bims-nenemi 2025-04-27 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–04–27
fourteen papers selected by
Marco Tigano, Thomas Jefferson University

Mitochondrial DNA signals driving immune responses: Why, How, Where?
TFAM Deficiency Triggers mtDNA Leakage and cGAS-STING-Mediated Intestinal Ischemia-Reperfusion Injury.
Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.
SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases.
Convolutional Neural Network approach to classify mitochondrial morphologies.
Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.
Diminished SUV3 expression and its functional implications in the IFN-enriched monocyte subset of childhood Sjögren's Disease.
Urolithin A alleviates radiation pneumonitis by activating PINK1/PRKN-mediated Mitophagy.
Oxidative stress-induced release of mitochondrial DNA (mtDNA) promotes the progression of vitiligo by activating the cGAS-STING signaling pathway in monocytes.
SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity.
ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels.
ZBP1 senses splicing aberration through Z-RNA to promote cell death.
Birch pollen allergen-induced dsDNA release activates cGAS-STING signaling and type 2 immune response in mice.
Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.

Cell Commun Signal. 2025 Apr 22. 23(1): 192

Mitochondrial DNA signals driving immune responses: Why, How, Where?

Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.

  There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.

Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA

DOI:  https://doi.org/10.1186/s12964-025-02042-0
Inflammation. 2025 Apr 21.

TFAM Deficiency Triggers mtDNA Leakage and cGAS-STING-Mediated Intestinal Ischemia-Reperfusion Injury.

Ke Ding, Lele Zhang, Yiguo Zhang, Yixin Jing, Huiyang Liao, Rong Chen, Qingtao Meng.

  Intestinal Ischemia-Reperfusion (IIR) injury is a common clinical pathophysiological condition, yet the complex molecular mechanisms underlying its pathology remain incompletely understood. This study aims to explore the precise molecular mechanisms of IIR injury, with a focus on the role of the cGAS-STING signaling pathway. Using a mouse IIR model and hypoxia/reoxygenation (HR) model in HT-29 cells and small intestinal organoids, we observed that IIR significantly induces oxidative stress and activates the cGAS-STING pathway, which is associated with exacerbated small intestinal tissue damage and enhanced inflammatory responses. Further investigation revealed that mitochondrial DNA (mtDNA) leakage is a critical trigger for the activation of the cGAS-STING pathway. The introduction of exogenous mtDNA into cells activated the STING pathway and exacerbated cellular damage. In contrast, the depletion of intracellular mtDNA effectively suppressed HR-induced activation of the cGAS-STING pathway. Mechanistically, we found that IIR downregulates mitochondrial transcription factor A (TFAM), which subsequently affects mtDNA stability, promoting the release of mtDNA into the cytoplasm and triggering the cGAS-STING pathway. Overexpression of TFAM stabilized mtDNA, reduced the accumulation of cytoplasmic mtDNA, inhibited cGAS-STING pathway activation, and alleviated cellular damage. Moreover, STING-deficient mice exhibited reduced inflammation, less tissue damage, and improved survival rates following IIR, highlighting the critical role of the STING pathway in IIR-induced injury. Our findings elucidate the close association between oxidative stress, inflammation, and cGAS-STING pathway activation in IIR. mtDNA leakage and TFAM downregulation are key mechanisms driving this activation. Importantly, TFAM plays a crucial role in stabilizing mtDNA and reducing mtDNA leakage during IIR. These results not only deepen our understanding of the molecular pathogenesis of IIR injury but also provide potential therapeutic strategies targeting the cGAS-STING pathway for treating IIR-related diseases.

Keywords:  Inflammation; Intestinal ischemia–reperfusion; MtDNA; STING; TFAM

DOI:  https://doi.org/10.1007/s10753-025-02302-8
Sci Rep. 2025 Apr 21. 15(1): 13811

Human RCC1L is involved in the maintenance of mitochondrial nucleoids and mtDNA.

Emi Matsumoto, Taeko Sasaki, Tetsuya Higashiyama, Narie Sasaki.

  Mitochondrial DNA (mtDNA) is organized with proteins into mitochondrial nucleoid (mt-nucleoid). The mt-nucleoid is a unit for the maintenance and function of mtDNA. The regulator of chromosome condensation 1-like protein (RCC1L) performs various functions in mitochondria, including translation, but its involvement in regulating mt-nucleoid maintenance is unknown. Herein, we found that human RCC1L was required to maintain mt-nucleoids and mtDNA. Human RCC1L has three splicing isoforms: RCC1LV1, RCC1LV2, and RCC1LV3. Knockout (KO) cells lacking all RCC1L isoforms, which were lethal without pyruvate and uridine, exhibited a decrease in mt-nucleoids and mtDNA, along with swollen and fragmented mitochondria. Among the three RCC1L isoforms, only RCC1LV1 recovered all phenotypes observed in RCC1L KO cells. As the treatment of wild-type cells with chloramphenicol, a mitochondrial translation inhibitor, did not lead to the decrease in mt-nucleoids accompanied by mtDNA depletion, the decrease in mt-nucleoids and mtDNA in RCC1L KO cells was not solely attributed to impaired mitochondrial translation. Using conditional RCC1L KO cells, we observed a rapid decrease in mt-nucleoids and mtDNA during a specific period following RCC1L loss. Our findings indicate that RCC1L regulates the maintenance of mt-nucleoids and mtDNA besides its role in mitochondrial translational regulation.

Keywords:  Mitochondrial DNA; Mitochondrial nucleoid; RCC1L

DOI:  https://doi.org/10.1038/s41598-025-98397-y
Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00359-6. [Epub ahead of print]44(5): 115588

SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases.

Doyeong Ku, Yewon Yang, Youngran Park, Daesong Jang, Namseok Lee, Yong-Ki Lee, Keonyong Lee, Jaeseon Lee, Yeon Bi Han, Soojin Jang, Se Rim Choi, You-Jung Ha, Yong Seok Choi, Woo-Jin Jeong, Yun Jong Lee, Kyung Jin Lee, Seunghee Cha, Yoosik Kim.

  Abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor driving dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop-interacting RNA-binding protein (SLIRP) as an amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and the targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and elevates their cytosolic levels to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in primary cells of patients with autoimmune disease and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of the interferon response through positive feedback amplification of antiviral signaling via mt-dsRNAs.

Keywords:  CP: Immunology; CP: Molecular biology; SLIRP; Sjögren’s disease; antiviral signaling; autoimmune disease; double-stranded RNAs; innate immune response; interferon response; mitochondrial RNAs; mitochondrial-nuclear communication; viral infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115588
Comput Biol Chem. 2025 Apr 17. pii: S1476-9271(25)00137-9. [Epub ahead of print]118 108477

Convolutional Neural Network approach to classify mitochondrial morphologies.

Soumaya Zaghbani, Lukas Faber, Ana J Garcia-Saez.

  The morphology of the mitochondrial network is a major indicator of cellular health and function, with changes often linked to various physiological and pathological conditions. As a result, efficient methods to quickly assess mitochondrial shape in cellular populations from microscopy images in a quantitative manner are of high interest for the health and life sciences. Here, we present MitoClass, a deep learning-based software designed for automated mitochondrial classification. MitoClass employs a classification algorithm that categorizes mitochondrial network shapes into three classes: fragmented, intermediate, and elongated. By leveraging super-resolution images, we curated a comprehensive dataset for training, including both high- and low-resolution representations of mitochondrial networks. Using a Convolutional Neural Network (CNN) architecture, our model effectively distinguishes between different mitochondrial morphologies. Through rigorous training and validation, MitoClass provides a fast, accurate, and user-friendly solution for researchers and clinicians to assess the organization of the mitochondrial network as a proxy for studying organelle health and dynamics.

Keywords:  Cellular imagin; Convolutional neural network; Deep learning; Image classification; Mitochondria classification; Mitochondria dynamics

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108477
PLoS Genet. 2025 Apr 25. 21(4): e1011678

Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity.

Xiaomeng Yang, Ruichen Wei, Fanfan Meng, Dianchen Liu, Xuan Gong, Gary Ruvkun, Wei Wei.

Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.

DOI: https://doi.org/10.1371/journal.pgen.1011678
Rheumatology (Oxford). 2025 Apr 23. pii: keaf193. [Epub ahead of print]

Diminished SUV3 expression and its functional implications in the IFN-enriched monocyte subset of childhood Sjögren's Disease.

Jimin Yoon, Daesong Jang, Myung-Chul Kim, Joon Paek, Rehae Miller, Beatriz Veronese, Rudy Alvarado, Akaluck Thatayatikom, Yoosik Kim, Seunghee Cha.

   OBJECTIVES: This study investigates the molecular and functional implications of reduced Suv3-like RNA helicase (SUV3) expression in the interferon (IFN)-enriched subset of monocytes from childhood Sjögren's disease (cSjD). SUV3 is known to unwind double-stranded RNAs (dsRNAs) for homeostatic RNA decay within mitochondria.
METHODS: Using single-cell RNA sequencing, we analysed highly inflammatory IFN-enriched CD14+ monocytes from cSjD patients. To model SUV3 deficiency, we performed SUV3 knockdown in monocytic cells and studied the origin, localization, and accumulation of dsRNAs in the cytosol. Formaldehyde-crosslinking-immunoprecipitation (fCLIP)-qPCR identified an intracellular sensor of dsRNAs. We further examined patient monocytes using J2 anti-dsRNA antibodies and transmission-electron-microscopy (TEM) for subcellular localization. In vitro assays assessed the impact of SUV3 knockdown on oxidative stress, ATP production, migration, and phagocytosis.
RESULTS: SUV3 knockdown led to the accumulation of mitochondrial-dsRNAs (mt-dsRNAs) outside of the mitochondria, where they interacted with protein kinase R (PKR). This activated PKR, triggering a type I IFN signature and upregulating proinflammatory cytokines linked to fatigue. TEM revealed mt-dsRNAs in mitochondrial-derived vesicles and muti-vesicular bodies. Notably, cSjD monocytes had a significantly higher frequency of dsRNA-positive cells compared with controls (39% vs 0.08%, p< 0.002). SUV3 depletion also increased superoxide and ROS production, while impairing ATP synthesis, migration, and phagocytosis, which are key innate immune functions. These defects were partially or fully reversed by co-knockdown of PKR.
CONCLUSION: SUV3 is the key driver for defective innate immune functions through mt-dsRNA-mediated PKR activation, which enhances cellular stress, mitochondrial dysfunction, and inflammatory signatures, uncovering a novel mechanism in cSjD pathogenesis.

Keywords:  SUV3; childhood Sjögren’s disease; mitochondrial double-stranded RNAs; monocytes; protein kinase R

DOI:  https://doi.org/10.1093/rheumatology/keaf193
Int Immunopharmacol. 2025 Apr 19. pii: S1567-5769(25)00661-7. [Epub ahead of print]156 114671

Urolithin A alleviates radiation pneumonitis by activating PINK1/PRKN-mediated Mitophagy.

Anqi Zhang, Shilan Luo, Peng Li, Lu Meng, Litang Huang, Hongxia Cheng, Chenhui Zhao, Hongbin Tu, Xiaomei Gong.

   BACKGROUND: Radiation pneumonitis (RP) is a common and severe complication of radiotherapy, whose pathogenesis involves complex inflammatory responses and cellular damage. Despite its clinical significance, effective treatments remain limited. This study investigates the role of radiation-induced PINK1/PRKN-mediated mitophagy and type I interferon responses in RP and evaluates the therapeutic potential of Urolithin A (UA) in regulating inflammation through mitophagy activation.
METHODS: We established RP mouse models (20 Gy thoracic irradiation) and radiation-induced BEAS-2B cell models (6 Gy). We systematically investigated mitochondrial damage, mtRNA release, RIG-I/MDA5-MAVS pathway activation, and PINK1/PRKN-mediated mitophagy changes. Moreover, the effects of UA and the mitophagy inhibitor Mdivi-1 on inflammation and lung injury were analyzed.
RESULTS: Radiation significantly caused mitochondrial damage in lung tissues, inducing mtRNA release and RIG-I/MDA5-MAVS-mediated type I interferon response. PINK1/PRKN-mediated mitophagy was significantly enhanced, clearing damaged mitochondria and reducing cytosolic mtRNA release, thereby suppressing inflammation. Pharmacological activation of mitophagy with UA markedly improved lung pathology, reduced inflammatory cytokine levels, and inhibited excessive activation of the RIG-I/MDA5-MAVS pathway. Conversely, the knockdown of PINK1 or PRKN weakened the protective effects of UA. Both in vitro and in vivo, UA reduced radiation-induced inflammation and improved lung tissue structure and function through mitophagy.
CONCLUSIONS: Radiation-induced mtRNA release activates the RIG-I/MDA5-MAVS-mediated type I interferon response, driving inflammation in RP. PINK1/PRKN-mediated mitophagy significantly alleviates inflammation by reducing cytosolic mtRNA release. As a mitophagy inducer, UA demonstrates therapeutic potential for RP, providing a new direction for the development of anti-inflammatory strategies.

Keywords:  Inflammation; Mitophagy; PINK1/PRKN; Radiation pneumonitis; Urolithin A

DOI:  https://doi.org/10.1016/j.intimp.2025.114671
Free Radic Biol Med. 2025 Apr 21. pii: S0891-5849(25)00243-6. [Epub ahead of print]

Oxidative stress-induced release of mitochondrial DNA (mtDNA) promotes the progression of vitiligo by activating the cGAS-STING signaling pathway in monocytes.

Tong Wu, Xiaoqi Chen, Jinrong Fan, Peina Ye, Jia Zhang, Zeqian Wang, Yuqi Zhou, Bo Wang, Xiaodong Jin, Shishi Xiong, Shanshan Gao, Yuqian Chang, Chunying Li, Zhe Jian.

  Vitiligo, driven by cytotoxic CD8+ T cells destroying melanocytes, has recently been linked to mtDNA, a DAMP known to trigger innate immunity. However, the precise role of mtDNA in vitiligo pathogenesis remains poorly understood. In this study, we observed significantly elevated mtDNA levels in both the serum and depigmented lesions of vitiligo patients. Importantly, we found that oxidative stress induces mtDNA production in keratinocytes and vascular endothelial cells, providing a plausible source for its systemic and localized accumulation. Using the vitiligo mouse model, we demonstrated that exogenous mtDNA administration markedly accelerated disease progression, as evidenced by pronounced tail depigmentation. Mechanistically, mtDNA can activate the cGAS-STING-IFN-α/β pathway in monocytes, leading to an increased production of IFN-γ by CD8+ T cells while simultaneously reducing the frequency and functionality of regulatory CD4+ T cells (Tregs). Consistent with these findings, mtDNA treatment in vitiligo mice led to heightened infiltration of IFN-γ+ CD8+ T cells into affected tissues, accompanied by a significant decrease in Treg numbers and activity, thereby exacerbating the autoimmune response. Collectively, these findings underscore the pivotal role of mtDNA-STING signaling in vitiligo progression and highlight this pathway as a promising target for therapeutic intervention. Our findings suggest that mtDNA may serve as a crucial mediator in the pathogenesis of vitiligo and other autoimmune diseases, providing new insights into potential therapeutic targets.

Keywords:  Vitiligo; cGAS-STING; monocytes; mtDNA; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.033
Nat Commun. 2025 Apr 22. 16(1): 3756

SAMD9 senses cytosolic double-stranded nucleic acids in epithelial and mesenchymal cells to induce antiviral immunity.

Gaopeng Hou, Wandy Beatty, Lili Ren, Yaw Shin Ooi, Juhee Son, Yinxing Zhu, Qingyu Sheng, Wanyi Huang, Dian Li, Constin Liu, Olivia L Welsh, Danica M Sutherland, Terence S Dermody, Chen Shen, Jia Liu, L David Sibley, Siyuan Ding.

Sensing of cytosolic, double-stranded (ds) DNA or dsRNA molecules derived from microbial or endogenous sources triggers cell-intrinsic innate immunity, but sensors recognizing both cytosolic dsDNA and dsRNA are sparsely reported. Here we find that full-length human SAMD9 protein directly binds to synthetic or viral dsDNA or dsRNA. Overexpression of SAMD9 from various vertebrate species leads to robust production of interferons and pro-inflammatory cytokines. By contrast, loss of endogenous SAMD9 impairs the interferon responses to cytosolic dsDNA and dsRNA stimulation in multiple cell types and enhances the infectivity of pathogenic dsDNA and dsRNA viruses. Mice lacking Samd9l, the human SAMD9 homolog, show increased viral load and severe clinical manifestations of rotavirus and reovirus infections. Rotavirus-encoded non-structural protein 1 targets SAMD9 for proteasomal degradation. Collectively, our data demonstrate that SAMD9 may serve as a pattern-recognition receptor for cytosolic dsDNA and dsRNA across different domains of life and represents a potential target of viral innate immune evasion.

DOI: https://doi.org/10.1038/s41467-025-59090-w
Respir Res. 2025 Apr 24. 26(1): 159

ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels.

Hui Jiang, Yaona Jiang, Ran Dong, Chang-Yong Fu.

   BACKGROUND: ETS2 has been identified as a pivotal regulator in the development of human inflammatory diseases. Nevertheless, the functional aspects of ETS2 in asthma remain inadequately characterized. The release of mitochondrial dsRNA is recognized as an initiator of innate immune responses and implicated in intensifying inflammation triggered by alternative immunogens. The interplay between these mechanisms remains poorly understood, and only a limited number of direct targets that underpin the pro-inflammatory role of ETS2 have been identified.
METHODS: The expression of ETS2 in epithelial cells under immune responses was analyzed, and its effects on asthma progression were examined through clinical specimens, human bronchial epithelial cells, and an allergic asthma mouse model. Additionally, the potential involvement of adenine nucleotide translocase-2 in mediating the immune responses regulated by ETS2 was explored.
RESULTS: Increased expression of ETS2 in lung epithelial cells was observed in both asthma patients and ovalbumin (OVA)-induced asthma mice. The deficiency of ETS2 resulted in a substantial decline in inflammatory cell infiltration and markedly diminished IL-6, IL-5, and IL-13 levels in epithelial cells. Mechanistically, ETS2 overexpression was associated with elevated cytosolic mitochondrial RNA levels, whereas knockdown resulted in their suppression. Furthermore, adenine nucleotide translocase-2 (ANT2) expression was robustly upregulated by ETS2 through direct promoter binding. The advantageous effects of ETS2 on asthma development were abrogated in ANT2-deficient mice.
CONCLUSIONS: The findings collectively underscore the role of ETS2 as an exacerbating factor in allergic airway inflammation during asthma progression, primarily by inducing ANT2 expression. Therapeutic targeting of epithelial ETS2 could represent a novel approach to asthma management.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  ANT2; Asthma; ETS2; Mitochondrial DsRNA; Mitochondrial function

DOI:  https://doi.org/10.1186/s12931-025-03233-6
Mol Cell. 2025 Apr 15. pii: S1097-2765(25)00299-0. [Epub ahead of print]

ZBP1 senses splicing aberration through Z-RNA to promote cell death.

Zhang-Hua Yang, Puqi Wu, Bo-Xin Zhang, Cong-Rong Yang, Jia Huang, Lei Wu, Shuang-Hui Guo, Yuenan Zhou, Yuanhui Mao, Yafei Yin, Xiurong Wu, Pu Cheng, Baizhou Li, Rongbin Zhou, Han-Ming Shen, Sheng Nie, Zhi-Yu Cai, Wei Mo.

  RNA splicing, a highly regulated process performed by the spliceosome, is essential for eukaryotic gene expression and cellular function. Numerous cellular stresses, including oncogenic insults, dysregulate RNA splicing, often provoking inflammatory responses and cell death. However, the molecular signals generated by splicing aberrations and the mechanism by which cells sense and respond to these signals remain poorly understood. Here, we demonstrate that spliceosome inhibition induces the widespread formation of left-handed Z-form double-stranded RNA (Z-RNA), predominantly derived from mis-spliced exonic and intronic RNA transcripts in the nucleus. These Z-RNAs are exported to the cytoplasm in a RanGTP-dependent manner. Cytosolic sensing of accumulated Z-RNA by the host sensor Z-DNA-binding protein 1 (ZBP1) initiates cell death, primarily through RIPK3-MLKL-dependent necroptosis. Together, these findings reveal a previously uncharacterized mechanism in which ZBP1-mediated detection of Z-RNA serves as a critical response to global RNA splicing perturbations, ultimately triggering inflammatory cell death.

Keywords:  Z-RNA; ZBP1; necroptosis; spliceosome; splicing aberration

DOI:  https://doi.org/10.1016/j.molcel.2025.03.023
iScience. 2025 May 16. 28(5): 112324

Birch pollen allergen-induced dsDNA release activates cGAS-STING signaling and type 2 immune response in mice.

Pauline Chenuet, Manon Mellier, Yasmine Messaoud-Nacer, Elodie Culerier, Quentin Marquant, Louis Fauconnier, Nathalie Rouxel, Aurélie Ledru, Stéphanie Rose, Bernhard Ryffel, Lionel Apetoh, Valérie F J Quesniaux, Dieudonnée Togbe.

  Detecting cytoplasmic or extracellular DNA from host or pathogen origin by DNA sensor cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) triggers immune responses with secretion of type I interferons and inflammatory cytokines. However, STING agonists function as type-2 adjuvant promoting allergic asthma. Here, we asked how cGAS/STING signaling pathway influences allergen-induced type-2 immune responses in models of allergic airway diseases induced by birch pollen extract, house dust mite, or ovalbumin plus Alum. We report increased extracellular dsDNA in the airways, together with cGAS and STING gene expression, following allergen challenge in these models, correlating dsDNA and type-2 cytokine IL-4, IL-5, and IL-13 release. Allergen-induced type-2 immune responses were reduced in cGAS- or STING-deficient mice. Further, blocking cGAS function with the specific inhibitor RU.521 protected mice from birch pollen allergen-induced airway inflammation and type-2 immune responses. Thus, DNA sensing by cGAS contributes to type-2 immune responses and may represent a therapeutic target for allergic lung inflammation.

Keywords:  Immune response; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112324
Pediatr Res. 2025 Apr 23.

Cardiac dysfunction due to mitochondrial impairment assessed by human iPS cells caused by DNM1L mutations.

Madori T Osawa, Yasunori Fujita, Kazuki Kagami, Masataka Ito, Yoshiteru Tamura, Shoichiro Tateishi, Junya Take, Fumi Hirose, Hidetoshi Hagiwara, Kohsuke Imai, Daisuke Yoshinaga, Shiro Baba, Mitsujiro Osawa, Hiroko Harashima, Kei Murayama, Yuko Akioka, Akira Ohtake, Ikuro Suzuki, Takeshi Adachi, Takeru Yamazaki, Satoshi Arai, Shiro Matsumoto, Tetsuya Kitaguchi, Megumu K Saito, Ikuroh Ohsawa, Shigeaki Nonoyama.

BACKGROUND: DNM1L encodes dynamin-related protein 1, which plays an important role in mitochondrial and peroxisomal division. The DNM1L mutation leads to cardiac dysfunction in patients and animal models. However, the mechanism of cardiac dysfunction caused by DNM1L mutation has not been elucidated clearly at least in the studies of human cardiomyocytes.
METHODS: We established human induced pluripotent stem cells (hiPSCs) from two pediatric patients with DNM1L mutation. The hiPSCs were differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). Mitochondrial morphology and function, cardiomyocyte Ca2+ dynamics, and contractile and diastolic function of hiPS-CMs were analyzed.
RESULTS: The morphology of the mitochondria was abnormally elongated in patient-derived hiPS-CMs. The mitochondrial membrane potential and oxygen consumption rate were significantly decreased, resulting in reduced ATP production. In the analysis of Ca2+ dynamics, the 50% time to decay was significantly longer in patient-derived hiPS-CMs than in healthy control. High-precision live-imaging system analysis revealed that contractile and diastolic function was significantly impaired under isoproterenol stimulation.
CONCLUSION: DNM1L mutations cause mitochondrial impairment with less production of ATP in cardiomyocytes. This leads to abnormal intracellular Ca2+ dynamics, resulting in contractile and diastolic dysfunction.
IMPACT: DNM1L mutations was identified in two pediatric patients who developed cardiac dysfunction and human induced pluripotent stem cells (hiPSCs) were established from these two patients and differentiated into hiPSC-derived cardiomyocytes (hiPS-CMs). DNM1L mutations induced abnormal mitochondrial morphology, mitochondrial dysfunction, and insufficient ATP production in hiPS-CMs. In addition, hiPS-CMs with DNM1L mutation showed abnormal Ca2+ kinetics and impaired contractile and diastolic function. This is the first study that elucidate the mechanism of cardiac dysfunction caused by DNM1L mutations by using hiPSCs.

DOI: https://doi.org/10.1038/s41390-025-04045-6