bims-imesem 2026-06-07 papers

bims-imesem

Biomed News

on Immunemetabolism

Issue of 2026–06–07
six papers selected by
Akshara Kulkarni , University of Cambridge

VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation.
Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.
ROS/SIRT1 signaling mediates mitochondrial dysfunction in hyperoxia-induced BEAS-2B cells injury.
Glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma by downregulating GLUD1 and promoting ROS-mediated inhibition of Wnt/β-catenin signaling.
Quantitative CDK2 Dynamics Are Linked to Cell Fate Decisions in Differentiating Trophoblast Stem Cells.

Cell Signal. 2026 Jun 03. pii: S0898-6568(26)00295-0. [Epub ahead of print] 112642

VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation.

Ren Yuqian, Guangyao Zhu, Zhang Yucai, Cui Yun, Gu Jie, Zhou Yiping.

  Sepsis, a life-threatening condition characterized by dysregulated immune responses, leads to high mortality and morbidity. While splenic T cells are pivotal in systemic inflammation, their underlying mechanisms remain elusive. Here, we investigated the impact of bacterial endotoxin lipopolysaccharide (LPS) on mouse spleen tissue and primary T cells. LPS challenge provoked splenic inflammation, as evidenced by elevated levels of TNF-α, IFN-γ, IL-6, and IL-18 in whole spleen tissue. Transcriptomic profiling of whole spleen tissue implicated the cytosolic DNA-sensing pathway. Mechanistic studies in purified primary splenic CD3+ T cells revealed that LPS triggered mitochondrial dysfunction, characterized by increased mitochondrial ROS (mtROS), Ca2+ mobilization, and mitochondrial DNA (mtDNA) release into the cytosol, concurrent with VDAC1 oligomerization. Mechanistically, VDAC1 oligomerization was essential for LPS-induced mtDNA release and subsequent activation of the cGAS-STING-TBK1 axis. Notably, the VDAC1 oligomerization inhibitor VBIT-12 reversed cGAS-STING activation and cytokine expression. Collectively, our findings unveil a novel pathway wherein LPS induces VDAC1 oligomerization, leading to mtDNA leakage and activation of the cGAS-STING-TBK1 pathway in T cells, thereby fueling inflammation. This mechanism not only deepens our understanding of T cell-mediated immunopathology in endotoxemia but also highlights VDAC1 and associated mitochondrial function as potential therapeutic targets for sepsis and related inflammatory diseases.

Keywords:  Inflammation; VDAC1 oligomerization; cGAS-STING; mtDNA

DOI:  https://doi.org/10.1016/j.cellsig.2026.112642
J Cancer Immunol (Wilmington). 2026 ;8(1): 17-22

Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.

Prakash Jeysankar, Sonal Srikanth, Beibei Wu, Yousang Gwack.

  Effector T cells rely on tightly coordinated metabolic and epigenetic programs to sustain immune function. Emerging evidence highlights a central role for mitochondria in integrating these programs through nutrient utilization and regulation of metabolite flux. The electron transport chain (ETC), localized to the inner mitochondrial membrane, directs cellular metabolism toward oxidative phosphorylation. The efficiency of ETC activity is governed by the highly folded architecture of the inner mitochondrial membrane into cristae. Although mitochondrial metabolism is well recognized as a key determinant of cellular metabolic states, the regulatory roles of cristae-organizing structural proteins, particularly in T cells, remain poorly defined. Our recent study identifies the inner mitochondrial membrane protein TMEM11 as a critical structural determinant of cristae organization and demonstrates how cristae integrity governs effector T cell function by controlling oxidative phosphorylation and metabolite flux. TMEM11 deficiency disrupts cristae architecture in T cells without affecting mitochondrial biogenesis or cell viability. Mechanistically, loss of TMEM11 impairs ETC function, leading to elevated mitochondrial reactive oxygen species (mtROS), which diverts acetyl-CoA away from histone acetylation toward fatty acid synthesis, thereby suppressing cytokine production. Collectively, these findings reveal a structural-metabolic-epigenetic axis that is essential for effector T cell immunity and suggest potential relevance for T cell-mediated cancer therapy.

Keywords:  Cristae; Effector T cells; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.33696/cancerimmunol.8.120
Front Vet Sci. 2026 ;13 1799048

BVDV utilizes PGC-1α downregulation to remodel the mitochondrial metabolic microenvironment, enhancing viral replication and impairing host immunity.

Hongming Zhou, Yixing Zhao, Yuxin Kong, Jiying Yin, Ning He, Qi Wang, Jiayin Liu, Tongbo Zhou, Yu Han, Shouyi Dong, Yaru Zhao, Naichao Diao, Kun Shi, Rui Du.

   Introduction: Bovine viral diarrhea virus (BVDV) is a major pathogen affecting global livestock production, and virus-induced mitochondrial remodeling is closely associated with viral replication. However, the role of PGC-1α-mediated mitochondrial quality control in cytopathic BVDV strain NADL infection remains unclear.
Methods: MDBK cells were infected with CP BVDV(NADL) to establish an in vitro infection model. Mitochondrial morphology, function, mitophagy levels, and the expression of related proteins were examined using transmission electron microscopy, fluorescence staining, confocal microscopy, Western blotting, and the pADV-CMV-FH-cox8-EGFP-mCherry vector dual-fluorescence system. PGC-1α expression was manipulated by plasmid-mediated overexpression or shRNA-mediated knockdown.Viral replication was quantified by qRT-PCR, and IFN-β secretion was assessed by ELISA.
Results: CP BVDV(NADL) infection caused mitochondrial structural damage and dysfunction, accompanied by persistent downregulation of PGC-1α and its downstream target TFAM. Meanwhile, Drp1 expression was increased, shifting mitochondrial dynamics toward excessive fission. CP BVDV(NADL) infection also markedly enhanced PINK1-mediated mitophagy. Functionally, PGC-1α overexpression restored mitochondrial homeostasis, inhibited PINK1-dependent mitophagy, reduced IFN-β expression, and ultimately suppressed CP BVDV(NADL) replication. Conversely, PGC-1α interference further promoted mitophagy and increased mPTP opening.
Discussion: These findings demonstrate for the first time that CP BVDV(NADL) promotes viral replication by manipulating PGC-1α-mediated mitochondrial quality control. This mechanism reveals a novel metabolic strategy used by BVDV and provides potential therapeutic targets for controlling CP BVDV(NADL) infection.

Keywords:  BVDV; PGC-1α; mitochondrial biogenesis; mitochondrial quality control; viral replication

DOI:  https://doi.org/10.3389/fvets.2026.1799048
Free Radic Res. 2026 May 31. 1-15

ROS/SIRT1 signaling mediates mitochondrial dysfunction in hyperoxia-induced BEAS-2B cells injury.

Kun Yang, Ting He, Rong Zhang, Shuai Zhao, Lan Kang, Xiaoping Lei, Wenbin Dong.

   BACKGROUND: Bronchopulmonary dysplasia is a common chronic lung disease in preterm infants with a complex pathogenesis, and it is necessary to search for the potential pathogenesis and therapeutic strategies of bronchopulmonary dysplasia at the cellular molecular level. The present study investigated the role of reactive oxygen species (ROS)/sirtuin 1 (SIRT1) axis in hyperoxia-induced BEAS-2B cells injury.
METHODS: Cell counting kit-8, cell scratch, ROS assay, immunofluorescence, mitochondrial membrane potential, transmission electron microscopy assay and Western blot were performed to investigate the impairment of BEAS-2B by hyperoxia as well as the roles of SIRT1 and ROS in hyperoxia-induced BEAS-2B injury.
RESULTS: (1) Hyperoxia increased ROS in a time-dependent manner and decreased the levels of SIRT1 and mitochondria-associated proteins in BEAS-2B. (2) The SIRT1 agonist reduced ROS and improved mitochondrial membrane potential levels, attenuated mitochondrial fragmentation and mitochondrial morphological damage, and reversed the hyperoxia-induced decrease in mitochondria-associated proteins expression in BEAS-2B. (3) The ROS scavenger N-Acetylcysteine reduced ROS levels, improved mitochondrial membrane potential levels, attenuated mitochondrial morphological damage, and reversed the hyperoxia-induced decrease in SIRT1 and mitochondria-associated proteins levels in BEAS-2B.
CONCLUSION: The ROS/SIRT1 axis is involved in hyperoxia-induced mitochondrial injury in BEAS-2B cells, and SIRT1 may be a potential therapeutic target for bronchopulmonary dysplasia.

Keywords:  BEAS-2b; Hyperoxia; SIRT1; mitochondrial injury; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1080/10715762.2026.2672452
Pathol Res Pract. 2026 May 18. pii: S0344-0338(26)00197-4. [Epub ahead of print]286 156544

Glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma by downregulating GLUD1 and promoting ROS-mediated inhibition of Wnt/β-catenin signaling.

Liyong Bai, Keying Wang, Lu Liu, Yuan Liu.

  Osteosarcoma is a highly malignant primary bone tumor that predominantly affects children and adolescents. Although chemotherapy has significantly improved overall survival, drug resistance remains a major cause of poor prognosis. Current studies largely focus on isolated signaling events and still lack a systematic understanding of the coordinated interplay among metabolic reprogramming, redox homeostasis, and cell death, thereby limiting translational relevance and the identification of effective therapeutic targets. The present study aimed to investigate how glutamine regulates reactive oxygen species (ROS) levels in osteosarcoma cells and to clarify the mechanism by which the Wnt/β-catenin pathway influences doxorubicin sensitivity. The effects of glutamine metabolism on osteosarcoma chemosensitivity were systematically evaluated using both in vitro and in vivo models. Integrated transcriptomic analysis was further performed to identify key metabolic and signaling regulators associated with redox balance and chemosensitivity. The results showed that glutamine deprivation or L-asparaginase treatment significantly enhanced the sensitivity of HOS, MNNG, and their doxorubicin-resistant derivatives to doxorubicin, as evidenced by reduced cell proliferation and increased expression of the apoptosis-related proteins Bax and cleaved caspase-3. Glutamine depletion also increased intracellular ROS levels, decreased glutathione content and mitochondrial membrane potential, altered cellular glycolytic status, and downregulated GLUD1 expression. Similarly, GLUD1 silencing recapitulated these effects, whereas NAC treatment partially reversed them. Moreover, both glutamine deprivation and ROS accumulation suppressed activation of Wnt/β-catenin signaling. In vivo, the combination of L-asparaginase and doxorubicin, as well as treatment with XAV-939, significantly inhibited tumor growth, whereas NAC attenuated these effects. In conclusion, glutamine deprivation enhances doxorubicin sensitivity in osteosarcoma. Mechanistically, this chemosensitizing effect is mediated by downregulation of GLUD1, which promotes intracellular ROS accumulation and subsequently suppresses Wnt/β-catenin signaling.

Keywords:  Chemosensitivity; Glutamine; Osteosarcoma; ROS; Wnt/β-catenin signaling

DOI:  https://doi.org/10.1016/j.prp.2026.156544
bioRxiv. 2026 May 20. pii: 2026.05.17.725805. [Epub ahead of print]

Quantitative CDK2 Dynamics Are Linked to Cell Fate Decisions in Differentiating Trophoblast Stem Cells.

Sage Indigo G Brill, Upasna Sharma, Estefania Sanchez-Vasquez, S Ali Shariati.

During early development of the placenta, a subset of murine trophectoderm stem cells (TSCs) undergo endoreplication, an unusual form of cell division cycle that decouples DNA synthesis from cytokinesis, resulting in physiological polyploidy. Oscillations in CDK2 activity are essential for the orderly progression of the cell cycle to ensure replicated DNA is accurately partitioned into two daughter cells. However, it remains underexplored how the dynamics of CDK2 activity regulate endoreplication in the context of TSCs differentiation. To address this question, we leveraged the variability in cell fate decisions in an established in vitro system of TSCs differentiation that relies on removal of a growth factor, FGF4, to induce endoreplication. Using quantitative single-cell live confocal microscopy of a precise CDK2 biosensor, DHB-Venus, we identified at least three different outcomes upon FG4 removal: self-renewal, endoreplication, and migration. Our quantitative analyses showed high levels of Cdk2 activity in self-renewing cells whereas intermediate DHB-Venus turnover is linked to increased nuclear and cell size, indicating a shift to endoreplication. Importantly, we also characterize a third class of differentiating TSCs with migratory characteristics that correlate with low levels Cdk2 activity without a change in nuclear size. In sum, our results demonstrated a correlation between different fate outcomes and specific thresholds of CDK2 activity. Our findings show that TSCs can distinguish between different outcomes through modulating the central kinase of the cell cycle, CDK2, positioning it as a key regulator of early trophoblast differentiation.

DOI: https://doi.org/10.64898/2026.05.17.725805