bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–08–11
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?
  2. Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.
  3. Artificial mitochondrial transplantation (AMT) reverses aging of mesenchymal stromal cells and improves their immunomodulatory properties in LPS-induced synoviocytes inflammation.
  4. A defective splicing machinery promotes senescence through MDM4 alternative splicing.
  5. Senotherapy preserves resilience in aging.
  6. Potential role of mitochondria and endoplasmic reticulum in the response elicited by D-aspartate in TM4 Sertoli cells.
  7. Hif1α-dependent mitochondrial acute O2 sensing and signaling to myocyte Ca2+ channels mediate arterial hypoxic vasodilation.
  8. p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.
  9. ALDH2 regulates mesenchymal stem cell senescence via modulation of mitochondrial homeostasis.
  10. Ca2+ as an essential signaling molecule controlling Snf1-mediated Atg1 activation.
  11. The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases.
  1. Cells. 2024 Jul 30. pii: 1281. [Epub ahead of print]13(15):
    Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?
    Yue Liu, Isabelle Lomeli, Stephen J Kron.
      Cellular senescence has been increasingly recognized as a hallmark of cancer, reflecting its association with aging and inflammation, its role as a response to deregulated proliferation and oncogenic stress, and its induction by cancer therapies. While therapy-induced senescence (TIS) has been linked to resistance, recurrence, metastasis, and normal tissue toxicity, TIS also has the potential to enhance therapy response and stimulate anti-tumor immunity. In this review, we examine the Jekyll and Hyde nature of senescent cells (SnCs), focusing on how their persistence while expressing the senescence-associated secretory phenotype (SASP) modulates the tumor microenvironment through autocrine and paracrine mechanisms. Through the SASP, SnCs can mediate both resistance and response to cancer therapies. To fulfill the unmet potential of cancer immunotherapy, we consider how SnCs may influence tumor inflammation and serve as an antigen source to potentiate anti-tumor immune response. This new perspective suggests treatment approaches based on TIS to enhance immune checkpoint blockade. Finally, we describe strategies for mitigating the detrimental effects of senescence, such as modulating the SASP or targeting SnC persistence, which may enhance the overall benefits of cancer treatment.
    Keywords:  SASP (senescence-associated secretory phenotype); cancer therapy; immune surveillance; immunosuppression; senescence; senolytics; therapy resistance; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells13151281
  2. Cell Mol Life Sci. 2024 Aug 09. 81(1): 340
    Mitochondrial copper overload promotes renal fibrosis via inhibiting pyruvate dehydrogenase activity.
    Saiya Zhu, Yangyang Niu, Wenqian Zhou, Yuqing Liu, Jing Liu, Xi Liu, Limin Lu, Chen Yu.
      Copper is a trace element essential for numerous biological activities, whereas the mitochondria serve as both major sites of intracellular copper utilization and copper reservoir. Here, we investigated the impact of mitochondrial copper overload on the tricarboxylic acid cycle, renal senescence and fibrosis. We found that copper ion levels are significantly elevated in the mitochondria in fibrotic kidney tissues, which are accompanied by reduced pyruvate dehydrogenase (PDH) activity, mitochondrial dysfunction, cellular senescence and renal fibrosis. Conversely, lowering mitochondrial copper levels effectively restore PDH enzyme activity, improve mitochondrial function, mitigate cellular senescence and renal fibrosis. Mechanically, we found that mitochondrial copper could bind directly to lipoylated dihydrolipoamide acetyltransferase (DLAT), the E2 component of the PDH complex, thereby changing the interaction between the subunits of lipoylated DLAT, inducing lipoylated DLAT protein dimerization, and ultimately inhibiting PDH enzyme activity. Collectively, our study indicates that mitochondrial copper overload could inhibit PDH activity, subsequently leading to mitochondrial dysfunction, cellular senescence and renal fibrosis. Reducing mitochondrial copper overload might therefore serve as a strategy to rescue renal fibrosis.
    Keywords:  Copper; Mitochondria; Pyruvate dehydrogenase; Renal fibrosis; Tricarboxylic acid (TCA) cycle
    DOI:  https://doi.org/10.1007/s00018-024-05358-1
  3. Biochim Biophys Acta Mol Cell Res. 2024 Aug 03. pii: S0167-4889(24)00149-6. [Epub ahead of print]1871(7): 119806
    Artificial mitochondrial transplantation (AMT) reverses aging of mesenchymal stromal cells and improves their immunomodulatory properties in LPS-induced synoviocytes inflammation.
    Lynda Bourebaba, Nabila Bourebaba, Larry Galuppo, Krzysztof Marycz.
      Nowadays, regenerative medicine techniques are usually based on the application of mesenchymal stromal cells (MSCs) for the repair or restoration of injured damaged tissues. However, the effectiveness of autologous therapy is limited as therapeutic potential of MSCs declines due to patient's age, health condition and prolonged in vitro cultivation as a result of decreased growth rate. For that reason, there is an urgent need to develop strategies enabling the in vitro rejuvenation of MSCs prior transplantation in order to enhance their in vivo therapeutic efficiency. In presented study, we attempted to mimic the naturally occurring mitochondrial transfer (MT) between neighbouring cells and verify whether artificial MT (AMT) could reverse MSCs aging and improve their biological properties. For that reason, mitochondria were isolated from healthy donor equine adipose-derived stromal cells (ASCs) and transferred into metabolically impaired recipient ASCs derived from equine metabolic syndrome (EMS) affected horses, which were subsequently subjected to various analytical methods in order to verify the cellular and molecular outcomes of the applied AMT. Mitochondria recipient cells were characterized by decreased apoptosis, senescence and endoplasmic reticulum stress while insulin sensitivity was enhanced. Furthermore, we observed increased mitochondrial fragmentation and associated PARKIN protein accumulation, which indicates on the elimination of dysfunctional organelles via mitophagy. AMT further promoted physioxia and regulated autophagy fluxes. Additionally, rejuvenated ASCs displayed an improved anti-inflammatory activity toward LPS-stimulated synoviocytes. The presented findings highlight AMT as a promising alternative and effective method for MSCs rejuvenation, for potential application in autologous therapies in which MSCs properties are being strongly deteriorated due to patients' condition.
    Keywords:  AMT; ASCs; Aging; EMS; Immunomodulation; Senescence
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119806
  4. Aging Cell. 2024 Aug 08. e14301
    A defective splicing machinery promotes senescence through MDM4 alternative splicing.
    Mathieu Deschênes, Mathieu Durand, Marc-Alexandre Olivier, Alicia Pellerin-Viger, Francis Rodier, Benoit Chabot.
      Defects in the splicing machinery are implicated in various diseases, including cancer. We observed a general reduction in the expression of spliceosome components and splicing regulators in human cell lines undergoing replicative, stress-induced, and telomere uncapping-induced senescence. Supporting the view that defective splicing contributes to senescence, splicing inhibitors herboxidiene, and pladienolide B induced senescence in normal and cancer cell lines. Furthermore, depleting individual spliceosome components also promoted senescence. All senescence types were associated with an alternative splicing transition from the MDM4-FL variant to MDM4-S. The MDM4 splicing shift was reproduced when splicing was inhibited, and spliceosome components were depleted. While decreasing the level of endogenous MDM4 promoted senescence and cell survival independently of the MDM4-S expression status, cell survival was also improved by increasing MDM4-S. Overall, our work establishes that splicing defects modulate the alternative splicing of MDM4 to promote senescence and cell survival.
    Keywords:  MDM4; RNA; alternative splicing; senescence; spliceosome; splicing factors
    DOI:  https://doi.org/10.1111/acel.14301
  5. Geriatr Gerontol Int. 2024 Aug 04.
    Senotherapy preserves resilience in aging.
    Takumi Mikawa, Kazumichi Yoshida, Hiroshi Kondoh.
      In aging societies, social and economic burdens of aging-related diseases are increasing significantly. Senotherapy, which targets aging by eliminating senescent cells (senolytics) or removing sources of chronic inflammation (senostatics), are proposed as novel strategies for aging-related diseases. Aged or frail people suffer a decline of tissue reserve capacity during aging. Resilience, which is much reduced in older people, is essential for recovery from diseases, stresses or crises. Impaired resilience is one of the reasons why aged people experience a gradual waning of their daily activity and an increase of multimorbidity. Calorie restriction results in senostatic alleviation of chronic inflammation, whereas senolytic drugs induce apoptosis of senescent cells, which exacerbate aging by excreting inflammatory factors. Thus, both senolytics and senostatics are expected to reduce sterile inflammation, originating from senescent cells. Geriatr Gerontol Int 2024; ••: ••-••.
    Keywords:  resilience; senescence‐associated secretor phenotype; senolysis; senostatics; senotherapy
    DOI:  https://doi.org/10.1111/ggi.14949
  6. Front Cell Dev Biol. 2024 ;12 1438231
    Potential role of mitochondria and endoplasmic reticulum in the response elicited by D-aspartate in TM4 Sertoli cells.
    Sara Falvo, Giulia Grillo, Debora Latino, Gabriella Chieffi Baccari, Maria Maddalena Di Fiore, Massimo Venditti, Giuseppe Petito, Alessandra Santillo.
      D-Aspartic Acid (D-Asp) affects spermatogenesis by enhancing the biosynthesis of the sex steroid hormones acting either through the hypothalamus-pituitary-testis axis or directly on Leydig cells. Recently, in vitro studies have also demonstrated the direct effects of D-Asp on the proliferation and/or activity of germ cells. However, although D-Asp is present in Sertoli cells (SC), the specific role of the amino acid in these cells remains unknown. This study investigated the effects of D-Asp on the proliferation and activity of TM4 SC, focusing on the mitochondrial compartment and its association with the endoplasmic reticulum (ER). We found that D-Asp enhanced the proliferation and activity of TM4 cells as evidenced by the activation of ERK/Akt/PCNA pathway and the increase in the protein levels of the androgen receptor. Furthermore, D-Asp reduced both the oxidative stress and apoptotic process. An increase in mitochondrial functionality and dynamics, as well as a reduction in ER stress, were also found in D-Asp-treated TM4 cells. It is known that mitochondria are closely associated with ER to form the Mitochondrial-Associated Endoplasmic Reticulum Membranes (MAM), the site of calcium ions and lipid transfer from ER to the mitochondria, and vice versa. The data demonstrated that D-Asp induced stabilization of MAM in TM4 cells. In conclusion, this study is the first to demonstrate a direct effect of D-Asp on SC activity and to clarify the cellular/molecular mechanism underlying these effects, suggesting that D-Asp could stimulate spermatogenesis by improving the efficiency of SC.
    Keywords:  D-aspartate; MAM; Sertoli cells; endoplasmic reticulum stress; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2024.1438231
  7. Nat Commun. 2024 Aug 05. 15(1): 6649
    Hif1α-dependent mitochondrial acute O2 sensing and signaling to myocyte Ca2+ channels mediate arterial hypoxic vasodilation.
    Alejandro Moreno-Domínguez, Olalla Colinas, Ignacio Arias-Mayenco, José M Cabeza, Juan L López-Ogayar, Navdeep S Chandel, Norbert Weissmann, Natascha Sommer, Alberto Pascual, José López-Barneo.
      Vasodilation in response to low oxygen (O2) tension (hypoxic vasodilation) is an essential homeostatic response of systemic arteries that facilitates O2 supply to tissues according to demand. However, how blood vessels react to O2 deficiency is not well understood. A common belief is that arterial myocytes are O2-sensitive. Supporting this concept, it has been shown that the activity of myocyte L-type Ca2+channels, the main ion channels responsible for vascular contractility, is reversibly inhibited by hypoxia, although the underlying molecular mechanisms have remained elusive. Here, we show that genetic or pharmacological disruption of mitochondrial electron transport selectively abolishes O2 modulation of Ca2+ channels and hypoxic vasodilation. Mitochondria function as O2 sensors and effectors that signal myocyte Ca2+ channels due to constitutive Hif1α-mediated expression of specific electron transport subunit isoforms. These findings reveal the acute O2-sensing mechanisms of vascular cells and may guide new developments in vascular pharmacology.
    DOI:  https://doi.org/10.1038/s41467-024-51023-3
  8. Nat Cell Biol. 2024 Aug 05.
    p16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells.
    Julia Majewska, Amit Agrawal, Avi Mayo, Lior Roitman, Rishita Chatterjee, Jarmila Sekeresova Kralova, Tomer Landsberger, Yonatan Katzenelenbogen, Tomer Meir-Salame, Efrat Hagai, Ilanit Sopher, Juan-Felipe Perez-Correa, Wolfgang Wagner, Avi Maimon, Ido Amit, Uri Alon, Valery Krizhanovsky.
      The accumulation of senescent cells promotes ageing and age-related diseases, but molecular mechanisms that senescent cells use to evade immune clearance and accumulate in tissues remain to be elucidated. Here we report that p16-positive senescent cells upregulate the immune checkpoint protein programmed death-ligand 1 (PD-L1) to accumulate in ageing and chronic inflammation. We show that p16-mediated inhibition of cell cycle kinases CDK4/6 induces PD-L1 stability in senescent cells via downregulation of its ubiquitin-dependent degradation. p16-expressing senescent alveolar macrophages elevate PD-L1 to promote an immunosuppressive environment that can contribute to an increased burden of senescent cells. Treatment with activating anti-PD-L1 antibodies engaging Fcγ receptors on effector cells leads to the elimination of PD-L1 and p16-positive cells. Our study uncovers a molecular mechanism of p16-dependent regulation of PD-L1 protein stability in senescent cells and reveals the potential of targeting PD-L1 to improve immunosurveillance of senescent cells and ameliorate senescence-associated inflammation.
    DOI:  https://doi.org/10.1038/s41556-024-01465-0
  9. Free Radic Biol Med. 2024 Aug 04. pii: S0891-5849(24)00586-0. [Epub ahead of print]223 172-183
    ALDH2 regulates mesenchymal stem cell senescence via modulation of mitochondrial homeostasis.
    Ying Shen, Yimei Hong, Xinran Huang, Jiaqi Chen, Ziqi Li, Jie Qiu, Xiaoting Liang, Cong Mai, Weifeng Li, Xin Li, Yuelin Zhang.
      Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated β-galactosidase (SA-β-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.
    Keywords:  Aldehyde dehydrogenase 2; Interferon regulatory factor 7; Mesenchymal stem cells; Mitochondria; Senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.07.040
  10. Autophagy. 2024 Aug 05.
    Ca2+ as an essential signaling molecule controlling Snf1-mediated Atg1 activation.
    Yanyang Wu, Cong Yi.
      Macroautophagy/autophagy is essential for maintaining glucose homeostasis, but the mechanisms by which cells sense glucose starvation and initiate autophagy are not yet fully understood. Recently, we reported that the assembly of a Ca2+-triggered Snf1-Bmh1/Bmh2-Atg11 complex initiates autophagy in response to glucose starvation. Our research reveals that during glucose starvation, the efflux of vacuolar Ca2+ increases cytoplasmic Ca2+ levels, which activates the protein kinase Rck2. Rck2-mediated phosphorylation of Atg11 enhances its interaction with Bmh1 and Bmh2. This interaction recruits the Snf1-Sip1-Snf4 complex, which is located on the vacuolar membrane, to the phagophore assembly site (PAS), leading to the activation of Atg1 and the initiation of autophagy. In summary, we have identified a previously unrecognized signaling pathway involved in glucose starvation-induced autophagy, where Ca2+ acts as a fundamental signaling molecule that links energy stress to the formation of the autophagy initiation complex.
    Keywords:  Atg11-Bmh1/2-Snf1 complex; Ca2+; Rck2; autophagy; glucose starvation
    DOI:  https://doi.org/10.1080/15548627.2024.2389483
  11. Acta Pharmacol Sin. 2024 Aug 08.
    The correlation between mitochondria-associated endoplasmic reticulum membranes (MAMs) and Ca2+ transport in the pathogenesis of diseases.
    Wen-Bin Zhao, Rui Sheng.
      Mitochondria and the endoplasmic reticulum (ER) are vital organelles that influence various cellular physiological and pathological processes. Recent evidence shows that about 5%-20% of the mitochondrial outer membrane is capable of forming a highly dynamic physical connection with the ER, maintained at a distance of 10-30 nm. These interconnections, known as MAMs, represent a relatively conserved structure in eukaryotic cells, acting as a critical platform for material exchange between mitochondria and the ER to maintain various aspects of cellular homeostasis. Particularly, ER-mediated Ca2+ release and recycling are intricately associated with the structure and functionality of MAMs. Thus, MAMs are integral in intracellular Ca2+ transport and the maintenance of Ca2+ homeostasis, playing an essential role in various cellular activities including metabolic regulation, signal transduction, autophagy, and apoptosis. The disruption of MAMs observed in certain pathologies such as cardiovascular and neurodegenerative diseases as well as cancers leads to a disturbance in Ca2+ homeostasis. This imbalance potentially aggravates pathological alterations and disease progression. Consequently, a thorough understanding of the link between MAM-mediated Ca2+ transport and these diseases could unveil new perspectives and therapeutic strategies. This review focuses on the changes in MAMs function during disease progression and their implications in relation to MAM-associated Ca2+ transport.
    Keywords:  Ca2+ homeostasis; cancer; cardiovascular diseases; mitochondria-associated ER membranes; neurodegenerative diseases
    DOI:  https://doi.org/10.1038/s41401-024-01359-9
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