bims-nenemi 2025-03-02 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–03–02
sixteen papers selected by
Marco Tigano, Thomas Jefferson University

Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.
MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
Mitochondrial RNA metabolism, a potential therapeutic target for mitochondria-related diseases.
BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK.
Accumulation of Damaging Lipids in the Arf1-Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia.
TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis.
TREM2 Alleviates Neuroinflammation by Maintaining Cellular Metabolic Homeostasis and Mitophagy Activity During Early Inflammation.
Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.
Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.
Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.
Nellie: automated organelle segmentation, tracking and hierarchical feature extraction in 2D/3D live-cell microscopy.
Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos.
Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy.
OAS cross-activates RNase L intercellularly through cell-to-cell transfer of 2-5A to spread innate immunity.
Deubiquitination enzyme USP35 negatively regulates MAVS signaling to inhibit anti-tumor immunity.
Mitofilin-mtDNA Axis Mediates Chronic Lead Exposure-Induced Synaptic Plasticity Impairment of Hippocampal and Cognitive Deficits.

bioRxiv. 2025 Feb 13. pii: 2025.02.10.637516. [Epub ahead of print]

Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.

Shiqi Diao, Jia Yi Zou, Shuo Wang, Nour Ghaddar, Jason E Chan, Hyungdong Kim, Nicolas Poulain, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.

The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation-indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4-is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.

DOI: https://doi.org/10.1101/2025.02.10.637516
Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]

MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.

Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.

  Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.

Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability

DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
Chin Med J (Engl). 2025 Feb 26.

Mitochondrial RNA metabolism, a potential therapeutic target for mitochondria-related diseases.

Tongyue Duan, Liya Sun, Kaiyue Ding, Qing Zhao, Lujun Xu, Chongbin Liu, Lin Sun.

ABSTRACT: In recent years, the roles of mitochondrial RNA and its associated human diseases have been reported to increase significantly. Treatments based on mtRNA metabolic processes and nuclear gene mutations are thus discussed. The mitochondrial oxidative phosphorylation process is affected by mtRNA metabolism, including mtRNA production, maturation, stabilization, and degradation, which leads to a variety of inherited human mitochondrial diseases. Moreover, mitochondrial diseases are caused by mitochondrial messenger RNA, mitochondrial transfer RNA, and mitochondrial ribosomal RNA gene mutations. This review presents the molecular mechanisms of human mtRNA metabolism and pathological mutations in mtRNA metabolism-related nuclear-encoded/nonencoded genes and mitochondrial DNA mutations to highlight the importance of mitochondrial RNA-related diseases and treatments.

DOI: https://doi.org/10.1097/CM9.0000000000003516
Cells. 2025 Feb 09. pii: 246. [Epub ahead of print]14(4):

BCL-B Promotes Lung Cancer Invasiveness by Direct Inhibition of BOK.

Palaniappan Ramesh, Amal R Al Kadi, Gaurav M Borse, Maximilian Webendörfer, Gregor Zaun, Martin Metzenmacher, Fabian Doerr, Servet Bölükbas, Balazs Hegedüs, Smiths S Lueong, Joelle Magne, Beiyun Liu, Greisly Nunez, Martin Schuler, Douglas R Green, Halime Kalkavan.

  Expression of BCL-B, an anti-apoptotic BCL-2 family member, is correlated with worse survival in lung adenocarcinomas. Here, we show that BCL-B can mitigate cell death initiation through interaction with the effector protein BOK. We found that this interaction can promote sublethal mitochondrial outer membrane permeabilization (MOMP) and consequently generate apoptosis-flatliners, which represent a source of drug-tolerant persister cells (DTPs). The engagement of endothelial-mesenchymal-transition (EMT) further promotes cancer cell invasiveness in such DTPs. Our results reveal that BCL-B fosters cancer cell aggressiveness by counteracting complete MOMP.

Keywords:  BCL-2 family; BCL-B; BOK; DTP; EMT; cancer; drug-resistance; invasiveness; mitochondrial permeabilization; persister phenotype

DOI:  https://doi.org/10.3390/cells14040246
Adv Sci (Weinh). 2025 Feb 28. e2414260

Accumulation of Damaging Lipids in the Arf1-Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia.

Xu Li, Shuhan Jin, Danke Wang, Ying Wu, Xiaoyu Tang, Yufan Liu, Tiange Yao, Shoufa Han, Lin Sun, Yuetong Wang, Steven X Hou.

  Lipid metabolism disorders in both neurons and glial cells have been found in neurodegenerative (ND) patients and animal models. However, the pathological connection between lipid droplets and NDs remains poorly understood. The recent work has highlighted the utility of a neuron-specific Arf1-knockout mouse model and corresponding cells for elucidating the nexus between lipid metabolism disorders and amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, it is found that Arf1 deficiency first induced surplus fatty acid synthesis through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further caused mitochondrial DNA (mtDNA) to be released into cytoplasm. Concurrently, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons might also induce accumulation of sphingolipids in lysosomes that caused dysfunction of autophagy and lysosomes, which further promoted lysosomal stress and mitochondria-derived extracellular vesicles (MDEVs) release. The released MDEVs carried mtDNA into microglia to activate the inflammatory pathways and neurodegeneration. The studies on neuronal lipid droplets (LDs) and recent studies of microglial LDs suggest a unified pathological function of LDs in NDs: activating the inflammatory pathways in microglia. This finding potentially provides new therapeutic strategies for NDs.

Keywords:  Arf1 ablation; accumulation of damaging lipids; mtDNA release; neurodegeneration

DOI:  https://doi.org/10.1002/advs.202414260
Mol Oncol. 2025 Feb 25.

TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis.

Ranakul Islam, Megan E Roche, Zhao Lin, Diana Whitaker-Menezes, Victor Diaz-Barros, Eurico Serrano, Maria Paula Martinez Cantarin, Nancy J Philp, Atrayee Basu Mallick, Ubaldo Martinez-Outschoorn.

  Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL-2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR-Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state.

Keywords:  OXPHOS; ROS; TOMM; apoptosis; mitochondria; redox

DOI:  https://doi.org/10.1002/1878-0261.70002
Diseases. 2025 Feb 16. pii: 60. [Epub ahead of print]13(2):

TREM2 Alleviates Neuroinflammation by Maintaining Cellular Metabolic Homeostasis and Mitophagy Activity During Early Inflammation.

Lingfeng Hu, Jie Liu, Jie Peng, Xiao Li, Zhangqiong Huang, Caixing Zhang, Shengtao Fan.

   AIMS: Inflammation is a pivotal characteristic of neurodegenerative diseases. The triggering receptor expressed on the myeloid cells 2 (TREM2) gene has previously been shown to suppress inflammation by directly inhibiting inflammation-related pathways. Mitochondrial dysfunction has recently emerged as another critical pathological manifestation of neurodegenerative diseases. Although TREM2 is involved in the regulation of cellular energy metabolism and mitochondrial autophagy, its role in the relationship between inflammation and mitochondrial autophagy remains unclear.
METHODS: In this study, we generated TREM2-overexpressing BV-2 cells and established a neuroinflammatory model with LPS. We compared these cells with wild-type cells in terms of inflammation, metabolism, autophagy, and mitochondria using methods such as RT-qPCR, Western blotting, immunocytochemistry, transmission electron microscopy, and flow cytometry.
RESULTS: Microglia overexpressing TREM2 exhibited increased resistance to inflammation. Additionally, these cells inhibited the metabolic reprogramming that occurs early in LPS-induced inflammation, reduced ROS release, mitigated mitochondrial damage, maintained a certain level of autophagic activity, and cleared damaged mitochondria. Consequently, they alleviated the inflammation caused by the mitochondrial barrier.
CONCLUSIONS: ur results suggest that TREM2 can alleviate inflammation by maintaining cellular metabolic homeostasis and mitochondrial autophagy activity.

Keywords:  TREM2; microglia; mitochondrial; mitophagy; neuroinflammation

DOI:  https://doi.org/10.3390/diseases13020060
J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00208-X. [Epub ahead of print] 108359

Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase.

Srijoni Majhi, Pronay Roy, Minshik Jo, Jiying Liu, Rebecca Hurto, Lydia Freddolino, E Neil G Marsh.

Increasing lines of evidence link the expression of the interferon-stimulated gene RSAD2, encoding the antiviral enzyme, viperin, to autoimmune disease. Autoimmune diseases are characterized by chronic over-production of cytokines such as interferons that upregulate the inflammatory response. Immune cells exposed to interferon selectively downregulate transcription of the mitochondrially-encoded components of the oxidative phosphorylation system, which leads to mitochondria becoming dysfunctional and impairing their ability to produce ATP. But the mechanism by which downregulation occurs has remained unknown. Here we show that 3'-deoxy-3',4'-didehydrocytidine triphosphate (ddhCTP) which is synthesized by viperin suppresses mitochondrial transcription by causing premature chain termination when misincorporated by the mitochondrial RNA polymerase (POLRMT). We show that expression of viperin in human cell lines downregulates mitochondrially encoded gene expression. A similar effect is observed across multiple cell lines when cells are exposed to ddhC, the precursor to ddhCTP. The pattern of gene downregulation fits well with a simple, quantitative model describing chain-termination. In vitro measurements with purified POLRMT demonstrate that ddhCTP competes effectively with CTP, leading to its misincorporation into RNA. These findings reveal a new molecular mechanism for mitochondrial transcriptional regulation that explains the reduction in mitochondrially-encoded transcript levels in response to chronic interferon stimulation, characteristic of inflammatory diseases.

DOI: https://doi.org/10.1016/j.jbc.2025.108359
Cell Stem Cell. 2025 Feb 17. pii: S1934-5909(25)00013-X. [Epub ahead of print]

Mechano-oncogenic cytoskeletal remodeling drives leukemic transformation with mitochondrial vesicle-mediated STING activation.

Zemin Song, Yali Cui, Lilan Xin, Ruijing Xiao, Jingjing Feng, Conghui Li, Zhinang Yin, Honghong Wang, Qiuzi Li, Mengxuan Wang, Baoyi Lin, Yiming Zhang, Ying Zhou, Li Huang, Yanli He, Xiaoqing Li, Xiaoyan Liu, Shangqin Liu, Fuling Zhou, Zheng Liu, Hai-Bing Zhou, Pingping Fang, Kaiwei Liang.

  Mitochondria are integrated within the cytoskeleton for structural integrity and functional regulation, yet the pathological exploitation of these interactions in cell fate decisions remains largely unexplored. Here, we identify a cytoskeleton-mitochondria remodeling mechanism underlying leukemic transformation by the core-binding factor subunit beta and smooth muscle myosin heavy-chain fusion (CBFβ-SMMHC). This chimera reconstructs a cytosolic filamentous cytoskeleton, inducing NMIIA phosphorylation and INF2-dependent filamentous actin (F-actin) assembly, which enhance cellular stiffness and tension, leading to calcium-mediated mitochondrial constriction, termed cytoskeletal co-option of mitochondrial constriction (CCMC). CCMC can also be triggered through diverse approaches independent of CBFβ-SMMHC, reconstructing a similar cytoskeleton and recapitulating acute myeloid leukemia (AML) with consistent immunophenotypes and inflammatory signatures. Notably, CCMC generates TOM20-PDH+mtDNA+ mitochondrial-derived vesicles that activate cGAS-STING signaling, with Sting knockout abrogating CCMC-induced leukemogenesis. Targeted inhibition of CCMC or STING suppresses AML propagation while sparing normal hematopoiesis. These findings establish CCMC as an intrinsic mechano-oncogenic process linking genetic mutations with cytoskeletal remodeling to oncogenic transformation, highlighting its promise as a therapeutic target.

Keywords:  CBFβ-SMMHC; CCMC; HSPCs; MDV; cGAS-STING signaling; cytoskeletal co-option of mitochondrial constriction; cytoskeleton; hematopoietic stem and progenitor cells; mitochondrial-derived vesicle

DOI:  https://doi.org/10.1016/j.stem.2025.01.013
Cell Rep. 2025 Feb 25. pii: S2211-1247(25)00166-4. [Epub ahead of print]44(3): 115395

Cardiolipin oxidized by ROS from complex II acts as a target of gasdermin D to drive mitochondrial pore and heart dysfunction in endotoxemia.

Yan Tang, Junru Wu, Xuejing Sun, Shasha Tan, Wenbo Li, Siyu Yin, Lun Liu, Yuanyuan Chen, Yuanyuan Liu, Qian Tan, Youxiang Jiang, Wenjing Yang, Wei Huang, Chunyan Weng, Qing Wu, Yao Lu, Hong Yuan, Qingzhong Xiao, Alex F Chen, Qingbo Xu, Timothy R Billiar, Jingjing Cai.

DOI: https://doi.org/10.1016/j.celrep.2025.115395
Nat Methods. 2025 Feb 27.

Nellie: automated organelle segmentation, tracking and hierarchical feature extraction in 2D/3D live-cell microscopy.

Austin E Y T Lefebvre, Gabriel Sturm, Ting-Yu Lin, Emily Stoops, Magdalena Preciado López, Benjamin Kaufmann-Malaga, Kayley Hake.

Cellular organelles undergo constant morphological changes and dynamic interactions that are fundamental to cell homeostasis, stress responses and disease progression. Despite their importance, quantifying organelle morphology and motility remains challenging due to their complex architectures, rapid movements and the technical limitations of existing analysis tools. Here we introduce Nellie, an automated and unbiased pipeline for segmentation, tracking and feature extraction of diverse intracellular structures. Nellie adapts to image metadata and employs hierarchical segmentation to resolve sub-organellar regions, while its radius-adaptive pattern matching enables precise motion tracking. Through a user-friendly Napari-based interface, Nellie enables comprehensive organelle analysis without coding expertise. We demonstrate Nellie's versatility by unmixing multiple organelles from single-channel data, quantifying mitochondrial responses to ionomycin via graph autoencoders and characterizing endoplasmic reticulum networks across cell types and time points. This tool addresses a critical need in cell biology by providing accessible, automated analysis of organelle dynamics.

DOI: https://doi.org/10.1038/s41592-025-02612-7
Cell Rep Methods. 2025 Feb 24. pii: S2667-2375(25)00025-6. [Epub ahead of print]5(2): 100989

Efficient cell-wide mapping of mitochondria in electron microscopic volumes using webKnossos.

Yi Jiang, Haoyu Wang, Kevin M Boergens, Norman Rzepka, Fangfang Wang, Yunfeng Hua.

  Recent technical advances in volume electron microscopy (vEM) and artificial-intelligence-assisted image processing have facilitated high-throughput quantifications of cellular structures, such as mitochondria, that are ubiquitous and morphologically diversified. A still often-overlooked computational challenge is to assign a cell identity to numerous mitochondrial instances, for which both mitochondrial and cell membrane contouring used to be required. Here, we present a vEM reconstruction procedure (called mito-SegEM) that utilizes virtual-path-based annotation to assign automatically segmented mitochondrial instances at the cellular scale, therefore bypassing the requirement of membrane contouring. The embedded toolset in webKnossos (an open-source online annotation platform) is optimized for fast annotation, visualization, and proofreading of cellular organelle networks. We demonstrate the broad applications of mito-SegEM on volumetric datasets from various tissues, including the brain, intestine, and testis, to achieve an accurate and efficient reconstruction of mitochondria in a use-dependent fashion.

Keywords:  CP: Cell biology; CP: Imaging; cell biology; image processing; mitochondrion; software; volume electron microscopy

DOI:  https://doi.org/10.1016/j.crmeth.2025.100989
Nat Commun. 2025 Feb 22. 16(1): 1884

Unveiling the cell-type-specific landscape of cellular senescence through single-cell transcriptomics using SenePy.

Mark A Sanborn, Xinge Wang, Shang Gao, Yang Dai, Jalees Rehman.

Senescent cells accumulate in most tissues with organismal aging, exposure to stressors, or disease progression. It is challenging to identify senescent cells because cellular senescence signatures and phenotypes vary widely across distinct cell types and tissues. Here we developed an analytical algorithm that defines cell-type-specific and universal signatures of cellular senescence across a wide range of cell types and tissues. We utilize 72 mouse and 64 human weighted single-cell transcriptomic signatures of cellular senescence to create the SenePy scoring platform. SenePy signatures better recapitulate in vivo cellular senescence than signatures derived from in vitro senescence studies. We use SenePy to map the kinetics of senescent cell accumulation in healthy aging as well as multiple disease contexts, including tumorigenesis, inflammation, and myocardial infarction. SenePy characterizes cell-type-specific in vivo cellular senescence and could lead to the identification of genes that serve as mediators of cellular senescence and disease progression.

DOI: https://doi.org/10.1038/s41467-025-57047-7
Immunity. 2025 Feb 19. pii: S1074-7613(25)00065-2. [Epub ahead of print]

OAS cross-activates RNase L intercellularly through cell-to-cell transfer of 2-5A to spread innate immunity.

Wanwan Huai, Kun Yang, Cong Xing, Kun Song, Heng Lyu, Noelle S Williams, Jianjun Wu, Nan Yan.

  The 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway is a classical antiviral innate immune pathway. Upon sensing dsRNA, OAS produces 2',5'-oligoadenylate (2-5A) as a second messenger to activate RNase L. Whether 2-5A can be transported to extend the reach of innate immune signaling has not been established. Here, we showed that 2-5A was transferred from cell to cell through connexin (CX43/CX45) gap junctions. 2-5A was also transferred through importers and exporters, allowing OAS to remotely activate RNase L and protect neighboring cells from viral infection. We identified ABCC10 as a 2-5A exporter. Loss of ABCC10 had no effect on 2-5A production but reduced 2-5A export and protection of neighboring cells. Furthermore, OAShi tumors such as MC38 naturally produced 2-5A in vivo, which was secreted via ABCC10 to activate host-not tumor-RNase L-mediated antitumor response. Therefore, 2-5A is an immunotransmitter that mediates short-range communication between cells in infection and cancer.

Keywords:  2-5A; ABCC10; OAS; RNase L; antitumor immunity; gap junction; immunotransmitter; type I interferon

DOI:  https://doi.org/10.1016/j.immuni.2025.01.016
Cell Death Dis. 2025 Feb 27. 16(1): 138

Deubiquitination enzyme USP35 negatively regulates MAVS signaling to inhibit anti-tumor immunity.

Heping Zhang, Jiali Zhu, Rong He, Lin Xu, Yunfei Chen, Haihong Yu, Xuejiao Sun, Shengpeng Wan, Xiaolan Yin, Yu'e Liu, Jie Gao, Yue Li, Zhixiong Li, Yi Lu, Qing Xu.

The RIG-I/MAVS signaling stimulates anti-tumor immunity by triggering the production of inflammatory cytokines. Activation of MAVS induced by viral RNA and RIG-I binding is critical in this pathway. However, the molecular mechanism underlying the regulation of MAVS activity and its function in anti-tumor immunity is not fully understood. Here, we report that the ubiquitin-specific protease 35 (USP35) negatively regulates the MAVS signaling. Mechanistically, USP35 interacts with MAVS and removes its K63-linked polyubiquitin chains, thereby inhibiting viral-induced MAVS-TBK1-IRF3 activation and downstream inflammatory gene expression. Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells. Thus, our study identifies USP35 as a negative regulator of MAVS signaling, representing a potential immunosuppressive factor in cutaneous melanoma.

DOI: https://doi.org/10.1038/s41419-025-07411-8
Biomolecules. 2025 Feb 12. pii: 272. [Epub ahead of print]15(2):

Mitofilin-mtDNA Axis Mediates Chronic Lead Exposure-Induced Synaptic Plasticity Impairment of Hippocampal and Cognitive Deficits.

Lihong Su, Jinchao Hou, Boxuan Wang, Yuqi Li, Xiaodong Huo, Tao Wang, Yuankang Zou, Gang Zheng.

  Neurotoxic damage resulting from lead pollution exposure constitutes a significant public health concern. The regulatory impact of lead (Pb) exposure on neuronal dendritic spine plasticity, a crucial mechanism for neuronal adaptation, warrants further investigation. To elucidate the role and mechanism of the Mitofilin-mtDNA axis in hippocampal synaptic plasticity and learning and memory impairment induced by lead exposure, in this study, both in vivo and in vitro models were subjected to chronic lead exposure. The results showed that the spatial learning and memory abilities of lead-exposed mice were significantly reduced. Furthermore, Western blotting and RT-PCR analyses demonstrated a significant down-regulation in the expression of the mitochondrial inner membrane protein Mitofilin. Extended exposure to lead has the potential to compromise the plasticity of dendritic spines within the CA1 region of hippocampal neurons and disrupt the structural integrity of neuronal mitochondria. Furthermore, lead exposure was associated with elevated levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in neurons. The study additionally demonstrated that the overexpression of Mitofilin ameliorated deficits in spatial learning and memory in mice subjected to chronic lead exposure. This overexpression also facilitated the normal formation of neuronal dendritic spines, preserved the structural integrity of the mitochondrial inner membrane, and mitigated mitochondrial damage. The study further revealed that the overexpression of Mitofilin markedly suppressed the release of mitochondrial DNA (mtDNA) in neurons subjected to chronic lead exposure, while concurrently reducing the expression levels of the inflammasome Nlrp3 and the inflammatory cytokine IL-1β. Additionally, there was a significant reduction in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in lead-exposed neurons with Mitofilin overexpression. These findings suggest that the mitochondrial inner membrane protein Mitofilin may play a role in mediating synaptic plasticity impairment following chronic lead exposure through the regulation of mitochondrial function.

Keywords:  lead exposure; mitofilin; mtDNA; neuron; synaptic plasticity

DOI:  https://doi.org/10.3390/biom15020272