bims-cesemi 2025-01-26 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–01–26
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Intracellular Membrane Contact Sites in Skeletal Muscle Cells.
The senolytic cocktail, dasatinib and quercetin, impacts the chromatin structure of both young and senescent vascular smooth muscle cells.
Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.
Intestine-specific disruption of mitochondrial superoxide dismutase extends longevity.
Multiplexed single-cell imaging reveals diverging subpopulations with distinct senescence phenotypes during long-term senescence induction.
V-ATPase in glioma stem cells: a novel metabolic vulnerability.
Optogenetic control of mitochondrial aggregation and function.
PSMC2 promotes resistance against temozolomide in glioblastoma via suppressing JNK-mediated autophagic cell death.

Membranes (Basel). 2025 Jan 14. pii: 29. [Epub ahead of print]15(1):

Intracellular Membrane Contact Sites in Skeletal Muscle Cells.

Matteo Serano, Stefano Perni, Enrico Pierantozzi, Annunziatina Laurino, Vincenzo Sorrentino, Daniela Rossi.

  Intracellular organelles are common to eukaryotic cells and provide physical support for the assembly of specialized compartments. In skeletal muscle fibers, the largest intracellular organelle is the sarcoplasmic reticulum, a specialized form of the endoplasmic reticulum primarily devoted to Ca2+ storage and release for muscle contraction. Occupying about 10% of the total cell volume, the sarcoplasmic reticulum forms multiple membrane contact sites, some of which are unique to skeletal muscle. These contact sites primarily involve the plasma membrane; among these, specialized membrane contact sites between the transverse tubules and the terminal cisternae of the sarcoplasmic reticulum form triads. Triads are skeletal muscle-specific contact sites where Ca2+ channels and regulatory proteins assemble to form the so-called calcium release complex. Additionally, the sarcoplasmic reticulum contacts mitochondria to enable a more precise regulation of Ca2+ homeostasis and energy metabolism. The sarcoplasmic reticulum and the plasma membrane also undergo dynamic remodeling to allow Ca2+ entry from the extracellular space and replenish the stores. This process involves the formation of dynamic membrane contact sites called Ca2+ Entry Units. This review explores the key processes in biogenesis and assembly of intracellular membrane contact sites as well as the membrane remodeling that occurs in response to muscle fatigue.

Keywords:  calcium signaling; endoplasmic reticulum; muscle contraction; sarcoplasmic reticulum

DOI:  https://doi.org/10.3390/membranes15010029
Geroscience. 2025 Jan 20.

The senolytic cocktail, dasatinib and quercetin, impacts the chromatin structure of both young and senescent vascular smooth muscle cells.

Agnieszka Gadecka, Natalia Nowak, Edyta Bulanda, Dorota Janiszewska, Magdalena Dudkowska, Ewa Sikora, Anna Bielak-Zmijewska.

  One promising strategy to alleviate aging symptoms is the treatment with senolytics that is compounds which selectively eliminate senescent cells. Some therapies aim to reduce symptoms of cellular senescence without senescent cell eradication (senomorphic activity). However, senotherapies raise many questions concerning the selectivity, safety and efficiency of senolitic drugs. A vital question is how the senolytic compounds affect young proliferating cells. In our study, we checked the impact of quercetin and dasatinib (D + Q), one of the promising drug mixtures of drugs, on chromatin structure in young and senescent cells. We analyzed the effect of a single and triple drug treatment on vascular smooth muscle cells. We have shown that D + Q impacts the chromatin in both young and senescent cells. In senescent cells, D + Q caused some symptoms of chromatin "rejuvenation" but in young cells some changes characteristic of senescent cells were observed. The alterations in young cells appeared only transiently and chromatin returned to the initial state after 24 h of recovery. The complexity of chromatin staining and nucleus morphology evaluation indicated that a triple treatment makes senescent cells more similar to the young ones than a single treatment. However, the analysis of senescence markers suggested that a single treatment with D + Q caused slightly less pronounced senescence characteristics and was more efficient in alleviating the features of senescence than a triple treatment. It is still an open question whether the alterations caused by D + Q are beneficial or harmful in the long term; however, so far, it can be concluded that the effects depend on cell type and the physiological context.

Keywords:  Aging; Chromatin structure; D + Q; Senescence; Senolytics; VSMC

DOI:  https://doi.org/10.1007/s11357-024-01504-6
Sci Adv. 2025 Jan 24. 11(4): eadu4369

Mitochondria complex III-generated superoxide is essential for IL-10 secretion in macrophages.

Joshua S Stoolman, Rogan A Grant, Leah K Billingham, Taylor A Poor, Samuel E Weinberg, Madeline C Harding, Ziyan Lu, Jason Miska, Marten Szibor, Gr Scott Budinger, Navdeep S Chandel.

Mitochondrial electron transport chain (ETC) function modulates macrophage biology; however, mechanisms underlying mitochondria ETC control of macrophage immune responses are not fully understood. Here, we report that mutant mice with mitochondria ETC complex III (CIII)-deficient macrophages exhibit increased susceptibility to influenza A virus (IAV) and LPS-induced endotoxic shock. Cultured bone marrow-derived macrophages (BMDMs) isolated from these mitochondria CIII-deficient mice released less IL-10 than controls following TLR3 or TLR4 stimulation. Unexpectedly, restoring mitochondrial respiration without generating superoxide using alternative oxidase (AOX) was not sufficient to reverse LPS-induced endotoxic shock susceptibility or restore IL-10 release. However, activation of protein kinase A (PKA) rescued IL-10 release in mitochondria CIII-deficient BMDMs following LPS stimulation. In addition, mitochondria CIII deficiency did not affect BMDM responses to interleukin-4 (IL-4) stimulation. Thus, our results highlight the essential role of mitochondria CIII-generated superoxide in the release of anti-inflammatory IL-10 in response to TLR stimulation.

DOI: https://doi.org/10.1126/sciadv.adu4369
Free Radic Biol Med. 2025 Jan 17. pii: S0891-5849(25)00038-3. [Epub ahead of print]

Intestine-specific disruption of mitochondrial superoxide dismutase extends longevity.

Thomas Liontis, Megan M Senchuk, Shusen Zhu, Suleima Jacob-Tomas, Ulrich Anglas, Annika Traa, Sonja K Soo, Jeremy M Van Raamsdonk.

  Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, suggesting that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan. We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for disruption of mitochondrial superoxide dismutase to increase longevity.

Keywords:  Aging; C. elegans; genetics; mitochondria; reactive oxygen species; superoxide dismutase; tissue specificity

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.032
Geroscience. 2025 Jan 23.

Multiplexed single-cell imaging reveals diverging subpopulations with distinct senescence phenotypes during long-term senescence induction.

Garrett A Sessions, Madeline V Loops, Brian O Diekman, Jeremy E Purvis.

  Cellular senescence is a phenotypic state that contributes to the progression of age-related disease through secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Understanding the process by which healthy cells become senescent and develop SASP factors is critical for improving the identification of senescent cells and, ultimately, understanding tissue dysfunction. Here, we reveal how the duration of cellular stress modulates the SASP in distinct subpopulations of senescent cells. We used multiplex, single-cell imaging to build a proteomic map of senescence induction in human epithelial cells induced to senescence over the course of 31 days. We map how the expression of SASP proteins increases alongside other known senescence markers such as p53, p21, and p16INK4a. The aggregated population of cells responded to etoposide with an accumulation of stress response factors over the first 11 days, followed by a plateau in most proteins. At the single-cell level, however, we identified two distinct senescence cell populations, one defined primarily by larger nuclear area and the second by higher protein concentrations. Trajectory inference suggested that cells took one of two discrete molecular paths from unperturbed healthy cells, through a common transitional subpopulation, and ending at the discrete terminal senescence phenotypes. Our results underscore the importance of using single-cell proteomics to identify the mechanistic pathways governing the transition from senescence induction to a mature state of senescence characterized by the SASP.

Keywords:  Cellular senescence; DNA damage; Senescence induction; Senescence-associated secretory phenotype (SASP)

DOI:  https://doi.org/10.1007/s11357-024-01503-7
J Exp Clin Cancer Res. 2025 Jan 17. 44(1): 17

V-ATPase in glioma stem cells: a novel metabolic vulnerability.

Alessandra Maria Storaci, Irene Bertolini, Cristina Martelli, Giorgia De Turris, Nadia Mansour, Mariacristina Crosti, Maria Rosaria De Filippo, Luisa Ottobrini, Luca Valenti, Elisa Polledri, Silvia Fustinoni, Manuela Caroli, Claudia Fanizzi, Silvano Bosari, Stefano Ferrero, Giorgia Zadra, Valentina Vaira.

   BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth.
METHODS: V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels.
RESULTS: Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes.
CONCLUSIONS: V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.

Keywords:  Bafilomycin A1; Glioma; Glioma stem cell; Metabolism; V-ATPase

DOI:  https://doi.org/10.1186/s13046-025-03280-3
Front Bioeng Biotechnol. 2024 ;12 1500343

Optogenetic control of mitochondrial aggregation and function.

Luhao Zhang, Xuechun Liu, Min Zhu, Yuanfa Yao, Zhichao Liu, Xianming Zhang, Xin Deng, Yi Wang, Liting Duan, Xiaogang Guo, Junfen Fu, Yingke Xu.

  The balance of mitochondrial fission and fusion plays an important role in maintaining the stability of cellular homeostasis. Abnormal mitochondrial fission and fragmentation have been shown to be associated with oxidative stress, which causes a variety of human diseases from neurodegeneration disease to cancer. Therefore, the induction of mitochondrial aggregation and fusion may provide an alternative approach to alleviate these conditions. Here, an optogenetic-based mitochondrial aggregation system (Opto-MitoA) developed, which is based on the CRY2clust/CIBN light-sensitive module. Upon blue light illumination, CRY2clust relocates from the cytosol to mitochondria where it induces mitochondrial aggregation by CRY2clust homo-oligomerization and CRY2clust-CIBN hetero-dimerization. Our functional experiments demonstrate that Opto-MitoA-induced mitochondrial aggregation potently alleviates niclosamide-caused cell dysfunction in ATP production. This study establishes a novel optogenetic-based strategy to regulate mitochondrial dynamics in cells, which may provide a potential therapy for treating mitochondrial-related diseases.

Keywords:  ATP; aggregation; imaging; mitochondria; optogenetics

DOI:  https://doi.org/10.3389/fbioe.2024.1500343
Biochem Pharmacol. 2025 Jan 15. pii: S0006-2952(25)00017-6. [Epub ahead of print] 116755

PSMC2 promotes resistance against temozolomide in glioblastoma via suppressing JNK-mediated autophagic cell death.

Pritam Kumar Roy, K Deepak, Chandan Kanta Das, Abhijit Das, Angana Biswas, Bikash Chandra Jena, Mahitosh Mandal.

  Temozolomide is universally used to treat glioblastoma due to its unique ability to cross the blood-brain barrier and inhibit tumor growth through DNA alkylation. However, over time, the inevitable emergence of resistance to temozolomide impedes successful treatment of this cancer. As a result, there is an urgent need to identify new therapeutic targets to improve treatment outcomes for this malignancy. In this work, acquired temozolomide-resistant glioblastoma cell lines LN18 (LN18-TR) and T98G (T98G-TR) exhibited stronger aggressiveness and lower endoplasmic reticulum (ER) stress than their parental cells.. Besides, temozolomide resistance was associated with elevated proteasome activity that suppressed ER stress, which was restored upon inhibition of the proteasome with MG132. Specifically, our study revealed that the 19S proteasomal regulatory subunit PSMC2, which was overexpressed in adapted temozolomide-resistant glioblastoma cells, reduced pro-death autophagy and decreased temozolomide sensitivity in parental cells when overexpressed. While autophagy increased in parental cells following temozolomide treatment, it was not elevated in temozolomide-resistant glioblastoma cells. Genetic suppression of PSMC2 triggered the JNK signalling pathway causing phosphorylation of BCL2, allowing Beclin1 to be released from the BCL2-Beclin1 complex. This boosted autophagosome nucleation, increased pro-death autophagy, and restored apoptosis in temozolomide-resistant glioblastoma cells. Finally, targeting PSMC2 provided a unique method for interrupting autophagy-mediated ER stress maintenance and temozolomide resistance in glioblastoma.

Keywords:  Autophagy; Glioblastoma; PSMC2; Proteasome; Temozolomide resistance

DOI:  https://doi.org/10.1016/j.bcp.2025.116755