bims-nenemi 2025-09-28 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–09–28
eighteen papers selected by
Marco Tigano, Thomas Jefferson University

Ribonucleotide incorporation into mitochondrial DNA drives inflammation.
MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.
Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.
Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.
Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.
The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.
Tumor intrinsic regulation of PD-L1 and of interferon Type I via an SLC25A1-driven mitochondrial pathway, influences the anti-tumor immune response.
Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.
Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial Pore Formation.
A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.
TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.
Mitochondria expel tainted DNA - spurring age-related inflammation.
Cross-Organ Mitochondrial Communication in Stress and Disease.
Human polynucleotide phosphorylase in mitochondrial RNA metabolism.
Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB-mediated inflammatory response in Triple Negative Breast Cancer.
Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.
VDAC1-interacting proteins: binding site mapping and their derived peptides induce apoptosis and multifaceted cellular effects.

Nature. 2025 Sep 24.

Ribonucleotide incorporation into mitochondrial DNA drives inflammation.

Amir Bahat, Dusanka Milenkovic, Eileen Cors, Mabel Barnett, Sadig Niftullayev, Athanasios Katsalifis, Marc Schwill, Petra Kirschner, Thomas MacVicar, Patrick Giavalisco, Louise Jenninger, Anders R Clausen, Vincent Paupe, Julien Prudent, Nils-Göran Larsson, Manuel Rogg, Christoph Schell, Isabella Muylaert, Erik Lekholm, Hendrik Nolte, Maria Falkenberg, Thomas Langer.

Metabolic dysregulation can lead to inflammatory responses1,2. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response through cGAS-STING signalling3. However, how nucleotide deficiency drives mtDNA-dependent inflammation has not been elucidated. Here we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME14, in various tissues of aged mice and in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases the ribonucleotide content of mtDNA in cell-cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleosides. Our results highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation and show that imbalanced nucleotide metabolism leads to age- and mtDNA-dependent inflammatory responses and SASP in senescence.

DOI: https://doi.org/10.1038/s41586-025-09541-7
BMC Genomics. 2025 Sep 25. 26(1): 810

MitoDelta: identifying mitochondrial DNA deletions at cell-type resolution from single-cell RNA sequencing data.

Haruko Nakagawa, Yasuyuki Shima, Yohei Sasagawa, Itoshi Nikaido.

   BACKGROUND: Deletion variants in mitochondrial DNA (mtDNA) are associated with various diseases, such as mitochondrial disorders and neurodegenerative diseases. Traditionally, mtDNA deletions have been studied using bulk DNA sequencing, but bulk methods average signals across cells, thereby masking the cell-type-specific mutational landscapes. Resolving mtDNA deletions at single-cell resolution is beneficial for understanding how these mutations affect distinct cell populations. To date, no specialized method exists for detecting cell-type-specific mtDNA deletions from single-cell RNA sequencing data. Notably, mtDNA possesses unique molecular features: a high copy number, stable transcription, and compact structure of the mitochondrial genome. This results in a relatively high abundance of mtDNA-derived reads even in single-cell RNA sequencing data, suggesting the possibility of detecting mtDNA deletion variants directly from transcriptomic data.
RESULTS: Here, we present MitoDelta, a computational pipeline that enables the detection of mtDNA deletions at cell-type resolution solely from single-cell RNA sequencing data. MitoDelta combines a sensitive alignment strategy with robust statistical filtering based on a beta-binomial distribution model, allowing accurate identification of deletion events even from noisy single-cell transcriptomes. To capture cell-type-specific deletion patterns, MitoDelta analyzes reads pooled by annotated cell types, enabling quantification of deletion burden across distinct cellular populations. We benchmarked MitoDelta against existing mtDNA deletion detection tools and demonstrated superior overall performance. As a practical application, we applied MitoDelta to a published single-nucleus RNA sequencing dataset for Parkinson's disease and revealed distinct mtDNA deletion burdens across neuronal subtypes.
CONCLUSIONS: MitoDelta enables the transcriptome-integrated, cell-type-specific detection of mtDNA deletions from single-cell RNA sequencing data alone, offering a valuable framework for reanalyzing public datasets and studying mitochondrial genome alterations at cell-type resolution. This integrated approach enables insights into how mtDNA deletions are distributed across specific cell types and cellular states, providing new opportunities to investigate the role of mtDNA deletions in cell-type-specific disease mechanisms. The tool is available at https://github.com/NikaidoLaboratory/mitodelta .

Keywords:  Deletion variant; Mitochondrial DNA; Single-cell transcriptomics; Variant caller

DOI:  https://doi.org/10.1186/s12864-025-11931-0
bioRxiv. 2025 Sep 20. pii: 2025.09.17.675534. [Epub ahead of print]

Cryo-mtscATAC-seq for single-cell mitochondrial DNA genotyping and clonal tracing in archived human tissues.

Maren Salla, Benedikt Obermayer, Marie Cotta, Ekaterina Friebel, Juliana Campo-Garcia, Georgia Charalambous, Roemel Jeusep Bueno, Dustin Lieu, Patryk Dabek, Ashley Helmuth, George Tellides, Roland Assi, Katrin Bankov, Marco Lodrini, Hedwig Deubzer, Dieter Beule, Hattie Chung, Helena Radbruch, David Capper, Frank Heppner, Sarah C Starossom, Caleb A Lareau, Ilon Liu, Leif S Ludwig.

High-throughput clonal tracing of primary human samples relies on naturally occurring barcodes, such as somatic mitochondrial DNA (mtDNA) mutations detected via single-cell ATAC-seq (mtscATAC-seq). Fresh-frozen clinical specimens preserve tissue architecture but compromise cell integrity, thereby precluding their use in multi- omic approaches such as mitochondrial genotyping at single-cell resolution. Here, we introduce Cryo-mtscATAC-seq, a broadly applicable method for diverse pathophysiological contexts to isolate nuclei with their associated mitochondria ("CryoCells") from frozen samples for high-throughput clonal analysis. We applied Cryo-mtscATAC-seq to the neurodegenerated human brain, glioblastoma (GBM), pediatric neuroblastoma, and human aorta, and implemented mitobender, a computational tool to reduce ambient mtDNA in single-cell assays. Our approach revealed regional clonal gliogenesis and microglial expansions in amyotrophic lateral sclerosis (ALS), persistence of oligodendrocyte progenitor cell (OPC)-like clones in GBM recurrence, mtDNA depth heterogeneity after neuroblastoma chemotherapy, and oligoclonal proliferation of smooth muscle cells in human aorta. In conclusion, Cryo-mtscATAC-seq broadly extends mtDNA genotyping to archival frozen specimens across tissue types, opening new avenues for investigation of cell state- informed clonality in human health and disease.

DOI: https://doi.org/10.1101/2025.09.17.675534
J Cell Sci. 2025 Sep 15. pii: jcs263691. [Epub ahead of print]138(18):

Charcot-Marie-Tooth type 2A variants of mitofusin 2 sensitize cells to apoptotic cell death.

Mariana Joaquim, Maria-Bianca Bulimaga, Marie A Mohn, Solenn Plouzennec, Leon Osinski, Selver Altin, Esther Mahabir, Arnaud Chevrollier, Mafalda Escobar-Henriques.

  The neuropathy Charcot-Marie-Tooth (CMT) is an incurable disease with a lack of genotype-phenotype correlation. Variants of the mitochondrial protein mitofusin 2 (MFN2), a large GTPase that mediates mitochondrial fusion, are responsible for the subtype CMT type 2A (CMT2A). Interestingly, beyond membrane remodelling, additional roles of MFN2 have been identified, expanding the possibilities to explore its involvement in disease. Here, we investigated how cellular functions of MFN2 are associated with variants present in individuals with CMT2A. Using human cellular models, we observed that cells expressing CMT2A variants display increased endoplasmic reticulum (ER) stress and apoptotic cell death. Increased cleavage of PARP1, caspase 9, caspase 7 and caspase 3, alongside BAX translocation to mitochondria, pointed towards effects on intrinsic apoptosis. Moreover, although disruption of fusion and fission dynamics per se did not correlate with cell death markers, expression of MFN1 or MFN2 alleviated the apoptosis markers of CMT2A variant cell lines. In sum, our results highlight excessive cell death by intrinsic apoptosis as a potential target in CMT2A disease.

Keywords:  Apoptosis; CMT2A; Cell death; Charcot–Marie–Tooth; Fusion; MFN2; Mitochondria

DOI:  https://doi.org/10.1242/jcs.263691
Antioxidants (Basel). 2025 Sep 21. pii: 1138. [Epub ahead of print]14(9):

Mitochondrial DNA Dysfunction in Cardiovascular Diseases: A Novel Therapeutic Target.

Mi Xiang, Mengling Yang, Lijuan Zhang, Xiaohu Ouyang, Alexey Sarapultsev, Shanshan Luo, Desheng Hu.

  Cardiovascular diseases hinge on a vicious, self-amplifying cycle in which mitochondrial deoxyribonucleic acid (mtDNA) dysfunction undermines cardiac bioenergetics and unleashes sterile inflammation. The heart's reliance on oxidative phosphorylation (OXPHOS) makes it exquisitely sensitive to mtDNA insults-mutations, oxidative lesions, copy-number shifts, or aberrant methylation-that impair ATP production, elevate reactive oxygen species (ROS), and further damage the mitochondrial genome. Damaged mtDNA fragments then escape into the cytosol, where they aberrantly engage cGAS-STING, TLR9, and NLRP3 pathways, driving cytokine storms, pyroptosis, and tissue injury. We propose that this cycle represents an almost unifying pathogenic mechanism in a spectrum of mtDNA-driven cardiovascular disorders. In this review, we aim to synthesize the pathophysiological roles of mtDNA in this cycle and its implications for cardiovascular diseases. Furthermore, we seek to evaluate preclinical and clinical strategies aimed at interrupting this cycle-bolstering mtDNA repair and copy-number maintenance, reversing pathogenic methylation, and blocking mtDNA-triggered innate immune activation-and discuss critical gaps that must be bridged to translate these approaches into precision mitochondrial genome medicine for cardiovascular disease.

Keywords:  cardiovascular disease; cellular biology; mitochondrial DNA; therapeutic strategy

DOI:  https://doi.org/10.3390/antiox14091138
J Biol Chem. 2025 Sep 18. pii: S0021-9258(25)02591-8. [Epub ahead of print] 110739

The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.

Wei-Hua Chu, Yu-Shan Lin, Jing Guo, Wann-Neng Jane, Wong-Jing Wang, Yu-Yang Lin, Pei-Han Liu, Po-Yu Huang, Wei-Chung Chiang.

PINK1/Parkin-mediated mitophagy is a major homeostatic mechanism by which cells selectively remove damaged, depolarized mitochondria. A signature event in this form of mitophagy is the rupture of the mitochondrial outer membrane (OMM), a process required for the proper disposal of the damaged, depolarized mitochondria. The OMM rupture results in the topological exposure of mitochondrial inner membrane (IMM) mitophagy receptors, which are recognized by autophagy machinery, thus promoting the turnover of the depolarized mitochondria. However, due to the lack of efficient tools to measure OMM rupture, our mechanistic understanding of this process has been limited. In this study, we identified ANKRD13A as a novel mitophagy factor that interacts with multiple mitochondrial proteins and re-localizes to the depolarized mitochondria. ANKRD13A promotes PINK1/Parkin-mediated mitophagy by recruiting Valosin-containing protein (VCP), an AAA-ATPase that functions to remodel protein complexes or membranes via the extraction of protein substrates. Through the development of a novel biosensor that fluorescently marks the sites of OMM rupture, we visualized the OMM rupture events in cellulo and revealed that VCP and its recruitment factors, including ANKRD13A, are required for the rupture of OMM. This finding demonstrated that VCP-dependent remodeling of OMM during PINK1/Parkin-mediated mitophagy is a key driving force behind the OMM rupture. Furthermore, our newly developed biosensor represents an effective, reliable method to detect OMM rupture during PINK1/Parkin-mediated mitophagy, and it is valuable for future mechanistic investigation of this process.

DOI: https://doi.org/10.1016/j.jbc.2025.110739
bioRxiv. 2025 Sep 21. pii: 2025.09.20.677512. [Epub ahead of print]

Tumor intrinsic regulation of PD-L1 and of interferon Type I via an SLC25A1-driven mitochondrial pathway, influences the anti-tumor immune response.

Rami Mosaoa, Maha Moussa, Aditya Kavuturu, Salan Preet Kaur, Garrett Graham, Chris Albanese, Marta Catalfamo, Maria Laura Avantaggiati.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, yet variable patient responses highlight the need to better define tumor-intrinsic regulators of immune sensitivity. Here, we identify the mitochondrial citrate carrier SLC25A1 as a determinant of ICI responsiveness through a dual regulation of type I interferon (IFN-I) signaling and of PD-L1 expression. SLC25A1 promotes a mitochondrial-to-nuclear retrograde signaling via cytosolic accumulation of mitochondrial DNA, activation of the cGAS-STAT1 axis, and establishment of a virus mimicry state that enhances the IFN-I response. This activation is enriched in cancer stem cell populations, linking SLC25A1 to immune evasion and tumor progression. Moreover, SLC25A1 also regulates PD-L1 protein levels through a newly identified fumarate-Keap1-PD-L1 axis, whereby fumarate destabilizes Keap1, leading to PD-L1 up-regulation. In vivo, tumors expressing high levels of SLC25A1 exhibit an inflammatory microenvironment and increased sensitivity to PD-L1 blockade, but accelerated growth in the absence of anti-PD-L1 treatment. These findings position SLC25A1 as a novel regulator of mitochondrial-driven immune signaling and PD-L1 stability, and suggest that SLC25A1 exploits PD-L1 signaling to evade immune surveillance, while at the same time creating an intrinsic tumor vulnerability to checkpoint blockade. Thus, SLC25A1 may serve both as a biomarker of response and as a target to enhance the efficacy of immunotherapy.

DOI: https://doi.org/10.1101/2025.09.20.677512
Mol Ther. 2025 Sep 23. pii: S1525-0016(25)00766-X. [Epub ahead of print]

Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.

Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.

DOI: https://doi.org/10.1016/j.ymthe.2025.09.037
Nat Aging. 2025 Sep 24.

Herbal terpenoids activate autophagy and mitophagy through modulation of bioenergetics and protect from metabolic stress, sarcopenia and epigenetic aging.

Gabriele Civiletto, Dario Brunetti, Giulia Lizzo, Kamila Muller, Guillaume E Jacot, Ioanna Daskalaki, Federico Sizzano, Minji Huh, Ivano Di Meo, Maria Nicol Colombo, José L Sanchez-Garcia, Bertrand J Bétrisey, Alix Zollinger, Patricia Lino, Christopher Neal, Anne-Laure Egesipe, Joy Richard, Myriam Chimen, Aurélie Hermant, Benjamin Brinon, Lorane Texari, Sylviane Metairon, Mohammed Adnan Qureshi, Dhaval S Patel, Siva A Vanapalli, Marco Malavolta, Arwen W Gao, Amelia Lalou, Mauro Provinciali, Fiorenza Orlando, Valeria Tiranti, Robert T Brooke, Steve Horvath, Johan Auwerx, Jerome N Feige, Philipp Gut.

Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.

DOI: https://doi.org/10.1038/s43587-025-00957-4
J Agric Food Chem. 2025 Sep 25.

Aflatoxin B1 Induces Pyroptosis and Apoptosis in Renal Cells by Mediating Mitophagy Dysfunction and Mitochondrial Pore Formation.

Xinyu Yao, Min Gao, Jing Lu, Xuming Deng, Shuang Guan.

  Aflatoxin B1 (AFB1), a potent mycotoxin, induces nephrotoxicity through previously unrecognized crosstalk between pyroptosis and apoptosis. Using in vivo and in vitro renal injury models, we demonstrate that AFB1 impairs mitophagy, leading to an excessive level of reactive oxygen species (ROS) accumulation. This ROS surge triggers lysosomal membrane permeabilization (LMP) and cathepsin B (CTSB)-dependent activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, initiating caspase-1-mediated pyroptosis via gasdermin D N-terminal (GSDMD-N) pore formation. Importantly, AFB1 also induces cardiolipin translocation to the mitochondrial outer membrane, where pyroptosis-derived GSDMD-N is recruited to form mitochondrial pores. This results in cytochrome c (Cyt-c) release and activation of a caspase-dependent noncanonical apoptotic cascade distinct from the classical apoptotic pathway. These findings establish GSDMD-N-mediated mitochondrial damage as a molecular bridge linking pyroptosis to apoptosis in AFB1 nephrotoxicity and highlight GSDMD-N inhibition as a promising therapeutic strategy. Given AFB1's persistence and bioaccumulation in the food chain, these mechanistic insights provide a molecular basis for developing targeted interventions to mitigate its health risks in agricultural production and food safety.

Keywords:  aflatoxin B1; apoptosis; mitophagy; nephrotoxicity; pyroptosis

DOI:  https://doi.org/10.1021/acs.jafc.5c07992
Biomolecules. 2025 Aug 26. pii: 1230. [Epub ahead of print]15(9):

A De Novo DNM1L Mutation in Twins with Variable Symptoms, Including Paraparesis and Optic Neuropathy.

Alessia Nasca, Alessia Catania, Andrea Legati, Rossella Izzo, Carola D'onofrio, Teresa Ciavattini, Eleonora Lamantea, Costanza Lamperti, Daniele Ghezzi.

  Mitochondrial network dynamics, encompassing processes like fission, fusion, and mitophagy, are crucial for mitochondrial function and overall cellular health. Dysregulation of these processes has been linked to various human diseases. Particularly, pathogenic variants in the gene DNM1L can lead to a broad range of clinical phenotypes, ranging from isolated optic atrophy to severe neurological conditions. DNM1L encodes DRP1 (dynamin-1-like protein), which is a key player in mitochondrial and peroxisomal fission. This study describes two twin sisters with a de novo heterozygous variant in DNM1L, due to possible paternal germline mosaicism identified through clinical exome sequencing. The two twins showed a variable clinical presentation, including paraparesis and optic neuropathy. Functional studies of patient-derived fibroblasts revealed altered mitochondrial and peroxisomal morphology, along with dysregulated DNM1L transcript levels, indicating the deleterious effect of the variant. These findings allowed us to reclassify the identified variant from a variant of uncertain significance to a likely pathogenic variant. Our report provides insight into the phenotypic spectrum of DNM1L-related disorders and highlights the need to combine genetic and functional analyses to accurately diagnose rare mitochondrial diseases.

Keywords:  DNM1L; mitochondrial and peroxisomes fission; mitochondrial disorders; mitochondrial dynamics; variant reclassification

DOI:  https://doi.org/10.3390/biom15091230
bioRxiv. 2025 Sep 16. pii: 2025.09.11.675705. [Epub ahead of print]

TRPML1 signaling at lysosomes-mitochondria nexus drives triple-negative breast cancer mitophagy, metabolic reprogramming and chemoresistance.

Alia K Syeda, Shekoufeh Almasi, J Cory Benson, Barry E Kennedy, Ryan M Yoast, Scott M Emrich, Logan Slade, Shanmugasundaram Pakkiriswami, Vishnu V Vijayan, Shashi Gujar, Thomas Pulinilkunnil, Mohamed Trebak, Yassine El Hiani.

Inter-organelle signaling mechanisms, particularly those at the lysosomes-mitochondria interface, are critical for cancer cell metabolism, mitophagy and survival. However, the incomplete understanding of these mechanisms has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we demonstrate the lysosomal Ca²⁺-release channel TRPML1 as a master regulator of mitochondrial bioenergetics in TNBC cells. TRPML1 knockdown (ML1-KD) in TNBC cells selectively compromises mitochondrial respiration, reprograms cell metabolism, and induces mitochondrial fragmentation without impacting non-cancerous cells. Mitochondria of ML1-KD TNBC cells sequester around the endoplasmic reticulum (ER), increasing mitochondria-ER contact sites at the expense of mitochondria-lysosomes contacts. Mechanistically, ML1-KD reduces lysosomal acidification, thus hindering autophagic flux and completion of autophagy. ML1-KD inhibits TFEB-mediated mitophagy and oxidative defense mechanisms while causing mitochondrial Ca 2+ overload, further impairing mitochondrial function. These alterations render ML1-KD TNBC cells highly sensitive to doxorubicin and paclitaxel at low doses that are typically ineffective on their own. Together, our findings establish TRPML1 as a critical inter-organelle regulator and highlight its potential as a therapeutic target to exploit the metabolic vulnerabilities of TNBC cells.

DOI: https://doi.org/10.1101/2025.09.11.675705
Nature. 2025 Sep 26.

Mitochondria expel tainted DNA - spurring age-related inflammation.

Gemma Conroy.



Keywords:  Ageing; Cell biology; Genetics; Metabolism

DOI:  https://doi.org/10.1038/d41586-025-03064-x
Annu Rev Pharmacol Toxicol. 2025 Sep 22.

Cross-Organ Mitochondrial Communication in Stress and Disease.

Koning Shen, Jenni Durieux, Andrew Dillin.

Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1146/annurev-pharmtox-062124-024150
Biosci Rep. 2025 Sep 25. 45(9): 531-546

Human polynucleotide phosphorylase in mitochondrial RNA metabolism.

Navid Bakshi, Madhuri Kanavalli, Karolina Z Nowak, Katarzyna J Bandyra.

  Ever since its discovery more than 70 years ago, the enzyme polynucleotide phosphorylase (PNPase) has been the subject of intensive research that has highlighted its key functional roles. The enzyme was first described in 1955 for its ability to synthesise RNA from nucleoside diphosphates. This discovery led to a Nobel Prize in Physiology or Medicine in 1959 for using PNPase to synthesise artificial RNA. However, it soon became evident that the primary function of this enzyme, conserved across diverse species, is 3'-5' RNA phosphorolysis rather than polymerisation. Remarkably, over 60 years later, it was discovered that PNPase has an even broader range of functions as it was shown to act as a conditional RNA chaperone in bacteria. In humans, PNPase (hPNPase) is located in mitochondria, where it plays a role in mitochondrial RNA (mtRNA) metabolism, thereby regulating mitochondrial function and the overall cell fitness. In this review, we present the current scope of knowledge of hPNPase, including its structure, subcellular localisation, metabolic activity, roles in mtRNA transport, processing and degradation, and its involvement in apoptosis.

Keywords:  PNPT1; human PNPase; mitochondrial RNA metabolism

DOI:  https://doi.org/10.1042/BSR20240504
bioRxiv. 2025 Sep 18. pii: 2025.09.18.677147. [Epub ahead of print]

Targeting DNA Polymerase Epsilon Leads to Tumor Clearance and Activation of an NF-κB-mediated inflammatory response in Triple Negative Breast Cancer.

Elizabeth F Sher, Kenji M Fujihara, Anthony Tao, Diana Erenburg, Vladislav O Sviderskiy, Hannan Mir, Triantafyllia R Karakousi, Cynthia Loomis, Jiehui Deng, Kwok-Kin Wong, Richard Possemato.

Breast cancer remains the second leading cause of cancer-related mortality among women, with triple-negative breast cancer (TNBC) exhibiting a particularly poor five-year prognosis 1 . Here, we demonstrate that among genetic and pharmacological perturbations targeting DNA replication, suppression of DNA polymerase epsilon (POLE) in TNBC, induces a potent, TNBC-specific gene expression signature enriched in inflammatory cytokines that are transcriptional targets of NF-κB. TNBC cells exhibit markedly higher levels of DNA damage and canonical NF-κB activation compared to luminal breast cancer cells. Notably, NF-κB activation in this context depends on the canonical component RELA, but not the non-canonical component RELB. Mechanistically, ATM, STING, and RIG-I each contribute to NF-κB activation following POLE suppression. In vivo, POLE suppression in a murine TNBC model leads to cancer cell-intrinsic elimination of tumor burden and increased immune cell infiltration. Together, these findings support a model in which replication stress from POLE inhibition triggers robust NF-κB-mediated inflammation and immune microenvironment remodeling in TNBC and can independently trigger tumor eradication. These results suggest a potential therapeutic avenue for targeting POLE in TNBC.

DOI: https://doi.org/10.1101/2025.09.18.677147
Nat Microbiol. 2025 Sep 22.

Oxaloacetate sensing promotes innate immune antiviral defence against influenza virus infection.

Shouheng Jin, Xing He, Zheyu Wang, Tao Zhou, Jun Wang, Guihong Pan, Yin Zhang, Ling Ma, Shuai Yang, Liqiu Wang, Yaoxing Wu, Yilin Zou, Nan Qi, Jun Cui.

Metabolic pathways determine cellular fate and function; however, the exact roles of metabolites in host defence against influenza virus remain undefined. Here we employed pharmacological inhibition and metabolomics analysis to show that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses to influenza virus. Cytosolic malate dehydrogenase 1 senses intracellular OAA to undergo dimerization and functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and supports optimal expression of TBK1, an indispensable activator of type I interferon responses. OAA supplementation provides a broad-spectrum antiviral ability, and OAA deficiency caused by Acly genetic ablation decreases antiviral immunity and renders mice more susceptible to lethal H1N1 virus infection. Our results uncover a signalling pathway through cellular OAA sensing that links metabolism and innate immunity to coordinate defence against viral challenge.

DOI: https://doi.org/10.1038/s41564-025-02107-3
Apoptosis. 2025 Sep 26.

VDAC1-interacting proteins: binding site mapping and their derived peptides induce apoptosis and multifaceted cellular effects.

Manikandan Santhanam, Venkatadri Babu, Anna Shteinfer-Kuzmine, Ran Zalk, Varda Shoshan-Barmaz.

  The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein plays a central role in regulating mitochondrial metabolism, energy production, and apoptosis. VDAC1 interacts with over 100 proteins across the cytosol, endoplasmic reticulum, plasma membrane, and mitochondrial membranes. These interactions coordinate metabolism, cell death, and signal transduction, integrating mitochondrial and cellular functions. To identify VDAC1 binding sites, we designed a peptide array of 768 peptides from 19 selected VDAC1-interacting proteins. We focused on three partners: GAPDH, gelsolin, and actin. Their VDAC1-binding sequences as peptides interacted with purified VDAC1 and, as cell-penetrating peptides, induced cell death, and elevated intracellular Ca2⁺ and ROS levels. Despite sequence diversity, the peptides converged on enhancing transcription factors p53 and c-Jun, upregulating VDAC1, promoting its oligomerization, and triggering apoptosis. Other effects related to their originated protein's function include no significant effect of the GAPDH-derived peptide on its catalytic activity, indicating its effects are independent of glycolysis. The gelsolin-derived peptide altered actin organization, increasing filopodia and focal adhesion, and actin-derived peptides reduced actin, gelsolin, and tubulin expression. This study is the first to identify VDAC1 binding sites on 19 interacting partners and to demonstrate their use as cell-penetrating peptides to modulate the VDAC1 network. These findings highlight VDAC1's multifaceted regulatory role and offer a novel approach for targeting VDAC1-protein interactions for therapeutic purposes.

Keywords:  Apoptosis; Mitochondria; Peptide array; Protein–protein interaction; VDAC1

DOI:  https://doi.org/10.1007/s10495-025-02185-y