bims-nenemi 2025-05-04 papers

bims-nenemi

Biomed News

on Neuroinflammation, neurodegeneration and mitochondria

Issue of 2025–05–04
sixteen papers selected by
Marco Tigano, Thomas Jefferson University

PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis.
Prkra dimer senses double-stranded RNAs to dictate global translation efficiency.
Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.
Ionizing radiation induces mild and dose-independent damage to mitochondria in newt cells.
Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA release.
Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.
MYC controls STING levels to downregulate inflammatory signaling in breast cancer cells upon DNA damage.
A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI-eIF2α-ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies.
Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways.
TFEB Orchestrates Stress Recovery and Paves the Way for Senescence Induction in Human Dermal Fibroblasts.
T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders.
Yellow fever virus infection alters mitochondrial network dynamics and trigger IFN-I response via TLR2 pathway.
Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.
Advances in research on mitochondrial dysfunction in neurodegenerative diseases.
NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Free Radic Biol Med. 2025 Apr 24. pii: S0891-5849(25)00247-3. [Epub ahead of print]235 95-108

PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis.

Weibin He, Jieying Wang, Wenlong He, Ling Zeng, Ruowen Zhao, Kailun Qiu, Guang Tong, Zhongchan Sun, Pengcheng He.

  Doxorubicin (DOX), a potent chemotherapeutic agent, is widely used for treating malignancies but is limited by its cardiotoxic side effects. Mitochondrial dynamics, encompassing fission and fusion processes, play a pivotal role in maintaining cardiomyocyte function under stress, yet their disruption contributes to DOX-induced cardiotoxicity (DIC). While mitochondrial quality control (MQC) mechanisms are implicated in DIC, the specific molecular players remain unclear. Here, we demonstrate that the mitochondrial phosphatase PGAM5 exacerbates DIC by disturbing mitochondrial dynamics and promoting oxidative stress and apoptosis. We show that DOX induces PGAM5 cleavage via activation of mitochondrial proteases OMA1 and YME1L1. Overexpression of PGAM5 blocks DOX-induced mitochondrial elongation and instead promotes mitochondrial fragmentation by disrupting the balance between fission and fusion, mediated by inducing DRP1 dephosphorylation at Ser637 and exacerbating MFN2 downregulation. In addition, our findings indicate that PGAM5's phosphatase activity, rather than its cleavage, mediates the suppression of DOX-induced mitochondrial elongation. However, PGAM5 overexpression fails to enhance mitophagic clearance of dysfunctional mitochondria. Instead, PGAM5 amplifies DOX-induced oxidative stress and cardiomyocyte apoptosis, without promoting other regulated cell death (RCD) pathways like ferroptosis or pyroptosis. These findings reveal a novel mechanism by which PGAM5 disrupts mitochondrial dynamics and contributes to DIC, highlighting its potential as a therapeutic target for mitigating DOX-induced cardiomyopathy.

Keywords:  Apoptosis; Cardiotoxicity; Doxorubicin; Mitochondrial dynamics; PGAM5

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.037
Mol Cell. 2025 Apr 16. pii: S1097-2765(25)00308-9. [Epub ahead of print]

Prkra dimer senses double-stranded RNAs to dictate global translation efficiency.

Tong Lu, Pengcheng Ma, Hailing Fang, Aijun Chen, Jianlin Xu, Xi Kuang, Mingyu Wang, Ling Su, Sen Wang, Yizhuang Zhang, Jiasheng Wang, Boya Yang, De-Li Shi, Yong Zhou, Qianqian Gong, Xiangguo Liu, Bingyu Mao, Ming Shao.

  Double-stranded RNAs (dsRNAs), known as conserved pathogen-associated molecular patterns, activate the integrated stress response via interferon-induced protein kinase R (PKR), leading to global translation inhibition. However, the interferon system is inactive in pluripotent cells, leaving the mechanisms of dsRNA sensing and translational control unclear. In this study, we utilized early zebrafish embryos as a model of pluripotent cells and discovered a PKR-independent blockage of translation initiation by dsRNA stimulation. Prkra dimer was identified as the genuine dsRNA sensor. Upon dsRNA binding, the dimerized dsRNA-binding domain 3 of Prkra becomes activated to sequester the eIF2 complexes from the translation machinery, inhibiting global protein synthesis. This distinctive embryonic stress response restricts RNA virus replication in zebrafish embryos, is conserved in mouse embryonic stem cells, and compensates PKR function in differentiated cells. Therefore, the Prkra-mediated dsRNA sensing and translation control may serve as a common strategy for cells to adapt to environmental stresses.

Keywords:  PACT/RAX; Prkra; double-stranded RNA; dsRNA sensor; early embryos; embryonic stem cells; translation initiation

DOI:  https://doi.org/10.1016/j.molcel.2025.04.005
Nat Commun. 2025 Apr 29. 16(1): 4029

Mitochondrial membrane hyperpolarization modulates nuclear DNA methylation and gene expression through phospholipid remodeling.

Mateus Prates Mori, Oswaldo A Lozoya, Ashley M Brooks, Carl D Bortner, Cristina A Nadalutti, Birgitta Ryback, Brittany P Rickard, Marta Overchuk, Imran Rizvi, Tatiana Rogasevskaia, Kai Ting Huang, Prottoy Hasan, György Hajnóczky, Janine H Santos.

Maintenance of the mitochondrial inner membrane potential (ΔΨm) is critical for many aspects of mitochondrial function. While ΔΨm loss and its consequences are well studied, little is known about the effects of mitochondrial hyperpolarization. In this study, we used cells deleted of ATP5IF1 (IF1), a natural inhibitor of the hydrolytic activity of the ATP synthase, as a genetic model of increased resting ΔΨm. We found that the nuclear DNA hypermethylates when the ΔΨm is chronically high, regulating the transcription of mitochondrial, carbohydrate and lipid genes. These effects can be reversed by decreasing the ΔΨm and recapitulated in wild-type (WT) cells exposed to environmental chemicals that cause hyperpolarization. Surprisingly, phospholipid changes, but not redox or metabolic alterations, linked the ΔΨm to the epigenome. Sorted hyperpolarized WT and ovarian cancer cells naturally depleted of IF1 also showed phospholipid remodeling, indicating this as an adaptation to mitochondrial hyperpolarization. These data provide a new framework for how mitochondria can impact epigenetics and cellular biology to influence health outcomes, including through chemical exposures and in disease states.

DOI: https://doi.org/10.1038/s41467-025-59427-5
Exp Cell Res. 2025 Apr 23. pii: S0014-4827(25)00171-5. [Epub ahead of print]448(2): 114575

Ionizing radiation induces mild and dose-independent damage to mitochondria in newt cells.

Md Mahmudul Hasan, Tsuyoshi Kawabata, Chen Yan, Reiko Sekiya, Shinji Goto, Yoshishige Urata, Tao-Sheng Li.

  In addition to remarkable regenerative abilities, newts demonstrate a heightened tolerance to radiation compared to mammals. Mitochondria play profound role in cell survival when cells undergo environmental stresses. Thus, our study sought to elucidate the impact of ionizing radiation (IR) on the mitochondria of a newt model Pleurodeles waltl. Primary cells derived from limb tissue of P. waltl were exposed to 0, 5, 10, or 15 Gy X-ray and analyzed at 24h post-irradiation (PIR). Analysis using MitoTracker Red labeling revealed a maximal (p < 0.001) in mitochondrial fission in cells exposed to 5 Gy IR, while mitochondrial fission in cells exposed to 10 and 15 Gy IR was comparable (p < 0.01). Mitochondrial superoxide levels increased in a reverse dose-dependent manner; notably, cells treated with 5 Gy IR produced significantly (p < 0.05) higher mitochondrial superoxide. Mitochondrial membrane potential (ΔΨm) decreased significantly (p < 0.01) with similar extent across all IR-treated groups. Though ΔΨm declined, the ATP content was not changed due to IR. Result from the MTT assay indicated no impairment in mitochondrial activity. Cell counting data suggest negligible impact of IR on viability of cells; however, the phase contrast imaging revealed senescent like morphology of cells. Taken together, cells of P. waltl show mild changes in morphology and function of the mitochondria in response to IR, but seem highly tolerant.

Keywords:  Ionizing radiation; Mitochondrial fission; Mitochondrial membrane potential; Mitochondrial superoxide; Pleurodeles waltl

DOI:  https://doi.org/10.1016/j.yexcr.2025.114575
J Immunother Cancer. 2025 Apr 29. pii: e010889. [Epub ahead of print]13(4):

Selective BCL-2 inhibitor triggers STING-dependent antitumor immunity via inducing mtDNA release.

Wenxin Zhang, Xiaohui Pan, Longsheng Wang, Wen Li, Xiaoyang Dai, Mingming Zheng, Hongjie Guo, Xi Chen, Yanjun Xu, Honghai Wu, Qiaojun He, Bo Yang, Ling Ding.

   BACKGROUND: The stimulator of interferon genes (STING) signaling pathway has been demonstrated to propagate the cancer-immunity cycle and remodel the tumor microenvironment and has emerged as an appealing target for cancer immunotherapy. Interest in STING agonist development has increased, and the candidates hold significant promise; however, most are still in the early stages of human clinical trials. We found that ABT-199 activated the STING pathway to enhance the immunotherapeutic effect, and provided a ready-to-use small molecule drug for STING signaling activation.
METHODS: Phosphorylation of STING, TBK1, and IRF3, as well as activation of the interferon-I (IFN-I) signaling pathway, were detected following ABT-199 treatment in various colorectal cancer cells. C57BL/6J and BALB/c mice with subcutaneous tumors were employed to evaluate the in vivo therapeutic effects of the ABT-199 and anti-PD-L1 combination. Flow cytometry and ELISA were employed to analyze the level and activity of tumor-infiltrating T lymphocytes. Immunofluorescence and quantitative real-time PCR were conducted to assess the source and accumulation of double stranded DNA (dsDNA) in the cytoplasm. Chemical cross-linking assay, co-immunoprecipitation, and CRISPR/Cas9-mediated knockout were performed to investigate the molecular mechanism underlying ABT-199-induced voltage-dependent anion channel protein 1 (VDAC1) oligomerization and mitochondrial DNA (mtDNA) release.
RESULTS: ABT-199 significantly activated the STING signaling pathway in various colorectal cancer cells, which was evidenced by increased phosphorylation of TBK1 and IRF3, and upregulation of C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 10 (CXCL10), and interferon beta transcription. By promoting chemokine expression and cytotoxic T-cell infiltration, ABT-199 promoted antitumor immunity and synergized with anti-PD-L1 therapy to improve antitumor efficacy. ABT-199 induced mtDNA accumulation in the cytoplasm and triggered STING signaling via the canonical pathway. cGAS or STING-KO models significantly abolished both STING signaling activation and the antitumor efficacy of ABT-199. Mechanically, ABT-199 promoted VDAC1 oligomerization by disturbing the binding between BCL-2 and VDAC1, thereby facilitating mtDNA release into the cytoplasm. ABT-199-triggered STING signaling was attenuated when VADC1 was knocked out. Consistently, the antitumor effect of ABT-199 in vivo was abolished in the absence of VDAC1.
CONCLUSIONS: Our results identify a ready-to-use small molecule compound for STING activation, reveal the underlying molecular mechanism through which ABT-199 activates the STING signaling pathway, and provide a theoretical basis for the use of ABT-199 in cancer immunotherapy.

Keywords:  Colorectal Cancer; Cytokine; Immune Checkpoint Inhibitor; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-010889
Nat Metab. 2025 May 02.

Cytosolic NADK is conditionally essential for folate-dependent nucleotide synthesis.

Kyle M Flickinger, Carlos A Mellado Fritz, Kimberly S Huggler, Gina M Wade, Gavin R Chang, Kathryn C Fox, Judith A Simcox, Jason R Cantor.

Nicotinamide adenine dinucleotide kinase (NADK) catalyses the phosphorylation of NAD+ to produce NAD phosphate, the oxidized form of NADPH, a cofactor that serves a critical role in driving reductive metabolism. Cancer cells co-express two distinct NAD kinases that differ by localization (NADK, cytosol; NADK2, mitochondria). CRISPR screens performed across hundreds of cancer cell lines indicate that both are dispensable for growth in conventional culture media. By contrast, NADK deletion impaired cell growth in human plasma-like medium. Here we trace this conditional NADK dependence to the availability of folic acid. NADPH is the preferred cofactor of dihydrofolate reductase (DHFR), the enzyme that mediates metabolic activation of folic acid. We find that NADK is required for enabling cytosolic NADPH-driven DHFR activity sufficient to maintain folate-dependent nucleotide synthesis under low folic acid conditions. Our results reveal a basis for conditional NADK essentiality and suggest that folate availability determines whether DHFR activity can be sustained by alternative electron donors such as NADH.

DOI: https://doi.org/10.1038/s42255-025-01272-3
J Biol Chem. 2025 Apr 29. pii: S0021-9258(25)00409-0. [Epub ahead of print] 108560

MYC controls STING levels to downregulate inflammatory signaling in breast cancer cells upon DNA damage.

Renske Linstra, Chantal Stappenbelt, Femke J Bakker, Marieke Everts, Arkajyoti Bhattacharya, Shibo Yu, Stella D van Bergen, Bert van der Vegt, G Bea A Wisman, Rudolf S N Fehrmann, Marco de Bruyn, Marcel A T M van Vugt.

  Amplification of the MYC proto-oncogene is frequently observed in various cancer types, including triple negative breast cancer (TNBC). Emerging evidence suggests that suppression of local anti-tumor immune responses by MYC, at least in part, explains the tumor-promoting effects of MYC. Specifically, MYC upregulation was demonstrated to suppress the tumor-cell intrinsic activation of a type I IFN response and thereby hamper innate inflammatory signaling, which may contribute to the disappointing response to immunotherapy in patients with TNBC. In this study, we show that MYC interferes with protein expression and functionality of the STING pathway. MYC-mediated STING downregulation in BT-549 and MDA-MB-231 triple-negative breast cancer cell lines require the DNA binding ability of MYC, and is independent of binding of MYC to its co-repressor MIZ1. Both STAT1 and STAT3 promote the steady-state expression levels of STING, and STAT3 cooperates with MYC in regulating STING. Conversely, MYC-mediated downregulation of STING affects protein levels of STAT1 and downstream chemokine production. Furthermore, we show that MYC overexpression hampers immune cell activation triggered by DNA damage through etoposide or irradiation treatment, and specifically impedes the activation of natural killer cells. Collectively, these results show that MYC controls STING levels and thereby regulates tumor cell-intrinsic inflammatory signaling. These results contribute to our understanding of how MYC suppresses inflammatory signaling in TNBC, and may explain why a large fraction of patients with TNBC do not benefit from immunotherapy.

Keywords:  Myc (c-MYC); breast cancer; innate immunity; interferon; transcription regulation; tumor immunology

DOI:  https://doi.org/10.1016/j.jbc.2025.108560
Mol Cancer Ther. 2025 Apr 28.

A Novel Squaramide Derivative, HR-19011, Induces the Integrated Stress Response via the HRI-eIF2α-ATF4 Pathway, Effectively Inhibiting Hematologic Malignancies.

Min-Jung Kim, Jinsook Kwak, Hyung Seok Kim, Jihyung Han, Ji An Kang, Jeyun Jo, Jisu Kim, Da-Jung Kim, Ho Sup Lee, Hwayoung Yun, Jee-Yeong Jeong.

We investigated the therapeutic potential and mechanisms of HR-19011, a novel eIF2α phosphorylation inducer, with a focus on its effects on the integrated stress response (ISR) pathway and cell cycle regulation in K562 cells. Our findings revealed that HR-19011 exerts its anticancer effects primarily through the activation of heme-regulated inhibitor (HRI), leading to the phosphorylation of eukaryotic translation initiation factor 2 (eIF2)α, the induction of ISR signaling, and subsequent G1/S cell cycle arrest. RNA sequencing analysis further highlighted significant changes in gene expression associated with the ISR pathway, particularly those involving the key components, activating transcription factor 4 (ATF4) and CHOP, underscoring the specific targeting of HRI by HR-19011. Additionally, HR-19011 suppressed the mTORC1 pathway, a critical regulator of cell growth and metabolism, through the downregulation of components such as phosphorylated (p)-S6K and p-4EBP1, mediated by ATF4 and CHOP. In vivo studies demonstrated that HR-19011 effectively inhibited tumor growth in a K562 xenograft model, without significant toxicity, and its broad efficacy across various hematologic malignancies further suggests its potential as a versatile anticancer agent. Our findings position HR-19011 as a promising candidate for targeting the HRI-eIF2α axis in cancer treatment, warranting further investigation and optimization for clinical application.

DOI: https://doi.org/10.1158/1535-7163.MCT-24-0998
J Inflamm Res. 2025 ;18 5399-5413

Fumarate Hydratase Restrains mtDNA Attenuates LPS-Induced Acute Lung Injury Through cGAS-STING Pathways.

Zewen Jiang, Ruyuan He, Yujian Zhong, Bohao Liu, Ziqi He.

   Background: The metabolic reprogramming of alveolar macrophages, particularly mitochondrial energy metabolism centered on the tricarboxylic acid (TCA) cycle, plays a pivotal role in acute lung injury (ALI). Fumarate hydratase (FH), a key enzyme catalyzing fumarate-to-malate conversion in the TCA cycle, is implicated in macrophage inflammatory responses, but its specific role in ALI remains unclear.
Methods: We employed FHIN1 to assess its regulatory effects in LPS-induced ALI models. Wildtype C57BL/6 mice were randomly divided into control group, FHIN1 group, LPS group and LPS+FHIN1 group. FHIN1 and RU.521 was used to explored the interaction of FH and cGAS-STING in THP-1 cells.
Results: LPS stimulation suppressed FH expression and induced fumarate accumulation in macrophages. Pharmacological FH inhibition exacerbated LPS-triggered inflammatory cytokine release, oxidative stress and aggravated lung injury in mice. Mechanistically, FH inhibition promoted mtDNA leakage, activating the cGAS-STING pathway to amplify inflammation. Blocking cGAS with RU.521 significantly attenuated FHIN1-driven inflammatory responses and mitigated lung injury exacerbation.
Conclusion: FH critically modulates ALI progression by restraining cGAS-STING-dependent inflammation. Targeting the FH-mtDNA-cGAS axis may offer therapeutic potential for ALI management.

Keywords:  ALI; fumarate hydratase; mtDNA

DOI:  https://doi.org/10.2147/JIR.S518589
Aging Cell. 2025 May 01. e70083

TFEB Orchestrates Stress Recovery and Paves the Way for Senescence Induction in Human Dermal Fibroblasts.

Lena Guerrero-Navarro, Pablo Monfort-Lanzas, Vinzenz Krichbaumer, Mariana E G De Araújo, Jlenia Monfregola, Lukas A Huber, Andrea Ballabio, Pidder Jansen-Dürr, Maria Cavinato.

  Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells show an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS. Our results reveal distinct signaling responses between the initial stress phase and the ensuing senescent phenotype. During the stress phase, treatment with tBHP, which undermines the antioxidant response, leads to elevated reactive oxygen species (ROS) and lysosomal damage. ROS accumulation activates AMP-activated protein kinase (AMPK) and inhibits Akt, which correlates with the suppression of mammalian target of rapamycin (mTOR). Inactivation of mTOR during this phase aligns with the activation of transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis. TFEB knockdown under stress increased apoptosis, highlighting the protective role of TFEB in the stress response. As cells transition to senescence, TFEB activity, required for the autophagic damage repair, becomes less critical. The decrease in ROS levels leads to the normalization of AMPK and Akt signaling, accompanied by the reactivation of mTOR. This reactivation of mTOR, which is critical for establishing the senescent state, is observed alongside the inactivation of TFEB. Consequently, as damage decreases, TFEB activity decreases. Our results suggest a dynamic interplay between TFEB and mTOR, highlighting a critical role of TFEB in ensuring cellular survival during SIPS induction but becoming dispensable once senescence is established.

Keywords:  SIPS; TFEB; mTOR; senescence; tBHP

DOI:  https://doi.org/10.1111/acel.70083
Nat Commun. 2025 May 01. 16(1): 4080

T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.

Qiuya Shao, Anas Khawaja, Minh Duc Nguyen, Vivek Singh, Jingdian Zhang, Yong Liu, Joel Nordin, Monika Adori, C Axel Innis, Xaquin Castro Dopico, Joanna Rorbach.

Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.

DOI: https://doi.org/10.1038/s41467-025-59388-9
Nat Commun. 2025 Apr 29. 16(1): 4024

Autophagy disruption and mitochondrial stress precede photoreceptor necroptosis in multiple mouse models of inherited retinal disorders.

Fay Newton, Mihail Halachev, Linda Nguyen, Lisa McKie, Pleasantine Mill, Roly Megaw.

Inherited retinal diseases (IRDs) are a leading cause of blindness worldwide. One of the greatest barriers to developing treatments for IRDs is the heterogeneity of these disorders, with causative mutations identified in over 280 genes. It is therefore a priority to find therapies applicable to a broad range of genetic causes. To do so requires a greater understanding of the common or overlapping molecular pathways that lead to photoreceptor death in IRDs and the molecular processes through which they converge. Here, we characterise the contribution of different cell death mechanisms to photoreceptor degeneration and loss throughout disease progression in humanised mouse models of IRDs. Using single-cell transcriptomics, we identify common transcriptional signatures in degenerating photoreceptors. Further, we show that in genetically and functionally distinct IRD models, common early defects in autophagy and mitochondrial damage exist, triggering photoreceptor cell death by necroptosis in later disease stages. These results suggest that, regardless of the underlying genetic cause, these pathways likely contribute to cell death in IRDs. These insights provide potential therapeutic targets for novel, gene-agnostic treatments for IRDs applicable to the majority of patients.

DOI: https://doi.org/10.1038/s41467-025-59165-8
Int Immunopharmacol. 2025 Apr 28. pii: S1567-5769(25)00689-7. [Epub ahead of print]157 114699

Yellow fever virus infection alters mitochondrial network dynamics and trigger IFN-I response via TLR2 pathway.

Carla Tomatis, Nancy Charo, María F Ferrer, Silvia Aquila, Federico Fuentes, María L Scalise, Mara C A M Aguiar, Gabriel Valdivieso, Eugenio A Carrera Silva, Ricardo M Gómez.

  It has been emphasized that mitochondria play a fundamental role not only in cellular bioenergetics but also in the defense against infections. Here, we investigated mitochondrial network dynamics (MND) and IFN-Iβ signaling response in epithelial A549 cells after yellow fever virus (YFV) infection. We analyze the MND when only some cells are infected at 1 day post-infection (dpi) and after the spread of viral infection, at 3 dpi. Confocal microscopy and MiNA analysis showed that YFV infection leads to a decrease in the number of branches at 3 dpi and an increase in the length of branches at 1 and 3 dpi, suggesting that mitochondrial fission and fusion occur. Consistent with both processes, we found increased transcription of mitofusin 1 and Drp1 and increased colocalization of mitochondria with Drp1 at 3 dpi. In addition, mitochondrial membrane polarization decreased, mtROS production increased, p62 expression decreased, and LC3 expression increased, suggesting an increase in mitophagy flux. We found decreased expression of the IFN inducers RIG-I and MAVS sensors in YFV-infected A549 cells a t 3 dpi. Surprisingly, increased IFN-Iβ levels were observed at transcriptional and protein levels along with IRF7 induction at 1 and 3 dpi. Using the blocking antibody against TLR2, we showed that IFN-Iβ and IL-6 synthesis is maintained by TLR2 signaling. Mechanistically, infection led to activation of the NFκB pathway by degradation of IkBα, and increased phosphorylation of P65 and ERK MAPK signaling. Our results show that YFV infection induces altered MND in epithelial cells and triggers TLR2 signaling.

Keywords:  A549 cells; IFN-I; Mitochondrial network dynamics; Mitophagy; TLR2; Yellow fever virus

DOI:  https://doi.org/10.1016/j.intimp.2025.114699
Front Cell Neurosci. 2025 ;19 1549265

Mitochondrial stress disassembles nuclear architecture through proteolytic activation of PKCδ and Lamin B1 phosphorylation in neuronal cells: implications for pathogenesis of age-related neurodegenerative diseases.

Adhithiya Charli, Yuan-Teng Chang, Jie Luo, Bharathi Palanisamy, Emir Malovic, Zainab Riaz, Cameron Miller, Manikandan Samidurai, Gary Zenitsky, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G Kanthasamy.

  Mitochondrial dysfunction and oxidative stress are central to the pathogenesis of neurodegenerative diseases, including Parkinson's, Alzheimer's and Huntington's diseases. Neurons, particularly dopaminergic (DAergic) ones, are highly vulnerable to mitochondrial stress; however, the cellular and molecular mechanisms underlying this vulnerability remain poorly understood. Previously, we demonstrated that protein kinase C delta (PKCδ) is highly expressed in DAergic neurons and mediates apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation. Herein, we further uncovered a key downstream molecular event of PKCδ signaling following mitochondrial dysfunction that governs neuronal cell death by dissembling nuclear architecture. Exposing N27 DAergic cells to the mitochondrial complex-1 inhibitor tebufenpyrad (Tebu) induced PKCδ phosphorylation at the T505 activation loop accompanied by caspase-3-dependent proteolytic activation. High-resolution 3D confocal microscopy revealed that proteolytically activated cleaved PKCδ translocates to the nucleus, colocalizing with Lamin B1. Electron microscopy also visualized nuclear membrane damage in Tebu-treated N27 cells. In silico analyses identified threonine site on Lamin B1 (T575) as a phosphorylation site of PKCδ. Interestingly, N27 DAergic cells stably expressing a PKCδ cleavage-resistant mutant failed to induce nuclear damage, PKCδ activation, and Lamin B1 phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown of PKCδ greatly attenuated Tebu-induced Lamin B1 phosphorylation. Also, studies using the Lamin B1T575G phosphorylation mutant and PKCδ-ΔNLS-overexpressing N27 cells showed that PKCδ activation and translocation to the nuclear membrane are essential for phosphorylating Lamin B1 at T575 to induce nuclear membrane damage during Tebu insult. Additionally, Tebu failed to induce Lamin B1 damage and Lamin B1 phosphorylation in organotypic midbrain slices cultured from PKCδ-/- mouse pups. Postmortem analyses of PD brains revealed significantly higher PKCδ activation, Lamin B1 phosphorylation, and Lamin B1 loss in nigral DAergic neurons compared to age-matched healthy controls, demonstrating the translational relevance of these findings. Collectively, our data reveal that PKCδ functions as a Lamin B1 kinase to disassemble the nuclear membrane during mitochondrial stress-induced neuronal death. This mechanistic insight may have important implications for the etiology of age-related neurodegenerative diseases resulting from mitochondrial dysfunction as well as for the development of novel treatment strategies.

Keywords:  Lamin B1; PKCδ; Parkinson’s disease; mitochondria; mitochondrial complex-1 inhibitor; neurodegenerative diseases; nuclear membrane disassembly; tebufenpyrad

DOI:  https://doi.org/10.3389/fncel.2025.1549265
J Neurol. 2025 Apr 28. 272(5): 364

Advances in research on mitochondrial dysfunction in neurodegenerative diseases.

Yao Zhang, Xiao-Wen Li, Yuan Zhang, Xing Li.

  Given the high energy demand of the nervous system, mitochondrial dysfunction is a key factor in the pathogenesis of neurodegenerative diseases. Thus, a comprehensive understanding of its mechanisms and potential therapeutic targets is essential. This review discusses the roles of mitochondrial oxidative stress, mitochondrial dynamics alterations, and mtDNA damage in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). In addition, it summarizes the contributions of novel technological approaches in detecting mitochondrial dysfunction, which assist in disease diagnosis. We also emphasize emerging therapeutic strategies and drugs aimed at enhancing mitochondrial quality control and reducing oxidative stress, thereby laying the groundwork for innovative therapeutic approaches in neurodegenerative disease treatment.

Keywords:  Detection technology; Mitochondrial dysfunction; Neurodegenerative diseases; Therapeutic targets

DOI:  https://doi.org/10.1007/s00415-025-13101-4
Cell Metab. 2025 Apr 24. pii: S1550-4131(25)00212-8. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD) is a ubiquitous electron carrier essential for energy metabolism and post-translational modification of numerous regulatory proteins. Dysregulations of NAD metabolism are widely regarded as detrimental to health, with NAD depletion commonly implicated in aging. However, the extent to which cellular NAD concentration can decline without adverse consequences remains unclear. To investigate this, we generated a mouse model in which nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis was disrupted in adult skeletal muscle. The intervention resulted in an 85% reduction in muscle NAD+ abundance while maintaining tissue integrity and functionality, as demonstrated by preserved muscle morphology, contractility, and exercise tolerance. This absence of functional impairments was further supported by intact mitochondrial respiratory capacity and unaltered muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings suggest that NAD depletion does not contribute to age-related decline in skeletal muscle function.

Keywords:  NAD metabolism; NAD(+) biosynthesis; NAMPT; aging; epigenetic clock; exercise; mitochondrial supercomplexes; nicotinamide; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1016/j.cmet.2025.04.002