bims-cesemi 2025-07-06 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–07–06
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor

Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise.
Mitochondria-Associated Endoplasmic Reticulum Membranes in Human Health and Diseases.
mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies.
Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation.
DNA methylation protects cancer cells against senescence.
Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.
Muscle needs NAD, but how much?
A constricted mitochondrial morphology formed during respiration.
GAT3-dependent regulation of glioma invasiveness via a lipid raft-associated PMCA4 Ca2+ transporter and a downstream CaMKII/CREB signaling - implications for compartmentalized signaling in glioma tumors.

Aging Cell. 2025 Jun 30. e70137

Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contacts Precede Major (Mal)Adaptations in Aging Skeletal Muscle and Are Prevented by Exercise.

Ryan J Allen, Ana Kronemberger, Qian Shi, R Marshall Pope, Elizabeth Cuadra-Muñoz, Wangkuk Son, Long-Sheng Song, Ethan J Anderson, Renata O Pereira, Vitor A Lira.

  Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres, forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice, we reveal that aging slows muscle relaxation, leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We also demonstrate that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are affected early in aging and are closely associated with the rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca2+ homeostasis, cytoskeleton integrity, and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

Keywords:  aging; endoplasmic reticulum; exercise; mitochondria; mitochondrial‐associated ER membranes; sarcopenia; sarcoplasmic reticulum; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70137
MedComm (2020). 2025 Jul;6(7): e70259

Mitochondria-Associated Endoplasmic Reticulum Membranes in Human Health and Diseases.

Yong Liu, Zi-Hui Mao, Junwen Huang, Hui Wang, Xiao Zhang, Xin Zhou, Yue Xu, Shaokang Pan, Dongwei Liu, Zhangsuo Liu, Qi Feng.

  As fundamental units of life activities, cells exhibit a high degree of structural refinement and functional specialization, forming the cornerstone of life complexity. Compartmentalization within cells is pivotal for maintaining the orderly progression of intracellular biochemical processes. Cellular compartments constitute the enclosed regions within the cytoplasm of all eukaryotic cells and are typically surrounded by a single or double layer of phospholipids, and include major organelles, such as the endoplasmic reticulum (ER) and mitochondria. Compartmentalization enables organelles to maintain distinct environments in terms of space, physics, and chemistry, thereby increasing their functionality. Human health is closely associated with cellular organelle homeostasis, and organelle dysfunction affects disease pathogenesis. In contrast to isolated cellular compartments, organelles are interdependent and communicate via membrane contact sites, with close membrane contact between the ER and mitochondria, forming mitochondria-associated ER membranes (MAMs), which are involved in multiple cellular functions and whose integrity and function are essential for cellular homeostasis, with dysfunction implicated in various diseases. Investigating MAMs structure, function, and disease-state alterations informs mechanisms and developing therapies. This article reviews the discovery, structure, function, and research progress of MAMs in human systemic diseases and cancer and explores their potential as therapeutic targets.

Keywords:  endoplasmic reticulum; human diseases; mitochondria; mitochondria‐associated endoplasmic reticulum membranes

DOI:  https://doi.org/10.1002/mco2.70259
Trends Cancer. 2025 Jul 02. pii: S2405-8033(25)00153-0. [Epub ahead of print]

mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.

Israel Cañadas, Takahiko Murayama, Lorenzo Galluzzi.

  Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.

Keywords:  NF-κB; PD-L1; SASP; STING; VDAC; prostate cancer

DOI:  https://doi.org/10.1016/j.trecan.2025.06.010
Front Pharmacol. 2025 ;16 1592596

Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies.

Li Nan, Pengchao Guo, Wang Hui, Fang Xia, Chenggang Yi.

  Aging is a multifactorial process that affects skin integrity through the progressive decline of dermal fibroblast function. Dermal fibroblasts are key regulators of extracellular matrix (ECM) composition, wound healing, and tissue homeostasis. However, their dysfunction contributes to structural deterioration, chronic inflammation, and impaired regenerative capacity. Cellular senescence, a fundamental characteristic of aging, results in the buildup of senescent fibroblasts that release growth factors, matrix-degrading enzymes, and pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This study examines the impact of fibroblast senescence on dermal aging, highlighting mechanisms such as DNA damage, mitochondrial dysfunction, oxidative stress, and telomere attrition. The role of SASP-driven ECM degradation, matrix metalloproteinases (MMPs) activation, and fibroblast-keratinocyte communication breakdown are explored, demonstrating their collective contribution to skin aging. Additionally, key signaling pathways, including p16INK4a/RB, p53, NF-κB, mTOR, and TGF-β, are implicated in fibroblast senescence and chronic inflammation. Recent advancements in therapeutic strategies targeting fibroblast aging, such as senolytics, extracellular vesicle-based interventions, and metabolic reprogramming, offer promising avenues for skin rejuvenation. This review delves into the molecular and cellular dynamics of dermal fibroblast aging, emphasizing their relevance for developing novel anti-aging interventions.

Keywords:  SASP; aging; dermal fibroblast; signaling pathways; skin

DOI:  https://doi.org/10.3389/fphar.2025.1592596
Circ Res. 2025 Jul 01.

Mitochondrial Calcium Uniporter Regulates ITAM-Dependent Platelet Activation.

Abigail Ajanel, Izabella Andrianova, Mia Kowalczyk, Javier Menéndez Pérez, Sradha R Bhatt, Irina Portier, Taylor Boone, Abigail Ballard-Kordeliski, Yasuhiro Kosaka, Dipayan Chaudhuri, David S Paul, Wolfgang Bergmeier, Frederik Denorme, Robert A Campbell.

   BACKGROUND: Platelet activation relies on changes in cytoplasmic calcium flux. However, little is known about the role mitochondrial calcium flux plays in platelet activation. Activation induces release of calcium from intracellular stores, which enters the mitochondrial matrix through the MCU (mitochondrial calcium uniporter) to regulate bioenergetics and reactive oxygen species (ROS) formation, as demonstrated in other cells. However, whether MCU contributes to platelet function is unclear.
METHODS: We generated platelet-specific Mcu-deficient mice (Mcuplt-/-) and compared them to littermate wild-type controls (Mcuplt+/+). In vitro approaches assessed mitochondrial calcium flux and platelet activation responses to stimulation of immunoreceptor tyrosine-based activation motif (ITAM) receptors and GPCRs (G protein-coupled receptors). In addition, we examined in vivo hemostasis and thrombosis. We also treated human platelets with MCU inhibitors, and platelet function was assessed.
RESULTS: Mcuplt-/- platelets had significantly reduced mitochondrial calcium flux in response to activation of ITAM receptors, whereas mitochondrial calcium flux in response to GPCR activation was unchanged. Platelet aggregation was significantly reduced by ITAM activation in Mcuplt-/- platelets, but GPCR-induced aggregation was unchanged. Similar findings were observed when MCU was inhibited in human platelets. In vivo, Mcuplt-/- mice had reduced arterial thrombosis and less ischemic stroke brain injury. Hemostasis was mildly altered in Mcuplt-/- mice. Mechanistically, mitochondrial ROS generation was significantly reduced in Mcuplt-/- platelets compared with Mcuplt+/+ platelets after ITAM-dependent activation, but not GPCR activation. Reduced mitochondrial ROS was associated with decreased ITAM signaling based on p-Syk (phospho-spleen tyrosine kinase) and p-PLCγ2 (phospho-phospholipase C-gamma 2) in Mcuplt-/- platelets. Inhibiting mitochondrial ROS decreased aggregation as well as downstream ITAM signaling in Mcuplt+/+ platelets. Conversely, treating Mcuplt-/- platelets with MitoParaquat to induce mitochondrial ROS increased platelet ITAM-dependent aggregation and signaling.
CONCLUSIONS: Our data support a role for mitochondrial calcium flux in regulating ITAM-dependent platelet activation through the generation of mitochondrial ROS.

Keywords:  ITAM; mitochondria; platelet; thrombosis

DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326443
Nat Commun. 2025 Jul 01. 16(1): 5901

DNA methylation protects cancer cells against senescence.

Xiaoying Chen, Kosuke Yamaguchi, Brianna Rodgers, Delphine Goehrig, David Vindrieux, Xavier Lahaye, Matthieu Nolot, Laure Ferry, Sophie Lanciano, Nadine Martin, Pierre Dubus, Fumihito Miura, Takashi Ito, Gael Cristofari, Nicolas Manel, Masato T Kanemaki, David Bernard, Pierre-Antoine Defossez.

Inhibitors of DNA methylation such as 5-aza-deoxycytidine are widely used in experimental and clinical settings. However, their mechanism of action is such that DNA damage inevitably co-occurs with loss of DNA methylation, making it challenging to discern their respective effects. Here we deconvolute the effects of decreased DNA methylation and DNA damage on cancer cells, by using degron alleles of key DNA methylation regulators. We report that cancer cells with decreased DNA methylation-but no DNA damage-enter cellular senescence, with G1 arrest, SASP expression, and SA-β-gal positivity. This senescence is independent of p53 and Rb, but involves p21, which is cytoplasmic and inhibits apoptosis, and cGAS, playing a STING-independent role in the nucleus. Xenograft experiments show that tumor cells can be made senescent in vivo by decreasing DNA methylation. These findings reveal the intrinsic effects of loss of DNA methylation in cancer cells and have practical implications for future therapeutic approaches.

DOI: https://doi.org/10.1038/s41467-025-61157-7
EMBO Mol Med. 2025 Jun 30.

Chemical reprogramming ameliorates cellular hallmarks of aging and extends lifespan.

Lucas Schoenfeldt, Patrick T Paine, Sara Picó, Nibrasul H Kamaludeen M, Grace B Phelps, Calida Mrabti, Gabriela Desdín-Micó, María Del Carmen Maza, Kevin Perez, Alejandro Ocampo.

  The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that chemical-induced partial reprogramming can improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan and healthspan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical-induced partial reprogramming, opening a path towards future translational applications.

Keywords:  Aging; Cellular Reprogramming; Chemical Reprogramming; Epigenetics; Lifespan

DOI:  https://doi.org/10.1038/s44321-025-00265-9
Cell Metab. 2025 Jul 01. pii: S1550-4131(25)00296-7. [Epub ahead of print]37(7): 1455-1456

Muscle needs NAD, but how much?

David W Frederick, Joseph P McGaunn, Joseph A Baur.

Supplements that increase nicotinamide adenine dinucleotide (NAD) have become increasingly popular, and much of the attention has focused on potential benefits to skeletal muscle. In this issue of Cell Metabolism, Chubanava et al.1 use an inducible model to lower NAD concentration in the muscles of adult mice, revealing a surprising lack of functional consequences.

DOI: https://doi.org/10.1016/j.cmet.2025.06.001
Nat Commun. 2025 Jul 01. 16(1): 5314

A constricted mitochondrial morphology formed during respiration.

Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.

Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.

DOI: https://doi.org/10.1038/s41467-025-60658-9
Cell Calcium. 2025 Jun 19. pii: S0143-4160(25)00059-4. [Epub ahead of print]130 103050

GAT3-dependent regulation of glioma invasiveness via a lipid raft-associated PMCA4 Ca2+ transporter and a downstream CaMKII/CREB signaling - implications for compartmentalized signaling in glioma tumors.

Marta Sobolczyk-Prawda, Agnieszka Kapsa, Malwina Lisek, Julia Tomczak, Katarzyna Sobierajska, Maciej Radek, Feng Guo, Tomasz Boczek.

  Emerging evidence underscores the crucial role of compartmentalized Ca²⁺ and GABA signaling in the development and progression of gliomas. Our findings reveal that low GAT3 expression and high PMCA4 levels are strongly associated with poor survival outcomes in glioma patients, suggesting their involvement in tumor progression. Using C6 glioma model, we uncovered a dynamic interaction between GAT3 and PMCA4 within lipid raft microdomains, which plays a key role in fine-tuning of localized Ca2+ dynamics in response to GABA stimulation. Knockdown of PMCA4 increased resting Ca2+concentration and enhanced Ca2+ accumulation in lipid rafts following 3-min pulse GABA stimulation, significantly impairing glioma cell migration and invasion. Interestingly, the expression of Ca2+ chelator parvalbumin in rafts abolished both baseline and GABA-stimulated Ca2+ rises, effectively restoring the migratory and invasive potential of tumor cells. We further demonstrated that GAT3 interacted with calmodulin, a pivotal regulator of PMCA4, and this interaction was decreased following 24 h GABA treatment. Long-term GABA stimulation also disrupted PMCA4/GAT3 complex, overloaded lipid rafts with Ca2+ and decreased glioma invasiveness in the presence of PMCA4. In these conditions, we observed GAT3- and Ca2+/calmodulin-dependent protein kinase II-dependent CREB phosphorylation at Ser133, which was controlled by Ca2+ events in lipid rafts and required to maintain glioma invasiveness. Our study uncovers a previously unrecognized GAT3-dependent mechanism of Ca2+compartmentalization in membrane microdomains, shedding new light on its potential role in tumor behavior. Understanding these local Ca²⁺ signaling partnerships will offer valuable insights into gliomagenesis and could lead to the development of novel therapeutic strategies for glioma treatment.

Keywords:  Calcium; Calmodulin; GABA; GABA transporter 3; Lipid rafts; Plasma membrane Ca²⁺-ATPase 4; cAMP response element binding protein

DOI:  https://doi.org/10.1016/j.ceca.2025.103050