bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–07–20
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
  2. Killing wisely: precision senolytics in the age of frailty.
  3. Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
  4. Mitochondrial age-classes expand the heterogeneity of tissue-resident stem cells.
  5. Mitochondria dysfunction: cause or consequence of physiologic aging?
  6. Diminished and altered cellular senescence response in delayed wound healing of aging.
  7. Characterizing primary and secondary senescence in vivo.
  8. mtKO: A dedicated guide RNA library for mitochondria research.
  9. β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail.
  10. The Role of Mitochondrial Dynamics in Doxorubicin-Induced Disease: Implications for Therapy.
  11. Found: a human gut microbe that makes cancer therapy more effective in mice.
  12. The Senescence Associated Secretory Phenotype, a key marker of cellular senescence, is elevated in depression and moderated by sex.
  1. Res Sq. 2025 Jun 26. pii: rs.3.rs-6346822. [Epub ahead of print]
    MICU proteins facilitate Ca2+-dependent mitochondrial metabolon formation to regulate cellular energetics - independent of MCU.
    John Elrod, Henry Cohen, Benjamin Gottschalk, Carmen Choya-Foces, Adam Chatoff, Anya Wilkinson, Joanne Garbincius, Adyson Johnson, Tyler Stevens, Jordan Howe, Emily Megill, Jennyfer Ngo, Dhanendra Tomar, Nathaniel Snyder, Wolfgang Graier.
      Mitochondrial matrix Ca2+ concentration ([matrixCa2+]) 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. This begs the question, what are the primary molecular mechanisms regulating calcium-dependent changes in metabolism? The primary function of MICU proteins (MICU1, MICU2, and MICU3) is reported to be gatekeeping of the mtCU and regulating mitochondrial Ca2+ uptake. Here, we demonstrate that MICU proteins function in coordination to impart Ca2+-dependent regulation to FADH2-dependent mitochondrial dehydrogenases through metabolon formation independent of the mtCU and [matrixCa2+]. 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. Utilizing an equimolar expression platform coupled with unbiased proteomics we reveal unique interactomes for MICU1/2 versus MICU1/3 heterodimers and demonstrate that MICU proteins control coupling of Mitochondrial Glycerol-3-Phosphate Dehydrogenase with Succinate Dehydrogenase/Complex II and impart Ca2+-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 Ca2+ signaling mechanism regulating homeostatic energetics - not mtCU-dependent changes in [matrixCa2+].
    DOI:  https://doi.org/10.21203/rs.3.rs-6346822/v1
  2. Genes Dev. 2025 Jul 15.
    Killing wisely: precision senolytics in the age of frailty.
    Valentin J A Barthet, Scott W Lowe.
      Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies has catalyzed efforts to develop therapeutics that preferentially kill senescent cells (also known as "senolytics"). However, clinical translation from bench to bedside remains challenging due to senescent state heterogeneity, limited biomarkers, off-target toxicities, and the frailty of aged patients. Small molecule senolytics, although promising, often lack defined mechanisms of action and pose safety concerns that may constrain their use in older adults. Emerging precision approaches, including those that exploit surface markers and leverage engineered immune therapies, offer a rational and potentially more selective path forward. Here we highlight recent advances in senescence profiling and targeted clearance strategies, emphasizing the need for therapies designed with both biological complexity and the needs of aging populations in mind.
    Keywords:  aging; senescence; senolytics
    DOI:  https://doi.org/10.1101/gad.353134.125
  3. Nat Metab. 2025 Jul 14.
    Old mitochondria regulate niche renewal via α-ketoglutarate metabolism in stem cells.
    Simon Andersson, Hien Bui, Arto Viitanen, Daniel Borshagovski, Ella Salminen, Sami Kilpinen, Angelika Gebhart, Emilia Kuuluvainen, Swetha Gopalakrishnan, Nina Peltokangas, Martyn James, Kaia Achim, Eija Jokitalo, Petri Auvinen, Ville Hietakangas, Pekka Katajisto.
      Cellular metabolism is a key regulator of cell fate1, raising the possibility that the recently discovered metabolic heterogeneity between newly synthesized and chronologically old organelles may affect stem cell fate in tissues2,3. In the small intestine, intestinal stem cells (ISCs)4 produce metabolically distinct progeny5, including their Paneth cell (PC) niche6. Here we show that asymmetric cell division of mouse ISCs generates a subset enriched for old mitochondria (ISCmito-O), which are metabolically distinct, and form organoids independently of niche because of their ability to recreate the PC niche. ISCmito-O mitochondria produce more α-ketoglutarate, driving ten-eleven translocation-mediated epigenetic changes that promote PC formation. In vivo α-ketoglutarate supplementation enhanced PC turnover and niche renewal, aiding recovery from chemotherapy-induced damage in aged mice. Our results reveal a subpopulation of ISCs whose old mitochondria metabolically regulate cell fate, and provide proof of principle for metabolically promoted replacement of specific aged cell types in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01325-7
  4. Nat Metab. 2025 Jul 14.
    Mitochondrial age-classes expand the heterogeneity of tissue-resident stem cells.
      
    DOI:  https://doi.org/10.1038/s42255-025-01326-6
  5. Genes Dev. 2025 Jul 11.
    Mitochondria dysfunction: cause or consequence of physiologic aging?
    G R Scott Budinger, Navdeep S Chandel.
      Mitochondria are no longer viewed solely as ATP- or metabolite-generating organelles but as key regulators of cellular signaling that shape physiologic aging. Contrary to earlier theories linking aging to mitochondrial DNA mutations and oxidative damage, current evidence shows that these factors do not causally limit physiologic aging. Instead, an evolving literature links age-related loss of mitochondrial signaling and function to important physiologic changes of aging. Moreover, mild inhibition of mitochondrial respiratory function with drugs like metformin promote health span. These findings open new paths for pharmacologically reprogramming mitochondrial signaling to extend healthy aging.
    Keywords:  aging; mitochondria; senescence
    DOI:  https://doi.org/10.1101/gad.353106.125
  6. bioRxiv. 2025 Jun 08. pii: 2025.06.08.658533. [Epub ahead of print]
    Diminished and altered cellular senescence response in delayed wound healing of aging.
    Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Qiaoling Wang, Grace Haeun Shin, Jannat Dhillon, Daniel Sam Roh.
      The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence-like response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated β-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16 + /p21 + /Ki67 - senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of pro-healing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling towards a more detrimental pro-inflammatory state, which ultimately can contribute to the delayed wound healing.
    DOI:  https://doi.org/10.1101/2025.06.08.658533
  7. Nat Aging. 2025 Jul 11.
    Characterizing primary and secondary senescence in vivo.
    Yuko Sogabe, Hirofumi Shibata, Mio Kabata, Akito Tanaka, Kanae Mitsunaga, Kazunori Sunadome, May Nakajima-Koyama, Michitada Hirano, Eisuke Nishida, Knut Woltjen, Hiroshi Seno, Yasuhiro Yamada, Takuya Yamamoto.
      There is robust evidence that senescence can be propagated in vitro through mechanisms including the senescence-associated secretory phenotype, resulting in the non-cell-autonomous induction of secondary senescence. However, the induction, regulation and physiological role of secondary senescence in vivo remain largely unclear. Here we generated senescence-inducible mouse models expressing either the constitutively active form of MEK1 or MKK6 and mCherry, to map primary and secondary senescent cells. Our models recapitulate characteristic features of senescence and demonstrate that primary and secondary phenotypes are highly tissue- and inducer-dependent. Spatially resolved RNA expression analyses at the single-cell level reveal that each senescence induction results in a unique transcriptional profile-even within cells of the same cell type-explaining the heterogeneity of senescent cells in vivo. Furthermore, we show that interleukin-1β, primarily derived from macrophages, induces secondary phenotypes. Our findings provide insight into secondary senescence in vivo and useful tools for understanding and manipulating senescence during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00917-y
  8. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2502285122
    mtKO: A dedicated guide RNA library for mitochondria research.
    Karambir Kaur, Javeria Zaheer, Fengchao Lang, Diego Luis Ribeiro, Meili Zhang, Hua Song, Wei Zhang, Raj Chari, Hussam Alkaissi, Chunzhang Yang.
      Mitochondria are multifunctional organelles central to both physiological and pathological processes. In malignant cancer cells, mitochondrial reprogramming establishes the metabolic foundation to meet cellular demands, which is particularly important in tumor cells with existing metabolic perturbations. To identify key mitochondrial pathways supporting cancer development, we developed mitochondria Knockout (mtKO), a robust and unbiased CRISPR screening platform to pinpoint critical mitochondria-associated pathways. The mtKO screen revealed that the mitochondrial antioxidant enzyme SOD2 is essential for cells harboring IDH1 mutations. Mechanistically, SOD2 activity determines the disease manifestation of IDH1-mutated cancers, through maintaining redox homeostasis and mitochondrial fitness. This study introduces a powerful functional genomic tool to identify mitochondrial-centered pathways and reveals the selective mitochondrial vulnerability in Krebs cycle-deficient cancers for future therapeutic intervention.
    Keywords:  CRISPR screen; IDH1; SOD2; metabolism; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2502285122
  9. Nat Commun. 2025 Jul 17. 16(1): 6592
    β-Hydroxybutyrate promotes cancer metastasis through β-hydroxybutyrylation-dependent stabilization of Snail.
    Wenna Jiang, Meng Wang, Jiayi Wang, Qianhui Hao, Yuxuan Li, Lin Liu, Tianxing Zhou, Wei Song, Jing Liu, Miao Liu, Yongjie Xie, Duo Zuo, Jiawei Xiao, Xiuse Zhang, Shan Gao, Li Ren, Jihui Hao.
      β-Hydroxybutyrylation (Kbhb) modification regulates protein molecular fates in either physiology or pathology, including cancer. However, the function and regulatory mechanism of Kbhb remain completely unknown in cancer metastasis. Here, we report that β-hydroxybutyrate (BHB) is clinically associated with the progression of pancreatic cancer and functionally promotes pancreatic cancer cell metastasis. Mechanistically, BHB induces Kbhb modification of Snail at lysine 152 to enhance Snail stabilization, which is regulated by Kbhb modification enzyme CREB-binding protein (CBP), and subsequently prevents Snail degradation by blocking recognition of E3 ubiquitin ligases FBXL14. Furthermore, either targeting Snail Kbhb modification or CBP inhibitor decreases cancer metastasis and enhances the therapeutic efficacy of gemcitabine in pancreatic cancer cells. Collectively, our study reveals that Kbhb of Snail is critical to promote metastasis and provides a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41467-025-61541-3
  10. J Cell Physiol. 2025 Jul;240(7): e70064
    The Role of Mitochondrial Dynamics in Doxorubicin-Induced Disease: Implications for Therapy.
    Huan Yue, Yousheng Chen, Junxiao Feng, Weiying Yue, Xingjuan Shi.
      As an anthracycline chemotherapy drug, doxorubicin (Dox) is generally prescribed to treat a variety of malignant tumors. Nevertheless, Dox exhibited toxicity at a high dosage, which might eventually lead to injury of the body. Mitochondrial dynamics, including mitochondrial fission and fusion, regulates mitochondrial homeostasis and cellular function. Mounting evidence has demonstrated that imbalance in mitochondrial dynamics, manifested by increased mitochondrial fission or decreased mitochondrial fusion, is associated with the development of Dox-induced diseases. In this paper, we will elaborate the role of mitochondrial dynamics in Dox-induced diseases, and discuss the regulatory mechanism of mitochondrial dynamics in Dox-induced diseases, including apoptosis, fibrosis, myocardial atrophy and inflammation. Elucidating these issues may provide important value in the diagnosis and potential therapeutic strategies for Dox-induced diseases through regulation of mitochondria dynamics.
    Keywords:  Dox‐induced diseases; apoptosis; fibrosis; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1002/jcp.70064
  11. Nature. 2025 Jul 14.
    Found: a human gut microbe that makes cancer therapy more effective in mice.
    Heidi Ledford.
      
    Keywords:  Cancer; Immunology; Microbiome
    DOI:  https://doi.org/10.1038/d41586-025-02224-3
  12. Int Psychogeriatr. 2025 Jul 12. pii: S1041-6102(25)00351-5. [Epub ahead of print] 100113
    The Senescence Associated Secretory Phenotype, a key marker of cellular senescence, is elevated in depression and moderated by sex.
    Nishika Navrange, Ana Paula Mendes-Silva, Charles F Reynolds, Julie Wetherell, Benoit Mulsant, Mary C Kimmel, Eric J Lenze, Breno Satler Diniz.
       OBJECTIVE: Studies have found elevation in a key biomarker of aging (the senescence-associated secretory phenotype (SASP) index) in depression. We investigated whether sex moderates the association between the SASP and major depression in older adults.
    METHODS: We included 423 older adults in a current major depressive episode and 140 adults with no history of depression. We measured the plasma levels of SASP biomarkers using multiplex immunoassays. The interaction effect between sex, depression diagnosis, and senescence markers were analyzed by general linear models, adjusted for confounding variables.
    RESULTS: Individuals with depression had a higher SASP index than the healthy comparison group (t-test= -3.902, p < 0.001). We found a significant diagnosis by sex interaction (F= 9.112, df= 1540, p = 0.003), with males with depression having the highest SASP index levels (F=20.678, df=1540, p < 0.001).
    CONCLUSIONS: In older adults, sex plays a significant role in senescence-related changes in depression. A higher senescence burden in males with depression may be an indicator of greater vulnerability to accelerated biological aging and a marker of elevated risk of adverse outcomes in this sex.
    Keywords:  Aging; Biomarkers; Depression; Senescence; Sex differences
    DOI:  https://doi.org/10.1016/j.inpsyc.2025.100113
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