bims-imesem Biomed News
on Immunemetabolism
Issue of 2026–07–12
eight papers selected by
Akshara Kulkarni, University of Cambridge
  1. The role of mitochondrial proteases in inflammation and immunity.
  2. Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum.
  3. PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
  4. Dynamic control of nucleotide metabolism in physiology and disease.
  5. Tricarboxylic Acid (TCA) Cycle Enzyme Alpha-Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization.
  6. The BmCPV-derived viral small peptide vsp1S4(-) suppresses viral replication by triggering apoptosis via the ROS-JNK signalling pathway.
  7. JQKD82 Inhibits HIV Infection of Macrophages Through Blocking Viral Entry and Enhancing Antiviral ISG Responses.
  8. Metabolic reprogramming of macrophages during mycobacterial infection: a review of immunometabolic crosstalk and pathogen manipulation.
  1. Front Immunol. 2026 ;17 1761658
    The role of mitochondrial proteases in inflammation and immunity.
    Anna Rebeka Oliveira Ferreira, Emily A Day.
      The global rise in chronic inflammatory and autoimmune disorders has intensified research to understand cellular stress response pathways that drive immune dysregulation. Mitochondria have emerged not only as central hubs of cellular metabolism but also as active modulators of immunity and inflammation. Mitochondrial proteases are essential regulators of mitochondrial protein quality control, dynamics, and stress responses. By selectively degrading misfolded or damaged proteins, they maintain mitochondrial function and bioenergetic capacity. Beyond housekeeping roles, mitochondrial proteases also influence immune signaling by modulating mitochondrial stress pathways, reactive oxygen species production, and the release of mitochondrial-derived danger signals. Dysregulation of these proteases has been linked to chronic inflammation and contributes to the pathogenesis of inflammatory diseases. This review summarizes current knowledge on the role of mitochondrial proteases CLPXP, LONP1, i-AAA, m-AAA, as well as processing peptidase OMA1, in immune cells and inflammatory pathologies. We explore the molecular mechanisms by which these mitochondrial proteases regulate immune signaling, integrating the results from immune cells as well as other non-immune cell types, including those involved in cancer, neurodegeneration, renal injury, and other inflammatory pathologies. We explore mitochondrial proteases function as context-dependent regulators of immunometabolic signaling, with effects shaped by cell type, metabolic state, and stress conditions. Finally, we discuss emerging small molecules and drugs targeting mitochondrial proteases to highlight their potential therapeutic role in modulating inflammation. By situating mitochondrial proteases at the crossroads of immunometabolism and therapeutic intervention, this review underscores their untapped potential in the development of innovative anti-inflammatory strategies.
    Keywords:  MAVS; cGAS-STING; immune cells; inflammatory disease; innate immunity; macrophages; mitochondrial dysfunction; mtDNA
    DOI:  https://doi.org/10.3389/fimmu.2026.1761658
  2. mSphere. 2026 Jul 10. e0034126
    Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum.
    Monique K Johnson, Juliana Naldoni, William H Lewis, Ross F Waller, Catherine J Merrick.
      Plasmodium spp. have different modes of cell division from most eukaryotes. Little is known about how these are controlled, and cell cycle checkpoints are particularly poorly characterized. However, parasites can arrest their cell cycle when treated with the frontline antimalarial drug artemisinin, and artemisinin-resistant parasites can modulate their cell cycle progression, so it is important to understand these aspects of Plasmodium biology. Here, we show that P. falciparum displays hallmarks of an intra-S-phase checkpoint when exposed to DNA damage, including acute reduction of DNA replication and phosphorylation of a putative damage-marker histone. Compounds that inhibit human checkpoint kinases can inhibit this arrest of DNA replication and synergize with DNA damage in parasite killing. This suggests the existence of checkpoint kinase activity in P. falciparum, yet these kinases have no clear homologues in Plasmodium genomes. Their closest homologs are the phosphatidylinositol lipid kinases. We hypothesize that phosphatidylinositol 3-kinase-which is reportedly upregulated in artemisinin-resistant parasites-may moonlight in this role, and we characterize this essential kinase for the first time via expansion microscopy. Finally, we show that the cryptic checkpoint-kinase activity may also regulate the ring-stage survival phenotype after artemisinin damage, which resembles a G1/S checkpoint. Hence, we suggest that checkpoint kinase inhibitors are candidates for synergy with artemisinin.IMPORTANCEMalaria parasites infect red blood cells, wherein they replicate to produce many new parasites. This is unusual because most cells replicate simply by copying their genome and splitting in half (called binary fission), but malaria parasites make ~20 genome copies and then partition them simultaneously into 20 new cells (called schizogony). Here, we studied how schizogony is controlled: in particular, are there "checkpoints," i.e., pathways that can pause the cell cycle? We found that DNA damage did cause checkpoint hallmarks, yet the key proteins that enforce this in other cells are absent in malaria parasites. Furthermore, this checkpoint activity may be involved in the response to an antimalarial drug, in which parasites pause their cycle before active replication begins. This implies that inhibiting the checkpoint could exacerbate parasite killing by such drugs. Cancer therapies often work like this-by damaging DNA and also preventing the cancer cells from repairing it.
    Keywords:  Malaria; PI3K; Plasmodium; cell cycle; checkpoint
    DOI:  https://doi.org/10.1128/msphere.00341-26
  3. Cell Death Dis. 2026 Jul 10.
    PARP inhibition modulates mitochondrial morphology and metabolism under hypoxic stress in cancer cells.
    José Manuel Rodríguez-Vargas, Jerónimo Borrego-Pérez, Vanesa Cabeza-Fernández, Esteban Zamudio-Martínez, Francisco Javier Ríos-Sola, David Martín-Oliva, Francisco Abadía-Molina, Françoise Dantzer, F Javier Oliver.
      Hypoxia, or low oxygen availability, is one of the main factors that determine tumor growth and metastatic survival. The hypoxic response is orchestrated by HIF transcription factors, which activate genetic and metabolic programs that promote angiogenesis, metabolic reprogramming, migration, and ultimately a clinically aggressive phenotype. Mitochondria play a central role in this process, as they are not only the main consumers of oxygen but also undergo morphological and biochemical adaptations that shape how tumor cells respond to a hostile microenvironment. Because the contribution of ADP ribosylation to these mitochondrial adaptations remains unclear, we aimed to define how PARP inhibition influences mitochondrial behavior during hypoxia. To address this question, we first examined how PARP inhibitors affect mitochondrial structure and function under oxygen deprivation. We found that PARP inhibition drives a shift toward a small, globular mitochondrial phenotype characterized by membrane depolarization (ΔΨm) and enhanced fission. Given that mitochondrial morphology is tightly linked to metabolic state, we next investigated whether these structural changes altered hypoxia induced metabolic reprogramming. PARP inhibition prevented the typical shift toward anaerobic glycolysis, forcing tumor cells to activate the AMPk/mitophagy axis as an alternative survival pathway. Finally, to determine the functional consequences of this adaptive response, we assessed tumor cell fitness when mitophagy was impaired. Blocking mitophagy markedly reduced the proliferative and malignant potential of hypoxic tumor cells, thereby increasing their sensitivity to PARP inhibition. Collectively, our results uncover a previously unrecognized pathway of mitochondrial adaptation to hypoxia and reveal a therapeutically relevant crosstalk between mitochondrial dynamics and ADP ribosylation that may be exploited in future anticancer strategies.
    DOI:  https://doi.org/10.1038/s41419-026-09079-0
  4. Nat Cell Biol. 2026 Jul 08.
    Dynamic control of nucleotide metabolism in physiology and disease.
    Dohun Kim, Gerta Hoxhaj.
      Nucleotides are essential for life, serving not only as the building blocks of the genome but also as cellular energy providers, metabolic cofactors and signalling molecules. To sustain cellular function and proliferation, cells must continuously generate, recycle and precisely balance nucleotide pools in response to fluctuating metabolic and environmental demands. Nucleotide metabolism is therefore not a static biosynthetic pathway, but a dynamic system tightly integrated with cell signalling and physiology. Here we highlight the regulatory logic of nucleotide metabolism, from acute post-translational regulation to transcriptional scaling, feedback control and higher-order spatial organization into multi-enzyme assemblies and filaments. Through the lens of human genetic disorders and cancer, we examine how nucleotide depletion, pool imbalance or intermediate toxicity produce striking tissue-selective pathologies. Together, these principles position nucleotide metabolism as a central regulatory axis linking cellular metabolism, signalling and fate in health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02004-9
  5. J Cell Biochem. 2026 Jul;127(7): e70104
    Tricarboxylic Acid (TCA) Cycle Enzyme Alpha-Ketoglutarate Dehydrogenase (KGDH) as a Nexus for the Regulation of Macrophage Polarization.
    Meijing Li, Ryan J Mailloux.
      Macrophage metabolism has been increasingly studied in recent years for its potential as a therapeutic target across multiple pathologies. In this article, we propose that the tricarboxylic acid (TCA) cycle enzyme alpha-ketoglutarate (KG) dehydrogenase (KGDH) serves as a nexus for regulating macrophage polarization toward pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes. This is achieved through modulation of mitochondrial hydrogen peroxide (mtH2O2) and the availability of the TCA cycle metabolites KG and succinate, which are important immunomodulatory molecules. We discuss the evidence showing KGDH is a potent source of mtH2O2 in various cell types and how it could use this reactive oxygen species (ROS) to modulate signaling pathways involved in macrophage differentiation. Coupled to this, we describe emerging evidence showing that KG and succinate exert opposite signaling effects in macrophages, with the former metabolite inducing an anti-inflammatory phenotype and the latter (succinate) promoting inflammation. This occurs through the regulation of dioxygenases involved in hypoxic signaling and epigenetic programming and the activation of G-protein coupled receptor 91 (GPR91) by succinate. Importantly, we contend that regulating KGDH influences the availability of these two metabolites, which, along with controlling mtH2O2 availability, helps control macrophage polarization. Collectively, increased mtH2O2 generation and succinate are known to induce a pro-inflammatory phenotype, whereas low mtH2O2 and high KG have the opposite effect. This suggests that KGDH is a key regulator of macrophage polarization by controlling the availabilities of these immunomodulatory metabolites.
    DOI:  https://doi.org/10.1002/jcb.70104
  6. Cell Mol Life Sci. 2026 Jul 06.
    The BmCPV-derived viral small peptide vsp1S4(-) suppresses viral replication by triggering apoptosis via the ROS-JNK signalling pathway.
    Xialing Chen, Xiaoyan Du, Lixuan Li, Yao Yao, Qian Teng, Haoni Xue, Min Zhu, Xing Zhang, Chengliang Gong, Xiaolong Hu.
      Viral antisense RNAs are generally considered noncoding. Here, we show that segment 4 of Bombyx mori cypovirus (BmCPV) encodes a 78-aa antisense-microprotein, vsp1S4(-), that triggers a host-restrictive reactive oxygen species (ROS)-c-Jun N-terminal kinase (JNK)-apoptosis axis. vsp1S4(-) localizes to mitochondria, induces superoxide release, and activates JNK signalling. Consequently, cells undergo caspase-3-dependent apoptosis and S-phase arrest, while the levels of the viral structural protein (VP7) and progeny virions are strongly suppressed. Pharmacologic interruption of either ROS with N-acetylcysteine (NAC) or JNK signalling with SP600125, a dominant-negative JNK effectively rescues VP7 expression and restores viral replication, confirming that vsp1S4(-)-elicited signalling shows antiviral activity. Thus, BmCPV autonomously limits its own propagation through an antisense-encoded peptide that weaponizes host mitochondrial ROS and JNK, representing a paradigm of programmed self-attenuation operating via antisense translation.
    Keywords:  Apoptosis; BmCPV; ROS-JNK pathway; Viral replication; vsp1S4(-)
    DOI:  https://doi.org/10.1007/s00018-026-06230-0
  7. J Med Virol. 2026 Jul;98(7): e71043
    JQKD82 Inhibits HIV Infection of Macrophages Through Blocking Viral Entry and Enhancing Antiviral ISG Responses.
    Jie Ma, Xu Wang, Priyanka Sarkar, Jinshan He, Li Song, Jian Zhu, Wenzhe Ho.
      JQKD82 is an epigenetic modulator that inhibits lysine-specific demethylase 5 (KDM5), a host factor implicated in HIV latency and cell survival. Although JQKD82 has been studied in latent HIV infection of T cell models, its effects on HIV infection in macrophages remain unclear. Here, we investigated the impact of JQKD82 on HIV infection of primary human monocyte-derived macrophages (MDMs). We observed that treatment of MDMs with non-cytotoxic concentrations of JQKD82 dose-dependently inhibited HIV replication, as evidenced by reduced virus-induced syncytium formation, decreased viral Gag mRNA expression, and lower p24 protein levels. Pretreatment of cells with JQKD82 was more effective than post-infection treatment, suggesting inhibition at the viral entry stage, which was confirmed using pseudotyped HIV NL4-3-ΔEnv-eGFP-Bal. Mechanistically, JQKD82 downregulated CD4 and CCR5 expression while inducing the CCR5 ligand RANTES in MDMs. In addition, JQKD82 enhanced interferon-stimulated gene (ISG) expression in HIV-infected macrophages. Together, these findings demonstrate that JQKD82 inhibits HIV infection through dual mechanisms-blocking viral entry and enhancing antiviral ISG responses-supporting further evaluation of KDM5 inhibition as a potential therapeutic strategy against HIV.
    Keywords:  CD4/CCR5 and ISGs; HIV; JQKD82; KDM5A/B; macrophages
    DOI:  https://doi.org/10.1002/jmv.71043
  8. Front Cell Infect Microbiol. 2026 ;16 1806805
    Metabolic reprogramming of macrophages during mycobacterial infection: a review of immunometabolic crosstalk and pathogen manipulation.
    Xiaohe Lu, Yanping Zhao, Pingfan Qin, Yongquan Shi, Xiong Xiao.
      Macrophages undergo dynamic metabolic reprogramming that critically shapes their functional polarization and antimicrobial responses during mycobacterial infection. This review integrates current knowledge on how infection reprograms major metabolic pathways in macrophages. Mycobacterial infection triggers a complex and often dual-purposed rewiring of glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Pathogens actively manipulate these pathways to simultaneously suppress host antimicrobial effector functions and acquire nutrients for their own survival. Enhanced glycolysis, typically linked to M1 macrophages, can be exploited by the pathogen. Reprogramming of the TCA cycle, particularly through metabolites like itaconate, drives macrophages polarization toward an M2 phenotype that favors bacterial persistence. Amino acid metabolism becomes a site of metabolic competition where the bacterium secures substrates such as arginine and tryptophan to induce M2 phenotype, while the host attempts to sustain M1 macrophage functions through glutamine metabolism and the arginine nitric oxide pathway. Fatty acid metabolism further contributes to macrophage polarization in a context dependent manner. Understanding this immunometabolic interplay provides novel insights into tuberculosis pathogenesis and highlights metabolic pathways as potential targets for host-directed therapies. Future research should clarify the heterogeneity of metabolic responses across different mycobacterial species, infection stages, and macrophage subsets to guide therapeutic strategies.
    Keywords:  TCA cycle; amino acid metabolism; fatty acid metabolism; glycolysis; immunometabolic interplay; macrophages; mycobacterial infection
    DOI:  https://doi.org/10.3389/fcimb.2026.1806805
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒12 at 0:06.