functions. To view this SnapShot, open or download the PDF.

Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration.

Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.

New insights into activation and function of the AMPK.

The classical role of AMP-activated protein kinase (AMPK) is as a cellular energy sensor activated by falling energy status, signalled by increases in AMP to ATP and ADP to ATP ratios. Once activated, AMPK acts to restore energy homeostasis by promoting ATP-producing catabolic pathways while inhibiting energy-consuming processes. In this Review, we provide an update on this canonical (AMP/ADP-dependent) activation mechanism, but focus mainly on recently described non-canonical pathways, including those by which AMPK senses the availability of glucose, glycogen or fatty acids and by which it senses damage to lysosomes and nuclear DNA. We also discuss new findings on the regulation of carbohydrate and lipid metabolism, mitochondrial and lysosomal homeostasis, and DNA repair. Finally, we discuss the role of AMPK in cancer, obesity, diabetes, nonalcoholic steatohepatitis (NASH) and other disorders where therapeutic targeting may exert beneficial effects.

Persistent Cancer Cells: The Deadly Survivors.

Persistent cancer cells are the discrete and usually undetected cells that survive cancer drug treatment and constitute a major cause of treatment failure. These cells are characterized by their slow proliferation, highly flexible energy consumption, adaptation to their microenvironment, and phenotypic plasticity. Mechanisms that underlie their persistence offer highly coveted and sought-after therapeutic targets, and include diverse epigenetic, transcriptional, and translational regulatory processes, as well as complex cell-cell interactions. Although the successful clinical targeting of persistent cancer cells remains to be realized, immense progress has been made in understanding their persistence, yielding promising preclinical results.

Cellular Control of Viscosity Counters Changes in Temperature and Energy Availability.

Cellular functioning requires the orchestration of thousands of molecular interactions in time and space. Yet most molecules in a cell move by diffusion, which is sensitive to external factors like temperature. How cells sustain complex, diffusion-based systems across wide temperature ranges is unknown. Here, we uncover a mechanism by which budding yeast modulate viscosity in response to temperature and energy availability. This "viscoadaptation" uses regulated synthesis of glycogen and trehalose to vary the viscosity of the cytosol. Viscoadaptation functions as a stress response and a homeostatic mechanism, allowing cells to maintain invariant diffusion across a 20°C temperature range. Perturbations to viscoadaptation affect solubility and phase separation, suggesting that viscoadaptation may have implications for multiple biophysical processes in the cell. Conditions that lower ATP trigger viscoadaptation, linking energy availability to rate regulation of diffusion-controlled processes. Viscoadaptation reveals viscosity to be a tunable property for regulating diffusion-controlled processes in a changing environment.