bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–07–28
fiveteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Therapy-induced senescent tumor cells in cancer relapse.
  2. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  3. The role of cellular senescence in ovarian aging.
  4. Cellular senescence impairs tendon extracellular matrix remodeling in response to mechanical unloading.
  5. mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
  6. Ring around the mitochondria.
  7. Achilles' spear: A new therapeutic target for age-related diseases.
  8. ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
  9. Brief guide to senescence assays using cultured mammalian cells.
  10. Molecular mechanisms of cancer cachexia. Role of exercise training.
  11. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
  12. Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
  13. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
  14. Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.
  15. Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
  1. J Natl Cancer Cent. 2023 Dec;3(4): 273-278
    Therapy-induced senescent tumor cells in cancer relapse.
    Ke-Xin Song, Jun-Xian Wang, De Huang.
      Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype (SASP). In an oncogenic context, senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease. However, recent studies have demonstrated that senescent tumor cells, which could spontaneously exist within cancer tissues or arise in response to various cancer interventions (the so-called therapy-induced senescence, TIS), can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse. This highlights the complex and multifaceted nature of cellular senescence in cancer biology. Here, we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse. We also discuss implications for future studies toward targeting these less appreciated cells.
    Keywords:  Cancer therapy; Relapse; Tumor cell senescence
    DOI:  https://doi.org/10.1016/j.jncc.2023.09.001
  2. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  3. NPJ Aging. 2024 Jul 20. 10(1): 35
    The role of cellular senescence in ovarian aging.
    Jéssica D Hense, José V V Isola, Driele N Garcia, Larissa S Magalhães, Michal M Masternak, Michael B Stout, Augusto Schneider.
      This review explores the relationship between ovarian aging and senescent cell accumulation, as well as the efficacy of senolytics to improve reproductive longevity. Reproductive longevity is determined by the age-associated decline in ovarian reserve, resulting in reduced fertility and eventually menopause. Cellular senescence is a state of permanent cell cycle arrest and resistance to apoptosis. Senescent cells accumulate in several tissues with advancing age, thereby promoting chronic inflammation and age-related diseases. Ovaries also appear to accumulate senescent cells with age, which might contribute to aging of the reproductive system and whole organism through SASP production. Importantly, senolytic drugs can eliminate senescent cells and may present a potential intervention to mitigate ovarian aging. Herein, we review the current literature related to the efficacy of senolytic drugs for extending the reproductive window in mice.
    DOI:  https://doi.org/10.1038/s41514-024-00157-1
  4. Aging Cell. 2024 Jul 22. e14278
    Cellular senescence impairs tendon extracellular matrix remodeling in response to mechanical unloading.
    Emma J Stowe, Madelyn R Keller, Brianne K Connizzo.
      Musculoskeletal injuries, including tendinopathies, present a significant clinical burden for aging populations. While the biological drivers of age-related declines in tendon function are poorly understood, it is well accepted that dysregulation of extracellular matrix (ECM) remodeling plays a role in chronic tendon degeneration. Senescent cells, which have been associated with multiple degenerative pathologies in musculoskeletal tissues, secrete a highly pro-inflammatory senescence-associated secretory phenotype (SASP) that has potential to promote ECM breakdown. However, the role of senescent cells in the dysregulation of tendon ECM homeostasis is largely unknown. To assess this directly, we developed an in vitro model of induced cellular senescence in murine tendon explants. This novel technique enables us to study the isolated interactions of senescent cells and their native ECM without interference from age-related systemic changes. We document multiple biomarkers of cellular senescence in induced tendon explants including cell cycle arrest, apoptosis resistance, and sustained inflammatory responses. We then utilize this in vitro senescence model to compare the ECM remodeling response of young, naturally aged, and induced-senescent tendons to an altered mechanical stimulus. We found that both senescence and aging independently led to alterations in ECM-related gene expression, reductions in protein synthesis, and tissue compositional changes. Furthermore, MMP activity was sustained, thus shifting the remodeling balance of aged and induced-senescent tissues towards degradation over production. Together, this demonstrates that cellular senescence plays a role in the altered mechano-response of aged tendons and likely contributes to poor clinical outcomes in aging populations.
    Keywords:  aging; explant; extracellular matrix; remodeling; senescence; tendon
    DOI:  https://doi.org/10.1111/acel.14278
  5. Cell Death Dis. 2024 Jul 23. 15(7): 523
    mtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
    Ying Li, Jie Cui, Lei Liu, William S Hambright, Yutai Gan, Yajun Zhang, Shifeng Ren, Xianlin Yue, Liwei Shao, Yan Cui, Johnny Huard, Yanling Mu, Qingqiang Yao, Xiaodong Mu.
      The mechanism regulating cellular senescence of postmitotic muscle cells is still unknown. cGAS-STING innate immune signaling was found to mediate cellular senescence in various types of cells, including postmitotic neuron cells, which however has not been explored in postmitotic muscle cells. Here by studying the myofibers from Zmpste24-/- progeria aged mice [an established mice model for Hutchinson-Gilford progeria syndrome (HGPS)], we observed senescence-associated phenotypes in Zmpste24-/- myofibers, which is coupled with increased oxidative damage to mitochondrial DNA (mtDNA) and secretion of senescence-associated secretory phenotype (SASP) factors. Also, Zmpste24-/- myofibers feature increased release of mtDNA from damaged mitochondria, mitophagy dysfunction, and activation of cGAS-STING. Meanwhile, increased mtDNA release in Zmpste24-/- myofibers appeared to be related with increased VDAC1 oligomerization. Further, the inhibition of VDAC1 oligomerization in Zmpste24-/- myofibers with VBIT4 reduced mtDNA release, cGAS-STING activation, and the expression of SASP factors. Our results reveal a novel mechanism of innate immune activation-associated cellular senescence in postmitotic muscle cells in aged muscle, which may help identify novel sets of diagnostic markers and therapeutic targets for progeria aging and aging-associated muscle diseases.
    DOI:  https://doi.org/10.1038/s41419-024-06863-8
  6. Sci Signal. 2024 Jul 23. 17(846): eadr8314
    Ring around the mitochondria.
    Wei Wong.
      Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adr8314
  7. Aging Cell. 2024 Jul;23(7): e14257
    Achilles' spear: A new therapeutic target for age-related diseases.
    Yang Xuan, Yue Duan.
      The role of the senescence-associated secretory phenotype (SASP) in the development of age-related diseases is significant, and its control promises to have a tremendous positive impact on health. A recent study has identified a new mechanism for SASP regulation, titled miMOMP. Failure to regulate SASP would dramatically increase the risk of various age-related health problems. Nonetheless, we have not completely comprehended how to modulate SASP. In this commentary, we summarise the specific mechanisms by which miMOMP regulates SASP and outline possible future research directions. Moreover, potential risks and obstacles to the clinical translation of miMOMP are also presented.
    Keywords:  SASP; age‐related diseases; miMOMP; mtDNA
    DOI:  https://doi.org/10.1111/acel.14257
  8. Nat Commun. 2024 Jul 21. 15(1): 6143
    ER calcium depletion as a key driver for impaired ER-to-mitochondria calcium transfer and mitochondrial dysfunction in Wolfram syndrome.
    Mailis Liiv, Annika Vaarmann, Dzhamilja Safiulina, Vinay Choubey, Ruby Gupta, Malle Kuum, Lucia Janickova, Zuzana Hodurova, Michal Cagalinec, Akbar Zeb, Miriam A Hickey, Yi-Long Huang, Nana Gogichaishvili, Merle Mandel, Mario Plaas, Eero Vasar, Jens Loncke, Tim Vervliet, Ting-Fen Tsai, Geert Bultynck, Vladimir Veksler, Allen Kaasik.
      Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.
    DOI:  https://doi.org/10.1038/s41467-024-50502-x
  9. Mol Cells. 2024 Jul 23. pii: S1016-8478(24)00127-4. [Epub ahead of print] 100102
    Brief guide to senescence assays using cultured mammalian cells.
    Euneok Kang, Chanhee Kang, Young-Sam Lee, Seung-Jae V Lee.
      Cellular senescence is a crucial biological process associated with organismal aging and many chronic diseases. Here, we present a brief guide to mammalian senescence assays, including the measurement of cell cycle arrest, change in cellular morphology, senescence-associated β-galactosidase (SA-β-gal) staining, and the expression of senescence-associated secretory phenotype (SASP). This work will be useful for biologists with minimum expertise in cellular senescence assays.
    Keywords:  Aging; SA-β-gal; SASP; Senescence; cell cycle arrest
    DOI:  https://doi.org/10.1016/j.mocell.2024.100102
  10. Mol Aspects Med. 2024 Jul 25. pii: S0098-2997(24)00052-9. [Epub ahead of print]99 101293
    Molecular mechanisms of cancer cachexia. Role of exercise training.
    Eva Tamayo-Torres, Amanda Garrido, Rafael de Cabo, Julián Carretero, María Carmen Gómez-Cabrera.
      Cancer-associated cachexia represents a multifactorial syndrome mainly characterized by muscle mass loss, which causes both a decrease in quality of life and anti-cancer therapy failure, among other consequences. The definition and diagnostic criteria of cachexia have changed and improved over time, including three different stages (pre-cachexia, cachexia, and refractory cachexia) and objective diagnostic markers. This metabolic wasting syndrome is characterized by a negative protein balance, and anti-cancer drugs like chemotherapy or immunotherapy exacerbate it through relatively unknown mechanisms. Due to its complexity, cachexia management involves a multidisciplinary strategy including not only nutritional and pharmacological interventions. Physical exercise has been proposed as a strategy to counteract the effects of cachexia on skeletal muscle, as it influences the mechanisms involved in the disease such as protein turnover, inflammation, oxidative stress, and mitochondrial dysfunction. This review will summarize the experimental and clinical evidence of the impact of physical exercise on cancer-associated cachexia.
    Keywords:  Cachexia; Cancer; Cancer patients; Experimental models; Molecular mechanisms; Physical exercise
    DOI:  https://doi.org/10.1016/j.mam.2024.101293
  11. Cell Rep. 2024 Jul 17. pii: S2211-1247(24)00825-8. [Epub ahead of print] 114496
    Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers.
    Kan Etoh, Hirotaka Araki, Tomoaki Koga, Yuko Hino, Kanji Kuribayashi, Shinjiro Hino, Mitsuyoshi Nakao.
      The senescent microenvironment and aged cells per se contribute to tissue remodeling, chronic inflammation, and age-associated dysfunction. However, the metabolic and epigenomic bases of the senescence-associated secretory phenotype (SASP) remain largely unknown. Here, we show that ATP-citrate lyase (ACLY), a key enzyme in acetyl-coenzyme A (CoA) synthesis, is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
    Keywords:  ACLY; CP: Cell biology; CP: Metabolism; H3K27 acetylation; SASP; acetyl-CoA; citrate metabolism; senescence; senostatics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114496
  12. Mol Cell. 2024 Jul 25. pii: S1097-2765(24)00542-2. [Epub ahead of print]84(14): 2593-2595
    Sweetening mitochondria: Hexokinase shields mitochondria from fission when glucose is low.
    Antigoni Diokmetzidou, Luca Scorrano.
      In this issue of Molecular Cell, Pilic et al.1 show that hexokinase, the first enzyme of glycolysis, forms perimitochondrial rings that prevent mitochondrial fragmentation when ATP levels drop.
    DOI:  https://doi.org/10.1016/j.molcel.2024.06.035
  13. Nat Commun. 2024 Jul 22. 15(1): 6162
    Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
    Benjamin Assouline, Rachel Kahn, Lutfi Hodali, Reba Condiotti, Yarden Engel, Ela Elyada, Tzlil Mordechai-Heyn, Jason R Pitarresi, Dikla Atias, Eliana Steinberg, Tirza Bidany-Mizrahi, Esther Forkosh, Lior H Katz, Ofra Benny, Talia Golan, Matan Hofree, Sheila A Stewart, Karine A Atlan, Gideon Zamir, Ben Z Stanger, Michael Berger, Ittai Ben-Porath.
      Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-50441-7
  14. EMBO J. 2024 Jul 23.
    Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.
    Neuza Domingues, Steve Catarino, Beatriz Cristóvão, Lisa Rodrigues, Filomena A Carvalho, Maria João Sarmento, Mónica Zuzarte, Jani Almeida, Teresa Ribeiro-Rodrigues, Ânia Correia-Rodrigues, Fábio Fernandes, Paulo Rodrigues-Santos, Trond Aasen, Nuno C Santos, Viktor I Korolchuk, Teresa Gonçalves, Ira Milosevic, Nuno Raimundo, Henrique Girão.
      A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.
    Keywords:  Actin-remodelling; Arp2; Connexin43; Exocytosis; Lysosomal Damage
    DOI:  https://doi.org/10.1038/s44318-024-00177-3
  15. Nat Metab. 2024 Jul 24.
    Mitochondrial respiration in microglia is essential for response to demyelinating injury but not proliferation.
    Joshua S Stoolman, Rogan A Grant, Taylor A Poor, Samuel E Weinberg, Karis B D'Alessandro, Jerica Tan, Jennifer Yuan-Shih Hu, Megan E Zerrer, Walter A Wood, Madeline C Harding, Sahil Soni, Karen M Ridge, Paul T Schumacker, G R Scott Budinger, Navdeep S Chandel.
      Microglia are necessary for central nervous system (CNS) function during development and play roles in ageing, Alzheimer's disease and the response to demyelinating injury1-5. The mitochondrial respiratory chain (RC) is necessary for conventional T cell proliferation6 and macrophage-dependent immune responses7-10. However, whether mitochondrial RC is essential for microglia proliferation or function is not known. We conditionally deleted the mitochondrial complex III subunit Uqcrfs1 (Rieske iron-sulfur polypeptide 1) in the microglia of adult mice to assess the requirement of microglial RC for survival, proliferation and adult CNS function in vivo. Notably, mitochondrial RC function was not required for survival or proliferation of microglia in vivo. RNA sequencing analysis showed that loss of RC function in microglia caused changes in gene expression distinct from aged or disease-associated microglia. Microglia-specific loss of mitochondrial RC function is not sufficient to induce cognitive decline. Amyloid-β plaque coverage decreased and microglial interaction with amyloid-β plaques increased in the hippocampus of 5xFAD mice with mitochondrial RC-deficient microglia. Microglia-specific loss of mitochondrial RC function did impair remyelination following an acute, reversible demyelinating event. Thus, mitochondrial respiration in microglia is dispensable for proliferation but is essential to maintain a proper response to CNS demyelinating injury.
    DOI:  https://doi.org/10.1038/s42255-024-01080-1
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