bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–11–30
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Calcium Tunneling: A Pervasive Signaling Module Mediated by Coupling Store-Operated Ca2+ Entry and Endoplasmic Reticulum Ca2+ Release.
  2. MICU2 controls mitochondrial calcium signaling and migration in neurons during development.
  3. CISD2 ensures adequate ER-mitochondrial coupling, critically supporting mitochondrial function in neurons.
  4. PGC1-α drives MFN2-linked mitochondrial fusion aiding glioblastoma cell survival under TMZ stress.
  5. A metabolic atlas of mouse aging.
  6. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
  7. Characterization of quiescent subpopulations and proliferative compartments in glioblastoma.
  8. Mitochondrial connexin 43 modulates metabolic stress adaptation in glioma cell lines.
  1. Cold Spring Harb Perspect Biol. 2025 Nov 24. pii: a041759. [Epub ahead of print]
    Calcium Tunneling: A Pervasive Signaling Module Mediated by Coupling Store-Operated Ca2+ Entry and Endoplasmic Reticulum Ca2+ Release.
    Raphael Courjaret, Khaled Machaca.
      The ability of the cell to generate precise and sustained intracellular Ca2+ signals is governed by multiple spatial and temporal restrictions. Ca2+ flowing into the cell through plasma membrane channels activates multiple effectors but is limited to targets in the vicinity of the channel. To reach distant effectors, cells developed a mechanism termed "Ca2+ tunneling" where extracellular Ca2+ entering the cell through "store-operated Ca2+ entry" is shuttled through the lumen of the cortical endoplasmic reticulum to be released by inositol 1,4,5-trisphosphate receptors toward distal targets. Here, we review the mechanisms and functions of Ca2+ tunneling in light of recent findings linking the structure of the cortical endoplasmic reticulum at membrane contact sites and the organization of the tunneling machinery.
    DOI:  https://doi.org/10.1101/cshperspect.a041759
  2. Cell Rep. 2025 Nov 20. pii: S2211-1247(25)01355-5. [Epub ahead of print]44(12): 116583
    MICU2 controls mitochondrial calcium signaling and migration in neurons during development.
    Elena Berezhnaya, Benjamín Cartes-Saavedra, Raghavendra Singh, Macarena Rodríguez-Prados, Orly Reiner, Fowzan S Alkuraya, György Hajnóczky.
      Neurological disorders are linked to mitochondrial dysfunction and calcium overload. Mitochondrial calcium uptake is mediated by the mitochondrial calcium uniporter (mtCU), regulated by MICU1, which can be either homodimerized or heterodimerized with MICU2 or MICU3. Though MICU2 is scarce in the adult brain, MICU2 loss in patients leads to a neurodevelopmental disorder. We hypothesized that MICU2 is required for developmental calcium signaling and neuronal migration. MICU2 is present in the developing mouse brain but disappears by maturation, contrasting with other mtCU subunits that increase. MICU2 loss in mice does not affect cytoplasmic calcium but augments the mitochondrial matrix calcium rise in primary cortical neurons, leading to neuronal overmigration in the cortex and behavioral changes at 2 but not 12 months. Consistently, mitochondrial calcium uptake is not significantly affected in the adult animal cortex. MICU2-deficient patient fibroblasts copy the mitochondria-confined calcium alteration in developing neurons. Thus, MICU2 is important during neurodevelopment, likely by regulating the mtCU, and is eliminated by brain maturation.
    Keywords:  CP: cell biology; CP: neuroscience; MCU; MICU2; MICU3; anxiety; brain development; calcium signaling; mitochondria; neurodevelopmental disorders; neurons; radial migration
    DOI:  https://doi.org/10.1016/j.celrep.2025.116583
  3. Acta Neuropathol Commun. 2025 Nov 26. 13(1): 242
    CISD2 ensures adequate ER-mitochondrial coupling, critically supporting mitochondrial function in neurons.
    Jens Loncke, Ian de Ridder, Rita La Rovere, Annika Vaarmann, Guizhen Fan, Karan Ahuja, Irina Serysheva, Catherine Verfaillie, Martijn Kerkhofs, Jan B Parys, Allen Kaasik, Geert Bultynck, Tim Vervliet.
      Loss of Cisd2, an iron-sulfur cluster transfer protein, results in type 2 Wolfram syndrome (WS2), a disorder associated with severe impacts on pancreatic β cell and neuronal functions. Cisd2 has been implicated in regulating intracellular Ca2+ signaling. However, the molecular basis and cellular consequences remain poorly understood. In this work, we demonstrate that Cisd2 intersects with intracellular Ca2+ dynamics at different levels, by interacting with the inositol-1,4,5-trisphosphate receptors and as a regulator of ER-mitochondria tethering. As such, loss of Cisd2 in HeLa cells results in reduced ER-mitochondrial Ca2+ transfer while only modestly impacting cytosolic Ca2+ signaling. In HeLa cells, Cisd2 deficiency promotes autophagic flux, yet has minimal impact on mitochondrial function. However, studying the impact of Cisd2 deficiency in human induced pluripotent stem cell -derived cortical neurons revealed a severe loss of glutamate-evoked Ca2+ responses in cytosol and associated uptake in mitochondria due to loss of ER-mitochondria contact sites. Correlating with the profound changes in cellular Ca2+ handling, mitochondrial function (oxygen consumption rate, ATP production, mitochondrial potential maintenance) declined severely, while autophagic flux was increased. Overall, these deficiencies further impact the resilience of Cisd2-deficient cortical neurons to cell stress as Cisd2-KO neurons were highly sensitive to staurosporine, an inducer of apoptosis. Overall, this work is one of the first to decipher the impact of Cisd2 on ER-mitochondria Ca2+ handling in a WS2 disease-relevant cell models, thereby revealing a unique dependence of neurons on Cisd2 for their mitochondrial health and cell stress resilience.
    Keywords:  Apoptosis; Ca2+ signaling; Cisd2; ER-mitochondria contact sites; Neurodegeneration; Wolfram syndrome
    DOI:  https://doi.org/10.1186/s40478-025-02132-7
  4. Int J Biol Macromol. 2025 Nov 26. pii: S0141-8130(25)09849-6. [Epub ahead of print] 149292
    PGC1-α drives MFN2-linked mitochondrial fusion aiding glioblastoma cell survival under TMZ stress.
    Anirudha K Sahu, Prasanthi L Kaja, Subhashree Chatterjee, Megha Chaudhary, Bhawna Bissa, Rajdeep Chowdhury, Sudeshna Mukherjee.
      Glioblastoma Multiforme (GBM) is an extremely aggressive primary brain-tumor with a median-survival rate of <2 years. Higher risk in surgery has shifted the treatment paradigm towards combined chemotherapies. Interestingly, arduous dependency on chemotherapy has shown recurrence. Recent studies have portrayed the role of mitochondrial dynamics for survival under drug-pressure leading to recurrence. However, such studies exploring the role of mitochondria in response to drug stress in GBM are limited. Here we show that PGC1α (Peroxisome Proliferator-activated Receptor Gamma coactivator-1 Alpha) upregulates Mfn2 (Mitofusin 2) enhancing mitochondrial-fusion in GBM cells contributing to survival under profound Temozolomide (TMZ) stress. The interaction of PGC1α with SET1 compass / compass-like complex induces H3K4me3 trimethylations at the promoter regions of Mfn2 leading to an open chromatin assisting Mfn2 upregulation. The latter is further involved in inducing mitochondrial fusion, promoting oxidative phosphorylation which supports cell survival under stress. Notably, this further corroborates with our observations in the patient samples and clinical data where upregulation of Mfn2 was concurrently observed with elevated levels of PGC1α simultaneously leading to poor prognosis. Thus, this study provides critical insights into the molecular regulation of mitochondrial dynamics-dependent survival mechanisms in GBM that could further be exploited to design future therapies.
    Keywords:  Glioblastoma; Mfn2; Mitochondrial fusion; PGC1α; Temozolomide
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149292
  5. Cell Metab. 2025 Nov 25. pii: S1550-4131(25)00476-0. [Epub ahead of print]
    A metabolic atlas of mouse aging.
    Steven E Pilley, Dominik Awad, Djakim Latumalea, Connie New, Edgar Esparza, Shuo Wang, Xuanyi Shi, Li Zhang, Maximilian Unfried, Jasinda H Lee, Ernst Schmid, Ipsita Mohanty, Jenna L E Blum, Shivaanishaa Raventhiran, Esther Wong, Preeti R Iyengar, Racheal Mulondo, Sriraksha Bharadwaj Kashyap, Darius Moaddeli, Peter Sajjakulnukit, Damien Sutton, Harrison K A Wong, Yaqi Gao, George Wang, Aeowynn J Coakley, Gilberto Garcia, Ryo Higuchi-Sanabria, Anja Karlstaedt, Timothy L Frankel, Marina Pasca di Magliano, Whitaker Cohn, Sophia Liu, Bingfei Yu, Pieter C Dorrestein, Ernest Fraenkel, Shawn M Davidson, William B Tu, Brian K Kennedy, Costas A Lyssiotis, Peter J Mullen.
      Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.
    Keywords:  LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.016
  6. Nat Commun. 2025 Nov 28. 16(1): 10761
    Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
    Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.
      Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-65798-6
  7. bioRxiv. 2025 Oct 06. pii: 2025.10.03.680278. [Epub ahead of print]
    Characterization of quiescent subpopulations and proliferative compartments in glioblastoma.
    Anca B Mihalas, Kelly Mitchell, Sonali Arora, Samantha A O'Connor, Anoop P Patel, Christopher L Plaisier, Patrick J Paddison.
      Glioblastoma (GBM) quiescent (Q) cell populations are hypothesized to contain cancer stem-like cells (CSC) that drive tumor growth, cellular heterogeneity, and recurrence. However, GBM tumors do not neatly resolve into developmental hierarchies and Q stem-like activities are difficult to assess. Here, we evaluated tumor Q subpopulations in patient-derived GBM xenograft tumors using live cell reporters, DNA label retention assays, and single cell genomics. Compared to adult neural stems cells (NSCs), GBM Q populations contain hybrid transcriptional states composed of networks found in both dormant and activated adult NSCs, resulting in constitutive expression of key Q egress transcription factors and their targets (e.g., AP-1 and CCND1/2 ). As a result, even the longest Q-residing cells (∼12 days) in xenograft tumors continuously cycle and fail to enter dormant Q states. We provide evidence and hypothesize that transient Q states in primary tumors arise as part of distinct proliferative compartments rather than deterministic developmental hierarchies driven by CSC activity. We further speculate that increases in basal translation rates drive Q instability in GBM tumors.
    DOI:  https://doi.org/10.1101/2025.10.03.680278
  8. Cell Commun Signal. 2025 Nov 27. 23(1): 512
    Mitochondrial connexin 43 modulates metabolic stress adaptation in glioma cell lines.
    Anna Gervasi, Simona Denaro, Simona D'Aprile, Maja Potokar, Jernej Jorgačevski, Robert Zorec, Daniele Tibullo, Agata Zappalà, Angela Maria Amorini, Rosalba Parenti, Nunzio Vicario.
       BACKGROUND: Connexin 43 (CX43) is a hemichannel (HC)- and gap junction (GJ)-forming protein that mediates the exchange of small molecules between the intracellular and extracellular environments, as well as intercellular communication. In addition to this canonical role, recent studies have shown that its functions range from transcriptional regulation to intracellular homeostasis. The ability of CX43 to translocate into mitochondria suggests its involvement in energy metabolism. However, the functions of mitochondrial CX43 (mt-CX43) in neural cells remain unexplored.
    METHODS: Our study investigated the expression and localisation of mt-CX43 through western blot and immunofluorescence analyses in four immortalised human glioma cell lines: T98-G, A-172, CCF-STTG1, and U-87 MG. Additionally, targeted metabolomic analysis was conducted to assess changes in key metabolic pathways.
    RESULTS: Basal CX43 expression and extracellular stress factors, particularly cell density and extracellular pH fluctuations, significantly modulated the mitochondrial localisation of CX43. Inhibition of the heat shock protein 90 (HSP90) chaperone system by geldanamycin (GA) resulted in a marked reduction in mt-CX43, suggesting an import mechanism involving HSP90 and the translocase of the outer membrane (TOM) complex. In addition, the assessment of key metabolites revealed increased purine biosynthesis in T98-G cells exposed to GA treatment, characterised by lower basal CX43 expression and reduced mt-CX43 levels under stress conditions. Conversely, U-87 MG cells exhibited a stable NAD+/NADH ratio and a significant increase in NADH levels, indicating a metabolic shift towards a more resilient state.
    CONCLUSIONS: Our results suggest that mt-CX43 serves as a multifunctional regulator of metabolic adaptation and stress response in glioma cell lines. Our results extend the role of mt-CX43 as an essential factor in cellular metabolic plasticity, providing new insights into the modulation of metabolic imbalances and mitochondrial dysfunction.
    Keywords:  CX43; Geldanamycin; Glioblastoma; Metabolism; Purine; pH
    DOI:  https://doi.org/10.1186/s12964-025-02523-2
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