bims-nenemi 2025-05-25 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–05–25
twenty papers selected by
Marco Tigano, Thomas Jefferson University

SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization.
Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.
Silencing mitochondrial gene expression in living cells.
Partial mitochondrial involvement in the antiproliferative and immunostimulatory effects of PT-112.
Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.
MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.
De novo serine biosynthesis is protective in mitochondrial disease.
PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation.
Crosstalk between myocardial autophagy and sterile inflammation in the development of heart failure.
ω-6 PUFA-enriched membrane phospholipid composition of cardiomyocytes increases the susceptibility to iron-induced ferroptosis and inflammation.
Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.
Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.
Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.
Radiation-induced senescent melanoma cells secrete soluble factors that trigger bystander senescence.
Metabolic traits shape responses to LSD1-directed therapy in glioblastoma tumor-initiating cells.
A lncRNA-mediated metabolic rewiring of cell senescence.
In vitro modelling of the neuropathophysiological features of mitochondrial epilepsy.
Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells.
NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma.
VDAC2 enforces a mitochondrial checkpoint to cancer immunity.

Int J Biol Sci. 2025 ;21(7): 2935-2953

SLC25A33-mediated mitochondrial DNA synthesis plays a critical role in the inflammatory response of M1 macrophages by contributing to mitochondrial ROS and VDAC oligomerization.

Daehoon Kim, Jonghwa Jin, Yu-Rim Lee, Dong-Ho Kim, Soo-Young Park, Jun-Kyu Byun, Yeon-Kyung Choi, Keun-Gyu Park.

M1 macrophage polarization is modulated by the release of mitochondrial DNA (mtDNA) and induces the inflammatory immune response, which is further increased by the generation of mitochondrial reactive oxygen species (mtROS). The pyrimidine nucleotide carrier SLC25A33 is located in the mitochondrial inner membrane and is linked to mtDNA synthesis, but its role in the M1 macrophage inflammatory immune response remains unclear. Here, we elucidate the regulatory mechanisms responsible for upregulation of SLC25A33 expression during M1 macrophage polarization, SLC25A33-mediated mtROS production, and the inflammatory response. SLC25A33 expression was significantly elevated in CD14+ monocytes derived from patients with sepsis and LPS/interferon-gamma (IFN-γ)-stimulated peritoneal macrophages (PMs). SLC25A33 was upregulated by ATF4 through the MyD88-PI3K-mTORC1 pathway in LPS/IFN-γ-stimulated PMs. Furthermore, SLC25A33 increased mtDNA synthesis and the release of mtDNA into the cytosol, which was facilitated by mtROS-mediated voltage-dependent anion channel (VDAC) oligomer formation, thereby contributing to activation of the cGAS-STING inflammatory pathway. Conversely, SLC25A33 knockdown and pyridoxal 5'-phosphate treatment, which inhibits SLC25A33 activity, decreased mtDNA release and reduced M1 macrophage polarization and associated inflammatory responses. These findings were consistent across in vitro and in vivo sepsis models, as well as in septic patients with liver abscesses. Our findings underscore the significant role of SLC25A33 in inflammation, suggesting that targeting of SLC25A33 could be a promising therapeutic strategy for the management of M1 macrophage-mediated inflammatory diseases, including sepsis.

DOI: https://doi.org/10.7150/ijbs.96563
Nat Commun. 2025 May 23. 16(1): 4782

Modelling POLG mutations in mice unravels a critical role of POLγΒ in regulating phenotypic severity.

Samantha Corrà, Alessandro Zuppardo, Sebastian Valenzuela, Louise Jenninger, Raffaele Cerutti, Sirelin Sillamaa, Emily Hoberg, Katarina A S Johansson, Urska Rovsnik, Sara Volta, Pedro Silva-Pinheiro, Hannah Davis, Aleksandra Trifunovic, Michal Minczuk, Claes M Gustafsson, Anu Suomalainen, Massimo Zeviani, Bertil Macao, Xuefeng Zhu, Maria Falkenberg, Carlo Viscomi.

DNA polymerase γ (POLγ), responsible for mitochondrial DNA replication, consists of a catalytic POLγA subunit and two accessory POLγB subunits. Mutations in POLG, which encodes POLγA, lead to various mitochondrial diseases. We investigated the most common POLG mutations (A467T, W748S, G848S, Y955C) by characterizing human and mouse POLγ variants. Our data reveal that these mutations significantly impair POLγ activities, with mouse variants exhibiting milder defects. Cryogenic electron microscopy highlighted structural differences between human and mouse POLγ, particularly in the POLγB subunit, which may explain the higher activity of mouse POLγ and the reduced severity of mutations in mice. We further generated a panel of mouse models mirroring common human POLG mutations, providing crucial insights into the pathogenesis of POLG-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POLγB in modulating the severity of POLG mutations.

DOI: https://doi.org/10.1038/s41467-025-60059-y
Science. 2025 May 22. eadr3498

Silencing mitochondrial gene expression in living cells.

Luis Daniel Cruz-Zaragoza, Drishan Dahal, Mats Koschel, Angela Boshnakovska, Aiturgan Zheenbekova, Mehmet Yilmaz, Marcel Morgenstern, Jan-Niklas Dohrke, Julian Bender, Anusha Valpadashi, Kristine A Henningfeld, Silke Oeljeklaus, Laura Sophie Kremer, Mirjam Breuer, Oliver Urbach, Sven Dennerlein, Michael Lidschreiber, Stefan Jakobs, Bettina Warscheid, Peter Rehling.

Mitochondria fulfill central functions in metabolism and energy supply. They express their own genome, which encodes key subunits of the oxidative phosphorylation system. However, central mechanisms underlying mitochondrial gene expression remain enigmatic. A lack of suitable technologies to target mitochondrial protein synthesis in cells has limited experimental access. Here, we silenced the translation of specific mitochondrial mRNAs in living human cells by delivering synthetic peptide-morpholino chimeras. This approach allowed us to perform a comprehensive temporal monitoring of cellular responses. Our study provides insights into mitochondrial translation, its integration into cellular physiology, and provides a strategy to address mitochondrial gene expression in living cells. The approach can potentially be used to analyze mechanisms and pathophysiology of mitochondrial gene expression in a range of cellular model systems.

DOI: https://doi.org/10.1126/science.adr3498
Oncoimmunology. 2025 Dec;14(1): 2507245

Partial mitochondrial involvement in the antiproliferative and immunostimulatory effects of PT-112.

Ruth Soler-Agesta, Manuel Beltrán-Visiedo, Ai Sato, Takahiro Yamazaki, Emma Guilbaud, Christina Y Yim, Maria T Congenie, Tyler D Ames, Alberto Anel, Lorenzo Galluzzi.

  PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma. Moreover, PT-112 monotherapy has led to durable clinical responses, some of which persisting after treatment discontinuation. Mitochondrial outer membrane permeabilization (MOMP) regulates the cytotoxicity and immunogenicity of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells to test whether genetic alterations affecting MOMP influence PT-112 activity. As previously demonstrated, PT-112 elicited robust antiproliferative and cytotoxic effects against TS/A cells, which were preceded by the ICD-associated exposure of calreticulin (CALR) on the cell surface, and accompanied by the release of HMGB1 in the culture supernatant. TS/A cells responding to PT-112 also exhibited eIF2α phosphorylation and cytosolic mtDNA accumulation, secreted type I IFN, and exposed MHC Class I molecules as well as the co-inhibitory ligand PD-L1 on their surface. Acute cytotoxicity and HMGB1 release caused by PT-112 in TS/A cells were influenced by MOMP competence. Conversely, PT-112 retained antiproliferative effects and its capacity to drive type I IFN secretion as well as CALR, MHC Class I and PD-L1 exposure on the cell surface irrespective of MOMP defects. These data indicate a partial involvement of MOMP in the mechanisms of action of PT-112, suggesting that PT-112 is active across various tumor types, including malignancies with MOMP defects.

Keywords:  CD8+ cytotoxic T lymphocytes; CGAS; PD-1; damage-associated molecular patterns; immune checkpoint inhibitors; mtDNA

DOI:  https://doi.org/10.1080/2162402X.2025.2507245
Nat Commun. 2025 May 20. 16(1): 4640

Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.

Jordyn J VanPortfliet, Yuanjiu Lei, Muthumeena Ramanathan, Camila Guerra Martinez, Jessica Wong, Tim J Stodola, Brian R Hoffmann, Kathryn Pflug, Raquel Sitcheran, Stephen C Kneeland, Stephen A Murray, Peter J McGuire, Carolyn L Cannon, A Phillip West.

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBP) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive cytokine secretion and activation of pyroptotic cell death pathways contribute to lung inflammation and morbidity after infection with PA. Our work provides a mechanistic framework for understanding innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

DOI: https://doi.org/10.1038/s41467-025-59907-8
Autophagy Rep. 2023 ;2(1): 2267882

MTFP1 is a mitophagy receptor that operates in PINK1/PRKN-dependent mitophagy and promotes oral cancer cell survival.

Debasna P Panigrahi, Sujit K Bhutia.

  MTFP1 (mitochondrial fission process 1), an inner mitochondrial membrane protein, plays a crucial role in mitochondrial fission to maintain mitochondrial morphology. Our study found that MTFP1 contains a LIR (LC3-interacting region) to interact with MAP1LC3B (microtubule-associated protein 1 light chain 3 beta) and serves as a mitophagy receptor to eliminate damaged mitochondria. Interestingly, mutation of MTFP1 LIR motif (MTFP1mLIR) inhibits this interaction, decreasing mitophagy in oral cancer cells. Moreover, knockdown of PRKN (parkin RBR E3 ubiquitin protein ligase) or PINK1 (PTEN-induced kinase 1) abolished mitophagy in MTFP1-overexpressing oral cancer cells. In this setting, we observed that MTFP1mLIR-expressing cells display a decrease in TOMM20 (translocase of outer mitochondrial membrane 20) levels without affecting those of COX4 (cytochrome c oxidase subunit 4). In contrast, loss of PRKN or PINK1 caused inhibition of both TOMM20 and COX4 degradation in MTFP1mLIR-expressing cells exposed to cellular stress, suggesting that PRKN may activate the rupture of outer mitochondrial membrane in MTFP1-overexpressing cells for effective mitophagy. We also observed that MTFP1 is beneficial to oral cancer cell survival exposed to anticancer drugs, such as cisplatin, through mitophagy, since inhibition of MTFP1-dependent mitophagy induced cell death. Thus, targeting MTFP1-associated mitophagy could represent a strategy for oral cancer therapy. Abbreviations: BBC3/PUMA, BCL2 binding component 3; BCL2L13, BCL2 like 13; BINIP3L, BCL2 interacting protein 3 like; BNIP3, BCL2 interacting protein 3; CCCP, Carbonyl cyanide m-chlorophenylhydrazone; COX4, cytochrome c oxidase subunit 4; DNM1L, dynamin 1 like;FKBP8, FKBP prolyl isomerase 8; FIS1, fission, mitochondrial 1; FUNDC1, FUN14 domain containing 1; LIR, LC3 interacting region; MTFP1, mitochondrial fission process 1; PHB2, prohibitin 2; PI3K, Phosphatidylinositol 3-kinase; PRKN, Parkin RBR E3 ubiquitin protein ligase; PINK1, PTEN induced kinase 1; TOMM20, translocase of outer mitochondrial membrane 20.

Keywords:  Apoptosis; MTFP1; Mitochondrial fission; Mitophagy; PRKN

DOI:  https://doi.org/10.1080/27694127.2023.2267882
Cell Rep. 2025 May 15. pii: S2211-1247(25)00481-4. [Epub ahead of print]44(5): 115710

De novo serine biosynthesis is protective in mitochondrial disease.

Christopher B Jackson, Anastasiia Marmyleva, Geoffray Monteuuis, Ryan Awadhpersad, Takayuki Mito, Nicola Zamboni, Takashi Tatsuta, Amy E Vincent, Liya Wang, Nahid A Khan, Thomas Langer, Christopher J Carroll, Anu Suomalainen.

  The importance of serine as a metabolic regulator is well known for tumors and is also gaining attention in degenerative diseases. Recent data indicate that de novo serine biosynthesis is an integral component of the metabolic response to mitochondrial disease, but the roles of the response have remained unknown. Here, we report that glucose-driven de novo serine biosynthesis maintains metabolic homeostasis in energetic stress. Pharmacological inhibition of the rate-limiting enzyme, phosphoglycerate dehydrogenase (PHGDH), aggravated mitochondrial muscle disease, suppressed oxidative phosphorylation and mitochondrial translation, altered whole-cell lipid profiles, and enhanced the mitochondrial integrated stress response (ISRmt) in vivo in skeletal muscle and in cultured cells. Our evidence indicates that de novo serine biosynthesis is essential to maintain mitochondrial respiration, redox balance, and cellular lipid homeostasis in skeletal muscle with mitochondrial dysfunction. Our evidence implies that interventions activating de novo serine synthesis may protect against mitochondrial failure in skeletal muscle.

Keywords:  CP: Metabolism; de novo serine synthesis; mitochondrial disease; mitochondrial integrated stress response; mitochondrial translation; tissue specificity; treatment

DOI:  https://doi.org/10.1016/j.celrep.2025.115710
Cell Rep. 2025 May 21. pii: S2211-1247(25)00506-6. [Epub ahead of print]44(6): 115735

PUS10-induced tRNA fragmentation impacts retrotransposon-driven inflammation.

Magdalena Madej, Phuong Cao Thi Ngoc, Sowndarya Muthukumar, Anna Konturek-Cieśla, Silvia Tucciarone, Alexandre Germanos, Christian Ashworth, Knut Kotarsky, Sudip Ghosh, Zhimeng Fan, Helena Fritz, Izei Pascual-Gonzalez, Alain Huerta, Nicola Guzzi, Anita Colazzo, Giulia Beneventi, Hang-Mao Lee, Maciej Cieśla, Christopher Douse, Hiroki Kato, Vinay Swaminathan, William W Agace, Ainara Castellanos-Rubio, Paolo Salomoni, David Bryder, Cristian Bellodi.

  Pseudouridine synthases (PUSs) catalyze the isomerization of uridine (U)-to-pseudouridine (Ψ) and have emerging roles in development and disease. How PUSs adapt gene expression under stress remains mostly unexplored. We identify an unconventional role for the Ψ "writer" PUS10 impacting intracellular innate immunity. Using Pus10 knockout mice, we uncover cell-intrinsic upregulation of interferon (IFN) signaling, conferring resistance to inflammation in vivo. Pus10 loss alters tRNA-derived small RNAs (tdRs) abundance, perturbing translation and endogenous retroelements expression. These alterations promote proinflammatory RNA-DNA hybrids accumulation, potentially activating cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING). Supplementation with selected tdR pools partly rescues these effects through interactions with RNA processing factors that modulate immune responses, revealing a regulatory circuit that counteracts cell-intrinsic inflammation. By extension, we define a PUS10-specific molecular fingerprint linking its dysregulation to human autoimmune disorders, including inflammatory bowel diseases. Collectively, these findings establish PUS10 as a viral mimicry modulator, with broad implications for innate immune homeostasis and autoimmunity.

Keywords:  CP: Molecular biology; PUS10; RNA-DNA hybrids; cGAS-STING; hematopoietic stem cell; inflammation; inflammatory bowel disease; interferon; pseudouridine; tRNA-derived small RNAs; transposable elements; viral mimicry

DOI:  https://doi.org/10.1016/j.celrep.2025.115735
Autophagy Rep. 2024 ;3(1): 2320605

Crosstalk between myocardial autophagy and sterile inflammation in the development of heart failure.

Jialing Tang, Eddie Tam, Erfei Song, Aimin Xu, Gary Sweeney.

  Heart failure, a leading driver of global mortality, remains a topic of intense contemporary research interest due to the prevailing unmet need in cardiometabolic therapeutics. Numerous mechanisms with the potential to influence the onset and development of heart failure remain incompletely understood. Firstly, myocardial autophagy, which involves lysosomal degradation of damaged cellular components, confers context-dependent beneficial and detrimental effects. Secondly, sterile inflammation may arise following cardiac stress and exacerbate the progression of heart failure. Inflammation changes in a temporal manner and its onset must be adequately resolved to limit progression of heart failure. Mitochondria are an important factor in contributing to sterile inflammation by releasing damage associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA). Accordingly, this is one reason why the selective autophagy of mitochondria to maintain optimal function is important in determining cardiac function. In this review, we examine the increasing evidence suggesting crosstalk between autophagy and sterile inflammation together with their role in the development of heart failure. In particular, this is exemplified in the preclinical models of ischaemia/reperfusion injury and pressure overload induced heart failure. We also highlight potential therapeutic approaches focusing on autophagy and addressing sterile inflammation, aiming to enhance outcomes in heart failure.

Keywords:  Autophagy; heart failure; ischaemia/reperfusion; pressure overload; sterile inflammation

DOI:  https://doi.org/10.1080/27694127.2024.2320605
Apoptosis. 2025 May 17.

ω-6 PUFA-enriched membrane phospholipid composition of cardiomyocytes increases the susceptibility to iron-induced ferroptosis and inflammation.

Sungji Cho, Eddie Tam, Khang Nguyen, Yubin Lei, Carine Fillebeen, Kostas Pantopoulos, Hye Kyoung Sung, Gary Sweeney.

  Ferroptosis is an attractive therapeutic target in cardiometabolic disease (CMD); however, its contribution to myocardial damage requires further elucidation. This study was designed to examine whether altered phospholipid composition in cardiomyocytes enhanced ferroptosis susceptibility, and the underlying mechanisms. Human iPSC-derived cardiomyocytes and H9c2 cells were used to study iron-induced lipid peroxidation, cell death, and inflammation after exposure to different types of fatty acids. Lipidomic analysis was performed using LC/MS to assess changes in phospholipid composition, with a focus on ω-6 PUFA-containing phospholipids. Cellular and mitochondrial lipid peroxidation, sterile inflammation, and cell death were evaluated. Additionally, the release of damage-associated molecular patterns (DAMPs) and macrophage responses, including STING and type I interferon (IFN-I) signaling, were investigated. LC/MS lipidomic analysis indicated that treating cells with arachidonic acid (AA) elevated ω-6 PUFA-containing phospholipids, particularly phosphatidylethanolamines (PE) and phosphatidylcholines (PC). This significantly increased susceptibility to iron-induced total cellular as well as mitochondrial lipid peroxidation. Subsequently, increased release of mitochondrial DNA to cytosol was detected, resulting in both sterile inflammation and subsequent cell death. Furthermore, iron-induced release of one or more damage associated molecular patterns (DAMP) from AA-treated cells that induced crosstalk with macrophages eliciting a STING and type I interferon (IFN-I) response. These results indicate that cardiomyocytes enriched with ω-6 PUFA-containing phospholipids are more susceptible to lipid peroxidation, underscoring ferroptosis as a critical factor in myocardial damage associated with CMD.

Keywords:  Ferroptosis; Lipid peroxidation; Mitochondrial DNA; PUFA-containing phospholipids; Sterile inflammation

DOI:  https://doi.org/10.1007/s10495-025-02121-0
Sci Adv. 2025 May 23. 11(21): eadv2930

Image-guided targeting of mitochondrial metabolism sensitizes pediatric malignant rhabdoid tumors to low-dose radiotherapy.

Wenxi Xia, Esther Need, Carmine Schiavone, Neetu Singh, Jiemin Huang, Matthew Goff, Joseph Cave, David L Gillespie, Randy L Jensen, Mark D Pagel, Prashant Dogra, Sixiang Shi, Shreya Goel.

Tumor hypoxia leads to radioresistance and markedly worse clinical outcomes for pediatric malignant rhabdoid tumors (MRTs). Our transcriptomics and bioenergetic profiling data reveal that mitochondrial oxidative phosphorylation is a metabolic vulnerability of MRT and can be exploited to overcome consumptive hypoxia by repurposing an FDA-approved antimalarial drug, atovaquone (AVO). We then establish the utility of oxygen-enhanced-multispectral optoacoustic tomography, a label-free, ionizing radiation-free imaging modality, to visualize and quantify spatiotemporal changes in tumor hypoxia in response to AVO. We show a potent but transient increase in tumor oxygenation upon AVO treatment that results in complete elimination of tumors in all tested mice when combined with 10-gray radiotherapy, a dose several times lower than the current clinic standard. Last, we use translational mathematical modeling for systematic evaluation of dosing regimens, administration timing, and therapeutic synergy in a virtual patient cohort. Together, our work establishes a framework for safe and pediatric patient-friendly image-guided metabolic radiosensitization of rhabdoid tumors.

DOI: https://doi.org/10.1126/sciadv.adv2930
Nat Microbiol. 2025 May 22.

Kaposi's sarcoma-associated herpesvirus induces mitochondrial fission to evade host immune responses and promote viral production.

Qing Zhu, Robert McElroy, Janvhi Suresh Machhar, Joel Cassel, Zihan Zheng, Behzad Mansoori, Hongrui Guo, Sen Guo, Christian Pangilinan, Jinghui Liang, Dongliang Shen, Lu Zhang, Qin Liu, Andrew V Kossenkov, Dario C Altieri, Paul M Lieberman, Shou-Jiang Gao, Pinghui Feng, Maureen E Murphy, Jikui Song, Joseph M Salvino, Qiming Liang, Jae U Jung, Chengyu Liang.

Mitochondrial dynamics are pivotal for host immune responses upon infection, yet how viruses manipulate these processes to impair host defence and enhance viral fitness remains unclear. Here we show that Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus also known as human herpesvirus 8, encodes Bcl-2 (vBcl-2), which reprogrammes mitochondrial architecture. It binds with NM23-H2, a host nucleoside diphosphate (NDP) kinase, to stimulate GTP loading of the dynamin-related protein (DRP1) GTPase, which triggers mitochondrial fission, inhibits mitochondrial antiviral signalling protein (MAVS) aggregation and impairs interferon responses in cell lines. An NM23-H2-binding-defective vBcl-2 mutant fails to evoke fission, leading to defective virion assembly due to activated MAVS-IFN signalling. Notably, we identify two key interferon-stimulated genes restricting vBcl-2-dependent virion morphogenesis. Using a high-throughput drug screening, we discover an inhibitor targeting vBcl-2-NM23-H2 interaction that blocks virion production in vitro. Our study identifies a mechanism in which KSHV manipulates mitochondrial dynamics to allow for virus assembly and shows that targeting the virus-mitochondria interface represents a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41564-025-02018-3
Nat Nanotechnol. 2025 May 21.

Nanoinducer-mediated mitochondria-selective degradation enhances T cell immunotherapy against multiple cancers.

Xueting Pan, Zhihang Wang, Mixiao Tan, Ziying Fu, Guangjun Nie, Hai Wang.

Cancer immunotherapy utilizing cytotoxic T lymphocytes has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondrial content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumour therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T cell therapy, CAR-T cell therapy and tumour-vaccine-based immunotherapy.

DOI: https://doi.org/10.1038/s41565-025-01909-0
Int J Radiat Biol. 2025 May 21. 1-10

Radiation-induced senescent melanoma cells secrete soluble factors that trigger bystander senescence.

Leonardo Salvarredi, Héctor Agüero, María Elisa Millan, María Fernanda Marra, Eduardo Callegari, Claudia Castro, Luis Lopez.

   PURPOSE: Senescence is a key cellular response to ionizing radiation. Senescent cells experience irreversible growth arrest while remaining metabolically active and secrete a distinct set of proteins, collectively referred to as the senescence-associated secretory phenotype (SASP). These secreted factors influence neighboring non-irradiated cells through a mechanism known as the bystander effect. This study aimed to investigate and characterize the bystander effect in a melanoma cell model.
MATERIAL AND METHODS: Murine melanoma B16F0 cells were exposed to X-irradiation (10 Gy), and senescence was induced 3 days later. Conditioned media from the senescent cells was collected and used to culture non-irradiated B16F0 cells. Proliferation, viability, clonogenic capacity, DNA damage foci formation, apoptosis, and senescence were assessed. The composition of the senescence-associated secretory phenotype was analyzed using mass spectrometry and bioinformatics tools.
RESULTS: Conditioned media from senescent cells induced by radiation reduced growth and promoted senescence in tumor cell cultures not exposed to ionizing radiation. Mass spectrometry analysis revealed greater protein diversity and abundance in conditioned media from senescent cells compared to that from non-irradiated cells. Additionally, conditioned media from senescent cells contained higher concentrations of proteins related to immune response, cellular aging, and responses to oxidative stress.
CONCLUSIONS: Cells undergoing radiation-induced senescence promote bystander senescence by secreting soluble factors involved in the induction and maintenance of senescence.

Keywords:  Ionizing radiation; bystander effect; melanoma; senescence

DOI:  https://doi.org/10.1080/09553002.2025.2505525
Sci Adv. 2025 May 23. 11(21): eadt2724

Metabolic traits shape responses to LSD1-directed therapy in glioblastoma tumor-initiating cells.

Giulia Marotta, Daniela Osti, Elena Zaccheroni, Brunella Costanza, Stefania Faletti, Adriana Marinaro, Cristina Richichi, Deborah Mesa, Simona Rodighiero, Chiara Soriani, Enrica Migliaccio, Federica Ruscitto, Chiara Priami, Sara Sigismund, Francesco Manetti, Dario Polli, Galina V Beznusenko, Mara-Camelia Rusu, Francesco Favero, Davide Corà, Domenico A Silvestris, Angela Gallo, Valentina Gambino, Fabio Alfieri, Sara Gandini, Matthias J Schmitt, Gaetano Gargiulo, Roberta Noberini, Tiziana Bonaldi, Giuliana Pelicci.

Lysine-specific histone demethylase 1A (LSD1) is an epigenetic regulator involved in various biological processes, including metabolic pathways. We demonstrated the therapeutic potential of its pharmacological inhibition in glioblastoma using DDP_38003 (LSD1i), which selectively targets tumor-initiating cells (TICs) by hampering their adaptability to stress. Through biological, metabolic, and omic approaches, we now show that LSD1i acts as an endoplasmic reticulum (ER) stressor, activating the integrated stress response and altering mitochondrial structure and function. These effects impair TICs' oxidative metabolism and generate reactive oxygen species, further amplifying cellular stress. LSD1i also impairs TICs' glycolytic activity, causing their metabolic decline. TICs with enhanced glycolysis benefit from LSD1-directed therapy. Conversely, metabolically silent TICs mantain ER and mitochondrial homeostasis, adapting to stress conditions, including LSD1i treatment. A dropout short hairpin RNA screening identifies postglycosylphosphatidylinositol attachment to proteins inositol deacylase 1 (PGAP1) as a mediator of resistance to LSD1i. Disruptions in ER and mitochondrial balance holds promise for improving LSD1-targeted therapy efficacy and overcoming treatment resistance.

DOI: https://doi.org/10.1126/sciadv.adt2724
Cell Rep. 2025 May 21. pii: S2211-1247(25)00518-2. [Epub ahead of print]44(6): 115747

A lncRNA-mediated metabolic rewiring of cell senescence.

Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte.

  Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.

Keywords:  CP: Metabolism; CP: Molecular biology; RNA-binding proteins; lncRNA; metabolism; senescence; therapy resistance

DOI:  https://doi.org/10.1016/j.celrep.2025.115747
Seizure. 2025 May 10. pii: S1059-1311(25)00121-9. [Epub ahead of print]

In vitro modelling of the neuropathophysiological features of mitochondrial epilepsy.

Laura A Smith, Ella B Keane, Kate Connor, Felix Chan, Mark O Cunningham.

  Epilepsy is a common and severe neurological manifestation of primary mitochondrial disease, affecting approximately 60 % of paediatric patients and 20 % of adult patients. Many of the mitochondrial epilepsies, particularly those presenting in childhood, are refractory to anti-epileptic treatment. Moreover, these conditions are typically characterised by severe neurodegeneration and closely associated with neurological decline and premature death. Indeed, there persists an urgent need to delineate the mechanisms underpinning mitochondrial epilepsy in order to develop effective treatments. In this review, we provide an overview of currently available in vitro models of the mitochondrial epilepsies. Such models offer opportunities to characterise early disease pathophysiology and interrogate novel mitochondrial-targeting and anti-epileptic treatments, with an overall aim to modulate seizure associated pathology and activity for the mitochondrial epilepsies. We discuss the use of acute cortical and subcortical brain slice preparations, obtained from both neurosurgical patients and rodents, for modelling the common neuropathophysiological features of mitochondrial epilepsy. We also review the use of induced pluripotent stem cell derived neural and glial culture models, and the development of three-dimensional cerebral organoids, generated from fibroblasts obtained from patients with primary mitochondrial disease. Human-derived, disease-relevant in vitro model systems which recapitulate the complexity and pathological features observed in patient brain tissues are crucial to help bridge the gap between animal models and patients living with mitochondrial epilepsy.

Keywords:  Alpers’ syndrome; MELAS; MERRF; Oxidative phosphorylation (OXPHOS); POLG; mtDNA

DOI:  https://doi.org/10.1016/j.seizure.2025.05.005
J Biochem Mol Toxicol. 2025 Jun;39(6): e70273

Olaparib Triggers Mitochondrial Fission Through the CDK5/Drp-1 Signaling Pathway in Ovarian Cancer Cells.

Xun Gao, Qinghua Yin, Zhilian Wang.

  Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Alterations in mitochondrial metabolism are considered defining characteristics and therapeutic targets of OC. Olaparib, an oral inhibitor of poly (ADP-ribose) polymerase, has been approved for the treatment of OC. However, the precise mechanisms by which it exerts its effects remain unclear. In this study, we uncover a novel pharmacological function of Olaparib by demonstrating that it induces mitochondrial dysfunction in human SKOV3 ovarian cancer cells. Our findings revealed that Olaparib exposure induced mitochondrial oxidative stress by elevating mitochondrial ROS levels and diminishing GPx activity. Additionally, treatment with Olaparib led to mitochondrial dysfunction, as evidenced by decreased complex I and complex IV activity and reduced ATP production. We observed that Olaparib induced mitochondrial fission by decreasing the average length of mitochondria. Olaparib did not affect the levels of Mfn1, Mfn2, or the total expression of Drp-1. Intriguingly, Olaparib increased the levels of phosphorylated Drp-1 at Ser616. Further investigation revealed that Olaparib facilitated the activation of the CDK5 signaling pathway and induced Caspase 3 activation. Notably, inhibition of CDK5 signaling using roscovitine mitigated the effects of Olaparib on mitochondrial fission and dysfunction, indicating a role for CDK5 in this process. In summary, our research identifies that CDK5/Drp-1-mediated mitochondrial fission may represent a novel mechanism through which Olaparib exerts its anticancer effects in OC.

Keywords:  CDK5; Drp‐1; mitochondrial fission; olaparib; ovarian cancer

DOI:  https://doi.org/10.1002/jbt.70273
Cell Death Differ. 2025 May 22.

NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma.

Guohang Xiong, Fang Yun, Lu Jiang, Zihan Yi, Xiaojia Yi, Lijuan Yang, Xuedan Zhang, Xiaoyu Li, Zhe Yang, Qiao Zhang, Buqing Sai, Yingmin Kuang, Yuechun Zhu.

NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer. NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.

DOI: https://doi.org/10.1038/s41418-025-01525-4
Nat Immunol. 2025 May 19.

VDAC2 enforces a mitochondrial checkpoint to cancer immunity.

Katia Cosentino, Joost Verduijn, Lorenzo Galluzzi.

DOI: https://doi.org/10.1038/s41590-025-02171-1