bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–05–25
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Shaping the waves: Mitochondrial regulation of calcium oscillations in smooth muscle.
  2. Radiation-induced senescent melanoma cells secrete soluble factors that trigger bystander senescence.
  3. Mitochondria-Associated Membranes: A Key Point of Neurodegenerative Diseases.
  4. Histone Lactylation Antagonizes Senescence and Skeletal Muscle Aging by Modulating Aging-Related Pathways.
  5. The Social Lives of Mitochondria: When these energy-giving organelles thrive, so do we.
  6. How axolotl cells 'remember' development to rebuild a lost limb.
  7. A lncRNA-mediated metabolic rewiring of cell senescence.
  8. Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.
  9. SIRT4 Controls Acetyl-CoA Synthesis to Promote Stemness and Invasiveness of Hepatocellular Carcinoma through Deacetylating MCCC2.
  10. Adenine nucleotide translocase 2 silencing promotes metabolic reprogramming in P19 embryonal carcinoma stem cells.
  11. Degrading cancer cell mitochondria to improve T cell-mediated killing.
  1. J Physiol. 2025 May 21.
    Shaping the waves: Mitochondrial regulation of calcium oscillations in smooth muscle.
    Harold A Coleman, Helena C Parkington.
      
    Keywords:  IP3; calcium store; calcium wave; endoplasmic reticulum; intracellular calcium; mitochondria; smooth muscle; voltage‐dependent calcium channel
    DOI:  https://doi.org/10.1113/JP288974
  2. Int J Radiat Biol. 2025 May 21. 1-10
    Radiation-induced senescent melanoma cells secrete soluble factors that trigger bystander senescence.
    Leonardo Salvarredi, Héctor Agüero, María Elisa Millan, María Fernanda Marra, Eduardo Callegari, Claudia Castro, Luis Lopez.
       PURPOSE: Senescence is a key cellular response to ionizing radiation. Senescent cells experience irreversible growth arrest while remaining metabolically active and secrete a distinct set of proteins, collectively referred to as the senescence-associated secretory phenotype (SASP). These secreted factors influence neighboring non-irradiated cells through a mechanism known as the bystander effect. This study aimed to investigate and characterize the bystander effect in a melanoma cell model.
    MATERIAL AND METHODS: Murine melanoma B16F0 cells were exposed to X-irradiation (10 Gy), and senescence was induced 3 days later. Conditioned media from the senescent cells was collected and used to culture non-irradiated B16F0 cells. Proliferation, viability, clonogenic capacity, DNA damage foci formation, apoptosis, and senescence were assessed. The composition of the senescence-associated secretory phenotype was analyzed using mass spectrometry and bioinformatics tools.
    RESULTS: Conditioned media from senescent cells induced by radiation reduced growth and promoted senescence in tumor cell cultures not exposed to ionizing radiation. Mass spectrometry analysis revealed greater protein diversity and abundance in conditioned media from senescent cells compared to that from non-irradiated cells. Additionally, conditioned media from senescent cells contained higher concentrations of proteins related to immune response, cellular aging, and responses to oxidative stress.
    CONCLUSIONS: Cells undergoing radiation-induced senescence promote bystander senescence by secreting soluble factors involved in the induction and maintenance of senescence.
    Keywords:  Ionizing radiation; bystander effect; melanoma; senescence
    DOI:  https://doi.org/10.1080/09553002.2025.2505525
  3. CNS Neurosci Ther. 2025 May;31(5): e70378
    Mitochondria-Associated Membranes: A Key Point of Neurodegenerative Diseases.
    Yiwei Zhang, Xiuqin Rao, Jiayi Wang, Hantian Liu, Qixian Wang, Xifeng Wang, Fuzhou Hua, Xilong Guan, Yue Lin.
       BACKGROUND: Neurodegenerative diseases pose significant health challenges in the 21st century, with increasing morbidity and mortality, particularly among the elderly population. One of the key factors contributing to the pathogenesis of these diseases is the disrupted crosstalk between mitochondria and the endoplasmic reticulum. Mitochondria-associated membranes (MAMs), which are regions where the ER interfaces with mitochondria, serve as crucial platforms facilitating communication between these organelles.
    OBJECTIVES: This review focuses on the structural composition and functions of MAMs and highlights their roles. Additionally, in this review, we summarize the relationship between MAM dysfunction and various neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and others. The involvement of key proteins such as Sig-1R, IP3R, and VAPB in maintaining ER-mitochondrial communication and their dysfunction in neurodegenerative diseases is emphasized.
    CONCLUSION: Through analyzing the effects of MAM on neurodegenerative diseases, we provide the newest insights and potential therapeutic targets for the treatment of these debilitating conditions.
    Keywords:  Alzheimers' disease; Ca2+ homeostasis; IP3R; Parkinson's disease; Sig‐1R; VAPB; mitochondria‐associated membranes; neurodegenerative disease
    DOI:  https://doi.org/10.1111/cns.70378
  4. Adv Sci (Weinh). 2025 May 19. e2412747
    Histone Lactylation Antagonizes Senescence and Skeletal Muscle Aging by Modulating Aging-Related Pathways.
    Fanju Meng, Jianuo He, Xuebin Zhang, Wencong Lyu, Ran Wei, Shiyi Wang, Zhehao Du, Haochen Wang, Jinlong Bi, Xueyang Hua, Chao Zhang, Yiting Guan, Guoliang Lyu, Xiao-Li Tian, Lijun Zhang, Wenbing Xie, Wei Tao.
      Epigenetic alterations are among the prominent drivers of cellular senescence and/or aging, intricately orchestrating gene expression programs during these processes. This study shows that histone lactylation, plays a pivotal role in counteracting senescence and mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, histone lactylation and lactyl-CoA levels markedly decrease during cellular senescence but are restored under hypoxic conditions primarily due to elevated glycolytic activity. The enrichment of histone lactylation at promoters is essential for sustaining the expression of genes involved in the cell cycle and DNA repair pathways. Furthermore, the modulation of enzymes crucial for histone lactylation, leads to reduced histone lactylation and accelerated cellular senescence. Consistently, the suppression of glycolysis and the depletion of histone lactylation are also observed during skeletal muscle aging. Modulating the enzymes can also lead to the loss of histone lactylation in skeletal muscle, downregulating DNA repair and proteostasis pathways and accelerating muscle aging. Running exercise increases histone lactylation, which in turn upregulate key genes in the DNA repair and proteostasis pathways. This study highlights the significant roles of histone lactylation in modulating cellular senescence as well as muscle aging, providing a promising avenue for antiaging intervention via metabolic manipulation.
    Keywords:  epigenetics; histone lactylation; senescence; skeletal muscle aging
    DOI:  https://doi.org/10.1002/advs.202412747
  5. Sci Am. 2025 Jun 01. 332(6): 50
    The Social Lives of Mitochondria: When these energy-giving organelles thrive, so do we.
    Martin Picard.
      
    DOI:  https://doi.org/10.1038/scientificamerican062025-QhEeouFRPCYEr2tKQNWqM
  6. Nature. 2025 May 21.
    How axolotl cells 'remember' development to rebuild a lost limb.
    S Y Celeste Wu, Jessica L Whited.
      
    Keywords:  Cell biology; Developmental biology; Regeneration
    DOI:  https://doi.org/10.1038/d41586-025-01447-8
  7. Cell Rep. 2025 May 21. pii: S2211-1247(25)00518-2. [Epub ahead of print]44(6): 115747
    A lncRNA-mediated metabolic rewiring of cell senescence.
    Elena Grossi, Francesco P Marchese, Jovanna González, Enrique Goñi, José Miguel Fernández-Justel, Alicia Amadoz, Nicolás Herranz, Leonor Puchades-Carrasco, Marta Montes, Maite Huarte.
      Despite not proliferating, senescent cells remain metabolically active to maintain the senescence program. However, the mechanisms behind this metabolic reprogramming are not well understood. We identify senescence-induced long noncoding RNA (sin-lncRNA), a previously uncharacterized long noncoding RNA (lncRNA), a key player in this response. While strongly activated in senescence by C/EBPβ, sin-lncRNA loss reinforces the senescence program by altering oxidative phosphorylation and rewiring mitochondrial metabolism. By interacting with dihydrolipoamide S-succinyltransferase (DLST), it facilitates its mitochondrial localization. Depletion of sin-lncRNA causes DLST nuclear translocation, leading to transcriptional changes in oxidative phosphorylation (OXPHOS) genes. While not expressed in highly proliferative cancer cells, it is strongly induced upon cisplatin-induced senescence. Depletion of sin-lncRNA in ovarian cancer cells reduces oxygen consumption and increases extracellular acidification, sensitizing cells to cisplatin treatment. Altogether, these results indicate that sin-lncRNA is specifically induced in senescence to maintain metabolic homeostasis, unveiling an RNA-dependent metabolic rewiring specific to senescent cells.
    Keywords:  CP: Metabolism; CP: Molecular biology; RNA-binding proteins; lncRNA; metabolism; senescence; therapy resistance
    DOI:  https://doi.org/10.1016/j.celrep.2025.115747
  8. Nature. 2025 May 21.
    Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.
    Ashutosh Gulati, Do-Hwan Ahn, Albert Suades, Yurie Hult, Gernot Wolf, So Iwata, Giulio Superti-Furga, Norimichi Nomura, David Drew.
      ATP generated in the mitochondria is exported by an ADP/ATP carrier of the SLC25 family1. The endoplasmic reticulum (ER) cannot synthesize ATP but must import cytoplasmic ATP to energize protein folding, quality control and trafficking2,3. It was recently proposed that a member of the nucleotide sugar transporter family, termed SLC35B1 (also known as AXER), is not a nucleotide sugar transporter but a long-sought-after ER importer of ATP4. Here we report that human SLC35B1 does not bind nucleotide sugars but indeed executes strict ATP/ADP exchange with uptake kinetics consistent with the import of ATP into crude ER microsomes. A CRISPR-Cas9 cell-line knockout demonstrated that SLC35B1 clusters with the most essential SLC transporters for cell growth, consistent with its proposed physiological function. We have further determined seven cryogenic electron microscopy structures of human SLC35B1 in complex with an Fv fragment and either bound to an ATP analogue or ADP in all major conformations of the transport cycle. We observed that nucleotides were vertically repositioned up to approximately 6.5 Å during translocation while retaining key interactions with a flexible substrate-binding site. We conclude that SLC35B1 operates by a stepwise ATP translocation mechanism, which is a previously undescribed model for substrate translocation by an SLC transporter.
    DOI:  https://doi.org/10.1038/s41586-025-09069-w
  9. Int J Biol Sci. 2025 ;21(7): 2973-2990
    SIRT4 Controls Acetyl-CoA Synthesis to Promote Stemness and Invasiveness of Hepatocellular Carcinoma through Deacetylating MCCC2.
    Tianjiao Sun, Congcong Xu, Qingru Song, Xiaodan Yang, Guo An, Guogui Sun, Zhiqian Zhang.
      SIRT4 is well-known as a tumor suppressor by controlling several metabolic pathways, although it is highly expressed in certain cancers including hepatocellular carcinoma (HCC). Here, we reported that SIRT4 was highly expressed in the voltage-gated calcium channel α2δ1 subunit-positive HCC tumor-initiating cells (TIC), and was upregulated by α2δ1-mediated calcium signaling. Moreover, the expression of SIRT4 in HCC tissues was predictive of poor prognosis of the patients. Interestingly, SIRT4 was functionally sufficient and indispensable to promote TIC properties and invasiveness of HCC cells by directly deacetylating the leucine catabolism pathway enzyme-3-methylcrotonyl-CoA carboxylase 2 (MCCC2) at K269, leading to the formation of a stable MCCC1/MCCC2 complex with robust MCCC enzymatic activity to produce more acetyl-CoA, which resulted in increased H3K27 acetylation and stem cell-like properties at doses≤2 µM. However, 10 µM acetyl-CoA was neither able to enhance H3K27 acetylation, nor to promote stem cell-like properties, while forced expression of SIRT4 in α2δ1+ cells resulted in retardation of tumor growth in vivo. Thus, SIRT4 serves as an oncogene to promote stemness and invasiveness by controlling the production of acetyl-CoA, linking α2δ1-mediated calcium signaling to SIRT4-mediated epigenetic reprogramming of HCC TICs which hold significant potential for the development of novel therapeutic strategies targeting TICs, and the dual roles of SIRT4 in HCC might be dependent on the production levels of acetyl-CoA.
    Keywords:  Acetyl-CoA; MCCC2; SIRT4; cancer stem cells; hepatocellular carcinoma
    DOI:  https://doi.org/10.7150/ijbs.99004
  10. Biochim Biophys Acta Mol Basis Dis. 2025 May 15. pii: S0925-4439(25)00250-9. [Epub ahead of print]1871(6): 167902
    Adenine nucleotide translocase 2 silencing promotes metabolic reprogramming in P19 embryonal carcinoma stem cells.
    Gabriela L Oliveira, Jaromir Novak, Zuzana Nahacka, Petra Brisudova, Sandra I Mota, Jiri Neuzil, Paulo J Oliveira, Ricardo Marques.
      Although controversial, cancer stem cells (CSCs) are thought to be one tumor component, being characterized by their strong self-renewal and survival properties. Cancer cells, CSCs included, are thought to rely mostly on glycolysis, even in the presence of oxygen, which confers them adaptive advantages. Adenine nucleotide translocator 2 (ANT2), responsible for the exchange of ADP and ATP in the mitochondrial inner membrane, has been correlated with a higher glycolytic metabolism and is known to be overexpressed in cancer cells. Using P19 embryonal carcinoma stem cells, we inhibited ANT2 translation by using siRNA. ANT2 protein levels were shown to be overexpressed in P19 undifferentiated cells (P19SCs) when compared to their differentiated counterparts (P19dCs). Furthermore, we showed here that the OXPHOS machinery and mitochondrial membrane potential are compromised after ANT2 depletion, leading to a metabolic adaptation towards a less oxidative phenotype. Interestingly, hexokinase II levels were downregulated, which was also accompanied by decreased cell growth, and reduced ability to form spheroids. Our findings underscore ANT2 as a key regulator of metabolic remodeling and cell survival of cancer stem-like cells, suggesting its potential as a therapeutic target for controlling CSC-driven tumor progression.
    Keywords:  ANT2; Hexokinase II; Metabolism; Mitochondria; Spheroids; cancer stem cells
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167902
  11. Nat Nanotechnol. 2025 May 21.
    Degrading cancer cell mitochondria to improve T cell-mediated killing.
    Luca Simula, Emmanuel Donnadieu.
      
    DOI:  https://doi.org/10.1038/s41565-025-01928-x
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