bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–09–22
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Elimination of physiological senescent cutaneous cells in a novel p16-dependent senolytic mouse model impacts lipid metabolism in skin aging.
  2. Therapy-induced senescence in breast cancer: an overview.
  3. Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum.
  4. The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
  5. The paradox of senescent-marker positive cancer cells: challenges and opportunities.
  6. Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle.
  7. The role of mitofusin 2 in regulating endothelial cell senescence: Implications for vascular aging.
  1. Genes Cells. 2024 Sep 16.
    Elimination of physiological senescent cutaneous cells in a novel p16-dependent senolytic mouse model impacts lipid metabolism in skin aging.
    Yuma Sugiyama, Yoichiro Kawabe, Tanenobu Harada, Yu Aoki, Keiko Tsuji, Daijiro Sugiyama, Mitsuo Maruyama.
      The evidence of the correlation between cellular senescence and aging has increased in research with animal models. These models have been intentionally generated to target and regulate cellular senescent cells with the promoter activity of p16Ink4a or p19Arf, genes that are highly expressed in aging cells. However, the senolytic efficiency in various organs and cells from these models represents unexpected variation and diversity in some cases. We have generated a novel knock-in model, p16tdT-hDTR mice, which possess tdTomato and human diphtheria toxin receptor (hDTR) downstream of Cdkn2a, an endogenous p16Ink4a gene. We successfully demonstrated that p16-derived tdTomato and hDTR expressions are observed in these mouse embryo fibroblasts and following treatment with diphtheria toxin (DT) eliminates those cells. Furthermore, we demonstrated the efficacy of eliminating p16-positive cells in vivo, and also observed a tendency to decrease their cutaneous SA-β-gal activity after subcutaneous DT injection into p16tdT-hDTR mice. In particular, comprehensive gene expression analysis in skin revealed that upregulated genes related to lipid metabolisms with aging exhibited remarkable expressions under the senolysis. These results clearly unveiled p16-positive senescent cells contribute to age-related changes in skin.
    Keywords:  cellular senescence; lipid metabolism; p16ink4a; senolytic mouse model; skin aging
    DOI:  https://doi.org/10.1111/gtc.13163
  2. Explor Target Antitumor Ther. 2024 ;5(4): 902-920
    Therapy-induced senescence in breast cancer: an overview.
    Suraj Narayanan Chembukavu, Andrew J Lindsay.
      Outcomes for women with breast cancer have improved dramatically in recent decades. However, many patients present with intrinsic drug resistance and others are initially sensitive to anti-cancer drugs but acquire resistance during the course of their treatment, leading to recurrence and/or metastasis. Drug therapy-induced senescence (TIS) is a form of drug resistance characterised by the induction of cell cycle arrest and the emergence of a senescence-associated secretory phenotype (SASP) that can develop in response to chemo- and targeted- therapies. A wide range of anticancer interventions can lead to cell cycle arrest and SASP induction, by inducing genotoxic stress, hyperactivation of signalling pathways or oxidative stress. TIS can be anti-tumorigenic in the short-term, but pro-tumorigenic in the long-term by creating a pro-inflammatory and immunosuppressive microenvironment. Moreover, the SASP can promote angiogenesis and epithelial-mesenchymal transition in neighbouring cells. In this review, we will describe the characteristics of TIS in breast cancer and detail the changes in phenotype that accompany its induction. We also discuss strategies for targeting senescent cancer cells in order to prevent or delay tumour recurrence.
    Keywords:  Drug resistance; iron metabolism; membrane trafficking; senotherapeutics; therapy-induced senescence
    DOI:  https://doi.org/10.37349/etat.2024.00254
  3. Nat Cell Biol. 2024 Sep 17.
    Plasma membrane curvature regulates the formation of contacts with the endoplasmic reticulum.
    Yang Yang, Luis A Valencia, Chih-Hao Lu, Melissa L Nakamoto, Ching-Ting Tsai, Chun Liu, Huaxiao Yang, Wei Zhang, Zeinab Jahed, Wan-Ru Lee, Francesca Santoro, Jen Liou, Joseph C Wu, Bianxiao Cui.
      Contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules, we hypothesize that PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, whereas the ubiquitously expressed extended synaptotagmin-2 does not show a preference for PM curvature. At the mechanistic level, we find that the low-complexity region (LCR) and membrane occupation and recognition nexus (MORN) motifs of junctophilins can bind independently to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins-Eps15 homology domain-containing proteins-that interact with the MORN_LCR motifs and facilitate the preferential tethering of junctophilins to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.
    DOI:  https://doi.org/10.1038/s41556-024-01511-x
  4. Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2400531121
    The p53 target DRAM1 modulates calcium homeostasis and ER stress by promoting contact between lysosomes and the ER through STIM1.
    Xiying Wang, Ji Geng, Suman Rimal, Yuxiu Sui, Jie Pan, Zhenghong Qin, Bingwei Lu.
      It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain. Excess DRAM1 disrupts endoplasmic reticulum (ER) structure, triggers ER stress, and induces protective ER-phagy. Mechanistically, DRAM1 interacts with stromal interacting molecule 1 (STIM1) to tether lysosomes to the ER and perturb STIM1 function in maintaining intracellular calcium homeostasis. STIM1 overexpression promotes cellular health by restoring calcium homeostasis, ER stress response, ER-phagy, and AMP-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) signaling in cells with excess DRAM1. Thus, by promoting organelle contact between lysosomes and the ER, DRAM1 modulates ER structure and function and cell survival under stress. Our results suggest that DRAM1 as a lysosomal protein performs diverse roles in cellular homeostasis and stress response. These findings may have significant implications for our understanding of the role of the p53/DRAM1 axis in human diseases, from cancer to neurodegenerative diseases.
    Keywords:  DRAM1; ER; ER-phagy; calcium homeostasis; lysosome
    DOI:  https://doi.org/10.1073/pnas.2400531121
  5. NPJ Aging. 2024 Sep 14. 10(1): 41
    The paradox of senescent-marker positive cancer cells: challenges and opportunities.
    Emily A O'Sullivan, Ryan Wallis, Federica Mossa, Cleo L Bishop.
      Senescence is an anti-tumour mechanism and hallmark of cancer. Loss or mutation of key senescence effectors, such as p16INK4A, are frequently observed in cancer. Intriguingly, some human tumours are both proliferative and senescent-marker positive (Sen-Mark+). Here, we explore this paradox, focusing on the prognostic consequences and the current challenges in classifying these cells. We discuss future strategies for Sen-Mark+ cell detection together with emerging opportunities to exploit senescence for cancer.
    DOI:  https://doi.org/10.1038/s41514-024-00168-y
  6. Geroscience. 2024 Sep 19.
    Resistance training suppresses accumulation of senescent fibro-adipogenic progenitors and senescence-associated secretory phenotype in aging rat skeletal muscle.
    Yung-Li Hung, Ayami Sato, Yuka Takino, Akihito Ishigami, Shuichi Machida.
      Accumulation of senescent cells in tissues contributes to multiple aging-related pathologies. Senescent fibro-adipogenic progenitors (FAPs) contribute to aging-related muscle atrophy. Resistance training can help to maintain skeletal muscle mass, improve mobility, and reduce certain health risks commonly associated with aging. We investigated, using rat model, the impact of resistance training on FAPs in aging skeletal muscle, which remains unclear. Twenty-two-month-old female rats were divided into sedentary and training groups. The training group rodents were trained to climb a ladder while bearing a load for 20 training sessions over 2 months, after which, the flexor hallucis longus muscles were collected and analyzed. Senescent cells were identified using a senescence-associated β-galactosidase stain and p21 immunohistochemistry (IHC), and FAPs were identified using platelet-derived growth factor receptor alpha IHC. The results indicate that resistance training in rats prevented aging-associated skeletal muscle atrophy and suppressed M2 polarization of macrophages. The number of senescent cells was significantly reduced in the 24-month-old training group, with most of them being FAPs. Conversely, the number of senescent FAPs increased significantly in the 24-month-old sedentary group compared with that in the 18-month-old sedentary group. The number of senescent FAPs in the 24-month-old training group decreased significantly. Resistance training also suppressed the senescence-associated secretory phenotype (SASP). The killer T cell-specific marker, CD8α, was elevated in the skeletal muscles of the aging rats following resistance training, indicating upregulation of recognition and elimination of senescent cells. Overall, resistance training suppressed the accumulation of senescent FAPs and acquisition of SASP in aging skeletal muscles.
    Keywords:  Fibro-adipogenic progenitors; Resistance training; Sarcopenia; Senescent cells
    DOI:  https://doi.org/10.1007/s11357-024-01338-2
  7. iScience. 2024 Sep 20. 27(9): 110809
    The role of mitofusin 2 in regulating endothelial cell senescence: Implications for vascular aging.
    Jiayin Li, Zheming Yang, Haixu Song, Lin Yang, Kun Na, Zhu Mei, Shuli Zhang, Jing Liu, Kai Xu, Chenghui Yan, Xiaozeng Wang.
      Endothelial cell dysfunction contributes to age-related vascular diseases. Analyzing public databases and mouse tissues, we found decreased MFN2 expression in senescent endothelial cells and angiotensin II-treated mouse aortas. In human endothelial cells, Ang II reduced MFN2 expression while increasing senescence markers P21 and P53. siMFN2 treatment worsened Ang II-induced senescence, while MFN2 overexpression alleviated it. siMFN2 or Ang II treatment caused mitochondrial dysfunction and morphological abnormalities, including increased ROS production and reduced respiration, mitigated by ovMFN2 treatment. Further study revealed that BCL6, a negative regulator of MFN2, significantly contributes to Ang II-induced endothelial senescence. In vivo, Ang II infusion decreased MFN2 expression and increased BCL6, P21, and P53 expression in vascular endothelial cells. The shMfn2+Ang II group showed elevated senescence markers in vascular tissues. These findings highlight MFN2's regulatory role in endothelial cell senescence, emphasizing its importance in maintaining endothelial homeostasis and preventing age-related vascular diseases.
    Keywords:  Biochemistry; Biological sciences; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110809
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