bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–09–21
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics.
  2. BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.
  3. Interaction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1.
  4. Advancing biological understanding of cellular senescence with computational multiomics.
  5. Boosted mitochondria reverse cognitive impairment in mice.
  6. The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells.
  7. Metabolic regulation in the senescence process of stem cells.
  8. Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.
  1. bioRxiv. 2025 Sep 04. pii: 2025.08.30.673265. [Epub ahead of print]
    InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics.
    Gaomin Feng, Elizabeth M Ruark, Alexandra G Mulligan, Eric K F Donahue, Anthony Hoang, Brianne Jacquet-Cribe, Li Peng, Kristopher Burkewitz.
      Certain forms of mitochondrial impairment confer longevity, while mitochondrial dysfunction arising from aging and disease-associated mutations triggers severe pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/ nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca 2+ channel, InsP3R. We find that the InsP3R promotes mitochondrial respiration, but the mitochondrial calcium uniporter is dispensable for both respiration and lifespan extension in Complex I mutants, suggesting InsP3R action is independent of matrix Ca 2+ flux. Transcriptomic profiling and imaging reveal a previously unrecognized role for the InsP3R in regulating mitochondrial scaling, where InsP3R impairment results in maladaptive hyper-expansion of dysfunctional mitochondrial networks. We reveal a conserved InsP3R signaling axis through which calmodulin and actomyosin remodeling machineries, including Arp2/3, formin FHOD-1, and MLCK, constrain mitochondrial expansion and promote longevity. Disruption of actin remodeling or autophagy mimics InsP3R loss. Conversely, driving fragmentation ameliorates mitochondrial expansion and rescues longevity, supporting a model in which InsP3R-dependent actin remodeling sustains mitochondrial turnover. These findings establish an inter-organelle signaling axis by which ER calcium release orchestrates mitochondrial-based longevity through cytoskeletal effectors.
    DOI:  https://doi.org/10.1101/2025.08.30.673265
  2. Nat Metab. 2025 Sep 16.
    BDH2-driven lysosome-to-mitochondria iron transfer shapes ferroptosis vulnerability of the melanoma cell states.
    Francesca Rizzollo, Abril Escamilla-Ayala, Nicola Fattorelli, Natalia Barbara Lysiak, Sanket More, Pablo Hernández Varas, Lucia Barazzuol, Chris Van den Haute, Joris Van Asselberghs, David Nittner, Jonathan Coene, Vivek Venkataramani, Bernhard Michalke, Christine Gaillet, Tatiana Cañeque, Irwin Davidson, Steven H L Verhelst, Peter Vangheluwe, Tito Calì, Jean-Christophe Marine, Raphaël Rodriguez, Julie Bonnereau, Patrizia Agostinis.
      Iron sustains cancer cell plasticity, yet it also sensitizes the mesenchymal, drug-tolerant phenotype to ferroptosis. This posits that iron compartmentalization must be tightly regulated. However, the molecular machinery governing organelle Fe(II) compartmentalization remains elusive. Here, we show that BDH2 is a key effector of inter-organelle Fe(II) redistribution and ferroptosis vulnerability during melanoma transition from a melanocytic (MEL) to a mesenchymal-like (MES) phenotype. In MEL cells, BDH2 localizes at the mitochondria-lysosome contacts (MLCs) to generate the siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA), which ferries iron into the mitochondria. Fe(II) transfer by BDH2 supports mitochondrial bioenergetics, which is required to maintain lysosomal acidification and MLC formation. Loss of BDH2 alters lysosomal pH and MLC tethering dynamics, causing lysosomal iron sequestration, which primes MES cells for ferroptosis. Rescuing BDH2 expression, or supplementing 2,5-DHBA, rectifies lysosomal pH and MLCs, protecting MES cells from ferroptosis and enhancing their ability to metastasize. Thus, we unveil a BDH2-dependent mechanism that orchestrates inter-organelle Fe(II) transfer, linking metabolic regulation of lysosomal pH to the ferroptosis vulnerability of the mesenchymal, drug-tolerant cancer cells.
    DOI:  https://doi.org/10.1038/s42255-025-01352-4
  3. Commun Biol. 2025 Sep 19. 8(1): 1348
    Interaction of the mitochondrial calcium/proton exchanger TMBIM5 with MICU1.
    Li Zhang, Benjamin Gottschalk, Felicia Dietsche, Sara Bitar, Diones Bueno, Liliana Rojas-Charry, Anshu Kumari, Vivek Garg, Wolfgang F Graier, Axel Methner.
      Ion transport within mitochondria influences their structure, energy production, and cell death regulation. TMBIM5, a conserved calcium/proton exchanger in the inner mitochondrial membrane, contributes to mitochondrial structure, ATP synthesis, and apoptosis regulation. The relationship of TMBIM5 with the mitochondrial calcium uniporter complex formed by MCU, MICU1-3, and EMRE remains undefined. We generated Tmbim5-deficient Drosophila that exhibit disrupted cristae architecture, premature mitochondrial permeability transition pore opening, reduced calcium uptake, and mitochondrial swelling - resulting in impaired mobility and shortened lifespan. Crossing these with flies lacking mitochondrial calcium uniporter complex proteins was generally detrimental, but partial MICU1 depletion ameliorated the Tmbim5-deficiency phenotype. In human cells, MICU1 rescues morphological defects in TMBIM5-knockout mitochondria, while TMBIM5 overexpression exacerbates size reduction in MICU1-knockout mitochondria. Both proteins demonstrated opposing effects on submitochondrial localization and coexisted in the same macromolecular complex. Our findings establish a functional interplay between TMBIM5 and MICU1 in maintaining mitochondrial integrity, with implications for understanding calcium homeostasis mechanisms.
    DOI:  https://doi.org/10.1038/s42003-025-08839-6
  4. Nat Genet. 2025 Sep 15.
    Advancing biological understanding of cellular senescence with computational multiomics.
    SenNet Consortium
      Cellular senescence is a complex biological process that plays a pathophysiological role in aging and age-related diseases. The biological understanding of senescence at the cellular and tissue levels remains incomplete due to the lack of specific biomarkers as well as the relative rarity of senescent cells, their phenotypic heterogeneity and dynamic features. This Review provides a comprehensive overview of multiomic approaches for the characterization and biological understanding of cellular senescence. The technical capability and challenges of each approach are discussed, and practical guidelines are provided for selecting tools for identifying, characterizing and spatially mapping senescent cells. The importance of computational analyses in multiomics research, including senescent cell identification, signature detection and interactions of senescent cells with microenvironments, is highlighted. Moreover, tissue-specific case studies and experimental design considerations for individual organs are presented. Finally, future directions and the potential impact of multiomic approaches on the biological understanding of cellular senescence are discussed.
    DOI:  https://doi.org/10.1038/s41588-025-02314-y
  5. Nat Biotechnol. 2025 Sep;43(9): 1425
    Boosted mitochondria reverse cognitive impairment in mice.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-025-02823-5
  6. J Oncol Res Ther. 2025 ;pii: 10299. [Epub ahead of print]10(3):
    The Nuclear-Encoded Cytochrome c Oxidase Subunit COX4-1 Enhances Hypoxia Tolerance in Glioblastoma Cells.
    Claudia R Oliva, Susanne Flor, Md Yousuf Ali, Corinne E Griguer.
      Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. While chemo- and radiotherapy are often effective in treating newly diagnosed GBM, increasing evidence suggests that treatment-induced metabolic alterations promote tumor recurrence and further resistance. In addition, GBM tumors are typically hypoxic, which further contributes to treatment resistance. Recent studies have shown that changes in glioma cell metabolism driven by a shift in the isoform expression of mitochondrial cytochrome c oxidase (CcO) subunit 4 (COX4), a key regulatory subunit of mammalian CcO, may underlie the treatment-induced metabolic alterations in GBM cells. However, the impact of hypoxia on GBM energetics is not fully understood. Using isogenic GBM cell lines expressing either COX4-1 or the alternative COX4 isoform, COX4-2, we found that COX4-1 expressing cells maintained a more oxidative metabolism under hypoxia, characterized by increased CcO activity and ATP production, enhanced assembly of CcO-containing mitochondrial supercomplexes, and reduced superoxide production. Furthermore, COX4-1 expression was sufficient to increase radioresistance under hypoxic conditions. Untargeted metabolomic analysis revealed that the most significantly upregulated pathways in COX4-1-expressing cells under hypoxia were purine and methionine metabolism. In contrast, COX4-2-expressing cells showed increased activation of glycolysis and the Warburg effect. Our study provides new insights into how CcO regulatory subunits influence cellular metabolic networks and radioresistance in GBM under hypoxia, identifying potential therapeutic targets for improved treatment strategies.
    Keywords:  COX4–1; Cytochrome c oxidase; Glioma; Hypoxia; Mitochondrial supercomplexes; Radioresistance
    DOI:  https://doi.org/10.29011/2574-710x.10299
  7. Stem Cells Transl Med. 2025 Sep 11. pii: szaf041. [Epub ahead of print]14(9):
    Metabolic regulation in the senescence process of stem cells.
    YingYing Wei, Bin Zhang, Qingli Bie, Baoyu He.
       BACKGROUND: Aging is an inevitable and complex biological process characterized by progressive cellular and functional deterioration, leading to increased disease susceptibility and mortality. Stem cells, endowed with unique self-renewal and multipotent differentiation capabilities, play a pivotal role in tissue homeostasis and regenerative processes. However, the aging process triggers stem cell senescence, manifested by diminished proliferative capacity and differentiation potential, ultimately compromising tissue regeneration and contributing to the pathogenesis of various age-related disorders, including neurodegeneration, cardiovascular diseases, and metabolic syndromes.
    MAIN FINDINGS: Metabolic plasticity serves as a fundamental mechanism enabling stem cells to dynamically adapt their energy requirements during self-renewal and lineage commitment. Emerging evidence indicates that cellular metabolism extends beyond its conventional role in energy production, actively participating in the regulation of stem cell fate decisions. Notably, nutrient-sensitive metabolites constitute a sophisticated metabolism-epigenetic axis that integrates metabolic flux, signaling pathways, and epigenetic modifications to precisely orchestrate cellular behavior. This regulatory axis is indispensable for maintaining tissue homeostasis and facilitating regeneration, thereby positioning metabolic reprogramming as a promising therapeutic strategy for mitigating aging-associated decline.
    CONCLUSIONS: In conclusion, elucidating the intricate crosstalk between stem cell metabolism and the aging process unveils novel opportunities for developing innovative anti-aging interventions and enhancing tissue repair. Future investigations should focus on the precise manipulation of metabolic pathways to effectively counteract age-related functional deterioration and promote longevity.
    Keywords:  anti-aging interventions; metabolic reprogramming; metabolites; stem cell senescence; therapeutic targets
    DOI:  https://doi.org/10.1093/stcltm/szaf041
  8. Aging Cell. 2025 Sep 17. e70235
    Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.
    Sheeja Navakkode, Brian K Kennedy.
      Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.
    Keywords:  Alzheimer's disease; CP‐AMPA; CaAKG; NMDA; alpha‐ketoglutarate; autophagy; hippocampus; long‐term potentiation; rapamycin; synaptic plasticity
    DOI:  https://doi.org/10.1111/acel.70235
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