Joy Edwards-Hicks

Max Planck Institute of Immunobiology and Epigenetics

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Erika L. Pearce

Bloomberg (United States)

David E. Sanin

Max Planck Institute of Immunobiology and Epigenetics

Edward J. Pearce

Bloomberg (United States)

Katarzyna M. Grzes

Max Planck Institute of Immunobiology and Epigenetics

Agnieszka M. Kabat

Max Planck Institute of Immunobiology and Epigenetics

Matteo Villa

Max Planck Institute of Immunobiology and Epigenetics

Mauro Corrado

Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases

Jonathan D. Curtis

Max Planck Institute of Immunobiology and Epigenetics

Michal A. Stanczak

Max Planck Institute of Immunobiology and Epigenetics

George Caputa

Max Planck Institute of Immunobiology and Epigenetics

Cooperative Institutions

Max Planck Institute of Immunobiology and Epigenetics

University of Freiburg

University of Edinburgh

National Institutes of Health

National Institute of Allergy and Infectious Diseases

Medical Research Council

University Medical Center Freiburg

University Hospital of Basel

University of Basel

University of Cambridge

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Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells

Molecular Cell (2022)

Patricia Altea‐Manzano Anke Vandekeere Joy Edwards-Hicks Mar Roldán Emily Abraham

Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis—the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.

Malate dehydrogenase

Cellular respiration

10.1016/j.molcel.2022.10.005

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Citations (22)

Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy

Nature Metabolism (2020)

Ramon I. Klein Geltink Joy Edwards-Hicks Petya Apostolova David O’Sullivan David E. Sanin

Adoptive Cell Transfer

Cell therapy

10.1038/s42255-020-0256-z

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Citations (108)

Research Techniques Made Simple: Profiling Cellular Energy Metabolism

Journal of Investigative Dermatology (2021)

Mario Fabri Matteo Villa Michal A. Stanczak Joy Edwards-Hicks Mauro Corrado

Cellular metabolism

Profiling (computer programming)

Cell metabolism

10.1016/j.jid.2021.09.004

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Citations (3)

Metabolic and functional remodeling of colonic macrophages in response to high-fat diet-induced obesity

iScience (2023)

Ângela Castoldi David E. Sanin Nikki van Teijlingen Bakker Cristhiane Fávero de Aguiar Lauar de Brito Monteiro

Lipid droplet

Lipogenesis

Lamina propria

efferocytosis

10.1016/j.isci.2023.107719

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HIGHLY PHAGOCYTIC LIPID-ASSOCIATED MACROPHAGES (LAMs) ARE INCREASED IN COLONIC LAMINA PROPRIA IN OBESITY

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Ângela Castoldi David E. Sanin Nikki van Teijlingen Bakker Christiane F Aguiar Lauar de Brito Monteiro

Abstract Little is known about the effects of high fat diet (HFD)-induced obesity on resident colonic lamina propria (LP) macrophages (LPMs) function and metabolism. Here, we report that obesity and diabetes resulted in increased macrophage infiltration in the colon. These macrophages exhibited the residency phenotype CX3CR1 hi MHCII hi , and were CD4 − TIM4 − . During HFD, resident colonic LPM exhibited a lipid metabolism gene expression signature that overlapped that used to define lipid associated macrophages (LAMs). Via single cell RNA sequencing, we identified a sub-cluster of macrophages, increased in HDF, that were responsible for the LAM signature. Compared to other macrophages in the colon, these cells were characterized by elevated glycolysis, phagocytosis and efferocytosis signatures. CX3CR1 hi MHCII hi colonic resident LPMs had fewer lipid droplets (LD) and decreased triacylglycerol (TAG) content compared to equivalent cells in lean mice, and exhibited increased phagocytic capacity, suggesting that HFD induces adaptive responses in LPMs to limit bacterial translocation.

Lamina propria

Lipid droplet

CX3CR1

10.1101/2022.12.20.521239

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Resident T cells orchestrate adipose tissue remodeling in a site peripheral to infection

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Agnieszka M. Kabat Alexandra Hackl David E. Sanin Patrice Zeis Katarzyna M. Grzes

Abstract Infection with helminth parasites can affect adiposity, but underlying mechanisms that regulate this process are unclear. We found that fat content of mesenteric adipose tissue (mAT) declined in mice during infection with gut-restricted parasitic worms. This was associated with the accumulation of metabolically activated, immunostimulatory cytokine- and extracellular matrix-secreting multipotent stromal cells, which had potential to differentiate into preadipocytes. Concomitantly, mAT became infiltrated with Th2 lymphocytes that took up long-term residence and responded to signals from stromal cells by producing stromal cell-stimulating cytokines, including Amphiregulin. Signals delivered by Amphiregulin to stromal cells were required for immunity to infection. Our findings reveal intricate intercellular communication between Th2 cells and adipocyte progenitors and link immunity to intestinal infection to T cell-dependent effects on the adipocyte lineage.

3T3-L1

10.1101/2022.02.24.481701

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Triacylglycerol synthesis enhances macrophage inflammatory function

Nature Communications (2020)

Ângela Castoldi Lauar de Brito Monteiro Nikki van Teijlingen Bakker David E. Sanin Nisha Rana

Abstract Foamy macrophages, which have prominent lipid droplets (LDs), are found in a variety of disease states. Toll-like receptor agonists drive triacylglycerol (TG)-rich LD development in macrophages. Here we explore the basis and significance of this process. Our findings indicate that LD development is the result of metabolic commitment to TG synthesis on a background of decreased fatty acid oxidation. TG synthesis is essential for optimal inflammatory macrophage activation as its inhibition, which prevents LD development, has marked effects on the production of inflammatory mediators, including IL-1β, IL-6 and PGE2, and on phagocytic capacity. The failure of inflammatory macrophages to make PGE2 when TG-synthesis is inhibited is critical for this phenotype, as addition of exogenous PGE2 is able to reverse the anti-inflammatory effects of TG synthesis inhibition. These findings place LDs in a position of central importance in inflammatory macrophage activation.

10.1038/s41467-020-17881-3

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Citations (213)

A metabolic dependency of EBV can be targeted to hinder B cell transformation

Science (2024)

Bojana Durovic J. Jäger Christine Engelmann Patrick Schuhmachers Sabine Altermatt

After infection of B cells, Epstein-Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates nicotinamide adenine dinucleotide (NAD) de novo biosynthesis by driving expression of the metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match adenosine triphosphate (ATP) production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is therefore a druggable metabolic vulnerability of EBV-driven B cell transformation, opening therapeutic possibilities for EBV-related diseases.

10.1126/science.adk4898

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Citations (15)

An LKB1–mitochondria axis controls TH17 effector function

Nature (2022)

Francesc Baixauli Klara Piletič Daniel J. Puleston Matteo Villa Cameron S. Field

10.1038/s41586-022-05264-1

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Citations (50)

MYC sensitises cells to apoptosis by driving energetic demand

Nature Communications (2022)

Joy Edwards-Hicks Huizhong Su Maurizio Mangolini Kubra K Yoneten Jimi Wills

Abstract The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.

Catabolism

10.1038/s41467-022-32368-z

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Citations (21)