bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–08–17
thirteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. RNA triggers chronic stress during neuronal aging.
  2. Mitochondria protect against an intracellular pathogen by restricting access to folate.
  3. Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
  4. Respiration defects limit serine synthesis required for lung cancer growth and survival.
  5. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  6. Analyzing RNA Localization Using the RNA Proximity Labeling Method OINC-seq.
  7. Principles of cotranslational mitochondrial protein import.
  8. Double-Stranded RNA Induces Retinal Pigment Epithelium Cell Degeneration and Inflammation.
  9. GRSF1 loss in THP-1 macrophages promotes senescence-associated transcription in neighboring fibroblasts.
  10. Unraveling the power of TOMM40: Driving PHB1-mediated mtDNA release and mitophagy to fuel breast cancer progression.
  11. Mitochondrial ROS and HIF-1α signaling mediate synaptic plasticity in the critical period.
  12. The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration.
  13. Progressive mitochondrial dysfunction impairs visual signal transduction and induces retinal degeneration in Drosophila.
  1. bioRxiv. 2025 Aug 05. pii: 2025.08.04.668575. [Epub ahead of print]
    RNA triggers chronic stress during neuronal aging.
    Kevin Rhine, Elle Epstein, Natasha M Carlson, Xuezhen Ge, Orel Mizrahi, Anika Kamat, Anita Hermann, William R Brothers, John Ravits, Eric J Bennett, Gülçin Pekkurnaz, Gene W Yeo.
      Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might contribute to aging and neurodegeneration. Here, we leverage directed transdifferentiation of human fibroblasts into aged neurons to determine the source of ISR activation. We demonstrate that increased accumulation of cytoplasmic double-stranded RNA (dsRNA) activates the eIF2α kinase PKR, which in turn triggers the ISR in aged neurons and leads to sequestration of dsRNA in stress granules. Aged neurons accumulate endogenous mitochondria-derived dsRNA that directly binds to PKR. This mitochondrial dsRNA leaks through damaged mitochondrial membranes and forms cytoplasmic foci in aged neurons. Finally, we demonstrate that PKR inhibition leads to the cessation of stress, resumption of cellular translation, and restoration of RNA-binding protein expression. Together, our results identify a source of RNA stress that destabilizes aged neurons and may contribute to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.08.04.668575
  2. Science. 2025 Aug 14. 389(6761): eadr6326
    Mitochondria protect against an intracellular pathogen by restricting access to folate.
    Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, Tim Bartsch, Silvia Reato, John C Crow, Michelle Tellez Sutterlin, Bruna Martins Garcia, Irina Rais, Kira Allmeroth, Matías D Hartman, Martin S Denzel, Martin Purrio, Andrea Mesaros, Kit-Yi Leung, Nicholas D E Greene, Lilach Sheiner, Patrick Giavalisco, Lena Pernas.
      As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen Toxoplasma gondii, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited Toxoplasma access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against Toxoplasma.
    DOI:  https://doi.org/10.1126/science.adr6326
  3. EMBO Mol Med. 2025 Aug 11.
    Rewriting nuclear epigenetic scripts in mitochondrial diseases as a strategy for heteroplasmy control.
    María J Pérez, Rocío B Colombo, Sebastián M Real, María T Branham, Sergio R Laurito, Carlos T Moraes, Lía Mayorga.
      Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations-m.13513 G > A and m.8344 A > G-at varying heteroplasmies, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern critical for the survival of high-heteroplasmy cells but not for low-heteroplasmy ones. Treatment with FDA-approved DNA methylation inhibitors selectively impacted high-heteroplasmy cybrids and reduced heteroplasmy. These findings were validated in cultured cells and xenografts. Our findings highlight nuclear DNA methylation as a key regulator of heteroplasmic cell survival and a potential therapeutic target for mitochondrial diseases.
    Keywords:  DNA Methylation; Epigenetics; Heteroplasmy; Mitochondrial DNA; Mitochondrial Diseases
    DOI:  https://doi.org/10.1038/s44321-025-00285-5
  4. Nat Commun. 2025 Aug 15. 16(1): 7621
    Respiration defects limit serine synthesis required for lung cancer growth and survival.
    Eduardo Cararo Lopes, Fuqian Shi, Akshada Sawant, Maria Ibrahim, Maria Gomez-Jenkins, Zhixian Hu, Pranav Manchiraju, Vrushank Bhatt, Wenping Wang, Christian S Hinrichs, Douglas C Wallace, Xiaoyang Su, Joshua D Rabinowitz, Chang S Chan, Jessie Yanxiang Guo, Shridar Ganesan, Edmund C Lattime, Eileen White.
      Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show that a proofreading mutant of DNA polymerase gamma (PolGD256A) increases the mtDNA mutation burden in non-small-cell lung cancer (NSCLC). This mutation promotes the accumulation of defective mitochondria, reduces tumor cell proliferation and viability, and improves cancer survival. In NSCLC, pathogenic mtDNA mutations enhance glycolysis and create a glucose dependency to support mitochondrial energy, but at the expense of a lower NAD+/NADH ratio that hinders de novo serine synthesis. Thus, mitochondrial function in NSCLC is essential for maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for tumor growth, explaining why these cancers preserve functional mtDNA.
    DOI:  https://doi.org/10.1038/s41467-025-62911-7
  5. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  6. Bio Protoc. 2025 Aug 05. 15(15): e5403
    Analyzing RNA Localization Using the RNA Proximity Labeling Method OINC-seq.
    Megan C Pockalny, Hei-Yong G Lo, Raeann Goering, J Matthew Taliaferro.
      Thousands of RNAs are localized to specific subcellular locations, and these localization patterns are often required for optimal cell function. However, the sequences within RNAs that direct their transport are unknown for almost all localized transcripts. Similarly, the RNA content of most subcellular locations remains unknown. To facilitate the study of subcellular transcriptomes, we developed the RNA proximity labeling method OINC-seq. OINC-seq utilizes photoactivatable, spatially restricted RNA oxidation to specifically label RNA in proximity to a subcellularly localized bait protein. After labeling, these oxidative RNA marks are then read out via high-throughput sequencing due to their ability to induce predictable misincorporation events by reverse transcriptase. These induced mutations are then quantitatively assessed for each gene using our software package PIGPEN. The observed mutation rate for a given RNA species is therefore related to its proximity to the localized bait protein. This protocol describes procedures for assaying RNA localization via OINC-seq experiments as well as computational procedures for analyzing the resulting data using PIGPEN. Key features • OINC-seq assays the RNA content of a variety of subcellular locations. • OINC-seq utilizes a photoactivatable, proximity-dependent RNA oxidation reaction to label RNAs. • Oxidative RNA marks are read using high-throughput sequencing without the need for enrichment. • Oxidative RNA marks are identified and quantified using the associated PIGPEN software.
    Keywords:  Proximity labeling; RNA localization; RNA modifications; RNA oxidation; RNA trafficking
    DOI:  https://doi.org/10.21769/BioProtoc.5403
  7. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  8. FASEB J. 2025 Aug 31. 39(16): e70786
    Double-Stranded RNA Induces Retinal Pigment Epithelium Cell Degeneration and Inflammation.
    Kyle Bond, Garrett Klokman, YongYao Xu, Xiaoqiu Wu, Joshua Schustak, Jorgi Mandelbaum, Michael Twarog, Hongwei Han, Fumiaki Aihara, Mary-Kate Paulina, Matthew Coble, Christopher Hayden, Jean-Rene Galarneau, John T Demirs, Yubin Qiu, Robert Esterberg, Qian Huang, Ganesh Prasanna, Christopher W Wilson, Magali Saint-Geniez, Jorge Aranda, Yi Bao.
      RIG-I signaling has been previously implicated as a driver of inflammation to the retinal pigment epithelium (RPE) during age-related macular degeneration (AMD). Double-stranded RNA (dsRNA) is known to initiate RIG-I signaling and lead to a type I interferon response. We show through shRNA knockdown that RIG-I is essential for initiating an interferon response in iPS-RPE in response to both synthetic dsRNA-mimetic 3p-hpRNA and the double-stranded retrotransposable element Alu. Analysis of human tissue from patients suffering from AMD show accumulation of dsRNA, peaking at the geographic atrophy (GA) stage. Using a new murine model of 3p-hpRNA subretinal challenge to RPE cells, we confirmed that accumulation of dsRNA initiates a type I interferon response, as well as RPE and photoreceptor degeneration. Although RPE response to synthetic dsRNA was acute, extensive leukocyte migration was observed. The results from this study verify the importance of RIG-I signaling in regulating inflammation in the subretinal space and implicates dsRNA accumulation as a driver of AMD pathogenesis.
    Keywords:  RIG‐I; age‐related macular degeneration; dsRNA; inflammation; retinal pigment epithelial cells
    DOI:  https://doi.org/10.1096/fj.202402181R
  9. Sci Rep. 2025 Aug 14. 15(1): 29851
    GRSF1 loss in THP-1 macrophages promotes senescence-associated transcription in neighboring fibroblasts.
    Younggi Lee, Seokwoo Jo, Mi-Hee Lim, Sangik Hwang, Sohyeon Jang, Kyuseok Kim, Sung-Jin Yoon, Jian Sima, M Laura Idda, Kyoung Mi Kim, Myriam Gorospe, Chungoo Park, Ji Heon Noh.
      Immunosenescence, the age-associated decline in immune function, is accompanied by altered macrophage phenotypes and increased chronic inflammation. Here, we examined the role of the mitochondrial RNA-binding protein GRSF1 in regulating macrophage-driven inflammation and its impact on neighboring fibroblasts. We found that macrophages differentiated from GRSF1-deficient THP-1 monocytes, particularly M(IL-4 + IL-13) macrophages, displayed elevated IL6 mRNA expression levels and TNF-α secretion, without inducing overt senescence in macrophages themselves. Conditioned media from these macrophages triggered robust senescence-associated transcriptional changes in fibroblasts, including increased expression of IL6, TNF, DPP4, and IL8, as well as elevated SA-β-gal activity. Notably, expression of NF-κB-regulated long noncoding RNAs, such as ANRIL and PACER, was also induced in fibroblasts, suggesting the engagement of an NF-κB-linked inflammatory program. These transcriptional responses were mitigated by red ginseng extract, an anti-inflammatory compound known to suppress TNF-α signaling. Collectively, our findings suggest that GRSF1 depletion in macrophages contributes to a paracrine inflammatory niche that promotes senescence-associated gene expression in surrounding cells.
    Keywords:  Cell senescence; GRSF1; THP-1 macrophages
    DOI:  https://doi.org/10.1038/s41598-025-11385-0
  10. Biochim Biophys Acta Gen Subj. 2025 Aug 13. pii: S0304-4165(25)00096-0. [Epub ahead of print] 130851
    Unraveling the power of TOMM40: Driving PHB1-mediated mtDNA release and mitophagy to fuel breast cancer progression.
    Lei Pan, Feixia Ma, Hongchen Zhang, Yin Duan.
       BACKGROUND: In breast cancer (BRCA), mitophagy is essential for the survival and metastasis of cancer cells. However, the interaction between translocase of the outer mitochondrial membrane 40 (TOMM40) and prohibitin 1 (PHB1) in regulating mitophagy in BRCA remains poorly understood.
    METHODS: Based on bioinformatics analysis, the interaction between PHB1 and key mitophagy regulators in BRCA was explored. The effects of mitochondrial division inhibitor-1 (Mdivi-1) and Fluorizoline on mitophagy, cell viability, and sphere formation ability in MDA-MB-231 cells were assessed. In the cell model activated by carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce mitophagy, the effects of TOMM40 on cell viability, sphere formation ability, mitochondrial membrane potential, reactive oxygen species (ROS) levels, mitochondrial DNA (mtDNA) release, and PHB1 regulation were analyzed. In vivo, the impact of TOMM40 knockdown on tumor progression and mitophagy was also evaluated.
    RESULTS: PHB1 interacted with TOMM40. Mdivi-1 or Fluorizoline treatment inhibited mitophagy, and significantly reduced BRCA cell viability and sphere formation. CCCP treatment induced mitophagy, increased mtDNA release and PHB1 levels, decreased mitochondrial membrane potential and ROS, and promoted cell viability and sphere formation ability, which were all reversed by TOMM40 knockdown. Additionally, TOMM40 knockdown led to decreased PHB1 levels and increased ROS accumulation in tumor tissue, thus repressing tumor progression.
    CONCLUSION: This study identifies TOMM40 as a key regulator that enhances PHB1-mediated mtDNA release and induces mitophagy in BRCA cells, thus promoting breast cancer progression.
    Keywords:  Breast cancer; Mitochondrial DNA; Mitophagy; Prohibitin 1; Translocase of the outer mitochondrial membrane 40
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130851
  11. PLoS Biol. 2025 Aug 13. 23(8): e3003338
    Mitochondrial ROS and HIF-1α signaling mediate synaptic plasticity in the critical period.
    Daniel Sobrido-Cameán, Bramwell Coulson, Michael Miller, Matthew C W Oswald, Tom Pettini, David M D Bailey, Richard A Baines, Matthias Landgraf.
      As developing networks transition from spontaneous irregular to patterned activity, they undergo plastic tuning phases, termed "critical periods"; "critical" because disturbances during these phases can lead to lasting changes in network development and output. Critical periods are common to developing nervous systems, with analogous features shared from insects to mammals, yet the core signaling mechanisms that underlie cellular critical period plasticity have remained elusive. To identify these, we exploited the Drosophila larval locomotor network as an advantageous model system. It has a defined critical period and offers unparalleled access to identified network elements, including the neuromuscular junction as a model synapse. We find that manipulations of a single motoneuron or muscle cell during the critical period lead to predictable, and permanent, cell-specific changes. This demonstrates that critical period adjustments occur at a single-cell level. Mechanistically, we identified mitochondrial reactive oxygen species (ROS) as causative. Specifically, we show that ROS produced by Complex-I of the mitochondrial electron transport chain, generated by the reverse flow of electrons, is necessary and instructive for critical period-regulated plasticity. Downstream of ROS, we identified the Drosophila homologue of hypoxia-inducible factor (HIF-1α), as required for transducing the mitochondrial ROS signal to the nucleus. This signaling axis is also sufficient to cell autonomously specify changes in neuronal properties and animal behavior but, again, only when activated during the embryonic critical period. Thus, we have identified specific mitochondrial ROS and HIF-1α as primary signals that mediate critical period plasticity.
    DOI:  https://doi.org/10.1371/journal.pbio.3003338
  12. Bone Res. 2025 Aug 12. 13(1): 72
    The mitochondrial E3 ligase MAPL SUMOylates Drp1 to facilitate mitochondrial fission in intervertebral disc degeneration.
    Zhidi Lin, Xiao Lu, Guangyu Xu, Jian Song, Hongli Wang, Xinlei Xia, Feizhou Lu, Jianyuan Jiang, Wei Zhu, Zuochong Yu, Xiaosheng Ma, Fei Zou.
      Intervertebral disc degeneration (IVDD) is the primary contributor to a range of spinal diseases. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission has recently been identified as a new cause of nucleus pulposus cell (NPC) death and IVDD, but the underlying mechanisms remain unclear. Although the effects of Drp1 phosphorylation in IVDD have been studied, it is currently unknown if small ubiquitin-like modifications (SUMOylation) of Drp1 regulate IVDD. This study aimed to investigate the functions and mechanisms of mitochondria-anchored protein ligase (MAPL), a mitochondrial SUMO E3 ligase, during IVDD progression. The expression of genes related to SUMOylation and mitochondrial dynamics in TNF-α-stimulated NPCs was analysed via RNA sequencing. The levels of total and mitochondrial SUMO1 conjugates were elevated with MAPL upregulation in TNF-α-treated NPCs. Additionally, mitochondrial fragmentation and dysfunction were induced by TNF-α stimulation. MAPL overexpression promoted mitochondrial SUMOylation and SUMO1 modification of Drp1, thereby facilitating the mitochondrial translocation of Drp1 and mitochondrial fission. MAPL-induced ROS accumulation and ΔΨm loss led to increased NPC apoptosis. Mutation of the SUMO-acceptor lysine residues of Drp1 hindered its SUMOylation and rescued the mitochondrial phenotypes caused by MAPL. SENP5 overexpression phenocopied MAPL silencing, negatively modulating the SUMO1 modification of Drp1 and mitochondrial fission in NPCs. In a rat IVDD model, forced expression of MAPL by using an adeno-associated virus (AAV) vector aggravated IVD tissue damage, whereas the knockdown of MAPL delayed IVDD progression. Our findings highlight the importance of SUMOylation in IVDD. The inhibition of MAPL-mediated Drp1 SUMOylation alleviates mitochondrial fission and limits IVDD development, providing a potential strategy for IVDD treatment.
    DOI:  https://doi.org/10.1038/s41413-025-00449-6
  13. Front Insect Sci. 2025 ;5 1596020
    Progressive mitochondrial dysfunction impairs visual signal transduction and induces retinal degeneration in Drosophila.
    Jinguo Cao, Yining Li, Xiaohui Hu, Zhaoqi Wu, Jiting Zhang, Yue Zhou, Wei Luan, Wen Hu, Jianhong Tang.
      Mitochondrial dysfunction is closely associated with the pathogenesis of retinitis pigmentosa (RP), often through the generation of reactive oxygen species (ROS), which disrupts visual signal transduction. However, in certain instances, mitochondrial dysfunction does not correlate with an increase in ROS, and the precise mechanisms by which mitochondrial dysfunction contributes to RP remain poorly understood. In this study, we demonstrate that mitochondrial dysfunction can also impair visual signal transduction through ROS-independent mechanisms. Specifically, we identify that mitochondrial dysfunction affects key processes in phototransduction, including activation and bleaching, leading to the degradation of photoreceptor proteins and, ultimately, retinal degeneration. Our findings reveal that mitochondrial dysfunction influences RP through multifaceted pathways, underscoring its role in both hereditary and age-related forms of visual diseases. This study enhances our understanding of the molecular mechanisms underlying RP and establishes a novel model for investigating mitochondrial dysfunction in visual pathologies.
    Keywords:  Drosophila; mitochondrial dysfunction; phototransduction; reactive oxygen species; retinitis pigmentosa
    DOI:  https://doi.org/10.3389/finsc.2025.1596020
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