bims-imicid 2025-02-23 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2025–02–23
twenty papers selected by
Dylan Ryan, University of Cambridge

CD4+ T-cell metabolism in the pathogenesis of Sjogren's syndrome.
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.
Metabolic reprogramming shapes post-translational modification in macrophages.
B cell immunometabolism in health and disease.
Metabolic and stress response adaptations in T cells to fever and physiological heat.
Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis.
RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.
Linking macrophage metabolism to function in the tumor microenvironment.
Development of itaconate polymer microparticles for intracellular regulation of pro-inflammatory macrophage activation.
Hydroxychloroquine corrects mitochondrial recycling dysfunction in natural killer cells from patients with systemic lupus erythematosus.
Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.
Amino Acid Metabolism and Immune Dysfunction in Urea Cycle Disorders: T and B Cell Perspectives.
Galloflavin mitigates acute kidney injury by suppressing LDHA-dependent macrophage glycolysis.
Perturbation of de novo lipogenesis hinders MERS-CoV assembly and release, but not the biogenesis of viral replication organelles.
Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.
The flux of energy in critical illness and the obesity paradox.
Zika virus NS1 drives tunneling nanotube formation for mitochondrial transfer and stealth transmission in trophoblasts.
TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy.
Identification of Glycolysis-Related Signature and Molecular Subtypes in Child Sepsis Through Machine Learning and Consensus Clustering: Implications for Diagnosis and Therapeutics.
Necrosis drives susceptibility to Mycobacterium tuberculosis in PolgD257A mutator mice.

Int Immunopharmacol. 2025 Feb 18. pii: S1567-5769(25)00310-8. [Epub ahead of print]150 114320

CD4+ T-cell metabolism in the pathogenesis of Sjogren's syndrome.

Baixi Chen, Chenji Zhang, Mengyuan Zhou, Hongyu Deng, Jiabao Xu, Junhao Yin, Changyu Chen, Dahe Zhang, Yiping Pu, Lingyan Zheng, Baoli Wang, Jiayao Fu.

  The abnormal effector function of CD4+ T cells plays a key role in the pathogenesis of Sjogren's syndrome (SS) and its associated systematic autoimmune response. Cellular metabolism, including glucose metabolism, lipid metabolism and amino acid metabolism, supports proliferation, migration, survival and differentiation into distinct CD4+ T-cell subsets. Different subtypes of T cells have significantly different demands for related metabolic processes, which enables us to finely regulate CD4+ T cells through different metabolic processes in autoimmune diseases such as SS. In this review, we summarize the effects of disturbances in distinct metabolic processes, such as glycolysis, fatty acid metabolism, glutamine decomposition, mitochondrial dynamics, and ferroptosis, on how to support the effector functions of CD4+ T cells in the SS. We also discuss potential drugs with high value in the treatment of SS through metabolic normalization in CD4+ T cells. Finally, we propose possible directions for future targeted therapy for immunometabolism in SS.

Keywords:  Autoimmunity; Fatty acid; Glycolysis; Immunometabolism; OXPHOS; Sjogren's syndrome; T cell

DOI:  https://doi.org/10.1016/j.intimp.2025.114320
Nat Metab. 2025 Feb 19.

Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation.

Alva M Casey, Dylan G Ryan, Hiran A Prag, Suvagata Roy Chowdhury, Eloïse Marques, Keira Turner, Anja V Gruszczyk, Ming Yang, Dane M Wolf, Jan Lj Miljkovic, Joyce Valadares, Patrick F Chinnery, Richard C Hartley, Christian Frezza, Julien Prudent, Michael P Murphy.

Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.

DOI: https://doi.org/10.1038/s42255-025-01224-x
Mol Aspects Med. 2025 Feb 19. pii: S0098-2997(25)00002-0. [Epub ahead of print]102 101338

Metabolic reprogramming shapes post-translational modification in macrophages.

Ziyi Han, Yinhao Shen, Yuqi Yan, Peng Bin, Meimei Zhang, Zhending Gan.

  Polarized macrophages undergo metabolic reprogramming, as well as extensive epigenetic and post-translational modifications (PTMs) switch. Metabolic remodeling and dynamic changes of PTMs lead to timely macrophage response to infection or antigenic stimulation, as well as its transition from a pro-inflammatory to a reparative phenotype. The transformation of metabolites in the microenvironment also determines the PTMs of macrophages. Here we reviewed the current understanding of the altered metabolites of glucose, lipids and amino acids in macrophages shape signaling and metabolism pathway during macrophage polarization via PTMs, and how these metabolites in some macrophage-associated diseases affect disease progression by shaping macrophage PTMs.

Keywords:  Innate immunity; Macrophage; Metabolic reprogramming; Post-translational modifications

DOI:  https://doi.org/10.1016/j.mam.2025.101338
Nat Immunol. 2025 Feb 21.

B cell immunometabolism in health and disease.

Eleonora Martinis, Silvia Tonon, Alessandra Colamatteo, Antonio La Cava, Giuseppe Matarese, Carlo Ennio Michele Pucillo.

B cells have crucial roles in the initiation and progression of many pathological conditions, and several therapeutic strategies have targeted the function of these cells. The advent of immunometabolism has provided compelling evidence that the metabolic reprogramming of immune cells can dramatically alter physiopathological immune activities. A better knowledge of the metabolic profiles of B cells can provide valuable means for developing therapies tuning defined cell pathways. Here we review the cellular and molecular mechanisms by which immunometabolism controls the physiology and pathophysiology of B cells and discuss the experimental evidence linking B cell metabolism to health, autoimmunity, and cancer. Considering that several metabolic pathways in B cells are involved differently, or even in opposite ways, in health and disease, we discuss how targeted modulation of B cell immunometabolism could be exploited mechanistically to rebalance abnormal B cell functions that have become altered in disease states.

DOI: https://doi.org/10.1038/s41590-025-02102-0
Trends Immunol. 2025 Feb 20. pii: S1471-4906(25)00025-0. [Epub ahead of print]

Metabolic and stress response adaptations in T cells to fever and physiological heat.

Benjamin A Wilander, Jeffrey C Rathmell.

  Fevers are an ancient feature of the inflammatory microenvironment. While fevers may improve the immune response to pathogens, mechanisms are unclear. We explore recent studies of how fever-range temperatures inform mammalian T cell metabolism, differentiation, and stress responses. Recent evidence indicates that metabolic programs initiated by fever are maintained upon return to thermo-normality, potentially providing a lasting benefit. Despite its impact, temperature remains overlooked and warrants further study. This is especially apparent when considering the wide temperature differential between tissues within the body and during inflammatory disease progression. We propose that differences in the metabolic and stress responses between T cell subsets upon thermal stress contribute to determining immune cell makeup and fate during inflammation.

Keywords:  T cells; fever; immunometabolism; stress

DOI:  https://doi.org/10.1016/j.it.2025.01.007
bioRxiv. 2025 Jan 29. pii: 2025.01.27.635146. [Epub ahead of print]

Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis.

Matthew T Stier, Allison E Sewell, Erin L Mwizerwa, Chooi Ying Sim, Samantha M Tanner, Casey M Nichols, Heather H Durai, Erin Q Jennings, Paul Lindau, Erin M Wilfong, Dawn C Newcomb, Julie A Bastarache, Lorraine B Ware, Jeffrey C Rathmell.

Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults. CD4 T cells in critical illness showed increased subset-specific metabolic plasticity, with regulatory T cells (Tregs) acquiring glycolytic capacity that stabilized suppressive markers FOXP3 and TIGIT and correlated with clinical illness severity. Single-cell transcriptomics identified differential kynurenine metabolism in Tregs, which was validated ex vivo as a mechanism of Treg glycolytic adaptation and suppressive rewiring. These findings underscore immunometabolic dysfunction as a driver of CD4 T cell remodeling in sepsis and suggest therapeutic avenues to restore an effective immune response.

DOI: https://doi.org/10.1101/2025.01.27.635146
Cell Metab. 2025 Feb 11. pii: S1550-4131(25)00013-0. [Epub ahead of print]

RBM43 controls PGC1α translation and a PGC1α-STING signaling axis.

Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman.

  Obesity is associated with systemic inflammation that impairs mitochondrial function. This disruption curtails oxidative metabolism, limiting adipocyte lipid metabolism and thermogenesis, a metabolically beneficial program that dissipates chemical energy as heat. Here, we show that PGC1α, a key governor of mitochondrial biogenesis, is negatively regulated at the level of its mRNA translation by the RNA-binding protein RBM43. RBM43 is induced by inflammatory cytokines and suppresses mitochondrial biogenesis in a PGC1α-dependent manner. In mice, adipocyte-selective Rbm43 disruption elevates PGC1α translation and oxidative metabolism. In obesity, Rbm43 loss improves glucose tolerance, reduces adipose inflammation, and suppresses activation of the innate immune sensor cGAS-STING in adipocytes. We further identify a role for PGC1α in safeguarding against cytoplasmic accumulation of mitochondrial DNA, a cGAS ligand. The action of RBM43 defines a translational regulatory axis by which inflammatory signals dictate cellular energy metabolism and contribute to metabolic disease pathogenesis.

Keywords:  PGC1α; adipocyte; adipose thermogenesis; adipose tissue; cGAS-STING; inflammation; mRNA translation; mitochondria; obesity; oxidative metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.01.013
Nat Cancer. 2025 Feb 17.

Linking macrophage metabolism to function in the tumor microenvironment.

Robbie Jin, Luke Neufeld, Tracy L McGaha.

Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.

DOI: https://doi.org/10.1038/s43018-025-00909-2
bioRxiv. 2025 Feb 05. pii: 2025.01.30.635692. [Epub ahead of print]

Development of itaconate polymer microparticles for intracellular regulation of pro-inflammatory macrophage activation.

Kaitlyn E Woodworth, Zachary S C S Froom, Natasha D Osborne, Christian N Rempe, Brenden Wheeler, Kyle Medd, Neal I Callaghan, Huikang Qian, Abhinav P Acharya, Carlie Charron, Locke Davenport Huyer.

Itaconate (IA) is an endogenous metabolite and a potent regulator of the innate immune system. Its use in immunomodulatory therapies has faced limitations due to inherent challenges in achieving controlled delivery and requirements for high extracellular concentrations to achieve internalization of the highly polar small molecule to achieve its intracellular therapeutic activity. Microparticle (MP)-based delivery strategies are a promising approach for intracellular delivery of small molecule metabolites through macrophage phagocytosis and subsequent intracellular polymer degradation-based delivery. Toward the goal of intracellular delivery of IA, degradable polyester polymer-(poly(itaconate-co-dodecanediol)) based IA polymer microparticles (IA-MPs) were generated using an emulsion method, forming micron-scale (∼ 1.5 µm) degradable microspheres. IA-MPs were characterized with respect to their material properties and IA release kinetics to inform particle fabrication. Treatment of murine bone marrow-derived macrophages with an optimized particle concentration of 0.1 mg/million cells enabled phagocytosis-mediated internalization and low levels of cytotoxicity. Flow cytometry demonstrated IA-MP-specific regulation of IA-sensitive inflammatory targets. Metabolic analyses demonstrated that IA-MP internalization inhibited oxidative metabolism and induced glycolytic reliance, consistent with the established mechanism of IA-associated inhibition of succinate dehydrogenase. This development of IA-based polymer microparticles provides a basis for additional innovative metabolite-based microparticle drug delivery systems for the treatment of inflammatory disease.

DOI: https://doi.org/10.1101/2025.01.30.635692
medRxiv. 2025 Jan 28. pii: 2025.01.28.25321013. [Epub ahead of print]

Hydroxychloroquine corrects mitochondrial recycling dysfunction in natural killer cells from patients with systemic lupus erythematosus.

Natalia Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.

Objectives: Natural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration.
Methods: We characterized mitochondrial structure and function in NK cells from the peripheral blood of SLE patients and healthy controls using flow cytometry, electron microscopy, and proteomics. Key mitophagy-related gene expressions were quantified using qPCR. The ability of hydroxychloroquine (HCQ) to restore mitochondrial recycling and NK cell function were assessed in vitro .
Results: SLE NK cells displayed accumulated enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with HCQ restored mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity by acidifying lysosomes.
Conclusions: This study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE patients. HCQ can correct these abnormalities by acidifying the lysosomes and highlights the potential of HCQ to restore NK cell functionality. These findings provide new insights into the immunometabolic mechanisms underlying SLE and suggest avenues for targeted therapeutic interventions.
WHAT IS KNOWN ON THE TOPIC: ➢ SLE is a complex inflammatory disease characterized by the development of autoreactive cells and a breakdown of self-tolerance (1, 2).➢ Natural Killer (NK) cells, pivotal players in the innate immune system, exhibit reduced numbers, diminished cytotoxicity, and impaired cytokine production in SLE patients (3-5). ➢ Peripheral CD56 dim CD57 + NK cells from SLE patients exhibit increased endogenous apoptosis and higher levels of mitochondrial (mt)ROS, contributing to their altered function (6).
WHAT THE STUDY ADDS: ➢ This study reveals a full spectrum of immunometabolic alterations in Natural Killer (NK) cells from SLE patients, including hyperpolarized mitochondria accumulation, cristae disorganization and impaired mitophagy. These results identify mitochondrial recycling dysfunction as a central factor in NK cell abnormalities in SLE.➢ It demonstrates for the first time that hydroxychloroquine (HCQ), a standard treatment for SLE, effectively restores mitochondrial recycling in NK cells by modulating lysosomal acidification, reducing cytosolic leakage of mtDNA and enhancing the expression of mitophagy-related genes.➢ These results highlight a new mechanism by which HCQ attenuates immune dysregulation, making it a potential targeted approach for treating the specific dysfunction of NK cells in SLE.
HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY: ➢ Understanding how mitochondrial recycling dysfunction impacts SLE pathogenesis can pave the way for the development of targeted therapies and improved disease management for SLE patients.

DOI: https://doi.org/10.1101/2025.01.28.25321013
bioRxiv. 2025 Feb 08. pii: 2025.02.03.636312. [Epub ahead of print]

Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.

Jorgo Lika, James A Votava, Rupsa Datta, Aleksandr M Kralovec, Frances M Smith, Anna Huttenlocher, Melissa C Skala, Jing Fan.

Neutrophils are highly abundant innate immune cells that are constantly produced from myeloid progenitors in the bone marrow. Differentiated neutrophils can perform an arsenal of effector functions critical for host defense. This study aims to quantitatively understand neutrophil mitochondrial metabolism throughout differentiation and activation, and to elucidate the impact of mitochondrial metabolism on neutrophil functions. To study metabolic remodeling throughout neutrophil differentiation, murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils were assessed as models. To study the metabolic remodeling upon neutrophil activation, differentiated ER-Hoxb8 neutrophils and primary human neutrophils were activated with various stimuli, including ionomycin, MSU crystals, and PMA. Characterization of cellular metabolism by isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy revealed dynamic changes in mitochondrial metabolism. As neutrophils mature, mitochondrial metabolism decreases drastically, energy production is fully offloaded from oxidative phosphorylation, and glucose oxidation through TCA cycle is substantially reduced. Nonetheless, mature neutrophils retain the capacity for mitochondrial metabolism. Upon stimulation with certain stimuli, TCA cycle is rapidly activated. Mitochondrial pyruvate carrier inhibitors reduce this re-activation of the TCA cycle and inhibit the release of neutrophil extracellular traps. Mitochondrial metabolism also impacts neutrophil redox status, migration, and apoptosis without significantly changing overall bioenergetics. Together, these results demonstrate that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophil function and fate. Furthermore, these findings point to the therapeutic potential of mitochondrial pyruvate carrier inhibitors in a range of conditions where dysregulated neutrophil response drives inflammation and contributes to pathology.

DOI: https://doi.org/10.1101/2025.02.03.636312
J Inherit Metab Dis. 2025 Mar;48(2): e70009

Amino Acid Metabolism and Immune Dysfunction in Urea Cycle Disorders: T and B Cell Perspectives.

Betul Gemici Karaaslan, Ayca Kiykim, Nihan Burtecene, Meltem Gokden, Mehmet Serif Cansever, Duhan Hopurcuoglu, Gökçe Nuran Cengiz, Birol Topcu, Tanyel Zubarioğlu, Ertugrul Kiykim, Haluk Cokuğras, Ayse Cigdem Aktuglu Zeybek.

  Urea cycle disorders (UCDs) are a group of genetic metabolic conditions characterized by enzyme deficiencies responsible for detoxifying ammonia. Hyperammonemia, the accumulation of intermediate metabolites, and a deficiency of essential amino acids-due to a protein-restrictive diet and the use of ammonia scavengers-can increase the risk of infections, particularly during metabolic crises. While the underlying mechanisms of immune suppression are still being fully elucidated, hyperammonemia may impair the function of immune cells, particularly T cells and macrophages, inhibiting the proliferation of T cells and cytokine production. Arginine, which is essential for T-cell activation and function, may also be limited in these patients, and its depletion can increase their vulnerability to infections. Twenty-four UCD patients and 31 healthy donors were recruited for the study. Peripheral lymphocyte subset analysis, intracellular protein and cytokine staining, and proliferation assays were performed by flow cytometry. Amino acid levels were measured using the HPLC method. The UCD patients exhibited low lymphocyte-proliferation capacity in both proximal and distal defects in response to phytohaemagglutinin (PHA) and anti-CD2, anti-CD3, and anti-CD28 (CD-mix), which was lower than healthy controls. Proximal-UCD patients exhibited a significantly higher response for IFN-γ compared to both distal-UCD patients and healthy controls. The different amino acids in the culture medium were changed significantly in the groups. This study highlights significant immune dysfunctions in UCD patients, particularly impaired T-cell proliferation and altered amino acid metabolism. Proximal UCD patients exhibited a higher IFN-γ response, indicating a potential for hyperinflammation. Despite this, infection rates did not significantly differ between proximal UCD and distal UCD patients, although distal UCD patients had higher hospitalization rates. Amino acid analysis revealed distinct metabolic disruptions, emphasizing the complex interplay between metabolism and immune function. These findings suggest that UCDs cause profound immune alterations, necessitating further research to develop targeted therapeutic strategies.

Keywords:  T‐cell proliferation; hyperammonemia; immune dysfunction; urea cycle disorders (UCD)

DOI:  https://doi.org/10.1002/jimd.70009
Int Immunopharmacol. 2025 Feb 15. pii: S1567-5769(25)00255-3. [Epub ahead of print]150 114265

Galloflavin mitigates acute kidney injury by suppressing LDHA-dependent macrophage glycolysis.

Jie Wei, Xin-Yu Chen, Zhi-Juan Wang, Xiang-Yu Li, Meng-Meng Zhang, Tao Sun, Xin-Ru Zhang, De-Guang Wang, Chao Hou, Xiao-Ming Meng.

  Macrophage-mediated inflammation is closely linked to the pathogenesis of acute kidney injury (AKI) and the shift of macrophages to a pro-inflammatory phenotype being reliant on glycolytic metabolism. Galloflavin, a polyphenol derived from tea, functions as a lactate dehydrogenase A (LDHA) inhibitor, effectively obstructing glycolytic metabolic pathways. However, the specific immunometabolic regulatory functions of galloflavin in macrophages remain unclear. Here, we observed that galloflavin drives alleviation of glycolytic metabolism levels in lipopolysaccharide (LPS)-induced macrophages (RAW264.7 cells and human peripheral blood mononuclear cells-derived macrophages) through downregulation of LDHA expression, thereby inhibiting macrophage conversion to a pro-inflammatory phenotype and reducing the release of inflammatory cytokines. However, the overexpression of LDHA counteracts the effects of galloflavin in macrophages. In addition, in vivo experiments observed a protective effect of galloflavin against cecal ligation and puncture (CLP) and cisplatin-induced renal injury. The ability of galloflavin to inhibit glycolysis in renal macrophages, thereby regulating their phenotypic transition during AKI was further validated through the isolation of renal primary macrophages. This intervention ultimately ameliorated the inflammatory response and decelerated the progression of AKI. Collectively, galloflavin confers protection against AKI by suppressing glycolysis in macrophages through a LDHA-dependent mechanism, thereby positioning it as a potential therapeutic option for AKI in the future.

Keywords:  Acute kidney injury; Galloflavin; Glycolysis; Lactate dehydrogenase A; Macrophage

DOI:  https://doi.org/10.1016/j.intimp.2025.114265
J Virol. 2025 Feb 20. e0228224

Perturbation of de novo lipogenesis hinders MERS-CoV assembly and release, but not the biogenesis of viral replication organelles.

M Soultsioti, A W M de Jong, N Blomberg, A Tas, M Giera, E J Snijder, M Bárcena.

  Coronaviruses hijack host cell metabolic pathways and resources to support their replication. They induce extensive host endomembrane remodeling to generate viral replication organelles and exploit host membranes for assembly and budding of their enveloped progeny virions. Because of the overall significance of host membranes, we sought to gain insight into the role of host factors involved in lipid metabolism in cells infected with Middle East respiratory syndrome coronavirus (MERS-CoV). We employed a single-cycle infection approach in combination with pharmacological inhibitors, biochemical assays, lipidomics, and light and electron microscopy. Pharmacological inhibition of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), key host factors in de novo fatty acid biosynthesis, led to pronounced inhibition of MERS-CoV particle release. Inhibition of ACC led to a profound metabolic switch in Huh7 cells, altering their lipidomic profile and inducing lipolysis. However, despite the extensive changes induced by the ACC inhibitor, the biogenesis of viral replication organelles remained unaffected. Instead, ACC inhibition appeared to affect the trafficking and post-translational modifications of the MERS-CoV envelope proteins. Electron microscopy revealed an accumulation of nucleocapsids in early budding stages, indicating that MERS-CoV assembly is adversely impacted by ACC inhibition. Notably, inhibition of palmitoylation resulted in similar effects, while supplementation of exogenous palmitic acid reversed the compound's inhibitory effects, possibly reflecting a crucial need for palmitoylation of the MERS-CoV spike and envelope proteins for their role in virus particle assembly.IMPORTANCEMiddle East respiratory syndrome coronavirus (MERS-CoV) is the etiological agent of a zoonotic respiratory disease of limited transmissibility between humans. However, MERS-CoV is still considered a high-priority pathogen and is closely monitored by WHO due to its high lethality rate of around 35% of laboratory-confirmed infections. Like other positive-strand RNA viruses, MERS-CoV relies on the host cell's endomembranes to support various stages of its replication cycle. However, in spite of this general reliance of MERS-CoV replication on host cell lipid metabolism, mechanistic insights are still very limited. In our study, we show that pharmacological inhibition of acetyl-CoA carboxylase (ACC), a key enzyme in the host cell's fatty acid biosynthesis pathway, significantly disrupts MERS-CoV particle assembly without exerting a negative effect on the biogenesis of viral replication organelles. Furthermore, our study highlights the potential of ACC as a target for the development of host-directed antiviral therapeutics against coronaviruses.

Keywords:  2-BP; TOFA; acetyl-CoA carboxylase; coronavirus; lipid metabolism; palmitoylation

DOI:  https://doi.org/10.1128/jvi.02282-24
Nat Commun. 2025 Feb 18. 16(1): 1738

Macrophage SUCLA2 coupled glutaminolysis manipulates obesity through AMPK.

Chang Peng, Haowen Jiang, Liya Jing, Wenhua Yang, Xiaotong Guan, Hanlin Wang, Sike Yu, Yutang Cao, Min Wang, Huan Ma, Zan Lv, Hongyu Gu, Chunmei Xia, Xiaozhen Guo, Bin Sun, Aili Wang, Cen Xie, Wenbiao Wu, Luyiyi Lu, Jiayi Song, Saifei Lei, Rui Wu, Yi Zang, Erjiang Tang, Jia Li.

Obesity is regarded as a chronic inflammatory disease involving adipose tissue macrophages (ATM), but whether immunometabolic reprogramming of ATM affects obesity remains unclarified. Here we show that in ATM glutaminolysis is the fundamental metabolic flux providing energy and substrate, bridging with AMP-activated protein kinase (AMPK) activity, succinate-induced interleukin-1β (IL-1β) production, and obesity. Abrogation of AMPKα in myeloid cells promotes proinflammatory ATM, impairs thermogenesis and energy expenditure, and aggravates obesity in mice fed with high-fat diet (HFD). Conversely, IL-1β neutralization or myeloid IL-1β abrogation prevents obesity caused by AMPKα deficiency. Mechanistically, ATP generated from glutaminolysis suppresses AMPK to decrease phosphorylation of the β subunit of succinyl-CoA synthetase (SUCLA2), thereby resulting in the activation of succinyl-CoA synthetase and the overproduction of succinate and IL-1β; by contrast, siRNA-mediated SUCLA2 knockdown reduces obesity induced by HFD in mice. Lastly, phosphorylated SUCLA2 in ATM correlates negatively with obesity in humans. Our results thus implicate a glutaminolysis/AMPK/SUCLA2/IL-1β axis of inflammation and obesity regulation in ATM.

DOI: https://doi.org/10.1038/s41467-025-57044-w
Physiol Rev. 2025 Feb 21.

The flux of energy in critical illness and the obesity paradox.

Ariel Jaitovich, Jesse B Hall.

  During critical illness, systemic inflammation causes organ-specific metabolic changes. In the immune and inflammatory compartments, predominantly anabolic reprogramming supports cellular replication and inflammatory response execution. Pari passu, catabolism of adipose tissue and skeletal muscle supplies carbon skeletons and enthalpy for inflammatory and immune cell anabolism. The liver plays a key role during these metabolic shifts in enabling adequate supply of glucose and ketone bodies to the circulation. While often perceived as passive surrogates of prehospitalization frailty, body mass constituents are active parties of an over-arching metabolic trade-off that is key for survival following acute insults. Muscle and adipose tissue remodel in response to critical illness and thus profoundly influence the systemic metabolic landscape during and after hospitalization. Whether obesity's effect on patient systemic metabolism and survival is paradoxically beneficial or not remains controversial. Substrate-induced epigenetic changes lead to abnormal transcriptional programs which in turn regulate metabolic pathways critical to patient survival. We present a summary of major mechanisms involved in the flux of energy in critical illness from body mass into immune response execution and suggest future research avenues focused on perturbed immune metabolic and epigenetic programs that could lead to improved understanding of these process, and eventually to better outcomes for the critically ill.

Keywords:  Body mass; Immune reprogramming; critical illness; obesity paradox; skeletal muscle

DOI:  https://doi.org/10.1152/physrev.00029.2024
Nat Commun. 2025 Feb 20. 16(1): 1803

Zika virus NS1 drives tunneling nanotube formation for mitochondrial transfer and stealth transmission in trophoblasts.

Rafael T Michita, Long B Tran, Steven J Bark, Deepak Kumar, Shay A Toner, Joyce Jose, Indira U Mysorekar, Anoop Narayanan.

Zika virus (ZIKV) is unique among orthoflaviviruses in its vertical transmission capacity in humans, yet the underlying mechanisms remain incompletely understood. Here, we show that ZIKV induces tunneling nanotubes (TNTs) in placental trophoblasts which facilitate transfer of viral particles, proteins, mitochondria, and RNA to neighboring uninfected cells. TNT formation is driven exclusively via ZIKV non-structural protein 1 (NS1). Specifically, the N-terminal 1-50 amino acids of membrane-bound ZIKV NS1 are necessary for triggering TNT formation in host cells. Trophoblasts infected with TNT-deficient ZIKVΔTNT mutant virus elicited a robust antiviral IFN-λ 1/2/3 response relative to WT ZIKV, suggesting TNT-mediated trafficking allows ZIKV cell-to-cell transmission camouflaged from host defenses. Using affinity purification-mass spectrometry of cells expressing wild-type NS1 or non-TNT forming NS1, we found mitochondrial proteins are dominant NS1-interacting partners. We demonstrate that ZIKV infection or NS1 expression induces elevated mitochondria levels in trophoblasts and that mitochondria are siphoned via TNTs from healthy to ZIKV-infected cells. Together our findings identify a stealth mechanism that ZIKV employs for intercellular spread among placental trophoblasts, evasion of antiviral interferon response, and the hijacking of mitochondria to augment its propagation and survival and offers a basis for novel therapeutic developments targeting these interactions to limit ZIKV dissemination.

DOI: https://doi.org/10.1038/s41467-025-56927-2
bioRxiv. 2025 Feb 01. pii: 2025.01.31.635900. [Epub ahead of print]

TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy.

Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.

Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin- and receptor- mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.

DOI: https://doi.org/10.1101/2025.01.31.635900
Mol Biotechnol. 2025 Feb 20.

Identification of Glycolysis-Related Signature and Molecular Subtypes in Child Sepsis Through Machine Learning and Consensus Clustering: Implications for Diagnosis and Therapeutics.

Chenyu Ma, Jianlong Wang.

  Pediatric sepsis remains one of the leading causes of mortality in children worldwide. Despite advances in medical care, the prognosis of pediatric sepsis is still poor, necessitating the need for more precise diagnostic and therapeutic strategies. Recently, metabolic reprogramming, particularly glycolysis, has been implicated in the pathogenesis of sepsis, offering new avenues for biomarker discovery and targeted therapy. We applied the GSVA algorithm to the GSE26440 dataset to score glycolysis pathways and identified key glycolysis-related genes (GRGs) using LASSO and logistic regression. We then constructed a predictive nomogram with these GRGs and used consensus clustering to define new molecular subgroups, followed by analyzing their metabolic and immune characteristics. The signature genes were validated by animal experiments. We found increased glycolysis pathway activity in sepsis patients. Through the application of LASSO and logistic regression, GNPDA2, PRKACB, and TGFBI emerged as potential glycolysis-based diagnostic markers. The nomogram showed significant diagnostic accuracy in both the original (GSE26440) and the separate validation datasets (GSE13904 and GSE26378). We distinguished two sepsis subtypes, with the C2 subtype exhibiting higher GRGs, glucose metabolism, and inflammation. Immune infiltration and checkpoint gene expression also varied between the subtypes. Our research identifies glycolysis-based diagnostic markers and molecular subtypes in sepsis, enhancing our understanding and potentially leading to better diagnosis and treatment strategies, including immunotherapy.

Keywords:  Diagnostic biomarkers; Glycolysis; Immune cell infiltrations; Immunotherapy; Sepsis; Subtypes

DOI:  https://doi.org/10.1007/s12033-025-01379-8
Infect Immun. 2025 Feb 19. e0032424

Necrosis drives susceptibility to Mycobacterium tuberculosis in PolgD257A mutator mice.

C J Mabry, C G Weindel, L W Stranahan, J J VanPortfliet, J R Davis, E L Martinez, A P West, K L Patrick, R O Watson.

  The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines of evidence demonstrate that mitochondrial dysfunction can exacerbate mycobacterial disease severity, and mutations in some mitochondrial genes confer susceptibility to mycobacterial infection in humans. Here, we report that mutations in mitochondria DNA (mtDNA) polymerase gamma potentiate susceptibility to Mtb infection in mice. PolgD257A mutator mtDNA mice fail to mount a protective innate immune response at an early infection time point, evidenced by high bacterial burdens, reduced M1 macrophages, and excessive neutrophil infiltration in the lungs. Immunohistochemistry reveals signs of enhanced necrosis in the lungs of Mtb-infected PolgD257A mice, and PolgD257A mutator macrophages are hypersusceptible to extrinsic triggers of necroptosis ex vivo. By assigning a role for mtDNA mutations in driving necrosis during Mtb infection, this work further highlights the requirement for mitochondrial homeostasis in mounting balanced immune responses to Mtb.

Keywords:  Mycobacterium tuberculosis; Polg; innate immunity; necrosis

DOI:  https://doi.org/10.1128/iai.00324-24