bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–12–08
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.
  2. Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
  3. Daily briefing: What is ageing? Even gerontologists don't agree.
  4. Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.
  5. CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling.
  6. Nicotinamide mononucleotide suppresses cellular senescence and increases aquaporin 5 expression in the submandibular gland of aged male mice to ameliorate aging-related dry mouth.
  7. Endoplasmic reticulum stress-related deficits in calcium clearance promote neuronal dysfunction that is prevented by SERCA2 gene augmentation.
  8. Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
  9. Ageing of stem cells reduces their capacity to form tumours.
  10. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
  11. Calcium connects lysosomal damage to stress granule formation.
  1. Aging (Albany NY). 2024 Dec 03. 16
    Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing.
    Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Joy Ha, Jannat Dhillon, Grace H Shin, Jack Crouch, Adam C Gower, Sami Gritli, Daniel S Roh.
      Senescent cells accumulate in aging tissues, impairing their ability to undergo repair and regeneration following injury. Previous research has demonstrated that targeting tissue senescence with senolytics can enhance tissue regeneration and repair by selectively eliminating SnCs in specific aged tissues. In this study, we focused on eliminating senescent skin cells in aged mice to assess the effects on subsequent wound healing. We applied ABT-263 directly to the skin of 24-month-old mice over a 5-day period. Following topical ABT-263, aged skin demonstrated decreased gene expression of senescence markers p16 and p21, accompanied by reductions in SA-β-gal- and p21-positive cells compared to DMSO controls. However, ABT-263 also triggered a temporary inflammatory response and macrophage infiltration in the skin. Bulk RNA sequencing of ABT-263-treated skin revealed prompt upregulation of genes associated with wound healing pathways, including hemostasis, inflammation, cell proliferation, angiogenesis, collagen synthesis, and extracellular matrix organization. Aged mice skin pre-treated with topical ABT-263 exhibited accelerated wound closure. In conclusion, topical ABT-263 effectively reduced several senescence markers in aged skin, thereby priming the skin for improved subsequent wound healing. This enhancement may be attributed to ABT-263-induced senolysis which in turn stimulates the expression of genes involved in extracellular matrix remodeling and wound repair pathways.
    Keywords:  ABT-263; aging; senescence; senolytic; wound healing
    DOI:  https://doi.org/10.18632/aging.206165
  2. EMBO Rep. 2024 Dec 02.
    Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses.
    Magdalena Shumanska, Dmitri Lodygin, Christine S Gibhardt, Christian Ickes, Ioana Stejerean-Todoran, Lena C M Krause, Kira Pahl, Lianne J H C Jacobs, Andrea Paluschkiwitz, Shuya Liu, Angela Boshnakovska, Niels Voigt, Tobias J Legler, Martin Haubrock, Miso Mitkovski, Gereon Poschmann, Peter Rehling, Sven Dennerlein, Jan Riemer, Alexander Flügel, Ivan Bogeski.
      T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector T-cells display elevated mCa2+ and increased bioenergetic and metabolic output. Transcriptome and proteome analyses reveal molecular determinants involved in the TCR-induced functional reprogramming and identify signalling pathways and cellular functions regulated by MCU. Knockdown of MCUa (MCUaKD), diminishes mCa2+ uptake, mitochondrial respiration and ATP production, as well as T-cell migration and cytokine secretion. Moreover, MCUaKD in rat CD4+ T-cells suppresses autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model. In summary, we demonstrate that mCa2+ uptake through MCU is essential for proper T-cell function and has a crucial role in autoimmunity. T-cell specific MCU inhibition is thus a potential tool for targeting autoimmune disorders.
    Keywords:  Autoimmunity; Calcium; MCU; Mitochondria; T-cell
    DOI:  https://doi.org/10.1038/s44319-024-00313-4
  3. Nature. 2024 Dec 03.
    Daily briefing: What is ageing? Even gerontologists don't agree.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-03984-0
  4. Aging Cell. 2024 Dec 04. e14386
    Skeletal muscle mitochondrial fragmentation predicts age-associated decline in physical capacity.
    Richie P Goulding, Braeden T Charlton, Ellen A Breedveld, Matthijs van der Laan, Anne R Strating, Wendy Noort, Aryna Kolodyazhna, Brent Appelman, Michèle van Vugt, Anita E Grootemaat, Nicole N van der Wel, Jos J de Koning, Frank W Bloemers, Rob C I Wüst.
      Ageing substantially impairs skeletal muscle metabolic and physical function. Skeletal muscle mitochondrial health is also impaired with ageing, but the role of skeletal muscle mitochondrial fragmentation in age-related functional decline remains imprecisely characterized. Here, using a cross-sectional study design, we performed a detailed comparison of skeletal muscle mitochondrial characteristics in relation to in vivo markers of exercise capacity between young and middle-aged individuals. Despite similar overall oxidative phosphorylation capacity (young: 99 ± 17 vs. middle-aged: 99 ± 27 pmol O2.s-1.mg-1, p = 0.95) and intermyofibrillar mitochondrial density (young: 5.86 ± 0.57 vs. middle-aged: 5.68 ± 1.48%, p = 0.25), older participants displayed a more fragmented intermyofibrillar mitochondrial network (young: 1.15 ± 0.17 vs. middle-aged: 1.55 ± 0.15 A.U., p < 0.0001), a lower mitochondrial cristae density (young: 23.40 ± 7.12 vs. middle-aged: 13.55 ± 4.10%, p = 0.002) and a reduced subsarcolemmal mitochondrial density (young: 22.39 ± 6.50 vs. middle-aged: 13.92 ± 4.95%, p = 0.005). Linear regression analysis showed that 87% of the variance associated with maximal oxygen uptake could be explained by skeletal muscle mitochondrial fragmentation and cristae density alone, whereas subsarcolemmal mitochondrial density was positively associated with the capacity for oxygen extraction during exercise. Intramuscular lipid accumulation was positively associated with mitochondrial fragmentation and negatively associated with cristae density. Collectively, our work highlights the critical role of skeletal muscle mitochondria in age-associated declines in physical function.
    Keywords:  ageing; maximal oxygen uptake; mitochondrial morphology; mitochondrial respiration; skeletal muscle
    DOI:  https://doi.org/10.1111/acel.14386
  5. Stem Cell Res Ther. 2024 Dec 02. 15(1): 460
    CX43-mediated mitochondrial transfer maintains stemness of KG-1a leukemia stem cells through metabolic remodeling.
    Huihui Fu, Xiaoqing Xie, Liuyue Zhai, Yi Liu, Yifeng Tang, Sanxiu He, Jun Li, Qing Xiao, Guofa Xu, Zailin Yang, Xiaomei Zhang, Yao Liu.
       BACKGROUND: Acute myeloid leukemia (AML) is characterized by abundant immature myeloid cells, relapse and refractory due to leukemia stem cells (LSCs). Bone marrow mesenchymal stem/ stromal cells (BMSCs) supported LSCs survival, meanwhile, chemotherapy improved connexin43 (CX43) expression. CX43, as the most intercellular gap junction, facilitated transmit mitochondria from BMSCs into AML. We hypothesized that increased mitochondria transferred from BMSCs supported metabolic remodeling in LSCs to sustain their stemness.
    METHODS: Primary BMSCs from AML patients were isolated. CX43-BMSCs, overexpressing CX43, were cocultured with KG-1a cells. Fluorescence and confocal microscopy observed mitochondrial transfer. Flow cytometry, EdU assay, and clonogenicity evaluated cell cycle, proliferation, and clonogenic potential. Xenograft mouse models were used to evaluate the tumorigenicity of KG-1a in vivo. Seahorse, RNA-seq, and LC-MS assessed mitochondrial function, transcriptomes, and metabolites post-coculture.
    RESULTS: CX43-BMSCs promoted unidirectional mitochondrial transfer, enhancing KG-1a adhesion and proliferation to maintain LSCs stemness in vitro and vivo. RNA-seq revealed coculture with CX43-BMSCs upregulated genes related to adhesion, proliferation, and migration in KG-1a cells. Elevated CX43 expression strengthened BMSCs-KG-1a interaction, facilitating mitochondrial transfer and nucleoside metabolism, fueling KG-1a cells. This enhanced mitochondrial energy metabolism, promoting metabolic reprogramming and clonogenicity.
    CONCLUSION: CX43-mediated mitochondrial transfer from BMSCs to KG-1a enhances LSCs adhesion, proliferation, clonogenicity, and metabolic reprogramming. CX43 emerges as a potential therapeutic target for AML by sustaining LSCs stemness through metabolic remodeling.
    Keywords:  Adhesion; Bone marrow microenvironment; Connexin; Leukemia stem cells; Metabolic remodeling; Mitochondrial transfer
    DOI:  https://doi.org/10.1186/s13287-024-04079-3
  6. Biogerontology. 2024 Dec 04. 26(1): 18
    Nicotinamide mononucleotide suppresses cellular senescence and increases aquaporin 5 expression in the submandibular gland of aged male mice to ameliorate aging-related dry mouth.
    Jun Wakabayashi, Takahiro Hamaguchi, Masashi Morifuji, Masashi Nagata.
      Dry mouth results from decreased saliva secretion due to aging or drug side effects. Decreased saliva secretion causes dryness in the oral cavity that makes swallowing difficult and increases the risk of aspiration pneumonia. There are few fundamental treatments for dry mouth. Here we investigated whether treatment of old mice with nicotinamide mononucleotide (NMN) improved factors associated with dry mouth. Young (16-week-old) and old (113-week-old) male mice were treated subcutaneously with saline or NMN (300 mg/kg) once every two days for four weeks and saliva secretion was measured. The amount of nicotinamide adenine dinucleotide (NAD+) in salivary gland tissues was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Gene expression in the intestinal tract and salivary glands was measured by real-time PCR. The population of cells with acetylation in the submandibular gland was quantified by immunohistological staining. SA-β-gal activity in the submandibular gland was measured to assess cell senescence. Statistical analysis was performed by one-way analysis of variance with Tukey post hoc analysis. The submandibular glands from old mice treated with NMN exhibited increased saliva secretion and NAD+ levels, which both decrease with aging. In addition, the submandibular glands from NMN-treated old mice had decreased acetylation, numbers of senescent cells, and levels of senescence-associated secretory phenotype (SASP) factors, which all increase with aging, as well as increased aquaporin5 (AQP5) mRNA expression. NMN administration may improve dry mouth by regulating cellular senescence in the submandibular gland and increasing expression of AQP5, a water channel involved in saliva secretion, to inhibit age-related decreases in saliva secretion. It is necessary to elucidate further mechanism and confirm its effectiveness in humans.
    Keywords:  Aquaporin5; Dry mouth; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide; Saliva secretion; Senescence
    DOI:  https://doi.org/10.1007/s10522-024-10162-2
  7. Cell Rep Med. 2024 Nov 26. pii: S2666-3791(24)00610-4. [Epub ahead of print] 101839
    Endoplasmic reticulum stress-related deficits in calcium clearance promote neuronal dysfunction that is prevented by SERCA2 gene augmentation.
    Yukihiro Shiga, Aline Giselle Rangel Olguin, Sana El Hajji, Nicolas Belforte, Heberto Quintero, Florence Dotigny, Luis Alarcon-Martinez, Arjun Krishnaswamy, Adriana Di Polo.
      Disruption of calcium (Ca2+) homeostasis in neurons is a hallmark of neurodegenerative diseases. Here, we investigate the mechanisms leading to Ca2+ dysregulation and ask whether altered Ca2+ dynamics impinge on neuronal stress and circuit dysfunction. Using two-photon microscopy, we show that ocular hypertension, a major risk factor in glaucoma, and optic nerve crush injury disrupt the capacity of retinal neurons to clear cytosolic Ca2+ leading to impaired light-evoked responses. Gene- and protein expression analysis reveal the loss of the sarco-endoplasmic reticulum (ER) Ca2+-ATPase2 pump (SERCA2/ATP2A2) in injured retinal neurons from mice and patients with primary open-angle glaucoma. Pharmacological activation or neuron-specific gene delivery of SERCA2 is sufficient to rescue single-cell Ca2+ dynamics and promote robust survival of damaged neurons. Furthermore, SERCA2 gene supplementation reduces ER stress, reestablishes circuit balance, and restores visual behaviors. Our findings reveal that enhancing the Ca2+ clearance capacity of vulnerable neurons alleviates organelle stress and promotes neurorecovery.
    Keywords:  calcium homeostasis; endoplasmic reticulum stress; gene therapy; glaucoma; in vivo imaging; neurodegeneration; organelle stress; retinal ganglion cell; sarco-endoplasmic reticulum (ER) calcium-ATPase2 pump (SERCA2/ATP2A2); traumatic optic neuropathy
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101839
  8. BMC Med. 2024 12 05. 22(1): 578
    Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma.
    Tomás Duraj, Miriam Kalamian, Giulio Zuccoli, Joseph C Maroon, Dominic P D'Agostino, Adrienne C Scheck, Angela Poff, Sebastian F Winter, Jethro Hu, Rainer J Klement, Alicia Hickson, Derek C Lee, Isabella Cooper, Barbara Kofler, Kenneth A Schwartz, Matthew C L Phillips, Colin E Champ, Beth Zupec-Kania, Jocelyn Tan-Shalaby, Fabiano M Serfaty, Egiroh Omene, Gabriel Arismendi-Morillo, Michael Kiebish, Richard Cheng, Ahmed M El-Sakka, Axel Pflueger, Edward H Mathews, Donese Worden, Hanping Shi, Raffaele Ivan Cincione, Jean Pierre Spinosa, Abdul Kadir Slocum, Mehmet Salih Iyikesici, Atsuo Yanagisawa, Geoffrey J Pilkington, Anthony Chaffee, Wafaa Abdel-Hadi, Amr K Elsamman, Pavel Klein, Keisuke Hagihara, Zsófia Clemens, George W Yu, Athanasios E Evangeliou, Janak K Nathan, Kris Smith, David Fortin, Jorg Dietrich, Purna Mukherjee, Thomas N Seyfried.
      Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a universally lethal prognosis despite maximal standard therapies. Here, we present a consensus treatment protocol based on the metabolic requirements of GBM cells for the two major fermentable fuels: glucose and glutamine. Glucose is a source of carbon and ATP synthesis for tumor growth through glycolysis, while glutamine provides nitrogen, carbon, and ATP synthesis through glutaminolysis. As no tumor can grow without anabolic substrates or energy, the simultaneous targeting of glycolysis and glutaminolysis is expected to reduce the proliferation of most if not all GBM cells. Ketogenic metabolic therapy (KMT) leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function. Suggested best practices are provided to guide future KMT research in metabolic oncology, offering a shared, evidence-driven framework for observational and interventional studies.
    Keywords:  Cancer; Glioblastoma; Glutaminolysis; Metabolism; Precision medicine; Research design; Warburg Effect
    DOI:  https://doi.org/10.1186/s12916-024-03775-4
  9. Nature. 2024 Dec 04.
    Ageing of stem cells reduces their capacity to form tumours.
    Tatiana Cañeque, Raphaël Rodriguez.
      
    Keywords:  Ageing; Cancer; Stem cells
    DOI:  https://doi.org/10.1038/d41586-024-03721-7
  10. Nature. 2024 Dec 04.
    Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis.
    Xueqian Zhuang, Qing Wang, Simon Joost, Alexander Ferrena, David T Humphreys, Zhuxuan Li, Melissa Blum, Klavdija Krause, Selena Ding, Yuna Landais, Yingqian Zhan, Yang Zhao, Ronan Chaligne, Joo-Hyeon Lee, Sebastian E Carrasco, Umeshkumar K Bhanot, Richard P Koche, Matthew J Bott, Pekka Katajisto, Yadira M Soto-Feliciano, Thomas Pisanic, Tiffany Thomas, Deyou Zheng, Emily S Wong, Tuomas Tammela.
      Ageing is associated with a decline in the number and fitness of adult stem cells1,2. Ageing-associated loss of stemness is posited to suppress tumorigenesis3,4, but this hypothesis has not been tested in vivo. Here we use physiologically aged autochthonous genetically engineered5,6 mouse models and primary cells5,6 to demonstrate that ageing suppresses lung cancer initiation and progression by degrading the stemness of the alveolar cell of origin. This phenotype is underpinned by the ageing-associated induction of the transcription factor NUPR1 and its downstream target lipocalin-2 in the cell of origin in mice and humans, which leads to functional iron insufficiency in the aged cells. Genetic inactivation of the NUPR1-lipocalin-2 axis or iron supplementation rescues stemness and promotes the tumorigenic potential of aged alveolar cells. Conversely, targeting the NUPR1-lipocalin-2 axis is detrimental to young alveolar cells through ferroptosis induction. Ageing-associated DNA hypomethylation at specific enhancer sites is associated with increased NUPR1 expression, which is recapitulated in young alveolar cells through DNA methylation inhibition. We uncover that ageing drives functional iron insufficiency that leads to loss of stemness and tumorigenesis but promotes resistance to ferroptosis. These findings have implications for the therapeutic modulation of cellular iron homeostasis in regenerative medicine and in cancer prevention. Furthermore, our findings are consistent with a model whereby most human cancers initiate at a young age, thereby highlighting the importance of directing cancer prevention efforts towards young individuals.
    DOI:  https://doi.org/10.1038/s41586-024-08285-0
  11. Nat Rev Mol Cell Biol. 2024 Dec 03.
    Calcium connects lysosomal damage to stress granule formation.
    Kim Baumann.
      
    DOI:  https://doi.org/10.1038/s41580-024-00817-w
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