bims-nenemi 2025-10-26 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–10–26
eleven papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.
Macrophage PTP1B regulates mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and activates the cGAS/STING signaling pathway.
Bacterial effector OspB hijacks apoptosis through peptide-bond recombination of BH3 domain proteins.
Mitochondrial DNA contributes to dysbiosis-associated mastitis via activation of the cGAS-STING pathway.
Large transient assemblies of Apaf1 constitute the apoptosome in cells.
Dimethyl fumarate reprograms cervical cancer cells to enhance antitumor immunity by activating mtDNA-cGAS-STING pathway.
Small-molecule perturbation profiling reveals a mechanistic link between STING signaling and lipid metabolism in macrophages and dendritic cells.
Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.
Proteomic landscape of lung adenocarcinoma precancerous lesions reveals mitochondrial dsRNA-associated immune and stress responses.
Trans-localization of p210 BCR-ABL to the mitochondria is mediated by the interaction of its PH domain with cardiolipin exposed on the outer membrane.
Condensate nanovaccine adjuvants augment CD8+ T-Cell-dependent antitumor immunity through mtDNA leakage-triggered cGAS-STING axis activation.

Sci Immunol. 2025 Oct 24. 10(112): eads9456

Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells.

Jordy Saravia, Nicole M Chapman, Yu Sun, Xiaoxi Meng, Isabel Risch, Wei Li, Cliff Guy, Hao Shi, Haoran Hu, Yogesh Dhungana, Jia Li, Zhiyuan You, Anil Kc, Seon Ah Lim, Jana L Raynor, Sharad Shrestha, Erienne G Norton, Sarah E La Grange, Camenzind G Robinson, Peter Vogel, Hongbo Chi.

Immunotherapies targeting regulatory T (Treg) cells often trigger inflammation and autoimmunity. How Treg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates Treg cell metabolic and functional fitness. Treg cell-specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of Treg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate-activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, Treg cell-specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency-associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient Treg cells were enriched in a terminal "metabolic quiescence reset" state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria-lysosome interplay control Treg cell differentiation and function.

DOI: https://doi.org/10.1126/sciimmunol.ads9456
Front Immunol. 2025 ;16 1644289

Macrophage PTP1B regulates mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and activates the cGAS/STING signaling pathway.

Xuefeng Lei, Diandian Qian, Wenzheng Zhang, Bin'an Zhao, Yabin Li, Hua Hao, Jing Yuan, Le Zhao, Centao Liu.

  Tendinopathy is characterized by degenerative changes in tendon tissue, with its pathogenesis closely associated with macrophage-mediated chronic inflammation and mitochondrial dysfunction. Bioinformatics analysis of tendinopathic tissues revealed a significant upregulation of protein tyrosine phosphatase 1B (PTP1B) in macrophages, which accompanied with robust immune activation and marked Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway inhibition. In tendinopathy mouse models, both pro-inflammatory cytokines and PTP1B were found to be highly expressed in tendon tissues. However, conditional deletion of Ptpn1 (encoding PTP1B, Ptpn1-/-) in macrophages significantly alleviated tendon inflammation and fibrosis, indicating a strong association between PTP1B and tendinopathy. Mechanistically, in vivo experiments demonstrated that macrophage PTP1B suppressed STAT3 activation by inhibiting JAK2 phosphorylation, and inhibited the mitochondrial fusion protein Optic Atrophy1 (OPA1), resulting in mitochondrial fragmentation and mitochondrial DNA (mtDNA) release. This process activated the Cyclic GMP-AMP synthase/Stimulator of interferon genes (cGAS/STING) pathway, elevating the levels of inflammation and exacerbating tendon injury. In summary, macrophage PTP1B was shown to regulate mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and trigger inflammation through activation of the cGAS/STING pathway, representing a key mechanism underlying the progression of tendinopathy. Targeting PTP1B or associated pathways may provide novel therapeutic strategies for tendinopathy.

Keywords:  JAK2/STAT3 signaling pathway; PTP1B; macrophages; mitochondrial dynamics; tendinopathy

DOI:  https://doi.org/10.3389/fimmu.2025.1644289
Cell Host Microbe. 2025 Oct 22. pii: S1931-3128(25)00413-5. [Epub ahead of print]

Bacterial effector OspB hijacks apoptosis through peptide-bond recombination of BH3 domain proteins.

Yue Shao, Dandan Yang, Xinguang Gao, Minghui Wang, Liyuan Meng, Tianye Niu, Li Xia, Jingjin Ding, Feng Shao, Yue Xu.

  Apoptosis is a defense response involving key players, including BH3-only proteins that engage BCL-2 family proteins BAX and BAK, initiating mitochondrial outer membrane permeabilization and caspase activation. However, Shigella flexneri subverts these death pathways to promote infection. Here, we identify the Shigella type III secretion system effector OspB as an enzyme that suppresses apoptosis by targeting BAX and BAK. OspB recognizes BAX/BAK in complex with BH3-only activators, notably tBID, and catalyzes a peptide-bond recombination between their BH3 domains. This reaction generates chimeric proteins comprising the N-terminal BH3-only segment fused to the C-terminal region of BAX or BAK, irreversibly inhibiting protein function and thus mitochondrial outer membrane permeabilization and apoptosis. OspB-mediated apoptosis inhibition enhances S. flexneri virulence in vivo. Homologous effectors with similar catalytic activity are conserved across various bacterial species. These findings reveal a bacterial strategy for apoptosis inhibition via remodeling of BCL-2 family proteins, offering avenues for therapeutic intervention.

Keywords:  BCL-2 family proteins; BH3 domain; OspB; Shigella flexneri; T3SS; apoptosis; host-pathogen interaction; peptide-bond recombination

DOI:  https://doi.org/10.1016/j.chom.2025.09.018
Int Immunopharmacol. 2025 Oct 22. pii: S1567-5769(25)01705-9. [Epub ahead of print]167 115717

Mitochondrial DNA contributes to dysbiosis-associated mastitis via activation of the cGAS-STING pathway.

Yihong Zhao, Miao Liu, Jiawen Xu, Hang Yu, Haiqi Li, Lijuan Bao, Jingyi Shi, Keyi Wu, Ruping Shan, Naisheng Zhang, Xiaoyu Hu, Yunhe Fu, Caijun Zhao, Feng Liang, Fanglei Han.

  Bovine mastitis is widely recognized as being primarily caused by exogenous pathogens. However, in clinical settings, pathogenic bacteria are frequently undetectable in the milk of affected cows. Recent studies have shown that gastrointestinal disorders, such as subacute ruminal acidosis (SARA), which disturb the balance of the gut microbiota, commonly occur as secondary conditions in conjunction with mastitis. The microbiota-gut-mammary axis is increasingly acknowledged as a key contributor to the progression of mastitis; however, the precise underlying mechanisms remain to be fully elucidated. In this study, we established a SARA-associated mastitis model in dairy goats by administering a high-concentrate diet (HCD). Our findings demonstrated that HCD feeding led to disruption of the rumen microbiota and structural damage to the rumen epithelium. Moreover, serum lipopolysaccharide (LPS) levels were significantly elevated, accompanied by increased systemic inflammation and damage to the blood-milk barrier. Notably, mitochondrial DNA (mtDNA) levels were elevated in both the rumen and mammary gland tissues. We further observed activation of the cGAS-STING signaling pathway, which subsequently triggered the NF-κB and NLRP3 inflammatory pathways, resulting in increased production of pro-inflammatory cytokines, including TNF-α and IL-1β. Importantly, mice that received rumen microbiota transplants (RMT) from SARA-affected goats developed mastitis with pathological features closely resembling those observed in the goat model. Additionally, mtDNA isolated from the mammary glands of SARA-associated mastitis goats induced inflammatory responses in recipient mammary tissues, as evidenced by increased tissue damage and elevated inflammatory markers. Our results collectively confirm that gut microbiota dysbiosis leads to elevated mammary mtDNA levels, which activate the cGAS-STING signaling pathway and contribute to the inflammatory processes underlying mastitis. These findings highlight a promising strategy for mastitis management through targeted regulation of the gut microbiota.

Keywords:  Gut microbiota; Mastitis; Mitochondrial DNA; cGAS-STING

DOI:  https://doi.org/10.1016/j.intimp.2025.115717
Nat Commun. 2025 Oct 24. 16(1): 9429

Large transient assemblies of Apaf1 constitute the apoptosome in cells.

Alicia C Borgeaud, Iva Ganeva, Calvin Klein, Amandine Stooss, Daniela Ross-Kaschitza, Liyang Wu, Joel S Riley, Stephen W G Tait, Thomas Lemmin, Thomas Kaufmann, Wanda Kukulski.

Upon cell death signals, the apoptotic protease-activating factor Apaf1 and cytochrome c interact to form the apoptosome complex. The apoptosome is crucial for mitochondrial apoptosis, as it activates caspases that dismantle the cell. However, the in vivo assembly mechanism and appearance of the apoptosome remain unclear. We show that upon onset of apoptosis, Apaf1 molecules accumulate into multiple foci per cell. Disassembly of the foci correlates with cell survival. Structurally, Apaf1 foci resemble organelle-sized, cloud-like assemblies. They form through specific interactions with cytochrome c, contain caspase-9, and depend on procaspase-9 expression for their formation. We propose that Apaf1 foci correspond to the apoptosome in cells. Transientness and ultrastructure of Apaf1 foci suggest that the dynamic spatiotemporal organisation of apoptosome components regulates progression of apoptosis.

DOI: https://doi.org/10.1038/s41467-025-64478-9
J Biomed Sci. 2025 Oct 20. 32(1): 92

Dimethyl fumarate reprograms cervical cancer cells to enhance antitumor immunity by activating mtDNA-cGAS-STING pathway.

Han Jiang, Liting Liu, Shan He, Shen Qu, Yifan Yang, Guijie Kang, Min Wu, Hangyu Liu, Yuwei Zhang, Zixuan Wang, Wenjing Tian, Ying Chen, Liming Wang, Qiangqiang Wang, Ting Ye, Junyan Han, Hui Wang, Yafei Huang.

   BACKGROUND: Cervical cancer (CC) remains a significant global health challenge for women, especially in advanced stages where effective treatments are limited. Current immunotherapies, including PD-1/PD-L1 blockades and adoptive T cell therapies, show limited response rates and durability. Dimethyl fumarate (DMF), an FDA-approved drug for autoimmune diseases, has demonstrated direct antitumor activity in several cancers. However, its influence on anti-tumor immunity and its function in CC remain poorly understood. This study aims to investigate the therapeutic potential of DMF in CC models and elucidate its underlying mechanisms of action.
METHODS: CC cell lines and mouse models were treated with DMF. Transcriptomics profiling of cervical cancer cells following DMF treatment were analyzed by RNA-seq and bioinformatic methods. Mitochondrial DNA (mtDNA) release, and cGAS-STING activation were assessed via qPCR, immunofluorescence, immunoblotting and ELISA. CD8+ T cell recruitment was analyzed by flow cytometry. Combinatorial therapies (DMF + anti-PD-1/TILs) were tested in syngeneic or patient-derived xenografts (PDX) models.
RESULTS: DMF treatment induces mitochondrial dysfunction in tumor cells, resulting in the release of mtDNA into the cytosol. The cytosolic mtDNA in turn activates the cGAS-STING-TBK1 pathway and type I interferon response, leading to the secretion of CCL5 and CXCL10, thereby enhancing CD8⁺ T cell infiltration. Additionally, DMF exhibits synergistic effect with PD-1 blockade in murine CC model, and can enhance the therapeutic efficacy of adoptively transferred T cells toward CC in patient-derived xenografts model.
CONCLUSION: This work elucidated that DMF reprograms CC cells to activate the mtDNA-cGAS-STING pathway, fostering a chemokine-rich microenvironment that recruits CD8+ T cells. The synergistic effect of DMF and PD-1 blockade or TIL therapy underscores its potential as an immunostimulatory adjuvant. These findings suggest that DMF holds promise as a novel immunotherapeutic strategy for improving clinical outcomes in CC.

Keywords:  CCL5; CD8+ T; CXCL10; Cervical cancer; Dimethyl fumarate; Immunotherapy

DOI:  https://doi.org/10.1186/s12929-025-01187-x
Mol Immunol. 2025 Oct 17. pii: S0161-5890(25)00234-2. [Epub ahead of print]187 255-262

Small-molecule perturbation profiling reveals a mechanistic link between STING signaling and lipid metabolism in macrophages and dendritic cells.

Lilah Gmyrek, Jianan Zhang, Maria Andrade, Kathryn R Hillette, Xu Wu, Jin Mo Park.

  The DNA sensor cGAS and the signaling adaptor STING play a key role in the innate immune response to microbial and endogenous DNA in the cytoplasm. The cGAS-STING signaling pathway has evolved to promote immune defense and organismal fitness, yet its dysregulation can lead to chronic inflammation, autoimmunity, and neurodegeneration. Upon sensing double-stranded DNA, cGAS produces a cyclic dinucleotide second messenger that binds to STING in the endoplasmic reticulum. Ligand-bound STING translocates to the Golgi and activates a signaling cascade that results in interferon (IFN) gene transcription. These molecular events are mechanistically linked to intracellular lipid membrane dynamics and protein lipidation. To explore whether STING signaling is controlled by the availability and metabolic flux of cellular lipids, we screened small-molecule compounds targeting lipid metabolic pathways for their influence on STING agonist-responsive IFN induction. These screens identified inhibitors of the fatty acid synthase FAS and lipases as potent suppressors of STING signaling. An inhibitor of the cholesterol-esterifying enzyme SOAT1 enhanced STING-dependent IFN induction in mouse cells while attenuating it in human cells. From an analysis of STING sequences, we detected a difference in their lipid binding motifs that likely accounted for the species-specific effects of SOAT1 inhibition. Our findings reveal a connection between STING signaling and lipid metabolism and opportunities for expanding the toolbox for treating clinical conditions that arise from aberrant STING activity.

Keywords:  STING / Signaling / Lipid / Metabolism

DOI:  https://doi.org/10.1016/j.molimm.2025.09.010
Neuro Oncol. 2025 Oct 25. pii: noaf248. [Epub ahead of print]

Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment.

Milan R Savani, Mohamad El Shami, Kenji Miki, Lauren C Gattie, Bailey C Smith, William H Hicks, Jacob O Weiss, Skyler S Oken, Lavanya N Katta, Tracey Shipman, Maged T Ghoche, Lauren G Zacharias, Misty S Martin-Sandoval, Eric Y Montgomery, Yi Xiao, Diana D Shi, Jeremy N Rich, Timothy E Richardson, Pascal O Zinn, Bradley C Lega, Thomas P Mathews, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

   BACKGROUND: In vivo stable isotope tracing is useful for natively surveying glioma metabolism but can be difficult to implement. Stable isotope tracing is tractable using in vitro glioma models, but most models lack nutrient conditions and cell populations relevant to human gliomas. This limits our ability to study glioma metabolism in the presence of an intact tumor microenvironment (TME) and immune-metabolic crosstalk.
METHODS: We optimized an in vitro stable isotope tracing approach for human glioma explants and glioma stem-like cell (GSC) lines that integrates human plasma-like medium (HPLM). We performed 15N2-glutamine tracing in GSC monocultures and human IDH-wildtype glioblastoma explants and developed an analytical framework to evaluate microenvironment-dependent metabolic features that distinguish them. We also conducted spatial transcriptomics to assess transcriptional correlates to metabolic activities.
RESULTS: HPLM culture preserved glioma explant viability and stemness while unmasking metabolic and immune programs suppressed by conventional culture conditions. Stable isotope tracing in HPLM revealed TME-dependent and TME-independent features of tumor metabolism. Tissue explants recapitulated tumor cell-intrinsic metabolic activities, such as synthesis of immunomodulatory purines. Unlike GSC monocultures, tissue explants captured tumor cell-extrinsic activities associated with stromal cell metabolism, as exemplified by astrocytic GDP-mannose production in heterocellular explants. Finally, glioma explants displayed tumor subtype-specific metabolic reprogramming, including robust pyrimidine degradation in mesenchymal cells.
CONCLUSIONS: We present a tractable approach to assess glioma metabolism in vitro under physiologic nutrient levels and in the presence of an intact TME. This platform opens new avenues to interrogate glioma metabolism and its interplay with the immune microenvironment.

Keywords:  Glioma; metabolism; organoids; preclinical models; stable isotope tracing

DOI:  https://doi.org/10.1093/neuonc/noaf248
Am J Cancer Res. 2025 ;15(9): 3888-3903

Proteomic landscape of lung adenocarcinoma precancerous lesions reveals mitochondrial dsRNA-associated immune and stress responses.

Xizhen Xu, Tianqi Gong, Zitian Huo, Yaqi Duan, Qian Chu, Jun Qin.

  Lung adenocarcinoma (LUAD) develops through a stepwise progression from pre-cancerous lesions, including atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA). Understanding the molecular dynamics underlying these transitions is critical for early detection and therapeutic interventions. A comprehensive proteomic analysis was performed on pre-cancerous and early LUAD samples using label-free quantitative mass spectrometry. Immunohistochemistry (IHC) and double fluorescence staining were applied to validate protein expression and mt-dsRNA localization. Trajectory inference was utilized to model dynamic proteomic changes during lesion progression. Mt-dsRNA levels were significantly elevated in pre-cancerous lesions, peaking in AIS. Double fluorescence staining revealed partial co-localization with the mitochondrial marker TOMM20, suggesting mitochondrial origin. Differential γ-H2AX staining patterns, with nuclear positivity in AAH and cytoplasmic positivity in AIS and MIA, indicated stage-specific dynamics of the DNA damage response. Upregulation of dsRNA sensors, including RIG-I and MDA5, and dsRNA-binding proteins (dsRBPs) such as ADAR1 and HNRNPA2/B1, highlighted a complex regulatory feedback network for both oncogenic and anti-tumorigenic effects. Notably, in dsRNA-IP assay, ASPH was enriched across all stages including LUAD, while TMED9 and HNRNPA2/B1 were specific to pre-cancerous lesions, reflecting their stage-dependent roles in tumor transformation. Finally, Trajectory analysis identified distinct proteomic shifts, with AAH lesions exhibiting high progression scores resembling AIS and MIA, underscoring their malignant potential. This study reveals the multifaceted roles of mt-dsRNA and its associated proteins in pre-cancerous lesions, providing insights into immune activation, stress adaptation, and early carcinogenesis. These findings establish a framework for developing biomarkers and targeted therapies aimed at preventing the transition to invasive LUAD.

Keywords:  Lung adenocarcinoma; adenocarcinoma in situ; atypical adenomatous hyperplasia; minimally invasive adenocarcinoma; mitochondrial double-stranded RNA; proteomics

DOI:  https://doi.org/10.62347/NUAU8342
Biochem Biophys Res Commun. 2025 Oct 17. pii: S0006-291X(25)01535-9. [Epub ahead of print]788 152819

Trans-localization of p210 BCR-ABL to the mitochondria is mediated by the interaction of its PH domain with cardiolipin exposed on the outer membrane.

Aoi Ikegami, Shuya Ishida, Nozomu Kono, Yuta Okuda, Jumpei Omi, Miho Watanabe-Takahashi, Kiyotaka Nishikawa.

  p210 BCR-ABL, a chimeric protein composed of breakpoint cluster region (BCR) and Abelson proto-oncogene (ABL) tyrosine kinase, is a principal driver of chronic myeloid leukemia (CML). We previously reported that the recombinant pleckstrin homology (PH) domain of p210 BCR-ABL (p210-PH) binds efficiently to cardiolipin (CL), a mitochondrial inner membrane-specific phospholipid, in vitro. Additionally, p210 BCR-ABL expressed in HEK293T cells trans-localizes from the cytosol to the mitochondria upon mitochondrial damage, inhibiting subsequent mitophagy and increasing reactive oxygen species production, thereby promoting CML cell proliferation. However, key evidence linking this trans-localization to PH domain-mediated CL binding has been missing. In this study, we demonstrate that p210-PH translocates to mitochondria following cyanide m-chlorophenylhydrazone-induced mitochondrial damage, whereas an R726A mutant deficient in CL binding does not, indicating that the PH domain is sufficient for mitochondrial targeting. Moreover, gene-knockdown of cardiolipin synthase 1, which substantially reduces total CL levels, including three major molecular species, significantly suppresses the mitochondrial localization of both p210 BCR-ABL and p210-PH. These findings establish that the PH domain-CL interaction mediates p210 BCR-ABL translocation to mitochondria, and underscore a pivotal role for CL in CML cell proliferation.

Keywords:  BCR-ABL; Cardiolipin; Chronic myeloid leukemia; Pleckstrin homology (PH) domain

DOI:  https://doi.org/10.1016/j.bbrc.2025.152819
Signal Transduct Target Ther. 2025 Oct 21. 10(1): 349

Condensate nanovaccine adjuvants augment CD8+ T-Cell-dependent antitumor immunity through mtDNA leakage-triggered cGAS-STING axis activation.

Yu Tang, Zhiyuan Luo, Zhanni Ma, Lingling Han, Yurong Zhou, Tianci Liang, Kangsen Yang, Lei Zhao, Xiaoyuan Chen, Pengfei Zhang.

The variety and functionality of current clinical vaccine adjuvants remain limited. Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses, particularly tumor antigen-specific cytotoxic CD8+ T lymphocytes (CTLs), which are essential for effective cancer vaccine performance. Inspired by natural biomolecular condensates, we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers. Our methodology employs amphiphilic molecules (sodium myristate/SMA and sodium dodecyl thiolate/SDT) as molecular bridges to mediate protein‒protein interactions through hydrophobic forces and disulfide bond formation. This process generates nanoscale protein condensate (PCD) vaccines with exceptional stability. As a novel adjuvant system, these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters: antigen loading capacity, lymph node targeting, cytosolic delivery, and lysosomal escape. Consequently, they induce robust antigen-specific CTL responses and humoral immunity, demonstrating potent antitumor efficacy. Importantly, we found that the synthetic protein condensate (PCD) alone can act as a nanoadjuvant. By increasing mitochondrial membrane permeability, PCD induces mitochondrial DNA leakage into the cytosol, activating the cGAS‒STING pathway and promoting DC maturation. This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering, and it facilitates the design of diverse modular antigens, including neoantigens and viral antigens. Given its straightforward manufacturing process and superior immunogenicity, this synthetic PCD vaccine adjuvant has significant potential for clinical application and translation.

DOI: https://doi.org/10.1038/s41392-025-02447-w