bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–02–23
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Uncovering a gut microbiota-derived metabolite that triggers host cellular senescence.
  2. Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy.
  3. Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
  4. Targeting Mitochondrial Integrity as a New Senolytic Strategy.
  5. Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.
  6. A Ketogenic Diet Enhances Aerobic Exercise Adaptation and Promotes Muscle Mitochondrial Remodeling in Hyperglycemic Mice.
  7. Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
  8. The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr-/-;hApoB100+/+ mice.
  9. Mitochondria-Targeted Temozolomide Probe for Overcoming MGMT-Mediated Resistance in Glioblastoma.
  1. Nat Aging. 2025 Feb 17.
    Uncovering a gut microbiota-derived metabolite that triggers host cellular senescence.
      
    DOI:  https://doi.org/10.1038/s43587-025-00831-3
  2. EMBO Mol Med. 2025 Feb 19.
    Targeting cIAP2 in a novel senolytic strategy prevents glioblastoma recurrence after radiotherapy.
    Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Suman Kanji, Lorena Samentar, Benjamin Russell Jordan, Ralf Kittler, Amyn A Habib, Jair Machado Espindola-Netto, Tamara Tchkonia, James L Kirkland, Terry C Burns, Jann N Sarkaria, Andrea Gilbert, John R Floyd, Robert Hromas, Weixing Zhao, Daohong Zhou, Patrick Sung, Bipasha Mukherjee, Sandeep Burma.
      Glioblastomas (GBM) are routinely treated with high doses of ionizing radiation (IR), yet these tumors recur quickly, and the recurrent tumors are highly therapy resistant. Here, we report that IR-induced senescence of tumor cells counterintuitively spurs GBM recurrence, driven by the senescence-associated secretory phenotype (SASP). We find that irradiated GBM cell lines and patient derived xenograft (PDX) cultures senesce rapidly in a p21-dependent manner. Senescent glioma cells upregulate SASP genes and secrete a panoply of SASP factors, prominently interleukin IL-6, an activator of the JAK-STAT3 pathway. These SASP factors collectively activate the JAK-STAT3 and NF-κB pathways in non-senescent GBM cells, thereby promoting tumor cell proliferation and SASP spreading. Transcriptomic analyses of irradiated GBM cells and the TCGA database reveal that the cellular inhibitor of apoptosis protein 2 (cIAP2), encoded by the BIRC3 gene, is a potential survival factor for senescent glioma cells. Senescent GBM cells not only upregulate BIRC3 but also induce BIRC3 expression and promote radioresistance in non-senescent tumor cells. We find that second mitochondria-derived activator of caspases (SMAC) mimetics targeting cIAP2 act as novel senolytics that trigger apoptosis of senescent GBM cells with minimal toxicity towards normal brain cells. Finally, using both PDX and immunocompetent mouse models of GBM, we show that the SMAC mimetic birinapant, administered as an adjuvant after radiotherapy, can eliminate senescent GBM cells and prevent the emergence of recurrent tumors. Taken together, our results clearly indicate that significant improvement in GBM patient survival may become possible in the clinic by eliminating senescent cells arising after radiotherapy.
    Keywords:  Glioblastoma Recurrence; Radiation Therapy; Senescence-associated Secretory Phenotype; Senolytic Therapy; Therapy-induced Senescence
    DOI:  https://doi.org/10.1038/s44321-025-00201-x
  3. Nature. 2025 Feb 19.
    Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
    Kate McArthur, Michael T Ryan.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00303-z
  4. Aging Dis. 2025 Feb 08.
    Targeting Mitochondrial Integrity as a New Senolytic Strategy.
    Eliska Vacurova, Edita Vlachova, Jan Stursa, Klara Bohacova, Tereza Havrlantova, Vojtech Skop, Barbora Judita Kasperova, Lukas Werner, Jiri Neuzil, Martin Haluzik, Sona Stemberkova Hubackova.
      Aging, characterized by accumulation of senescent cells, is a driving factor of various age-related diseases. These conditions pose significant health risks globally due to their increasing prevalence and serious complications. Reduction of senescent cells therefore represents a promising strategy promoting healthy aging. Here we demonstrate that targeting tamoxifen to mitochondria via triphenyl and tricyclohexyl phosphine selectively eliminates senescent cells. Our findings show a complex effect of mitochondrially targeted tamoxifen on mitochondrial function and integrity of senescent cells, including inhibition of oxidative phosphorylation and activity of respiratory complex IV. These changes result in activation of ferroptosis as the major mode of cell death, which results in rejuvenation of tissues. Targeting mitochondria of senescent cells represents a general senolytic strategy and may extend the healthspan and improve the quality of life in aging populations.
    DOI:  https://doi.org/10.14336/AD.2024.1100
  5. bioRxiv. 2025 Feb 05. pii: 2025.01.14.633043. [Epub ahead of print]
    Altered relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise.
    Ryan J Allen, Ana Kronemberger, Qian Shi, Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.
      Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice we reveal that aging slows muscle relaxation leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We reveal that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are also affected early in aging and are closely associated with rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca 2+ homeostasis, cytoskeleton integrity and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.
    DOI:  https://doi.org/10.1101/2025.01.14.633043
  6. Res Sq. 2025 Jan 29. pii: rs.3.rs-5814971. [Epub ahead of print]
    A Ketogenic Diet Enhances Aerobic Exercise Adaptation and Promotes Muscle Mitochondrial Remodeling in Hyperglycemic Mice.
    Sarah Lessard, Pattarawan Pattamaprapanont, Roberto Nava, Mia Formato, Eileen Cooney, Ana Pinto, Ana Alves-Wagner, Anamica Das, Yuntian Guan.
      VO2peak is a key health benefit of aerobic exercise; however, chronic hyperglycemia is associated with persistently low VO2peak due to an impaired adaptive response to training. Here, we tested whether reducing blood glucose with a low-carbohydrate/high-fat "ketogenic" diet could restore aerobic exercise adaptation in a mouse model of hyperglycemia. Hyperglycemia was induced by streptozotocin (STZ) and mice were stratified to standard chow (STZ-CHOW), or a ketogenic diet (STZ-KETO), which rapidly normalized blood glucose. After aerobic exercise training, improvements in VO2peak were blunted in STZ-CHOW, but exercise response was restored in STZ-KETO. Improved VO2peak in STZ-KETO was associated with enhanced aerobic remodeling of skeletal muscle, including a more oxidative fiber-type and increased capillary density, along with restoration of circulating angiogenic markers. Moreover, KETO induced exercise-independent effects on muscle mitochondrial remodeling and mitochondrial dynamics, significantly increasing fatty acid oxidation. Our results identify a ketogenic diet as a potential therapy to improve aerobic exercise response in the growing population with hyperglycemia due to diabetes and other metabolic conditions.
    DOI:  https://doi.org/10.21203/rs.3.rs-5814971/v1
  7. Cell Death Dis. 2025 Feb 14. 16(1): 99
    Creatine transporter (SLC6A8) knockout mice exhibit reduced muscle performance, disrupted mitochondrial Ca2+ homeostasis, and severe muscle atrophy.
    Irene Pertici, Donato D'Angelo, Denis Vecellio Reane, Massimo Reconditi, Ilaria Morotti, Elena Putignano, Debora Napoli, Giorgia Rastelli, Gaia Gherardi, Agnese De Mario, Rosario Rizzuto, Simona Boncompagni, Laura Baroncelli, Marco Linari, Marco Caremani, Anna Raffaello.
      Creatine (Cr) is essential for cellular energy homeostasis, particularly in muscle and brain tissues. Creatine Transporter Deficiency (CTD), an X-linked disorder caused by mutations in the SLC6A8 gene, disrupts Cr transport, leading to intellectual disability, speech delay, autism, epilepsy, and various non-neurological symptoms. In addition to neurological alterations, Creatine Transporter knockout (CrT-/y) mice exhibit severe muscle atrophy and functional impairments. This study provides the first characterization of the skeletal muscle phenotype in CrT-/y mice, revealing profound ultrastructural abnormalities accompanied by reduced fiber cross-sectional area and muscle performance. Notably, mitochondria are involved, as evidenced by disrupted cristae, increased mitochondrial size, impaired Ca2+ uptake, reduced membrane potential and ATP production. Mechanistically, the expression of atrophy-specific E3 ubiquitin ligases and suppression of the IGF1-Akt/PKB pathway, regulated by mitochondrial Ca2+ levels, further support the atrophic phenotype. These findings highlight the profound impact of Cr deficiency on skeletal muscle, emphasizing the need for targeted therapeutic strategies to address both the neurological and peripheral manifestations of CTD. Understanding the underlying mechanisms, particularly mitochondrial dysfunction, could lead to novel interventions for this disorder.
    DOI:  https://doi.org/10.1038/s41419-025-07381-x
  8. Geroscience. 2025 Feb 21.
    The senolytic ABT-263 improves cognitive functions in middle-aged male, but not female, atherosclerotic LDLr-/-;hApoB100+/+ mice.
    Mélanie Lambert, Géraldine Miquel, Louis Villeneuve, Nathalie Thorin-Trescases, Eric Thorin.
      Accumulation of cerebral senescent cells may compromise the continuum between vascular and neuronal function, leading to damage and cognitive decline. Elimination of senescent cells might therefore preserve vascular and neuronal functions. To test this hypothesis, we used male and female atherosclerotic LDLr-/-;hApoB100+/+ mice (ATX-mice), a model of vascular cognitive impairment (VCI), treated with the senolytic ABT-263 for 3 months (3- to 6-month or 9- to 12-month old). In young male ATX mice, prevention with ABT-263 improved spatial retention memory, in association with a higher endothelial sensitivity to shear stress and a higher hippocampal CD31+ endothelial cell density, lower activation of both astrocytes and glial cells. In young females, ABT-263 tended to improve delayed memory; however, atherosclerotic plaque was magnified by ABT-263, endothelial function was unaffected, hippocampal astrocyte activation increased and expression of CD31+ cells decreased. Hence, unlike in males, ABT-263 appears deleterious in young ATX females. In middle-aged males, the curative treatment improved the learning process and memory. Although no change in endothelial function was observed, the benefits of ABT-263 were associated with a decreased expression of several inflammaging markers, a higher density of CD31+ cells and a lower activation of glial cells. In middle-aged females, ABT-263 induced a surge of inflammaging markers, associated with a slower learning process. Altogether, our data demonstrate that ABT-263 differentially affects VCI, improving cognition in male while being deleterious in female ATX mice. More studies are needed to understand the mechanisms at the basis of the sexual dimorphic effects of the senolytic ABT-263.
    Keywords:   Inflammaging ; Cellular senescence; Cerebrovascular function; Endothelial function; Morris water maze; SASP; Vascular cognitive impairment
    DOI:  https://doi.org/10.1007/s11357-025-01563-3
  9. Chembiochem. 2025 Feb 19. e202400935
    Mitochondria-Targeted Temozolomide Probe for Overcoming MGMT-Mediated Resistance in Glioblastoma.
    Daniel Szames, Shana Kelley.
      Temozolomide (Tmz) is a DNA methylating agent used for the treatment of glioblastoma multiforme (GBM). Resistance to Tmz in GBM is caused by the DNA direct repair enzyme O6-methylguanine DNA methyltransferase (MGMT), which is expressed in ~50% of GBM tumours. It has yet to be confirmed that MGMT acts within mitochondria to repair mitochondrial DNA (mtDNA), and in this report we discuss the development of a novel mitochondria-targeted temozolomide probe (mtTmz) for evading MGMT-mediated resistance. Through conjugation of Tmz to a mitochondria-penetrating peptide (MPP), exclusive mitochondrial localization was achieved, and the probe retained alkylation activity demonstrated by chemical and DNA-based assays. Absence of nuclear DNA damage was assessed by detecting γH2AX foci. mtTmz demonstrated efficient cell killing capabilities independent of MGMT status in GBM cells as determined by cell viability assays. It was determined using a Proteinase K digestion assay that MGMT does not translocate to mitochondria in response to mtTmz treatment, and RT-qPCR analysis demonstrated that mtTmz does not induce MGMT gene expression compared to Tmz. The results reported highlight both the potential of mitochondrial targeting of Tmz and mitochondria as a therapeutic target in MGMT-expressing GBM.
    Keywords:  DNA Damage; Glioblastoma; Peptide; Temozolomide; mitochondria
    DOI:  https://doi.org/10.1002/cbic.202400935
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