bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–02–22
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Anti-apoptotic BCL-2 binds to all three IP3R isoforms, thereby limiting the Ca2+-flux properties of IP3R homo-tetramers.
  2. Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
  3. Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
  4. BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
  5. Induction of senescence during postpartum mammary gland involution supports tissue remodeling and promotes postpartum tumorigenesis.
  6. Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
  7. NF-κB and STAT3 signaling uniquely stratify survival in female glioblastoma patients.
  1. Open Biol. 2026 Feb 18. pii: 250150. [Epub ahead of print]16(2):
    Anti-apoptotic BCL-2 binds to all three IP3R isoforms, thereby limiting the Ca2+-flux properties of IP3R homo-tetramers.
    Ian de Ridder, Claire Cauwelier, Larry E Wagner Ii, Jens Loncke, Vikas Arige, Irina I Serysheva, David I Yule, Geert Bultynck.
      Anti-apoptotic B-cell lymphoma 2 (BCL-2) controls inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca²+ signalling. As cells typically express all three IP3R isoforms in variable abundances that assemble in hetero-tetrameric channels, the specific effects of BCL-2 on each isoform remain unclear. Here, we employed a reductionist approach using HEK293 cells triple-IP3R knockout reconstituted with a single IP3R isoform to elucidate the impact of BCL-2 on Ca2+ signalling by homo-tetrameric IP3R channels. Co-immunoprecipitation experiments demonstrated that BCL-2 interacts with each IP3R isoform. Live-cell Ca²+ imaging revealed that BCL-2 overexpression suppresses Ca²+ signals evoked by any of the three IP3R isoforms. Moreover, BCL-2 overexpression impaired mitochondrial Ca²+ uptake following IP3R-mediated Ca²+ release, irrespective of the IP3R isoform present. To investigate the effects on single IP3R-channel activity, we performed Ca²+-puff analysis using TIRF microscopy in response to UV-flash photolysis of caged IP3. BCL-2 overexpression reduced the number of Ca²+ puffs across all IP3R isoforms without affecting the amplitude or duration of individual puffs. Thus, BCL-2 acts as a universal inhibitor of all three IP3R isoforms, highlighting its critical role in fine-tuning intracellular Ca2+ dynamics to promote cell survival and its potential as a therapeutic target in cancer via its role in Ca2+ signalling.
    Keywords:  BCL-2 proteins; IP3 receptors; calcium signalling; organelles
    DOI:  https://doi.org/10.1098/rsob.250150
  2. PLoS One. 2026 ;21(2): e0343604
    Characterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts.
    Yufu Unten, Kazuaki Takafuji, Yumiko Masukagami, Isshin Shiiba, Keigo Horiuchi, Filip Husnik, Shigeru Yanagi, Norifumi Tateishi, Toshihide Suzuki.
      Age-associated declines in skeletal muscle function are linked to cellular senescence and mitochondrial alterations, yet mitochondrial phenotypes in aged human myoblasts remain insufficiently characterized. Here, we examined primary skeletal muscle myoblasts from young and elderly donors to assess mitochondrial function, morphology, and mitochondria-endoplasmic reticulum (ER) contact sites (MERCS). Myoblasts from older donors exhibited senescence features, including elevated SA-β-gal activity and reduced Lamin B1 expression, accompanied by increased mitochondrial oxidative stress. Despite marked mitochondrial hyperfusion and increased mitochondrial DNA content, mitochondrial oxygen consumption rate and membrane potential per mitochondrial area were comparable between young and old cells. MERCS were significantly elevated in aged myoblasts and were reduced by scavenging mitochondrial reactive oxygen species (mtROS), indicating an association between oxidative stress and MERCS formation. These findings suggest that mitochondrial hyperfusion and enhanced MERCS accompany cellular aging in human myoblasts and may contribute to maintaining mitochondrial function under elevated oxidative stress.
    DOI:  https://doi.org/10.1371/journal.pone.0343604
  3. Cell Death Discov. 2026 Feb 19.
    Mitochondrial bioenergetics-SASP crosstalk determines senolytic efficacy in therapy-induced senescence.
    Àngela Llop-Hernández, Sara Verdura, Júlia López, Begoña Martin-Castillo, Javier A Menendez, Elisabet Cuyàs.
      Mitochondria integrate senescence and apoptotic fates, yet it is unclear whether their ability to oxidize different fuels for energy production influences their vulnerability to senolytics in therapy-induced senescence (TIS). Using MitoPlates™ technology, we functionally mapped the mitophenotypes of TIS cancer cells by quantifying electron transport chain (ETC) flux from various NADH/FADH2 substrates. We then related these profiles to the responsiveness of TIS cancer cells to BCL-xL-targeting BH3 senolytics, as well as to inflammatory SASP signaling sensed by an NF-κB/miR-146a reporter. Mechanistically distinct senogenic stressors produced markedly different bioenergetic outputs and substrate diversity, establishing mitochondria as an emergent, stress-encoded property of TIS phenomena. Increased mitochondrial bioenergetic flexibility corresponded with senolytic permissiveness within each cell lineage. However, the magnitude of the senolytic response was largely limited by the pre-senescent bioenergetic configuration of the parental mitochondria, and baseline succinate oxidation served as a functional indicator of this inherited threshold. TIS SASPs were restricted by the secretome of the cell-of-origin, but only the miR146a-positive, fatty acid β-oxidation-related inflammatory SASP states were senolytically responsive. Inflachromene, an inhibitor of the chromatin remodelers HMGB1/2, decoupled mitochondrial bioenergetics from senolytic susceptibility, yielding SASP-null/miR146a-negative senescent cancer cells that were completely resistant to ABT-263/navitoclax and A1331852 despite extensive mitochondrial reprogramming. Thus, the senolytic response is governed by a layered circuit in which mitochondrial bioenergetic heritage establishes the senolytic ceiling, TIS-acquired bioenergetic flexibility fine-tunes the amplitude of the senolytic response, and establishing a mitochondria-inflammatory SASP crosstalk is required for BH3-mediated senolysis. These results support using functional readouts that integrate mitochondrial metabolic flexibility and inflammatory SASP to predict and potentially enhance senolytic efficacy in TIS cancer cells.
    DOI:  https://doi.org/10.1038/s41420-026-02967-6
  4. Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]
    BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
    Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.
    Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
  5. Nat Aging. 2026 Feb 18.
    Induction of senescence during postpartum mammary gland involution supports tissue remodeling and promotes postpartum tumorigenesis.
    Aurelie Chiche, Lamia Djoual, Elsa Charifou, Shuoyang Wang, Laurianne Temime, Marielle Saclier, Shaoxiang Wang, Jeremy Chantrel, Han Li.
      Cellular senescence is an evolutionarily conserved stress response that contributes to tissue repair and tumor suppression, yet its accumulation is also linked to aging and disease. Whether physiological senescence can be exploited by oncogenic events to promote tumorigenesis is unknown. Postpartum mammary gland involution is a major adult tissue remodeling event, resembling wound healing, and is closely associated with postpartum breast cancer. Here, we show that during mammary gland involution in mice, a p16Ink4a-dependent senescence response is induced in alveolar luminal cells. Eliminating senescent cells disrupts tissue remodeling and delays involution, demonstrating their physiological importance. However, in a postpartum breast cancer model where oncogenic activation coincides with involution, removing involution-associated senescent cells extended tumor latency. Mechanistically, senescent cells enhance tumor cell plasticity via the senescence-associated secretory phenotype, fostering metastasis. Our findings reveal that senescence, while required for postpartum tissue remodeling, can be hijacked to facilitate tumorigenesis, defining senescence as a unifying mechanism linking tissue repair to tumorigenesis.
    DOI:  https://doi.org/10.1038/s43587-025-01058-y
  6. Front Aging Neurosci. 2026 ;18 1689139
    Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
    Leah E Jamerson, Tara D Bradshaw, Patrick C Bradshaw.
      Changes in brain [NADPH]/[NADP+] and [NAD+]/[NADH] may contribute to aging. Anti-aging dietary restriction (DR) and intermittent fasting (IF) alter redox states that may contribute to their longevity effects. Pyruvate/lactate and acetoacetate/beta-hydroxybutyrate are indicators of the cytoplasmic and mitochondrial [NAD+]/[NADH], respectively, while the malate/pyruvate and isocitrate/alpha-ketoglutarate are indicators of the cytoplasmic [NADPH]/[NADP+]. Using these metabolite-pair ratios as redox indicators, the C57BL/6J mouse brain showed opposite redox changes with aging to the C57BL/6N mouse brain and human brain in the cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+]. Fasting caused universal reductive shifts in the brain cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+] and mitochondrial [NAD+]/[NADH]. The reductive shift in the cytoplasmic [NAD+]/[NADH] with fasting was opposite to that occurring with anti-aging ketone ester supplementation or ketogenic diet, which have been shown to cause an oxidative shift of the cytoplasmic [NAD+]/[NADH], but a reductive shift of the cerebral cortical cytoplasmic [NADPH]/[NADP+]. Several pathways that influence redox metabolism and aging are discussed, including fatty acid and cholesterol synthesis, the citric acid cycle, fatty acid beta-oxidation, glutaminolysis, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, the citrate-pyruvate shuttle, and the citrate-alpha-ketoglutarate shuttle. Brain proteome, brain single-cell RNA-Seq, and brain-region-specific bulk RNA-Seq data sets of aging and DR were examined, focusing on the pathways listed above to determine how they might contribute to the redox changes. Intermittent fasting has been shown to induce cyclic metabolic switching that contributes to neuroprotection and other health benefits resulting in delayed aging, while cyclic reductive redox shifts, especially in mitochondria, may be a driver of the beneficial effects.
    Keywords:  NAD+; NADPH; aging; astrocyte; brain; dietary restriction; fasting; redox
    DOI:  https://doi.org/10.3389/fnagi.2026.1689139
  7. iScience. 2026 Feb 20. 29(2): 114761
    NF-κB and STAT3 signaling uniquely stratify survival in female glioblastoma patients.
    Jason P Wong, Lorida Llaci, Lloyd Tripp, Myung Sik Jeon, Lihua Yang, Nicholas Reinhold, Nicole M Warrington, Jingqin Luo, Robi D Mitra, Joshua B Rubin.
      The mechanisms underlying sex differences in glioblastoma (GBM) incidence, treatment response, and survival are not well understood. Increased activation of nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling is associated with shorter survival in GBM. We looked at the expression of NF-κB- or STAT3-related genes in GBM for evidence of a sex skew in activity. Survival analysis of male and female GBM patients revealed that NF-κB- or STAT3-related gene expression was correlated with shorter survival only in female patients. We further explored mechanisms of this sex effect in an established murine model of sex differences in GBM. Concordant with human data, female murine GBM cells expressed stronger signatures of NF-κB and STAT3 genes and exhibited stronger responses to pathway stimulation and inhibition than their male counterparts. This study illustrates the advantage of sex-stratified data analysis in the development of sex-informed treatments for greater precision in cancer treatments.
    Keywords:  cancer; health disparity
    DOI:  https://doi.org/10.1016/j.isci.2026.114761
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