bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–05–17
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
  2. Whole-blood NAD+ levels do not reflect healthy ageing.
  3. Peroxisome calcium uptake is dependent on ER-peroxisome membrane contact.
  4. Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
  5. When calcium calls the shots in FAD-dependent respiration.
  6. Brain senescence drives sarcopenia-like transcriptomic remodeling in skeletal muscle.
  7. Clofoctol as a novel senolytic drug eliminating therapy-induced senescent glioma cells.
  8. Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
  9. Urinary detection of therapy-induced senescence and fibrosis using an injectable albumin-based nanoprobe.
  10. Bcl-2 upregulates calcium efflux through PMCA and NCX1 to preserve intracellular calcium homeostasis and confer resistance to apoptosis.
  11. The unbearable presence of senescent cells in ageing.
  12. Human whole-blood NAD+ levels do not vary with age or lifestyle interventions.
  1. Nat Metab. 2026 May 13.
    MICU proteins facilitate calcium-dependent mitochondrial metabolon formation to regulate cellular energetics independently of MCU.
    Henry M Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Elena Berezhnaya, Joanne F Garbincius, Adyson Johnson, Tyler L Stevens, Jordan E Howe, Hailey Lesniak, Anna Schmidt, Jennyfer Ngo, Emily Megill, Dhanendra Tomar, Nathaniel W Snyder, Wolfgang F Graier, John W Elrod.
      Mitochondrial matrix Ca2+ concentration ([Ca2+]m) is theorized to be an essential regulator of mitochondrial metabolism by positively regulating key mitochondrial dehydrogenases. However, ablation or functional inhibition of the mitochondrial calcium uniporter channel (mtCU) fails to significantly perturb basal metabolism and is largely phenotypically silent in the absence of stress. Here we demonstrate that MICU proteins, the reported gatekeepers of mtCU, function in coordination to impart calcium-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independently of the mtCU and [Ca2+]m. Our results demonstrate that MICU proteins differentially localize to mitochondrial microdomains and form heterodimers and interactomes in response to intermembrane space Ca2+ binding their respective EF-hand domains. Using an equimolar expression platform coupled with unbiased proteomics, we reveal unique interactomes for MICU1/MICU2 versus MICU1/MICU3 heterodimers and demonstrate that MICU proteins control coupling of mitochondrial glycerol-3-phosphate dehydrogenase and succinate dehydrogenase/complex II and impart calcium-dependent changes in activity. We propose that MICU-mediated mitochondrial metabolons are a fundamental system facilitating matching of mitochondrial energy production with cellular demand and is the primary physiological calcium signaling mechanism regulating homeostatic energetics, not mtCU-dependent changes in [Ca2+]m.
    DOI:  https://doi.org/10.1038/s42255-026-01513-z
  2. Nat Metab. 2026 May 14.
    Whole-blood NAD+ levels do not reflect healthy ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01540-w
  3. Cell Mol Life Sci. 2026 May 12. pii: 207. [Epub ahead of print]83(1):
    Peroxisome calcium uptake is dependent on ER-peroxisome membrane contact.
    Julia Kalinowski, Yelena Hartmann, Alexander Lütkemeyer, Sven Thoms.
      Peroxisomes are small, highly dynamic organelles involved in a plethora of metabolic pathways. They are essential for the efficient exchange of metabolites and cellular messengers orchestrating intracellular signaling. Calcium (Ca2+) is one of the most prominent physiological signaling elements and regulates a wide variety of processes in cellular homeostasis and function. Recently, we showed that peroxisomes participate in cellular Ca2+ dynamics by taking up and releasing Ca2+ following store-operated calcium entry (SOCE), however, the mechanism of peroxisomal Ca2+ uptake and its modulators remained unknown. Using live cell imaging in combination with genetically encoded calcium indicators (GECI), we show that peroxisomal calcium dynamics are independent of PEX11β and the pore protein PXMP2. Instead, we find that the ACBD5-dependent membrane contact site between peroxisomes and the endoplasmic reticulum (ER) is necessary for efficient peroxisomal Ca2+ uptake. Further, we identify the ACBD5-dependent peroxisome-ER contact site as the major factor restricting peroxisome motility within the cell. Microtubules and SOCE stimulation exert smaller and independent effects on peroxisome motility. This work expands the range of known functions of the peroxisome-ER contact site.
    Keywords:  Calcium signaling; FRET sensor; MCS; Membrane contact site; Peroxisomal disorders
    DOI:  https://doi.org/10.1007/s00018-026-06191-4
  4. Nat Aging. 2026 May 14.
    Glutamine-driven reductive TCA cycle metabolism supports aged muscle stem cell function via de novo lipogenesis.
    David E Lee, Lauren K McKay, Akshay Bareja, JiaCheng Yang, Wentao He, Demitrius A Hill, James R Bain, Shihuan Kuang, Guo-Fang Zhang, Christopher B Newgard, James P White.
      Sarcopenia and the age-related decline in muscular strength and regenerative capacity contribute directly to loss of autonomy, greater risk for hospitalization and healthcare utilization. One contributing cellular phenotype associated with skeletal muscle aging is a loss in the function and number of resident muscle stem cells (MuSCs) or satellite cells. MuSC activation leads to dramatic changes in cellular architecture and metabolic reprogramming, including both mitochondrial biogenesis and increased glycolysis. Despite these changes to increase energy production, high energy demands may not be fully met during periods of MuSC activation. Here we used in vitro and in vivo approaches in mice to demonstrate the function of glutaminase for age-related changes in MuSC function. By combining fluorescence-activated cell sorting (FACS) isolation with metabolomics and stable isotope tracing, we show an age-related decline in reductive (counterclockwise) flux of glutamine through the tricarboxylic acid (TCA) cycle, a pathway by which MuSCs build cellular fatty acid stores as necessary biomass for MuSC function.
    DOI:  https://doi.org/10.1038/s43587-026-01120-3
  5. Nat Metab. 2026 May 13.
    When calcium calls the shots in FAD-dependent respiration.
    Pablo Hernansanz-Agustín.
      
    DOI:  https://doi.org/10.1038/s42255-026-01516-w
  6. Geroscience. 2026 May 14.
    Brain senescence drives sarcopenia-like transcriptomic remodeling in skeletal muscle.
    Shoba Ekambaram, Roland Patai, Rafal Gulej, Tamas Kiss, Siva Sai Chandragiri, Dorina Nagy, Kiana Vali Kordestan, Tamas Lakat, Stefano Tarantini, Peter Mukli, Andriy Yabluchanskiy, Anna Ungvari, Zoltán Benyó, Anna Csiszar, Zoltan Ungvari.
      Aging is accompanied by a progressive decline in skeletal muscle mass and function, culminating in sarcopenia, a major contributor to frailty, disability, and mortality in older adults. While skeletal muscle aging has traditionally been attributed to cell-autonomous and local tissue mechanisms, increasing evidence suggests that systemic, cell non-autonomous processes play a central role in coordinating aging across organs. The brain, particularly the hypothalamus, has emerged as a key regulator of organismal aging, yet its contribution to skeletal muscle aging remains poorly defined. Here, we tested the hypothesis that senescence confined to the brain is sufficient to induce aging-like molecular remodeling in skeletal muscle via systemic mechanisms. To model brain senescence, young mice were subjected to fractionated whole-brain irradiation (WBI), a well-established approach that induces widespread cellular senescence and neuroinflammation in the brain while sparing peripheral tissues. Two months after WBI, transcriptomic profiling of quadriceps muscle was performed and compared with that of naturally aged mice. WBI-induced robust gene expression changes in skeletal muscle that closely mirrored those observed during chronological aging. Pathway-level analyses revealed marked downregulation of mitochondrial organization, respiratory chain assembly, and metabolic processes, alongside enrichment of remodeling- and stress-associated pathways. Upstream regulator analysis identified FOXO1, FOXO3, KLF15, and STAT3, which are key drivers of muscle catabolism and atrophy, as central mediators of the observed transcriptional program. Semantic similarity analysis further demonstrated a high concordance between WBI-induced and aging-associated biological processes. Collectively, these findings demonstrate that brain senescence is sufficient to drive sarcopenia-like transcriptomic remodeling in skeletal muscle, implicating central nervous system aging as an upstream regulator of peripheral muscle decline. This brain-muscle aging axis may contribute to frailty in individuals with accelerated brain aging and in cancer survivors exposed to cranial irradiation, highlighting brain senescence as a potential therapeutic target to mitigate systemic aging and skeletal muscle dysfunction.
    Keywords:  Accelerated aging; Cell non-autonomous aging; FOXO signaling; Frailty; Irradiation; Mitochondrial dysfunction; Sarcopenia; Senescence; Senescence-associated secretory phenotype (SASP); Skeletal muscle aging; Systemic aging; Transcriptomics
    DOI:  https://doi.org/10.1007/s11357-026-02205-y
  7. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag102
    Clofoctol as a novel senolytic drug eliminating therapy-induced senescent glioma cells.
    Yuxin Zhang, Zhixing Wang, Yue Wang, Enyan Li, Fan Wu, Lin Hou, Bin Yin, Boqin Qiang, Wei Han, Xiaozhong Peng.
       Background: Glioblastoma is the most common malignant brain glioma, accounting for ∼48% of malignant central nervous system tumors. Targeting glioma stem cells and senescent glioma cells represents promising therapeutic strategies. In our previous study, we identified the clofoctol as a candidate drug targeting glioma stem cells with good blood-brain barrier permeability and potent anti-glioblastoma efficacy. Comprehensively demonstrating the impact of clofoctol on glioblastoma might provide novel strategies for the treatment of glioblastoma.
    Methods: By utilizing single-cell RNA sequencing of tumor tissue, we demonstrated the suppression effect of clofoctol on senescent glioma cell. Cellular RNA sequencing, molecular docking and CETSA were used to further confirm target of clofoctol. Ultimately, GL261 and orthotopic patient-derived xenograft animal models was performed to assess whether the senolytic effect of clofoctol could enhance TMZ therapy.
    Results: Clofoctol treatment reduced the senescence level (SASPs, senescence-related genes, and the proportion of senescent cells) in GL261-derived tumor single-cell RNA sequencing. In vitro, clofoctol could target senescent glioma cells and induce cell death through apoptosis and ferroptosis. P53 was identified as the functional protein which elicited the effect of clofoctol. In vivo, clofoctol exhibited senolytic activity and synergized with TMZ, leading to extended survival in glioblastoma mouse model.
    Conclusions: Our study demonstrated the clinical drug clofoctol could target chemotherapy-induced senescent glioma cells through P53 and trigger cell apoptotic and ferroptotic death. We further confirmed a synergistic effect between clofoctol and temozolomide which could be a novel therapeutic approach for glioblastoma therapy.
    Keywords:  clofoctol; glioblastoma; p53; scRNA-seq; senescence
    DOI:  https://doi.org/10.1093/noajnl/vdag102
  8. Mech Ageing Dev. 2026 May 08. pii: S0047-6374(26)00043-6. [Epub ahead of print]231 112191
    Mitochondria-lysosome contacts in aging: A mechanistic interface linking organelle homeostasis and cellular decline.
    YiFan Yan, Yuetong Li, Heng Ma.
      Mitochondria-lysosome contacts (MLCs) are emerging as a dynamic membrane interface that integrates organelle communication with cellular homeostasis. Rather than acting solely as intermediates of degradative trafficking, MLCs organize local calcium transfer, lipid exchange, Rab7-dependent contact remodeling, and mitochondrial quality control. These functions place MLCs at the intersection of mitochondrial fitness, lysosomal competence, metabolic adaptation, and stress signaling. Aging provides a particularly informative setting in which to examine this interface, because mitochondrial dysfunction and lysosomal decline co-emerge and reinforce one another during cellular aging. Current evidence suggests that aging does not simply increase or decrease MLCs, but instead remodels their dynamics, molecular composition, and functional output. Such remodeling may impair mitophagy, alter calcium and lipid coupling, amplify oxidative and inflammatory stress, and contribute to age-related disease phenotypes. In this review, we summarize the structural organization and regulatory logic of MLCs, examine their mechanistic roles in organelle homeostasis, and discuss how aging reshapes this interface in physiological and pathological contexts. We also highlight key methodological challenges and therapeutic opportunities for the field.
    Keywords:  Aging; Lysosome; Membrane contact sites; Mitochondria-lysosome contacts; Mitochondrial quality control; Organelle homeostasis
    DOI:  https://doi.org/10.1016/j.mad.2026.112191
  9. Nat Aging. 2026 May 13.
    Urinary detection of therapy-induced senescence and fibrosis using an injectable albumin-based nanoprobe.
    Muhamad Hartono, Jianfeng Ge, Mary Denholm, Matthew G Ellis, Joaquín Araos Henríquez, Andrew G Baker, Robert C Rintoul, Tijmen Euser, Ljiljana Fruk, Daniel Muñoz-Espín.
      Cellular senescence is a hallmark of age-related disorders, including cancer, in which senescence contributes to tumor progression and treatment resistance. Targeting senescent cells therapeutically requires noninvasive methods to longitudinally monitor senescence burden. Here, we present an injectable nanoprobe for noninvasive detection of therapy-induced senescence in lung cancer and pulmonary fibrosis via urine testing. Using human biopsy samples, clinical transcriptomic datasets and mouse models, we identify matrix metalloproteinase-7 (MMP-7) as a specific biomarker of senescence in lung cancer and bleomycin-induced fibrosis. We develop ALBANC, a nanoprobe composed of human serum albumin linked to gold nanoclusters (AuNCs) through MMP-7-cleavable peptide linkers. MMP-7-mediated cleavage releases AuNCs that are renally excreted, enabling rapid and sensitive colorimetric urine detection via a nanoparticle growth-based assay, enabling longitudinal tracking of cisplatin-induced senescence and senolysis in mouse lung tumors and fibrosis. This approach offers a noninvasive and sensitive precision tool for monitoring senescence burden in lung cancer.
    DOI:  https://doi.org/10.1038/s43587-026-01116-z
  10. Cell Calcium. 2026 May 10. pii: S0143-4160(26)00044-8. [Epub ahead of print]136 103151
    Bcl-2 upregulates calcium efflux through PMCA and NCX1 to preserve intracellular calcium homeostasis and confer resistance to apoptosis.
    Tzu-Chien Lin, Ming-Jyun Lee, Ngoc Thang Nguyen, Shih-Chuan Hsiao, Ying-Chi Chen, Li-Hsien Chen, Sarinporn Visitsattapongse, Wen-Tai Chiu.
      Bcl-2 has been shown to regulate intracellular calcium (Ca²⁺) homeostasis, thereby influencing cellular metabolism, survival, and apoptosis. While previous studies have primarily focused on Bcl-2's role in modulating Ca²⁺ levels within the endoplasmic reticulum and mitochondria, extracellular Ca²⁺ is a major determinant of cellular activation and Ca²⁺ homeostasis. Therefore, it is important to investigate whether Bcl-2 also contributes to the regulation of Ca²⁺ flux across the plasma membrane. A vector control, wild-type Bcl-2, and a Bcl-2 mutant were stably expressed in MDCK (Madin-Darby Canine Kidney) cells that lacked endogenous Bcl-2 expression. Real-time intracellular Ca²⁺ measurements by a single-cell fluorimeter were performed to measure Ca²⁺ release and influx with the ratiometric Ca2+ indicator Fura-2 AM. Our results demonstrate that Bcl-2 enhances store-operated Ca²⁺ entry (SOCE)-mediated Ca²⁺ influx, a key mechanism underlying spontaneous Ca²⁺ oscillations. Furthermore, Bcl-2 upregulates the expression of plasma membrane Ca²⁺ ATPase (PMCA) and Na+-Ca²⁺ exchanger 1 (NCX1), which mediate Ca²⁺ extrusion from the cytosol. Pharmacological inhibition of PMCA with resveratrol (RES) and of NCX1 with ORM-10103 suppressed spontaneous Ca²⁺ oscillations, with PMCA playing a more dominant role than NCX1. Additionally, both RES and ORM-10103 exacerbated thapsigargin-induced Ca²⁺ cytotoxicity. Collectively, our findings reveal that Bcl-2 promotes Ca²⁺ influx to sustain oscillatory signaling and facilitates Ca²⁺ efflux to prevent cytotoxic accumulation, thereby maintaining Ca²⁺ homeostasis. This dual regulatory function provides new insights into Bcl-2-mediated Ca²⁺ signaling and its biological significance in apoptosis inhibition, independent of its interactions with other Bcl-2 family proteins.
    Keywords:  Bcl-2; Ca(2+) efflux; Ca²⁺ homeostasis; NCX1; PMCA; Store-operated Ca²⁺ entry
    DOI:  https://doi.org/10.1016/j.ceca.2026.103151
  11. Nat Rev Genet. 2026 May 12.
    The unbearable presence of senescent cells in ageing.
    Chanhee Kang.
      
    DOI:  https://doi.org/10.1038/s41576-026-00975-x
  12. Nat Metab. 2026 May 14.
    Human whole-blood NAD+ levels do not vary with age or lifestyle interventions.
    Maria M Trętowicz, Angelique M L Scantlebery, Bauke V Schomakers, Kaan D Eroğlu, Michel van Weeghel, Vera Spek, Kasper T Vinten, Luc Legon, Evrim Coskun, Fernando Millan-Domingo, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera, Silvia Montoro-García, Clara Noguera-Navarro, André B P van Kuilenburg, Sofia Moco, Juliette C van Hattum, Harald T Jørstad, Mohammed Benali, Jantine van der Helder, Esmee J M Biersteker, Maheswary Muniandy, Kirsi H Pietiläinen, Eija Pirinen, P Eline Slagboom, Marian Beekman, Joris Deelen, Rubén Zapata-Pérez, Peter J M Weijs, Michael Tieland, Georges E Janssens, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) levels in blood and tissues are widely proposed to decline with age, yet evidence in human blood is inconsistent. Using a rigorously validated ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry system that accounts for real-world analytical variability, we quantify NAD+ across seven independent human cohorts. We find that whole-blood NAD+ levels remain remarkably stable with age and across lifestyle interventions, but change in response to nicotinamide riboside supplementation, as expected. Our results challenge the utility of blood NAD+ levels as a biomarker of ageing or lifestyle factors.
    DOI:  https://doi.org/10.1038/s42255-026-01537-5
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