bims-nenemi 2025-11-09 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–11–09
sixteen papers selected by
Marco Tigano, Thomas Jefferson University

Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
A new model of gastric pre-neoplasia induced by aberrant ADAR1-mediated double-stranded RNA signaling.
G-quadruplex ligand RHPS4 compromises cellular radioresistance by inhibiting the mitochondrial adaptive response induced by ionizing irradiation.
Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
Fe-S Protein FDX1 Triggers Tumor-Intrinsic Innate Immunity via Mitochondrial Nucleic Acids Release to Orchestrate Ferroptosis in CCRCC.
Kaempferol attenuated LPS-induced microglial neurotoxicity by promoting mitophagy to inhibit mtDNA-mediated NLRP3 inflammasome activation.
Unraveling the Interactive Role of Mitochondrial Dysfunction in Promoting Macrophage Polarization in Pulmonary Fibrosis.
2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.
An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.
Mitofusin 1 in mitochondrial quality control and anti-inflammatory responses in nucleus pulposus cells during disc degeneration.
Heat stress-induced mitochondrial damage and its impact on leukocyte function.
Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
Elongator is required for pattern recognition receptor and type I interferon signaling in macrophages.

J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]

Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.

Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.

  Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.

Keywords:  Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone

DOI:  https://doi.org/10.1093/jb/mvaf062
Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):

Proteolytic cleavage activates the mitochondrial isoform of TOP3A.

Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.

The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.

DOI: https://doi.org/10.1093/nar/gkaf1140
Nat Genet. 2025 Nov 03.

Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.

Sonia Boscenco, Jacqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Tricia Park, Flora McNulty, Sergio Lilla, Sara Zanivan, Alejandro Huerta-Uribe, Benan Nalbant, Mark Zucker, David Sumpton, Geoffray Monteuuis, Christopher B Jackson, Wei Wei, Patrick F Chinnery, Ronan Chaligne, Caleb A Lareau, Ed Reznik, Payam A Gammage.

The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.

DOI: https://doi.org/10.1038/s41588-025-02374-0
Cell Mol Gastroenterol Hepatol. 2025 Nov 04. pii: S2352-345X(25)00214-0. [Epub ahead of print] 101673

A new model of gastric pre-neoplasia induced by aberrant ADAR1-mediated double-stranded RNA signaling.

Angela M Halstead, Chinye Nwokolo, Stella Hoft, Jinsheng Yu, Lifei Zhu, Brendan Tuley, Nancy Vargas, RuiRui Liu, Francisco Ramirez Victorino, Simrin Phatak, Wandy Beatty, Chun-Kan Chen, Richard DiPaolo, Paul Cliften, Tarin M Bigley, José B Sáenz.

   BACKGROUND: /AIMS: Recent evidence suggests that endogenously-derived double-stranded RNA (dsRNA) impacts multiple cellular processes, though its role in epithelial injury remains understudied. We previously identified the response to dsRNA as the most upregulated pathway across two distinct murine models of spasmolytic polypeptide-expressing metaplasia (SPEM), a critical pre-neoplastic transition in the progression to gastric cancer. The aim of this study was to define how dysregulation of the dsRNA response within gastric epithelium impacts gastric pre-neoplasia.
METHODS: We specifically deleted ADAR1, a central regulator of dsRNA signaling, from gastric parietal cells (Adar1ΔPC). Adar1ΔPC and age-matched controls stomachs were histologically, transcriptionally, and immunologically profiled. The source of dsRNA in Adar1ΔPC gastric epithelium was assessed by dsRNA immunoprecipitation and immune-electron microscopy. Finally, to define the contributions of IFN signaling, Adar1ΔPC;Ifnar1-/-and Adar1ΔPC;Ifnlr1-/- mice, defective in type I and type III IFN signaling, respectively, were characterized.
RESULTS: Adar1ΔPC mice spontaneously developed SPEM and gastric dysplasia, in the absence of exogenous injury. Our phenotype depended on Mavs, a key dsRNA signaling hub, implying that our model of gastric pre-neoplasia was specific to dsRNA signaling. Further characterization of this pre-neoplastic environment by single-cell RNA sequencing and flow cytometry noted a chronic and sustained transcriptional upregulation of the dsRNA response throughout gastric epithelium that was independent of adaptive immunity and that depended on both type I and type III IFN signaling. Finally, we identified an enrichment of mitochondrial dsRNA (mt-dsRNA) within the gastric epithelium of Adar1ΔPC stomachs.
CONCLUSIONS: Our new genetic model implicates ADAR1-mediated dsRNA signaling in gastric pre-neoplasia.

Keywords:  ADAR1; double-stranded RNA; interferon

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101673
NAR Cancer. 2025 Dec;7(4): zcaf033

G-quadruplex ligand RHPS4 compromises cellular radioresistance by inhibiting the mitochondrial adaptive response induced by ionizing irradiation.

Sabine Tricot, Capucine Siberchicot, Isaline Bontemps, Chantal Desmaze, Gueorgui Kratassiouk, Marie Vandamme, Guillaume Pinna, Ivan Nemazanyy, J Pablo Radicella, Guy Lenaers, Xavier Renaudin, Jérome Lebeau, Anna Campalans.

A major challenge in radiotherapy is to enhance tumour cell sensitivity to radiation while minimizing damage to healthy tissues. Enhancing the effectiveness of radiotherapy can be achieved by combining irradiation with small radiosensitizing molecules, which promote cancer cell death and allow for reduced radiation doses, thereby limiting harm to surrounding healthy tissues. Since mitochondria play a key role in tumour cell proliferation, they represent a promising therapeutic target for cancer treatment. In this study, we characterized the impact of irradiation on mitochondrial function in radioresistant cancer cells. Our findings revealed several adaptive responses that may contribute to radioresistance, including increased mitochondrial DNA (mtDNA) content, mitochondrial mass, enhanced activity, and hyperfusion of the mitochondrial network. Notably, the use of mitochondrial-targeted G-quadruplex (G4) ligands, which block mtDNA replication and transcription, disrupted these responses, reducing cancer cell survival in a mtDNA-dependent manner. These results demonstrate that mitochondrial adaptations contribute to radioresistance and highlight mitochondria as a novel target for the radiosensitizing effects of G4 ligands.

DOI: https://doi.org/10.1093/narcan/zcaf033
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]

Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.

Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.

  Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.

Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity

DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
Adv Sci (Weinh). 2025 Nov 07. e18323

Fe-S Protein FDX1 Triggers Tumor-Intrinsic Innate Immunity via Mitochondrial Nucleic Acids Release to Orchestrate Ferroptosis in CCRCC.

Xing Huang, Shaoqing Yu, Wenjie Wei, Wen Tao, Tianwei Cai, Lequan Wen, Jiali Ye, Chi Zhang, Huayi Feng, Senming Cao, Baojun Wang, Xin Ma, Yan Huang, Xu Zhang.

  Activation of cytosolic nucleic acid-sensing pathways represents a promising strategy to convert immunologically "cold" tumors into inflamed ones. Iron-sulfur (Fe-S) enzymes are critical regulators of innate immunity and nucleic acid sensing, yet their roles in cancer remain poorly defined. Here, ferredoxin-1 (FDX1), a mitochondrial Fe-S protein frequently downregulated in clear cell renal cell carcinoma (ccRCC), is identified as a dual regulator of ferroptosis and antitumor immunity. FDX1 overexpression triggers mitochondrial permeability transition pore opening, leading to cytosolic release of mitochondrial DNA (mtDNA) and double-stranded RNA (mt-dsRNA). This reveals an independent function of FDX1 as a tumor-intrinsic immunity activator linked to mitochondrial stress signaling. These damage-associated molecular patterns (DAMPs) engage cytosolic nucleic acid sensors-specifically cGAS and RIG-I/MDA5-triggering TBK1 phosphorylation and a robust type I interferon response that occurs prior to overt ferroptosis. This innate immune cascade reshapes the tumor microenvironment by enhancing MHC I/II antigen presentation, recruiting CD8+ T cells, and suppressing tumor growth and metastasis in orthotopic syngeneic models. These findings uncover a previously unrecognized antitumor axis through which FDX1 synergizes with mitochondrial nucleic acid release with ferroptosis to promote immunogenic inflammation and T cell infiltration in ccRCC, offering novel therapeutic opportunities targeting mitochondrial-immune crosstalk.

Keywords:  FDX1; ccRCC; dsRNA; ferroptosis; innate immunity; mitophagy; mtDNA

DOI:  https://doi.org/10.1002/advs.202518323
Phytomedicine. 2025 Oct 30. pii: S0944-7113(25)01123-7. [Epub ahead of print]148 157486

Kaempferol attenuated LPS-induced microglial neurotoxicity by promoting mitophagy to inhibit mtDNA-mediated NLRP3 inflammasome activation.

Li Xiao, Lu Liang, Shinan Zhou, Fan Peng, Chengfu Yuan.

   BACKGROUND: This study explored the protective effects of kaempferol (KAE) against neurotoxicity caused by microglial activation and its underlying mechanisms.
METHODS: Microglia BV2 cells were directly stimulated by LPS to assay the effect of KAE. More, C57BL/6 N mice received intraperitoneal LPS injections to prepare a mouse model of neuroinflammation. Autophagy inhibitors 3-MA and Mdivi-1 were utilized to evaluate the effect of KAE on mitophagy.
RESULTS: The results demonstrated that KAE effectively suppressed LPS-induced the production of inflammatory factors, cell proliferation, phagocytic activity and NF-κB signaling activation in microglia BV2 cells, showing the inhibitory effects on microglial activation and inflammation response. Mechanically, the ability of KAE to inhibit NLRP3 inflammasome activation was associated with its enhancement of mitophagy to reduce mitochondrial DNA (mtDNA) resynthesis and leakage. Inhibition of mitophagy significantly promotes mtDNA resynthesis and release, almost completely counteracting this anti-inflammatory effect of KAE. Next, we demonstrated that KAE treatment protected neurons against LPS-induced microglial neurotoxicity and attenuated depressive-like behavior in neuroinflammation mice. This effect was associated with the interference of KAE on NLRP3 inflammasomes activation mediated by reduced mitophagy in microglia, suggesting that promoting mitophagy was one of the mechanisms by which KAE exerted neuroprotective effects on neuroinflammatory mice.
CONCLUSION: This study showed that KAE exerted neuroprotective effects by inhibiting LPS-induced neuroinflammation mediated by microglial activation. The underlying mechanism was that KAE promoted mitophagy in microglia exposed to LPS, thereby inhibiting mtDNA leakage-induced NLRP3 inflammasome activation. It pointed to KAE as a promising therapeutic candidate for neuroinflammation-related diseases.

Keywords:  Kaempferol; Mitophagy; NLRP3 inflammasome; Neuroinflammation; mtDNA

DOI:  https://doi.org/10.1016/j.phymed.2025.157486
J Biochem Mol Toxicol. 2025 Nov;39(11): e70586

Unraveling the Interactive Role of Mitochondrial Dysfunction in Promoting Macrophage Polarization in Pulmonary Fibrosis.

Jiajia Zou, Junling Jian, Dehua Ge, Bin Zhou, Jiaxiang Zhang.

  Pulmonary fibrosis (PF) is a chronic, irreversible interstitial lung disease. There is no effective treatment or drug that can completely cure this disease. The pathogenesis is still unclear. In recent years, several scholars have reported that the main cause of PF is an imbalance in the inflammatory response and abnormal repair after lung injury. Lung macrophages, as immune cells in vivo, play an important role in regulating the immune response and immune tolerance and promoting lung injury repair through polarization. Recent studies have highlighted the importance of mitochondria in lung fibrosis, safeguarding cellular homeostasis and metabolic roles, and their ability to influence the progression of lung fibrosis by mediating macrophage polarization within lung cells. However, the regulation of macrophage polarization by impaired mitochondrial function remains largely unknown. In this review, we intend to summarize the associations of mitochondrial dysfunction, including mitochondrial dynamics, increased ROS production, mitochondrial DNA (mtDNA) leakage, and inflammatory vesicle activation, with the key mechanisms driving the polarization of both M1-type and M2-type macrophages, as well as further explore the role of mitochondria as key control centers for macrophage polarization, which may lead to novel therapeutic approaches to target and/or reverse disease progression.

Keywords:  inflammation; macrophage; mitochondrial dysfunction; pulmonary fibrosis

DOI:  https://doi.org/10.1002/jbt.70586
Sci Rep. 2025 Nov 06. 15(1): 38885

2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.

Payam Gharibani, Yu Guo, Shruthi Shanmukha, Judy J Lee, Katherine Kopp, Paul M Kim, Michael D Kornberg.

  Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.

Keywords:  2-Deoxy-D-Glucose; Immunometabolism; Mitochondrial dynamics; Mitochondrial function; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-025-22677-w
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894

An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.

Zachary L Sebo, Navdeep S Chandel.

Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.

DOI: https://doi.org/10.1016/j.molcel.2025.10.017
Nat Commun. 2025 Nov 03. 16(1): 9484

Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function.

Benjamin J Jenkins, Yasmin R Jenkins, Fernando M Ponce-Garcia, Chloe Moscrop, Iain A Perry, Matthew D Hitchings, Alejandro H Uribe, Federico Bernuzzi, Simon Eastham, James G Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Marta Williams, Morgan Marsden, Douglas J Veale, Luke C Davies, Micah Niphakis, David K Finlay, Linda V Sinclair, Benjamin F Cravatt, Andrew E Hogan, James A Nathan, Ian R Humphreys, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G McDonald, Gareth W Jones, James A Pearson, Emma E Vincent, Nicholas Jones.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T-cell metabolism and function is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T-cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using murine models of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T-cells and delays the onset of diabetes in vivo in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.

DOI: https://doi.org/10.1038/s41467-025-65417-4
Sci Rep. 2025 Nov 04. 15(1): 38530

Mitofusin 1 in mitochondrial quality control and anti-inflammatory responses in nucleus pulposus cells during disc degeneration.

Jae Won Shin, Young Mi Kang, Hak Sun Kim, Seong Hwan Moon, Kyung Soo Suk, Si Young Park, Byung Ho Lee, Ji Won Kwon.

  Mitochondrial dysfunction drives intervertebral disc degeneration, and mitochondrial dynamics are regulated by mitofusins (MFNs). In this study, we evaluated the roles of MFN1 and MFN2 in mitochondrial quality control and their responses to inflammation and antioxidant treatment in grade I and III disc nucleus pulposus cells (NPCs). Human NPCs were isolated from intervertebral disc tissues of patients. Tumor necrosis factor-α (TNF-α)-induced inflammation was treated with vitamin E (Vit E) or saponin. Mitochondrial quality control was evaluated via quantitative polymerase chain reaction, western blotting, and immunocytochemistry. Sulfated glycosaminoglycan levels were quantified to assess extracellular matrix (ECM) integrity. Mitochondrial morphology and function were assessed via transmission electron microscopy and a xenograft model using MFN1-knockout NPCs. TNF-α significantly upregulated MFN1 and MFN2, with MFN1 showing heightened sensitivity in grade III disc NPCs, leading to mitochondrial fragmentation and ECM degradation. Antioxidants mitigated these effects, with Vit E proving more effective than saponin in reducing MFN1 expression, preserving mitochondrial structure, and stabilizing ECM composition. Vit E maintained mitochondrial integrity, whereas TNF-α induced mitochondrial swelling. In vivo, MFN1-knockout NPCs exhibited reduced ECM proteoglycan levels, reinforcing its role in disc homeostasis. These findings suggest that although MFN1 and MFN2 respond to TNF-α, MFN1 reacts more robustly, making it a more promising target under inflammatory stress.

Keywords:  Degenerative disc diseases; Inflammation; Mitochondrial function; Mitochondrial quality control; Mitofusin; Nucleus pulposus cells

DOI:  https://doi.org/10.1038/s41598-025-19540-3
J Intensive Care. 2025 Nov 04. 13(1): 61

Heat stress-induced mitochondrial damage and its impact on leukocyte function.

Toshiaki Iba, Julie Helms, Isao Nagaoka, Ricard Ferrer, Jerrold H Levy.

  Heatstroke is characterized by systemic inflammation, immune dysregulation, and multiorgan failure, in which mitochondrial damage in leukocytes plays a pivotal role. This review examines the mechanisms by which heat stress induces leukocyte mitochondrial dysfunction and its downstream effects on immunity, coagulation, and organ integrity. Exposure to heat stress activates leukocytes through damage-associated molecular patterns (DAMPs), triggering the release of proinflammatory cytokines, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). These responses disrupt endothelial integrity, promote microvascular thrombosis, and contribute to the development of disseminated intravascular coagulation (DIC). Prolonged heat exposure further shifts the immune landscape toward immunosuppression, marked by monocyte deactivation and lymphocyte apoptosis. Mitochondrial dysfunction is central to this biphasic immune response. Heat stress reduces mitochondrial membrane potential, increases ROS production, and promotes the release of mitochondrial DNA and cytochrome c, amplifying inflammation and initiating cell death pathways, including apoptosis, pyroptosis, and ferroptosis. Biomarkers such as reduced mitochondrial membrane potential (ΔΨm), elevated mitochondrial ROS, cytochrome c, circulating mitochondrial DNA (mtDNA), and altered expression of mitophagy regulators (e.g., PINK1 and Parkin) provide insights into mitochondrial integrity and function in leukocytes. In addition to immune disruption, mitochondrial injury exacerbates coagulation abnormalities by promoting platelet activation and endothelial dysfunction, fostering a prothrombotic environment. In the microcirculation, leukocyte adhesion, NET formation, and endothelial damage create a self-amplifying cycle of ischemia and inflammation, ultimately leading to organ dysfunction, including hepatic failure, acute kidney injury, acute lung injury, and gastrointestinal barrier breakdown. Therapeutic strategies aimed at preserving mitochondrial function include antioxidants (e.g., N-acetylcysteine and MitoQ), mitochondrial biogenesis inducers (e.g., PGC-1α activators), and mitophagy enhancers. Understanding the central role of leukocyte mitochondrial damage in heat stress provides a foundation for the development of targeted diagnostics and interventions to prevent organ failure and improve clinical outcomes.

Keywords:  Cell death; Heat stress; Leukocyte; Mitochondria; Organ dysfunction

DOI:  https://doi.org/10.1186/s40560-025-00832-9
Cell Death Differ. 2025 Nov 01.

Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.

Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.

The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.

DOI: https://doi.org/10.1038/s41418-025-01603-7
J Biol Chem. 2025 Nov 05. pii: S0021-9258(25)02768-1. [Epub ahead of print] 110916

Elongator is required for pattern recognition receptor and type I interferon signaling in macrophages.

Jamie Murphy, Marcin Baran, Corinna Grünke, Darya Haas, Gillian Barber, Andreas Pichlmair, Andrew G Bowie.

  Innate immune detection of pathogens by macrophages requires a rapid and large scale mobilisation of cellular resources towards an appropriate immune response, mainly involving altered protein expression. Pathogen recognition is mediated by pattern recognition receptor (PRR) sensing of conserved microbial patterns, a prototypical example being recognition of lipopolysaccharide (LPS) by TLR4. This leads to induction of pro-inflammatory cytokines, chemokines and type I interferons (IFN Is) which together mobilise appropriate anti-pathogen responses. IFN Is signal to transcription of IFN-stimulated genes (ISG) which encode numerous anti-viral proteins. Many studies have contributed to a detailed understanding of transcriptional regulation of mRNA during such responses, however much less is known about the contribution of protein complexes required for mRNA translation. Here we examine the role of the evolutionarily conserved elongator complex in PRR signaling in macrophages. Elongator modifies tRNAs at U34 to facilitate more efficient wobble interactions between tRNAs and mRNA codons. In macrophages, deletion of Elp3, the catalytic subunit of elongator, led to an impaired PRR-IFN I-ISG signaling axis. The ELP3-dependent LPS-stimulated proteome was enriched with proteins involved in PRR activation of IRFs and in IFN signalling. Specifically, ELP3 was required for expression of key transcription factors regulating this axis, for TYK2-dependent IFN-I signaling and for IRF3 activation for some, but not all, PRRs. Importantly, ELP3 was also necessary for innate immune gene induction following virus infection. These data reveal specific roles for elongator in PRR signaling and illustrate the underappreciated importance of translational regulation in optimal anti-pathogen innate immune responses.

Keywords:  Innate immunity; STAT transcription factor; Toll-like receptor 4 (TLR4); elongator; interferon; interferon regulatory factor (IRF); lipopolysaccharide (LPS); macrophage; pattern recognition receptor (PRR); virus

DOI:  https://doi.org/10.1016/j.jbc.2025.110916