bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–08–10
seven papers selected by
Marco Tigano, Thomas Jefferson University
  1. Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.
  2. Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
  3. Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.
  4. Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury.
  5. A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
  6. Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.
  7. Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.
  1. EMBO Mol Med. 2025 Aug 05.
    Convergent activation of the integrated stress response and ER-mitochondria uncoupling in VAPB-associated ALS.
    Curran Landry, James P Costanzo, Miguel Mitne-Neto, Mayana Zatz, Ashleigh E Schaffer, Maria Hatzoglou, Alysson R Muotri, Helen C Miranda.
      Vesicle-associated membrane protein-associated protein-B (VAPB) is an endoplasmic reticulum (ER) membrane-bound protein. The P56S mutation in VAPB causes a dominant, familial form of amyotrophic lateral sclerosis (ALS). However, the mechanism by which this mutation leads to motor neuron (MN) degeneration remains unclear. Utilizing inducible pluripotent stem cell (iPSC)-derived MNs expressing either wild-type (WT) or P56S VAPB, we demonstrate that the mutant protein reduces neuronal firing and disrupts ER-mitochondria-associated membranes (ER MAMs), with a time-dependent decline in mitochondrial membrane potential (MMP), hallmarks of MN pathology. These findings were validated in patient-derived iPSC-MNs. Additionally, VAPB P56S MNs show increased susceptibility to ER stress, elevated expression of the Integrated Stress Response (ISR) regulator ATF4 under stress, and reduced global protein synthesis. Notably, pharmacological ISR inhibition using ISRIB rescued ALS-associated phenotypes in both VAPB P56S and patient-derived iPSC-MNs. We present the first evidence that the VAPB P56S mutation activates ISR signaling via mitochondrial dysfunction in human MNs. These findings support ISR modulation as a strategy for ALS intervention and highlight the need for patient stratification in clinical trials.
    Keywords:  ALS (Amyotrophic Lateral Sclerosis); ER-MAM (Endoplasmic Reticulum Mitochondria Associated Membrane); ISR (Integrated Stress Response); Neurodegeneration; VAPB ((Vesicle Associated Membrane Protein Associated Protein B)
    DOI:  https://doi.org/10.1038/s44321-025-00279-3
  2. bioRxiv. 2025 Jul 29. pii: 2025.07.28.667051. [Epub ahead of print]
    Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
    Casadora Boone, Sophie Judge, Ahmad Shami, Bezawit Danna, Andrea B Ball, Tejashree Pradip Waingankar, Hera Saqub, Ajit S Divakaruni, Samantha C Lewis.
      Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools available to cells is critical, as monounsaturated fatty acid supplementation rescued both ER proteostasis and mtDNA synthesis, even in the presence of excess saturated fat. We propose that shutoff of mtDNA synthesis conserves mtDNA-to-mitochondrial network scaling until cells can regain ER homeostasis.
    Summary: Overnutrition of cultured human cells causes endoplasmic reticulum dysfunction, which downregulates mitobiogenesis in turn by constraining mtDNA synthesis.
    DOI:  https://doi.org/10.1101/2025.07.28.667051
  3. bioRxiv. 2025 Jul 24. pii: 2025.07.24.666629. [Epub ahead of print]
    Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.
    Subrata Pradhan, Sagar Gaikwad, Chi-Lin Tsai, Charlene Smith, Nan Zhang, Keegan Bush, Anirban Chakraborty, Subo Yuan, Sanjeev Choudhary, C Dirk Keene, Lisa M Ellerby, Tapas K Hazra, Albert R La Spada, Yogesh P Wairkar, Tatsuo Ashizawa, John A Tainer, Tej K Pandita, Leslie M Thompson, Partha S Sarkar.
      Huntingtin (HTT) function is enigmatic, as the native protein plays critical roles in neuronal health, while mutant HTT (mHTT), carrying an expanded polyglutamine stretch, triggers neurotoxicity and contributes to the pathogenesis of Huntington's disease (HD). We recently found that HTT is part of a nuclear transcription-coupled DNA repair (TCR) complex with DNA repair enzymes including polynucleotide-kinase-3'-phosphatase (PNKP). This complex resolves DNA lesions during transcription to maintain genome integrity, while in HD, mHTT impairs the activity of this complex, resulting in accumulation of DNA lesions. Using molecular, cellular biology and computational methods, we find that HTT has a role in assembling a functional DNA repair complex in mitochondria. Together with mitochondrial RNA polymerase and transcription factors, HTT resolves mitochondrial DNA lesions to preserve mitochondrial genome integrity and function. Pathogenic mHTT impairs this activity, resulting in persistent DNA lesions and reduced mitochondrial function in HD. Importantly, restoring activity of this complex in a Drosophila HD model through ectopic HTT or PNKP expression significantly improves mitochondrial genome integrity and ameliorates motor deficits.
    HIGHLIGHTS: HTT organizes a functional, multifactorial mitochondrial DNA repair complexMutant HTT impairs the mitochondrial DNA repair complex causing DNA damage accumulationHTT-associated repair complex resolves mitochondrial DNA lesions and DNA integrityRestoring repair activity in HD flies rescues mitochondrial DNA integrity and motor defects.
    DOI:  https://doi.org/10.1101/2025.07.24.666629
  4. Cell Mol Life Sci. 2025 Aug 08. 82(1): 305
    Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury.
    Shishi Zou, Yifan Zuo, Yukai Chen, Tianyu Zhang, Tinglv Fu, Guorui Li, Rui Xiong, Bohao Liu, Yong Hu, Zhaoyu Hu, Chunguang Miao, Xiaojing Wu, Ning Li, Qing Geng.
      The stimulator of interferon genes (STING) pathway serves as a crucial nexus in inflammatory responses and cell death. Despite its role in Mitochondria-Endoplasmic Reticulum Contact (MERC), the mechanistic contributions to inflammatory outcomes remain poorly understood. In clinical acute respiratory distress syndrome (ARDS) models of COVID-19 infection and animal models of LPS-induced acute lung injury (ALI), the STING pathway is closely associated with the pyroptosis pathway. The macrophage STING-N-GSDMD-mtDNA positive feedback loop, upon LPS challenge, induces inflammatory responses and pyroptosis. The GSDMD inhibitor disulfiram (DSF) specifically abrogates the N-terminal portion of GSDMD anchored to the mitochondrial membrane. Furthermore, macrophage STING mediates the direct interaction between Drp1 and N-GSDMD on mitochondrial membrane by regulating mitochondrial calcium, linking mitochondrial fission to the induction of inflammatory responses. Targeting STING-mediated mitochondrial homeostasis, both genetically and pharmacologically, may play a protective role in preventing and treating sepsis-induced acute lung injury. Overall, our study posits that STING deficiency mitigates the cooperative interaction between N-GSDMD and Drp1 in mediating mitochondrial permeabilization and rupture following LPS challenge, paving the way for further investigations into inflammation and pyroptosis.
    Keywords:  Endoplasmic Reticulum-Mitochondria contact; Mitochondrial calcium; Mitochondrial dynamics; MtDNA release; Pyroptosis
    DOI:  https://doi.org/10.1007/s00018-025-05774-x
  5. bioRxiv. 2025 Aug 01. pii: 2025.07.29.667405. [Epub ahead of print]
    A molecular switch in NAC prevents mitochondrial protein mistargeting by SRP.
    Emir Maldosevic, Radoslaw Gora, Liangguang Leo Lin, Linyao Elina Zhou, Zexin Jason Li, Yelena Peskova, Ling Qi, Shu-Ou Shan, Ahmad Jomaa.
      The nascent polypeptide-associated complex (NAC) co-translationally screens all nascent proteins and regulates their access to the signal recognition particle (SRP) to ensure the fidelity of protein targeting to the endoplasmic reticulum (ER). However, the mechanism by which NAC prevents the mistargeting of nascent mitochondrial proteins remains unclear. Here, we identified a molecular switch in NAC that allows its central barrel domain to adopt a stabilized conformation on ribosomes exposing a mitochondrial targeting sequence (MTS). Mutations of the MTS on the nascent chain or in the NAC switch region increases NAC barrel dynamics and reduces its binding to the ribosome. This leads to an impaired ability of NAC to prevent mistargeting by SRP and causes ER stress in human cells. Our work reveals how NAC detects nascent mitochondrial proteins early in translation and prevents their promiscuous access to SRP, elucidating the structural basis that underlies this role and providing novel insights into protein targeting fidelity with broader implications for cellular proteostasis.
    DOI:  https://doi.org/10.1101/2025.07.29.667405
  6. bioRxiv. 2025 Aug 02. pii: 2025.08.01.668243. [Epub ahead of print]
    Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.
    Adarsh Rajesh, Aaron P Havas, Rouven Arnold, Kathryn Lande, K Garrett Evensen, Kelly Yichen Li, Sainath Mamde, Qian Yang, Armin Gandhi, Karl N Miller, Marcos Garcia Teneche, Zoe Yao, Jessica Proulx, Andrew Davis, Laurence Haddadin, Michael Alcaraz, Carolina Cano Macip, Brightany Li, Xue Lei, Charlene Miciano, Elizabeth Smoot, Allen Wang, Jeffrey H Albrecht, April E Williams, Bing Ren, Kevin Y Yip, Peter D Adams.
      Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.
    DOI:  https://doi.org/10.1101/2025.08.01.668243
  7. bioRxiv. 2025 Jul 31. pii: 2025.07.30.667736. [Epub ahead of print]
    Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.
    Johnathon Sturgis, Ke Jiang, Stephanie A Hagstrom, Maya Moorthy, Vera L Bonilha.
      Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet to be thoroughly explored. Our previous studies focused on the retinal phenotype observed in the PolgD257A mutator mice (D257A), revealing the effects of aging and mtDNA mutation accumulation in the retina. We have reported that this model exhibited significant morphological and functional deficits in the retina by 6 months of age, with notable alterations in the retinal pigment epithelium (RPE) occurring as early as 3 months, including changes in the cristae density and reduction in length of mitochondria. This study investigated how mtDNA mutations affect the metabolic interaction between the retina and RPE in young (3 months) and old (12 months) wild-type (WT) and D257A mice. We assessed cellular energy production using freshly dissected retina samples from both groups through Seahorse analysis, immunofluorescence, and Western blot experiments. The analysis of aged D257A retina punches revealed significantly reduced basal and maximal mitochondrial respiration, along with increased mitochondrial reserve capacity compared to WT. However, glycolytic flux, measured as a function of extracellular acidification rate (ECAR), did not differ between WT and D257A mice. Both D257A retina and RPE exhibited decreased expression of essential electron transport proteins involved in oxidative phosphorylation. Additionally, we observed a reduction in the expression of glucose transporter 1 (GLUT-1) and lactate transporter (MCT1) at the apical surface of the RPE. Enzymes associated with glycolysis, including hexokinase II and lactate dehydrogenase A, were significantly lower in the aged D257A retina, while hexokinase I and pyruvate kinase 2 were upregulated in the RPE. These findings indicate that the accumulation of mtDNA mutations leads to impaired metabolism in both the retina and RPE. Furthermore, it suggests that glucose from the choroidal blood supply is being utilized by the RPE rather than being transported to the neural retina. Mitochondrial dysfunction in RPE promotes a glycolytic state in these cells, leading to reduced availability of metabolites and, consequently, diminished overall retinal function. These results are essential for advancing our understanding of the mechanisms underlying retinal degeneration and provide a new perspective on the role of mtDNA mutations in these diseases.
    DOI:  https://doi.org/10.1101/2025.07.30.667736
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