bims-imesem 2026-05-31 papers

Issue of 2026–05–31
six papers selected by
Akshara Kulkarni , University of Cambridge

Cell Death Differ. 2026 May 27.

Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.

Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.

Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.

DOI: https://doi.org/10.1038/s41418-026-01769-8

Free Radic Biol Med. 2026 May 25. pii: S0891-5849(26)00791-4. [Epub ahead of print]253 221-237

Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.

Ehsaneh Khodadadi, Bingwei Lu.

Mitochondrial complex I (MCI) is the largest enzyme of the electron transport chain, catalyzing oxidation of NADH, reduction of ubiquinone, and translocation of protons across the inner mitochondrial membrane (IMM). In addition to driving ATP synthesis through oxidative phosphorylation (OxPhos), MCI is a dynamic redox regulator that couples bidirectional catalysis with redox signaling. MCI conducts electron transfer in both the forward and reverse directions. While forward electron transport (FET) is essential for OxPhos and ATP synthesis, reverse electron transport (RET), driven by high membrane potential and ubiquinol pool, transfers electrons from ubiquinol to NAD+ and produces excessive ROS. MCI-derived ROS and NAD+/NADH changes act as physiologically regulated signals mediating hypoxia sensing, immune activation, stem-cell metabolism, but they can also contribute to pathology when dysregulated as in ischemia-reperfusion, cancer, neurodegeneration, and aging. Recent cryo-EM structures, time-resolved studies, and multiscale molecular dynamics (MD) simulations have provided near-atomic views of MCI architecture and operational mechanics. Here we review these developments from a redox-centered perspective. By positioning MCI as a dynamic redox regulator within a spatially organized mitochondrial network, we aim to provide a unifying framework for understanding how directional electron transfer, proton translocation, and redox signaling are intertwined in mitochondrial biology.

Keywords: Mitochondrial Complex I; Proton-coupled electron transfer; Reactive oxygen species (ROS); Redox signaling; Reverse electron transport (RET)

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.05.311

EMBO Mol Med. 2026 May 27.

Mitochondrial activity promotes neutrophil degranulation and endothelial dysfunction in systemic infections.

Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation of the glycocalyx and increase of endothelial permeability. To identify targetable pathways regulating neutrophil degranulation in severe inflammation, we compared the proteomes of neutrophils isolated from patients with severe malaria and sepsis. We found significant upregulation of mitochondrial pathways, which was accompanied by increased rates of mitochondrial respiration and was linked to neutrophil immaturity. Malaria induced mitochondrial fusion and networking, while sepsis was associated with mitochondrial biogenesis. Immature neutrophils in both infections produced elevated levels of mitochondrial ROS, which enhanced release of primary and secondary granules via reorganization of cortical actin. Our study provides a mechanistic explanation for the hyperinflammatory nature of immature neutrophils and points to pharmacological scavenging of mitochondrial ROS as a potential therapeutic strategy to reduce endothelial damage in severe inflammation.

DOI: https://doi.org/10.1038/s44321-026-00453-1

FEBS J. 2026 May 29.

Wee1 kinase differentially regulates maize CDKA2;1a and CDKB1;1.

Mingyar N López-Hernández, Estefany D Guerrero-Molina, Ulises Martínez-Ortega, Aurora Lara-Núñez, Jorge M Vázquez-Ramos.

In eukaryotes, cyclin-dependent kinase/cyclin (CDK/Cyc) complexes regulate cell cycle progression by phosphorylating hundreds of substrates. Full CDK activation requires the phosphorylation of a conserved threonine residue and association with a cyclin that helps discriminate between different substrates. Kinase activity of the CDK/cyclin complex is also negatively regulated by phosphorylation of two conserved residues in the CDK (T14 and Y15 in human CDK1). This regulatory mechanism is particularly important in vertebrates for ensuring successful mitosis and is mediated by Wee1 kinase, an enzyme also conserved in plants, in which Wee1 function has been poorly studied. To investigate the conservation of Wee1 function in maize, we have studied the effect of Wee1 on maize CDKA2;1a and CDKB1;1 in vitro, two of the main CDKs that control cell cycle progression in plants. Unlike results reported for A. thaliana, we found that maize Wee1 phosphorylated CDKB1;1, but interestingly, inhibited kinase activity of CDKA2;1a and CDKB1;1 independently of its kinase activity; this inhibition was substrate-dependent. Previously, we reported that maize CDKs also participate in substrate recognition, and therefore, we suggest that Wee1 associates with CDKs and modifies their recognition of substrates. Additionally, CDKB1;1 phosphorylation by Wee1 inhibited autophosphorylation at the threonine residue necessary for its activation and also differentially affected substrate phosphorylation. Finally, both CDKA2;1a and CDKB1;1 acted on Wee1, differentially modifying its phosphorylation. Together, and differing from previous reports, our results show that in vitro, maize Wee1 modulates the kinase activity of CDKs through several mechanisms and does not only act as an inhibitor.

Keywords: Wee1; kinase activity regulation; maize CDKs

DOI: https://doi.org/10.1111/febs.70594

Front Cell Dev Biol. 2026 ;14 1807454

HMGB1 regulates mitochondrial structure and reactive oxygen species balance during the transition from naïve to primed pluripotency.

Tatiana Y Starkova, Sergey V Ponomartsev, Veniamin S Fishman, Nariman R Battulin, Nikolay D Aksenov, Evgeny I Bakhmet, Andrey A Kuzmin, Dmitry S Bogolyubov, Sergey A Sinenko, Alexey N Tomilin.

Introduction: Embryo implantation is characterized by the process of naïve-to-primed pluripotency transition in epiblast cells, involving an anabolic boost, mitochondrial remodeling, and increased proliferation. Yet, the molecular mechanisms underlying these extensive changes remain poorly understood. High mobility group box 1 (HMGB1) is a non-histone, redox-sensitive chromatin protein involved in diverse cellular processes, however its role in pluripotency control has not been fully characterized.
Methods: To determine the function of HMGB1 in mouse embryonic stem cells (ESCs), Hmgb1-knockout (KO) ESCs were generated using CRISPR/Cas9 system. KO ESCs were analyzed for cell proliferation, cell cycle progression, and apoptosis, as well as for levels of active mitochondria, mitochondrial membrane potential, and reactive oxygen species (ROS) using fluorescent-based reagents and flow cytometry. Pluripotency was assessed by analyzing the expression of pluripotency markers with immunocytochemistry, Western blotting, qRT-PCR, as well as by teratoma formation assay. Naïve-to-primed pluripotency transition was investigated by in vitro culture. Molecular analysis was performed with RNA sequencing, bioinformatics, qRT-PCR, and Western blotting. The ultrastructure of mitochondria was examined using transmission electron microscopy.
Results: We first successfully generated HMGB1 KO in mouse ESCs and showed that HMGB1 function is dispensable for both cell viability and pluripotency maintenance, while it is required for the cell proliferation boost during the naïve-to-primed pluripotency transition. Molecular and transcriptomic analysis identified the involvement of HMGB1 in the regulation of energy metabolism processes by regulating mitochondrial structure and function, as well as ROS homeostasis. Loss of HMGB1 function in mouse ESCs results in altered mitochondrial structure and excessive ROS production. HMGB1-dependent elevated ROS levels negatively regulate cell proliferation during the transition from naïve to primed pluripotency in vitro.
Conclusion: While HMGB1 deficiency does not impair self-renewal in the naïve state, it causes a marked reduction in proliferation as cells advance to primed pluripotency. Our findings thus identify HMGB1 as a key regulator of mitochondrial integrity and ROS homeostasis during the naïve-to-primed pluripotency transition.

Keywords: HMGB1; cell metabolism; differentiation; embryonic stem cells (ESCs); mitochondria; reactive oxygen species

DOI: https://doi.org/10.3389/fcell.2026.1807454

bioRxiv. 2026 May 14. pii: 2026.05.11.724393. [Epub ahead of print]

Spatial proteomics reveals CD8+ T cell signatures and cellular niches associated with active HIV-1 replication in lymph nodes.

Candace C Liu, Marta Calvet-Mirabent, Angie Spence, Mako Goldston, Magdalena Adrados de Llano, Sean C Bendall, Michael Angelo, Enrique Martín-Gayo.

Despite its effectiveness in suppressing active HIV-1 replication, antiretroviral therapy (ART) does not eliminate the persistent long-lived pool of HIV-1-infected reservoir cells, preventing the eradication of the infection. Lymphoid tissues are key anatomical sites where these reservoirs persist even in the presence of ART, but the mechanisms that are associated with viral persistence in lymphoid tissues and how tissue networks are reshaped in the setting of viral replication remain incompletely understood. Advances in tissue imaging offer a unique opportunity to characterize immune correlates of viral persistence. Here, we used a spatial proteomic method to map immune microenvironments in HIV-1-infected lymph nodes (LNs) at different stages of infection, including with or without ART. LNs from people with HIV-1 (PWH) were characterized by lower CD4+ T cell counts and higher CD8+ T cell counts in both the whole tissue and within follicles compared to people without HIV (PWOH). CD8+ T cells were more abundant in LN samples with active viral replication, defined by detection of the viral protein p24. Further characterization of p24+ LNs showed that CD8+ T cells located inside of B cell follicles exhibited higher levels of markers associated with immune activation and exhaustion, in addition to the inflammasome protein caspase-1. Using a spatial niche detection method, we found that LNs from PWH with varying levels of viral replication were differentially enriched for CD8+ T cells near antigen-presenting cells, myeloid cells, and fibroblasts. Notably, we found that p24+ cells were less enriched near CD8+ T cells but closer to follicular dendritic cells. Finally, comparing LNs from viremic and aviremic donors, where viremia was defined by detectable plasma viral load, we found low levels of activation markers in CD11c+ cells in aviremic donors, including NLRP3 inflammasome activation. Thus, using spatial proteomics to map the immune landscape in LNs, we identified novel markers characterizing immune cell subsets and tissue microenvironments that were differently enriched in PWH with varying levels of viremia, implying that HIV-1 infection confers long-term changes on the immune landscape in LN tissue. Collectively, these data provide new insights into the complex cell networks associated with viral replication at a key tissue reservoir site, which could be relevant for future HIV-1 cure strategies.

DOI: https://doi.org/10.64898/2026.05.11.724393