bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–09–21
nineteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. VDAC1 Oligomerization-Mediated mtDNA Release under Sublethal Oxidative Stress: A Novel Inflammatory Mechanism in Vitiligo.
  2. MitoScribe single-cell molecular recorder logs graded signaling dynamics into mitochondrial DNA.
  3. Manipulating mitochondrial gene expression.
  4. Mitochondrial RNA in Inflammation.
  5. The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.
  6. mtDNA base editing: Mind the gap.
  7. Neurons and astrocytes have distinct organelle signatures and responses to stress.
  8. Anticancer Effect of the Triphenylphosphonium-Conjugated Quinolone Antibiotics Targeting Mitochondrial DNA Replication.
  9. Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.
  10. Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.
  11. Cryo-EM structure of the prohibitin complex in open conformation.
  12. Mitochondrial Activity Regulates Human T Helper 17 Differentiation and Function.
  13. Nucleic Acid Sequence Determinants of Transcriptional Pausing by the Human Mitochondrial RNA Polymerase (POLRMT).
  14. Cryo-EM Reveals Regulatory Mechanisms Governing Substrate Selection and Activation of Human LONP1.
  15. SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.
  16. Towards a molecular and structural definition of cell death.
  17. Mitochondrial DNA mutations as a potential modifier for the clinical variability of marfan syndrome.
  18. Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression.
  19. Deciphering the RNA Landscapes on Mammalian Cell Surfaces.
  1. Free Radic Biol Med. 2025 Sep 11. pii: S0891-5849(25)00975-X. [Epub ahead of print]
    VDAC1 Oligomerization-Mediated mtDNA Release under Sublethal Oxidative Stress: A Novel Inflammatory Mechanism in Vitiligo.
    Rongyin Gao, Duo Meng, Zhilin Zhao, Hui Xue, Nan Hu, Peiwen Jiang, Wenhao Yu, Wenhui Xu, Chuanwei Yin, Huansha Zhang, Jinpeng Lv.
      Oxidative stress is a critical initiating factor in vitiligo, yet the early molecular events linking redox imbalance to melanocyte immune activation remain unclear. Here, we demonstrate that sub-lethal hydrogen peroxide (H2O2, 0.1 mM) exposure in human epidermal melanocytes induces a robust pro-inflammatory response independent of apoptosis or pyroptosis. This response is driven by the selective cytosolic release of mitochondrial DNA (mtDNA), which activates the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Mechanistically, voltage-dependent anion channel 1 (VDAC1) oligomerization cooperates with mitochondrial permeability transition pore (mPTP) opening to mediate mtDNA release. Both genetic VDAC1 knockdown and pharmacological inhibition blocked mtDNA leakage and downstream cytokine production. In H2O2-induced vitiligo mice, intradermal administration of the VDAC1 oligomerization inhibitor VBIT-4 restored melanin pigmentation, reduced CD8+ T cell infiltration, and alleviated cutaneous inflammation. These findings identify VDAC1-dependent mtDNA release as a key driver of innate immune activation in melanocytes and highlight VDAC1 as a potentially druggable therapeutic target for early intervention in vitiligo.
    Keywords:  VDAC1 oligomerization; cGAS-STING; melanocytes; mitochondrial DNA; sublethal oxidative stress; vitiligo
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.018
  2. bioRxiv. 2025 Sep 05. pii: 2025.09.05.674553. [Epub ahead of print]
    MitoScribe single-cell molecular recorder logs graded signaling dynamics into mitochondrial DNA.
    Linhan Wang, Nikolaos Poulis, Deepak Srivastava, Seth L Shipman.
      Genetically encoded DNA recorders convert transient biological events into stable genomic mutations, offering a means to reconstruct past cellular states. However, current approaches to log historical events by modifying genomic DNA have limited capacity to record the magnitude of biological signals within individual cells. Here, we introduce MitoScribe, a mitochondrial DNA (mtDNA)-based recording platform that uses mtDNA base editors (DdCBEs) to write graded biological signals into mtDNA as neutral, single-nucleotide substitutions at a defined site. Taking advantage of the hundreds to thousands of mitochondrial genome copies per cell, we demonstrate MitoScribe enables reproducible, highly sensitive, non-destructive, durable, and high-throughput measurements of molecular signals, including hypoxia, NF-κB activity, BMP and Wnt signaling. We show multiple modes of operation, including multiplexed recordings of two independent signals, and coincidence detection of temporally overlapping signals. Coupling MitoScribe with single-cell RNA sequencing and mitochondrial transcript enrichment, we further reconstruct signaling dynamics at the single-cell transcriptome level. Applying this approach during the directed differentiation of human induced pluripotent stem cells (iPSCs) toward mesoderm, we show that early heterogeneity in response to a differentiation cue predicts the later cell state. Together, MitoScribe provides a scalable platform for high-resolution molecular recording in complex cellular contexts.
    DOI:  https://doi.org/10.1101/2025.09.05.674553
  3. Biol Chem. 2025 Sep 15.
    Manipulating mitochondrial gene expression.
    Drishan Dahal, Luis D Cruz-Zargoza, Peter Rehling.
      Mitochondria are essential for cellular metabolism, serving as the primary source of adenosine triphosphate (ATP). This energy is generated by the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Impairments in this machinery are linked to serious human diseases, especially in tissues with high energy demands. Assembly of the OXPHOS system requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. The mitochondrial DNA encodes for 13 protein components, which are synthesized by mitochondrial ribosomes and inserted into the inner membrane during translation. Despite progress, key aspects of how mitochondrial gene expression is regulated remain elusive, largely due to the organelle's limited genetic accessibility. However, emerging technologies now offer new tools to manipulate various stages of this process. In this review, we explore recent strategies that expand our ability to target mitochondria genetically.
    Keywords:  RNA; gene expression; genetic tools; mitochondria
    DOI:  https://doi.org/10.1515/hsz-2025-0170
  4. Int J Biol Sci. 2025 ;21(12): 5378-5392
    Mitochondrial RNA in Inflammation.
    Jian Chen, Chen You, Haibo Xie, Qixing Zhu.
      Mitochondria are dynamic organelles integral to cellular energy metabolism and homeostasis. Beyond their traditional roles, a growing body of evidence underscores the importance of mitochondria as pivotal regulators of innate immune signaling pathways. Recently, mitochondrial RNA (mtRNA) has been identified as a novel modulator of inflammatory responses. mtRNA is detected by intracellular pattern recognition receptors (PRRs), which subsequently activate the mitochondrial antiviral-signaling protein (MAVS) and the interferon regulatory factor 3 (IRF3)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling axis, as well as inflammasome pathways. This activation leads to the production of type I interferons and pro-inflammatory cytokines. Furthermore, mtRNA facilitates the propagation of inflammatory signals through exosome-mediated intercellular transfer. Among the various forms of mtRNA, mitochondrial double-stranded RNA (mt-dsRNA) is particularly prone to activating inflammatory responses due to its distinctive double-helical structure. The aberrant accumulation of mt-dsRNA is strongly linked autoimmune diseases, degenerative disease, Liver Disease, kidney disease, cancers, cardiovascular diseases, and respiratory ailments. This review proposes innovative therapeutic strategies aimed at degrading pathological mtRNA or interrupting inflammatory pathways by targeting critical regulatory nodes in mtRNA metabolism and its downstream inflammatory processes.
    Keywords:  Inflammation; Mitochondrial; mt-dsRNA.; mtRNA
    DOI:  https://doi.org/10.7150/ijbs.119841
  5. bioRxiv. 2025 Sep 08. pii: 2025.09.05.671511. [Epub ahead of print]
    The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.
    Kelsey H Fisher-Wellman, Richard D Lutze, Logan G Kirkland, Ju Youn Beak, Samantha M Morrissey, Peyton B Sandroni, Wei Huang, Julian D Bailon, Melissa A Schroder, Lars A Albrecht, Mansi Goyal, Andrew L Chin, Thomas D Green, Joseph M McClung, McLane M Montgomery, James T Hagen, Brett R Chrest, Jon S Zawistowski, Timothy J Stuhlmiller, Shawn M Gomez, Nanthip Prathumsap, Qing Zhang, Jing Zhang, Weiyi Xu, Lilei Zhang, Jeremy A Meier, Lisa A Carey, Jonathan C Schisler, Gary L Johnson, Brian C Jensen.
      Trametinib (Trm) is a highly selective MEK inhibitor that potently and persistently abrogates ERK1/2 activation. Trm initially was used to treat BRAF V600E-mutated melanoma but its FDA-approved indications are expanding rapidly. Trm generally is well tolerated but it can cause dose-limiting cardiomyopathy and heart failure. Here we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo , Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part through blunted activity of Electron Transport System Complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial Damage-Associated Molecular Patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations but this lesion was reversed by expression of a phosphomimetic STAT3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trm's anti-cancer efficacy.
    DOI:  https://doi.org/10.1101/2025.09.05.671511
  6. Mol Cell. 2025 Sep 18. pii: S1097-2765(25)00713-0. [Epub ahead of print]85(18): 3351-3352
    mtDNA base editing: Mind the gap.
    Jose Domingo Barrera-Paez, Carlos T Moraes.
      In this issue of Molecular Cell, Xiang et al.1 provided insights into the mechanism and structure-guided engineering of DdCBE for mitochondrial DNA base editing. More precise editing was achieved by better defining the editing window.
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.028
  7. Cell Rep. 2025 Sep 15. pii: S2211-1247(25)01051-4. [Epub ahead of print]44(9): 116280
    Neurons and astrocytes have distinct organelle signatures and responses to stress.
    Shannon N Rhoads, Weizhen Dong, Chih-Hsuan Hsu, Ngudiankama R Mfulama, Ridhi Yarlagadda, Joey V Ragusa, Michael Ye, Andy Henrie, Maria Clara Zanellati, Graham H Diering, Todd J Cohen, Sarah Cohen.
      Neurons and astrocytes play critical yet divergent roles in brain physiology and neurological conditions. Intracellular organelles are integral to cellular function. However, an in-depth characterization of organelles in live neural cells has not been performed. Here, we use multispectral imaging to simultaneously visualize six organelles-endoplasmic reticulum (ER), lysosomes, mitochondria, peroxisomes, Golgi, and lipid droplets-in live primary rodent neurons and astrocytes. We generate a dataset of 173 z stack and 98 time-lapse images, accompanied by quantitative "organelle signature" analysis. Comparative analysis reveals a clear cell-type specificity in organelle morphology and interactions. Neurons are characterized by prominent mitochondrial composition and interactions, while astrocytes contain more lysosomes and lipid droplet interactions. Additionally, neurons display a more robust organelle response than astrocytes to acute oxidative or ER stress. Our data provide a systems-level characterization of neuron and astrocyte organelles that can be a reference for understanding cell-type-specific physiology and disease.
    Keywords:  CP: Cell biology; CP: Neuroscience; Golgi; astrocytes; endoplasmic reticulum; lipid droplets; lysosomes; microscopy; mitochondria; neurons; organelles; peroxisomes
    DOI:  https://doi.org/10.1016/j.celrep.2025.116280
  8. Cancer Sci. 2025 Sep 16.
    Anticancer Effect of the Triphenylphosphonium-Conjugated Quinolone Antibiotics Targeting Mitochondrial DNA Replication.
    Yuming Qiao, Yuki Kida, Xiaoyi Lai, Nobuko Koshikawa, Rie Igarashi, Atsushi Takatori, Keizo Takenaga.
      Antibacterial quinolones are widely used to treat bacterial infections in humans. They inhibit bacterial DNA gyrase and topoisomerase IV, whose analogous enzymes are present in mammalian mitochondria. Quinolones inhibit mitochondrial topoisomerases, thereby leading to mitochondrial DNA (mtDNA) replication suppression and cancer cell death. Meanwhile, high concentrations of quinolones are required to induce cancer cell death, possibly owing to poor delivery to the mitochondria. In this study, we synthesized nalidixic acid (NA) and ciprofloxacin (CFX) conjugated with the mitochondria-targeting moiety triphenylphosphonium (TPP), NX-TPP and CFX-TPP, to enhance mitochondrial delivery and examined their anticancer efficacy. NX-TPP and CFX-TPP markedly reduced the antibacterial activity, although CFX-TPP was more active than NX-TPP. However, both NX-TPP and CFX-TPP significantly induced cell death in colon HT-29, pancreatic MIAPaCa-2, and other cancer cells but not in non-cancerous cells including normal dermal fibroblasts and human vascular endothelial cells at a comparative level. NX-TPP induced necrosis-like cell death characterized by cell membrane ballooning and rupture. Mechanistically, NX-TPP was efficiently incorporated into the mitochondria, leading to increased mitochondrial reaction oxygen species (mtROS) generation and mitophagy, and decreased mtDNA copy number and mitochondrial respiration. NX-TPP inhibited tumor growth in HT-29 and MIAPaCa-2 xenograft mouse models without any apparent adverse effects. These results suggest that mtDNA replication-targeting quinolone derivatives, termed MitoQNs, that exhibit reduced antibacterial activity, thereby decreasing antibiotic resistance induction, and enhanced anticancer efficacy, are candidate drugs for cancer therapy.
    Keywords:  TPP; antibiotic resistance; mitochondria; mtDNA replication; quinolones
    DOI:  https://doi.org/10.1111/cas.70199
  9. J Biol Chem. 2025 Sep 16. pii: S0021-9258(25)02585-2. [Epub ahead of print] 110733
    Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.
    Avery S Ward, Vasudeva G Kamath, Chia-Heng Hsiung, Zachary J Lizenby, Alexander G Gillish, D Stave Kohtz, Edward E McKee.
      Deoxynucleotides (dNTPs) in post-mitotic tissues rely on deoxynucleoside salvage pathways in order to repair and replicate nuclear and mitochondrial DNA (mtDNA). Previous work from our laboratory showed in perfused rat heart and isolated mitochondria that the only substrate for TTP synthesis is thymidine. When thymidylate (TMP) is provided to bypass thymidine kinase 2 (TK2) the substrate is readily dephosphorylated to thymidine before salvage occurs suggesting compartmentalization within the heart mitochondrial matrix. The goal of this work extends these findings in the heart to mitochondria from other post-mitotic tissues, including rat liver, kidney, and brain. Using AZT to block mitochondrial thymidine kinase 2, we demonstrate that TMP cannot serve as a precursor for TTP synthesis in isolated mitochondria from any of these tissues unless it is de-phosphorylated to thymidine first. Broken mitochondria incubated with labeled TMP showed similar results as intact mitochondria, suggesting the findings are not related to TMP transport across the inner mitochondrial membrane. Further, using proximity labeling with immunofluorescence microscopy we provide evidence supporting the hypothesis that TMP compartmentation is accounted for by the interaction of TK2 and CMPK2 in the mitochondria. Differential fraction experiments provide additional evidence that association with TK2 allows CMPK2 to display TMPK2 activity. Together, the results indicate that a two-step phosphorylation of thymidine to TDP occurs because the proximity of TK2 and CMPK2 in the mitochondria prevents TMP from diffusing from the two enzymes.
    Keywords:  cytidine monophosphate kinase 2; mitochondrial disease; mitochondrial metabolism; nucleoside/nucleotide biosynthesis; nucleoside/nucleotide metabolism; thymidine kinase 2
    DOI:  https://doi.org/10.1016/j.jbc.2025.110733
  10. Nat Immunol. 2025 Sep 15.
    Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.
    Jianhui Sun, Jun Yang, Jie Tao, Yifan Yang, Rui Wang, Huacai Zhang, Wenyi Liu, Shulin Zhao, Runze Shao, Yuhui He, Shaolin Tao, Yaxiong Li, Hai Qu, Di Liu, Jingwen Li, Jianxin Jiang, Bo Deng, Chu Gao, Ping Lin, Ling Zeng, Ping Meng, Gan Wang.
      The formation of membrane pores by cleaved N-terminal gasdermin D (GSDMD-NT) results in the release of cytokines and inflammatory cell death, known as pyroptosis. Blocking GSDMD-NT pores is an attractive and promising strategy for mitigating inflammation. Here we demonstrate that SK56, an artificial intelligence-screened peptide, effectively obstructs GSDMD-NT pores and inhibits pyroptosis and cytokine release in macrophages and human peripheral blood leukocyte-induced pyroptosis. SK56 prevents septic death induced by lipopolysaccharide or cecal ligation and puncture surgery in mice. SK56 does not influence cleavage of interleukin-1β or GSDMD. Instead, SK56 inhibits the release of cytokines from pyroptotic macrophages, mitigates the activation of primary mouse dendritic cells triggered by incubation with pyroptotic cytomembranes and prevents widespread cell death of human alveolar organoids in an organoid-macrophage coculture model. SK56 blocks GSDMD-NT pores on lipid-bilayer nanoparticles and enters pyroptotic macrophages to inhibit mitochondrial damage. SK56 presents new therapeutic possibilities for counteracting inflammation, which is implicated in numerous diseases.
    DOI:  https://doi.org/10.1038/s41590-025-02280-x
  11. Proc Natl Acad Sci U S A. 2025 Sep 23. 122(38): e2512430122
    Cryo-EM structure of the prohibitin complex in open conformation.
    Sixing Hong, Zeyuan Guan, Liying Zhang, Jinjin Zhuang, Ling Yan, Yanjun Liu, Zhu Liu, Qiang Wang, Ping Yin.
      Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2), two conserved prohibitin members, are primarily localized to the mitochondrial inner membrane (MIM) to form a nanoscale macromolecular prohibitin complex. This prohibitin complex can facilitate the spatial organization of proteins and lipids, thus maintaining cellular metabolism and homeostasis, but its architecture remains largely unknown. Here, we report the cryo-EM structure of a prohibitin complex at 2.8 Å resolution, which contains 11 PHB1-PHB2 heterodimers. This complex displays a bell-like cage, consisting of a lid and a wall, which creates an intermembrane space-facing compartment for the MIM. The lid of the cage is stably assembled, and it is responsible for the prohibitin complex formation. In contrast, the wall of the cage is flexible and exhibits lateral openings, providing a channel for intramembrane exchange of proteins and lipids. These findings provide a structural basis for understanding the scaffold role of the prohibitin complex in organizing intramembrane proteins and lipids.
    Keywords:  cryo-EM; membrane microdomain; mitochondria; prohibitin complex; scaffold
    DOI:  https://doi.org/10.1073/pnas.2512430122
  12. Immunology. 2025 Sep 17.
    Mitochondrial Activity Regulates Human T Helper 17 Differentiation and Function.
    Xinlai Chen, Theodoros Ioannis Papadimitriou, Anne H G van Essen, Britt van Brunschot, Monique M Helsen, Annet Sloetjes, Elly L Vitters, Werner J H Koopman, Peter M van der Kraan, Arjan P M van Caam, Marije I Koenders.
      Immunometabolism plays a pivotal role in T cell fate decisions, yet its specific contribution to human Th17 differentiation remains incompletely understood. Th17 cells, a subset of CD4+ T cells, are central to autoimmune pathogenesis through their secretion of pro-inflammatory cytokines. Elucidating the metabolic drivers of Th17 differentiation may reveal novel therapeutic targets. We investigated the role of mitochondrial activity in Th17 differentiation using an in vitro model with naïve human CD4+ T cells. Single-cell metabolic profiling and functional assays were used to characterise metabolic changes during differentiation. Th17 cells exhibited a hyperpolarised mitochondrial membrane potential (ΔΨ) compared to non-Th17 cells. Hyperpolarised ΔΨ cells displayed increased metabolic activity and enhanced differentiation capacity. Metabolic profiling at 48 h revealed an early reliance on glycolysis, followed by a shift toward increased dependence on oxidative phosphorylation (OXPHOS) by 96 h. Gene expression analysis indicated early upregulation of TEFM, a mitochondrial transcription regulator, at 48 h. By 96 h, ΔΨ hyperpolarised cells exhibited a downregulation of DRP1 and MFN2, genes responsible for mitochondrial fission and fusion. Functionally, ΔΨ hyperpolarised cells expressed elevated activation markers (CD69, CD25) but also showed increased exhaustion markers (TIGIT, PD-1), indicating a link between high metabolic activity and exhaustion. Additionally, these cells triggered weaker NF-κB and AP-1 signalling and secreted lower levels of effector molecules (IFN-γ, Granzyme B) than ΔΨ depolarised cells. In conclusion, mitochondrial activity critically shapes Th17 differentiation. Although hyperpolarised ΔΨ cells exhibit greater activation, they are more prone to exhaustion and reduced effector function. These findings offer insights into Th17 metabolic regulation and its therapeutic potential in autoimmune diseases.
    Keywords:  T cell exhaustion; T cell metabolism; Th17 cells; Th17 differentiation; mitochondrial activity
    DOI:  https://doi.org/10.1111/imm.70037
  13. Biochemistry. 2025 Sep 17.
    Nucleic Acid Sequence Determinants of Transcriptional Pausing by the Human Mitochondrial RNA Polymerase (POLRMT).
    An H Hsieh, Tatiana V Mishanina.
      Transcription by RNA polymerase (RNAP) lies at the heart of gene expression in all organisms. The speed with which RNAPs produce RNA is tuned, in part, by signals in the transcribed nucleic acid sequences, which temporarily arrange RNAPs into a paused conformation that is unable to extend the RNA. In turn, the altered transcription kinetics of paused RNAPs determine the three-dimensional shape into which RNA ultimately folds and promote or inhibit cotranscriptional events. While pause sequence determinants have been characterized for multisubunit RNAPs in bacteria and in eukaryotic nuclei, this information is lacking for the single-subunit, T-odd phage-like RNAP of human mitochondria, POLRMT. Here, we developed a robust nucleic acid scaffold system to reconstitute POLRMT transcription in vitro and identified multiple transcriptional pause sites on the human mitochondrial DNA (mtDNA). Using one of the pause sequences as a representative, we performed a suite of mutational studies to pinpoint the nucleic acid elements that enhance, weaken, or completely abolish POLRMT pausing. Based on these mutational results, we constructed a consensus pause motif expected to cause strong pausing for POLRMT: 5'-R-10NNNNNNNGT-1G+1-3', where -1 is the 3' nascent RNA nucleotide in the POLRMT active site, +1 is the incoming NTP to be added to the nascent RNA, R is A or G, and N is any base. Strikingly, most of the consensus pause elements in this motif are the same for multisubunit prokaryotic and nuclear RNAPs, hinting at potentially shared features of the pausing mechanism despite the structural differences between polymerases. Finally, a search of the human mtDNA for this pause motif revealed multiple predicted pause sites with potential roles in mitochondrial cotranscriptional processes.
    DOI:  https://doi.org/10.1021/acs.biochem.5c00236
  14. bioRxiv. 2025 Sep 06. pii: 2025.09.05.674599. [Epub ahead of print]
    Cryo-EM Reveals Regulatory Mechanisms Governing Substrate Selection and Activation of Human LONP1.
    Jeffrey T Mindrebo, Lauren Alexandrescu, Jennifer R Baker, Garret Wang, Gabriel C Lander.
      The human AAA+ protease LONP1 plays a central role in maintaining mitochondrial proteostasis. LONP1 processes a vast array of substrates, ranging from damaged or unfolded proteins to specific subunits stably integrated into respiratory complexes. Previous cryo-EM studies of LONP1 uncovered two distinct conformational states corresponding to inactive or active forms of the enzyme. While these states have shed light on the intricacies of LONP1 substrate translocation and proteolytic processing, little is known about the decision-making involved in LONP1 substrate engagement and subsequent initiation of its unfoldase activity. Here, we use cryo-EM to determine a novel ADP-bound, C3-symmetric intermediate state of LONP1 (LONP1C3) with putative substrate "fold-sensing" capabilities. Our biochemical and structural data indicate that LONP1C3 is an on-pathway intermediate and that is stabilized by interaction with folded substrates. Moreover, we identify additional symmetric and asymmetric conformational states, including a two-fold symmetric split-hexamer conformation, that we associate with the transition from LONP1C3 to LONP1ENZ. We propose that the C3-state regulates substrate selection and enables LONP1 to efficiently surveil the matrix proteome to ensure selective removal of damaged and dysfunctional proteins as well as privileged LONP1 substrates. These findings collectively provide further mechanistic insights into LONP1 substrate recruitment and engagement and inform on its diverse roles in maintaining homeostasis within the mitochondria.
    DOI:  https://doi.org/10.1101/2025.09.05.674599
  15. Biochim Biophys Acta Mol Basis Dis. 2025 Sep 15. pii: S0925-4439(25)00391-6. [Epub ahead of print]1872(1): 168043
    SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.
    Sk Eashayan Tanbir, Sib Sankar Roy.
      Sterol regulatory element binding protein 1 (SREBP1) has emerged as a central regulator of lipid metabolism, playing a pivotal role in cancer progression. However, the oncogenic potential of SREBP1a is still underexplored. This study investigates the multifaceted contributions of SREBP1a on tumorigenesis, with a particular focus on ovarian cancer. Elevated expression of the SREBP1a isoform was found to enhance proliferation, migration, and invasion of ovarian cancer cells. Mechanistically, SREBP1a induces mitochondrial fission by upregulating DRP1 expression and promoting its activation through ser616 phosphorylation, resulting in a fragmented mitochondrial network that supports enhanced bioenergetic flexibility. In parallel, SREBP1a drives PINK1-Parkin-mediated mitophagy. This coupling of mitochondrial fission and mitophagy possibly ensures mitochondrial quality control, enhances cellular bioenergetics, and increases ATP production, supporting rapid cell proliferation and migration. Experimental evidences reveal that SREBP1 directly regulates DRP1 and PINK1 transcription, reinforcing its role in regulating mitochondrial dynamics. Furthermore, targeting SREBP1 using Fatostatin, a small-molecule inhibitor, effectively disrupts mitochondrial fission, impairs mitophagy, and attenuates tumor progression. These findings highlight the novel role of SREBP1a as a key regulator of mitochondrial dynamics, establishing it as a promising therapeutic target in ovarian cancer. Future studies should explore combinatorial strategies integrating SREBP1a inhibition with existing therapies to improve treatment outcomes.
    Keywords:  DRP1; Fatostatin; Ovarian cancer; PINK1-Parkin mitophagy; SREBP1a
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168043
  16. Nat Struct Mol Biol. 2025 Sep 18.
    Towards a molecular and structural definition of cell death.
    Eli Arama, Katia Cosentino, Peter E Czabotar, Boyi Gan, Elizabeth Hartland, Xuejun Jiang, Jonathan C Kagan, Shigekazu Nagata, Kate Schroder, Liming Sun, Daichao Xu, Junying Yuan.
      
    DOI:  https://doi.org/10.1038/s41594-025-01646-x
  17. QJM. 2025 Sep 18. pii: hcaf188. [Epub ahead of print]
    Mitochondrial DNA mutations as a potential modifier for the clinical variability of marfan syndrome.
    Yuduo Wu, Xu Zhang, Zhengyang Zhang, Peng An, Yihua He, Hongjia Zhang, Yongting Luo, Junjie Luo.
      Marfan syndrome (MFS) is an autosomal genetic disease caused by FBN1 mutation. Patients with the same FBN1 mutation type exhibit different phenotypes, which indicates additional risk factors. Mitochondrial dysfunction was observed in the aorta of both MFS patients and Marfan murine models. Single nucleotide variants in mitochondrial DNA (mtDNA) may have harmful consequences on a cell. However, the association of mtDNA mutations with MFS has been unclear. Here, we used targeted mtDNA sequencing to detect whole blood mtDNA mutations from 48 healthy controls and 77 MFS patients, including 7 mother-offspring pedigrees. Three rare mtDNA mutations, m.279T > C, m.2361G > A, and m.3316G > A, were identified in a family whose predominant phenotype was eye lesions. The MFS patients with these mutations had more severe symptoms than family members without the mutation. m.9738G > A was identified in a family whose dominant phenotype was aortic manifestation. A sporadic case with this rare mutation site has an aortic aneurysm. We also described the mutation frequency and mutation rate in MFS. The frequency of all solid variants, nonsynonymous variants, pathogenic or likely pathogenic variants and variants of uncertain significance were more abundant in MFS patients compared to the control group. The mutation rate of the coding region, MT-rRNA and MT-tRNA were higher in the MFS group. These data demonstrate frequent mitochondrial mutation in MFS and suggest that the mtDNA mutation might be a potential modifier of MFS phenotypes.
    Keywords:  Marfan syndrome; mitochondrial dysfunction; mtDNA sequencing; mtDNA variants
    DOI:  https://doi.org/10.1093/qjmed/hcaf188
  18. Biochim Biophys Acta Rev Cancer. 2025 Sep 16. pii: S0304-419X(25)00195-7. [Epub ahead of print] 189453
    Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression.
    Soumya Ranjan Mishra, Priyadarshini Mishra, Prakash Kumar Senapati, Kewal Kumar Mahapatra, Sujit Kumar Bhutia.
      The process of mitochondrial fission is a major determinant of mitochondrial homeostasis. DRP1 is the chief architect of the mitochondrial fission process, and the DRP1 recruitment to the mitochondrial outer membrane is necessary for the mitochondrial division. DRP1 contributes to cancer progression by promoting cell proliferation, enhancing resistance to therapy, inhibiting mitochondrial-mediated apoptosis, suppressing immune responses, and sustaining cancer stem cell heterogeneity and self-renewal. Moreover, DRP1 drives metabolic reprogramming to support enhanced energy production and biosynthesis required for tumor growth and survival. In addition, DRP1-mediated mitochondrial fission also favours NLRP3 inflammasome activation within the tumor microenvironment, which regulates cancer progression. Interestingly, elevated levels of DRP1 expression have been identified as a significant prognostic marker, correlating with poor survival outcomes across multiple cancer types. Many DRP1 inhibitors have been developed for cancer treatment, but more specific and selective agents are needed to improve efficacy and reduce off-target effects. A comprehensive understanding of DRP1's role in cancer cells is essential for developing DRP1 inhibitors, which hold promise as novel anticancer therapies and may enhance the effectiveness of conventional treatments.
    Keywords:  Cancer; Chemoresistance; DRP1; Metabolic reprograming; Mitochondrial fission; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189453
  19. Protein Cell. 2025 Sep 18. pii: pwaf079. [Epub ahead of print]
    Deciphering the RNA Landscapes on Mammalian Cell Surfaces.
    Xiao Jiang, Chu Xu, Enzhuo Yang, Danhua Xu, Yong Peng, Xue Han, Jingwen Si, Qixin Shao, Zhuo Liu, Qiuxiao Chen, Weizhi He, Shuang He, Yanhui Xu, Chuan He, Xinxin Huang, Lulu Hu.
      Cell surface RNAs, notably glycoRNAs, have been reported, yet the precise compositions of surface RNAs across different primary cell types remain unclear. Here, we introduce a comprehensive suite of methodologies for profiling, imaging, and quantifying specific surface RNAs. We present AMOUR, a method leveraging T7-based linear amplification, to accurately profile surface RNAs while preserving plasma membrane integrity. By integrating fluorescently labeled DNA probes with live primary cells, and employing imaging along with flow cytometry analysis, we can effectively image and quantify representative surface RNAs. Utilizing these techniques, we have identified diverse non-coding RNAs present on mammalian cell surfaces, expanding beyond the known glycoRNAs. We confirm the membrane anchorage and quantify the abundance of several representative surface RNA molecules in cultured HeLa cells and human umbilical cord blood mononuclear cells (hUCB-MNCs). Our imaging and flow cytometry analyses unequivocally confirm the membrane localization of Y family RNAs, spliceosomal snRNA U5, mitochondrial rRNA MTRNR2, mitochondrial tRNA MT-TA, VTRNA1-1, and the long non-coding RNA XIST. Our study not only introduces effective approaches for investigating surface RNAs but also provides a detailed portrayal of the surface RNA landscapes of hUCB-MNCs and murine blood cells, paving the way for future research in the field of surface RNAs.
    DOI:  https://doi.org/10.1093/procel/pwaf079
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒18 at 1:01.