bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–03–30
eleven papers selected by
Marco Tigano, Thomas Jefferson University
  1. In situ architecture of the human prohibitin complex.
  2. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  3. Immp2l gene knockout induces granulosa cell senescence by activation of cGAS-STING pathway via TFAM-mediated mtDNA leakage.
  4. Unclogging of the TOM complex under import stress.
  5. Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA.
  6. Oxidation of retromer complex controls mitochondrial translation.
  7. Ferroptosis spreads to neighboring cells via plasma membrane contacts.
  8. Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.
  9. Plasticity of the mammalian integrated stress response.
  10. A human brain map of mitochondrial respiratory capacity and diversity.
  11. SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.
  1. Nat Cell Biol. 2025 Mar 21.
    In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      Prohibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others. The human prohibitins prohibitin 1 and prohibitin 2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organization has remained elusive. Here we determined the molecular organization of the human prohibitin complex within the mitochondrial inner membrane using an integrative structural biology approach combining quantitative western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling. The proposed bell-shaped structure consists of 11 alternating prohibitin 1 and prohibitin 2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3% of the crista membrane area. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organization of the mitochondrial inner membrane.
    DOI:  https://doi.org/10.1038/s41556-025-01620-1
  2. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  3. Int J Biol Macromol. 2025 Mar 20. pii: S0141-8130(25)02920-4. [Epub ahead of print] 142368
    Immp2l gene knockout induces granulosa cell senescence by activation of cGAS-STING pathway via TFAM-mediated mtDNA leakage.
    Pengge Pan, Sinan Cao, Hui Gao, Xiaoya Qu, Yan Ma, Jinyi Yang, Xiuying Pei, Yanzhou Yang.
      Granulosa cell-produced inflammatory factors may be key contributors to ovarian dysfunction, and Immp2l deficiency accelerates ovarian aging via granulosa cell senescence; however, the role of inflammation in granulosa cell senescence is largely unknown. Therefore, in this study, cGAS-STING-mediated inflammation was explored in Immp2l deficiency-induced granulosa cell senescence. Immp2l deficiency led to senescence-associated secretory phenotype (SASP) and granulosa cell senescence. Immp2l knockout caused mitochondrial dysfunction and mitochondrial DNA (mtDNA) leakage into the cytoplasm. The cytoplasmic mtDNA was recognized by the DNA-sensing molecule cGAS-STING, which activates cGAS-STING and key downstream interferon-stimulated genes (ISGs) and then promotes the secretion of proinflammatory factors, leading to SASP in senescent granulosa cells. Interestingly, the mitochondrial inner membrane pore protein (Cyclophilin D40) CyPD40 and the outer membrane pore protein voltage-dependent-anion channel 1 (VDAC1) were markedly increased in senescent granulosa cells, accompanied by significantly increased expression of the mtDNA stability protein mitochondrial transcription factor A (TFAM). Downregulation of TFAM with siRNA in senescent granulosa cells improved mitochondrial function, significantly decreased mtDNA in the cytoplasm, inhibited the cGAS-STING pathway and markedly decreased CyPD40 and VDAC1 protein levels in TFAM-treated senescent granulosa cells. The SASP phenotype was also alleviated. In addition, senescent granulosa cells were treated with procyanidin B2 (PCB2), which has anti-inflammatory effects, and the TFAM-mediated mtDNA-cGAS-STING pathway was inhibited, accompanied by a markedly reduced SASP phenotype and granulosa cell senescence. In conclusion, Immp2l gene knockout induced granulosa cell senescence by activation of the cGAS-STING pathway via TFAM-mediated mtDNA leakage into the cytoplasm through the CyPD40 and the VDAC1.
    Keywords:  Cell senescence; Mitochondrial dysfunction; Procyanidin B2; SASP; TFAM; cGAS-STING
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142368
  4. Biol Chem. 2025 Mar 28.
    Unclogging of the TOM complex under import stress.
    Joshua Jackson, Thomas Becker.
      Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor proteins on cytosolic ribosomes. Mitochondrial protein translocases sort the precursor proteins into the mitochondrial sub-compartments: outer and inner membrane, the intermembrane space and the matrix. The translocase of the outer mitochondrial membrane (TOM complex) constitutes the major import site for most of these precursor proteins. Defective protein translocases, premature folding of the precursor, or depletion of the membrane potential can cause clogging of the TOM channel by a precursor protein. This clogging impairs further protein import and leads to accumulation of precursor proteins in the cell that perturbates protein homeostasis, leading to proteotoxic stress in the cell. Therefore, unclogging of the translocon is critical for maintaining mitochondrial and cellular function. Ubiquitylation and AAA-ATPases play a central role in the extraction of the precursor proteins to deliver them to the proteasome for degradation. Here we summarize our understanding of the molecular mechanisms that remove such translocation-stalled precursor proteins from the translocation channel to regenerate the TOM complex for protein import.
    Keywords:  AAA ATPases; TOM complex; mitochondria; protein import; quality control; ubiquitylation
    DOI:  https://doi.org/10.1515/hsz-2025-0110
  5. Nat Biotechnol. 2025 Mar 25.
    Leveraging base excision repair for efficient adenine base editing of mitochondrial DNA.
    Yuhang Fan, Wenchao Xu, Bao-Qing Gao, Huichao Qin, Xiaoyi Wu, Jia Wei, Qingyang Ni, Lina Zhou, Jiangchao Xiang, Jing Wu, Bei Yang, Li Yang, Jia Chen.
      Transcription activator-like effector-linked deaminases (TALEDs) use their single-stranded DNA (ssDNA)-specific adenosine deaminase TadA8e to mediate A-to-G editing in mitochondrial DNA (mtDNA). The working mechanism of this process is unknown, hindering the development of more effective TALEDs. Here we reveal that TALED-mediated A-to-G editing relies on the formation of an ssDNA region through base excision repair (BER), which is triggered by double-stranded DNA-specific cytidine deaminase (DddA)-induced C-to-U deamination. We develop a series of enhanced TALEDs (eTALED6s) with increased editing efficiency by replacing DddA with the high-activity variant DddA6 and fusing human uracil DNA glycosylase to TadA8e. By further engineering TadA8e, the resulting eTALED6Rs induces efficient on-target editing with reduced bystander editing and off-target editing at the DNA and RNA levels. Lastly, we use eTALED6 and eTALED6R to install a pathogenic mutation in mtDNA. Revealing the mechanism of TALED-mediated A-to-G editing demonstrates that enhancing BER increases editing efficiency.
    DOI:  https://doi.org/10.1038/s41587-025-02608-w
  6. Nature. 2025 Mar 26.
    Oxidation of retromer complex controls mitochondrial translation.
    Junbing Zhang, Md Yousuf Ali, Harrison Byron Chong, Pei-Chieh Tien, James Woods, Carolina Noble, Tristan Vornbäumen, Zehra Ordulu, Anthony P Possemato, Stefan Harry, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, MinGyu Choi, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Natalya N Pavlova, Michael Lawrence, Justin F Gainor, Sean A Beausoleil, Nabeel Bardeesy, Raul Mostoslavsky, David Pépin, Christopher J Ott, Brian Liau, Liron Bar-Peled.
      Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.
    DOI:  https://doi.org/10.1038/s41586-025-08756-y
  7. Nat Commun. 2025 Mar 26. 16(1): 2951
    Ferroptosis spreads to neighboring cells via plasma membrane contacts.
    Bernhard F Roeck, Sara Lotfipour Nasudivar, Michael R H Vorndran, Lena Schueller, F Isil Yapici, Matthias Rübsam, Silvia von Karstedt, Carien M Niessen, Ana J Garcia-Saez.
      Ferroptosis is a lytic, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and associated with necrosis spread in diseased tissues through unknown mechanisms. Using a novel optogenetic system for light-driven ferroptosis induction via degradation of the anti-ferroptotic protein GPX4, we show that lipid peroxidation and ferroptotic death can spread to neighboring cells through their closely adjacent plasma membranes. Ferroptosis propagation is dependent on cell distance and completely abolished by disruption of α-catenin-dependent intercellular contacts or by chelation of extracellular iron. Remarkably, bridging cells with a lipid bilayer or increasing contacts between neighboring cells enhances ferroptosis spread. Reconstitution of iron-dependent spread of lipid peroxidation between pure lipid, contacting liposomes provides evidence for the physicochemical mechanism involved. Our findings support a model in which iron-dependent lipid peroxidation propagates across proximal plasma membranes of neighboring cells, thereby promoting the transmission of ferroptotic cell death with consequences for pathological tissue necrosis spread.
    DOI:  https://doi.org/10.1038/s41467-025-58175-w
  8. Anal Chem. 2025 Mar 27.
    Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.
    Fei Peng, Xiangnan Ai, Bin Hao, Xiaoyu Bu, Zixuan Zhao, Linshuai Yang, Baoxiang Gao.
      Mitophagy is a vital lysosome-dependent process that maintains mitochondrial integrity and cellular homeostasis, where respiration and inner mitochondrial membrane (IMM) viscosity play key roles. Despite its critical importance, achieving a high-resolution and dynamic visualization of respiration and IMM viscosity during mitophagy remains a significant challenge. In this study, we designed two innovative fluorescent probes: SiR-C8, a viscosity-sensitive rotor-type probe based on silicon-rhodamine, specifically targeting the IMM, and OR-ATP, a rhodamine-derived probe utilizing an intramolecular spirolactam structure to respond to mitochondrial ATP levels. Leveraging fluorescence intensity and lifetime dual-modality imaging, we successfully enabled the high-resolution, real-time monitoring of lysosome-dependent mitophagy. Remarkably, our results unveiled a progressive increase in IMM viscosity alongside a significant attenuation in mitochondrial respiration during mitophagy induced by starvation, carbonyl cyanide, m-chlorophenyl hydrazone (CCCP), and Oligomycin. Significantly, utilizing structured illumination microscopy super-resolution imaging, we have uncovered a novel mitochondrial quality control mechanism by which lysosomes selectively engulf locally damaged mitochondrial regions. This discovery provides novel insights into the intricate processes governing mitophagy and introduces an innovative platform for studying mitochondrial dynamics, dysfunction, and their implications for cellular homeostasis and pathology.
    DOI:  https://doi.org/10.1021/acs.analchem.5c00464
  9. Nature. 2025 Mar 26.
    Plasticity of the mammalian integrated stress response.
    Chien-Wen Chen, David Papadopoli, Krzysztof J Szkop, Bo-Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M Asraf, Dawid Krokowski, Anastasios Vourekas, William C Merrick, Anton A Komar, Antonis E Koromilas, Myriam Gorospe, Matthew J Payea, Fangfang Wang, Benjamin L L Clayton, Paul J Tesar, Ashleigh Schaffer, Alexander Miron, Ilya Bederman, Eckhard Jankowsky, Christine Vogel, Leoš Shivaya Valášek, Jonathan D Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson, Ivan Topisirovic, Maria Hatzoglou.
      An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2α-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2α-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-08794-6
  10. Nature. 2025 Mar 26.
    A human brain map of mitochondrial respiratory capacity and diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .
    DOI:  https://doi.org/10.1038/s41586-025-08740-6
  11. Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00205-0. [Epub ahead of print]44(4): 115434
    SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.
    Nurul Khalida Ibrahim, Sabine Schreek, Buesra Cinar, Anna Sophie Stasche, Su Hyun Lee, Andre Zeug, Tim Dolgner, Julia Niessen, Evgeni Ponimaskin, Halyna Shcherbata, Beate Fehlhaber, Jean-Pierre Bourquin, Beat Bornhauser, Martin Stanulla, Andreas Pich, Alejandro Gutierrez, Laura Hinze.
      Adaptation to changes in amino acid availability is crucial for cellular homeostasis, which requires an intricate orchestration of involved pathways. Some cancer cells can maintain cellular fitness upon amino acid shortage, which has a poorly understood mechanistic basis. Leveraging a genome-wide CRISPR-Cas9 screen, we find that superoxide dismutase 2 (SOD2) has a previously unrecognized dismutase-independent function. We demonstrate that SOD2 regulates global proteasomal protein degradation and promotes cell survival under conditions of metabolic stress in malignant cells through the E3 ubiquitin ligases UBR1 and UBR2. Consequently, inhibition of SOD2-mediated protein degradation highly sensitizes different cancer entities, including patient-derived xenografts, to amino acid depletion, highlighting the pathophysiological relevance of our findings. Our study reveals that SOD2 is a regulator of proteasomal protein breakdown upon starvation, which serves as an independent catabolic source of amino acids, a mechanism co-opted by cancer cells to maintain cellular fitness.
    Keywords:  CP: Cancer; CP: Molecular biology; SOD2; UBR1; UBR2; amino acid starvation; cancer; drug resistance; leukemia; protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115434
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