bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–07–13
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
  2. Organelles share the load.
  3. Sarcoplasmic Reticulum-Mitochondria Microdomains: Hugging and Kissing in the Heart.
  4. A β-galactosidase activated near-infrared fluorescent probe for tracking cellular senescence in vitro and in vivo.
  5. The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.
  6. Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia.
  7. Early-life exercise extends healthspan but not lifespan in mice.
  1. FEBS J. 2025 Jul 07.
    A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
    Antigoni Diokmetzidou, Luca Scorrano.
      Organelles were once regarded as discrete entities, but it is now established that they interact through specialized membrane contacts maintained by protein tethers and lipid interactions. Among these, mitochondria-endoplasmic reticulum contact sites (MERCS) emerged as hubs for calcium signaling, lipid metabolism, and mitochondrial dynamics. Here, we critically appraise current methodologies for MERC visualization and quantification, survey the molecular toolbox for their selective perturbation, and highlight common experimental pitfalls. We also discuss key conceptual issues-defining MERCs on structural and functional grounds, addressing redundancy among tethering factors, and distinguishing primary MERC-mediated effects from secondary cellular responses. Finally, we propose that an integrative strategy combining imaging, precise biochemical isolation, proteomics, and functional assays will be essential to resolve outstanding questions about MERC dynamics in physiology and pathology.
    Keywords:  endoplasmic reticulum; imaging; membrane contact sites; mitochondria; mitochondria–ER contact sites
    DOI:  https://doi.org/10.1111/febs.70184
  2. Science. 2025 Jul 10. 389(6756): 130-131
    Organelles share the load.
    Marc Fransen.
      Peroxisome-mitochondria contact sites manage mitochondrial oxidative stress.
    DOI:  https://doi.org/10.1126/science.adz0109
  3. Am J Physiol Cell Physiol. 2025 Jul 11.
    Sarcoplasmic Reticulum-Mitochondria Microdomains: Hugging and Kissing in the Heart.
    Bong Sook Jhun, Jin O-Uchi, Brian Rhee, Ameneh Ahrari, Nathan DeMichaelis, Kye-Im Jeon, David M Booth, Shey-Shing Sheu.
      Endoplasmic reticulum (ER)-mitochondrial (ER-Mito) interface, termed mitochondrial-ER contacts (MERCs), plays significant roles in the maintenance of bioenergetics and basal cell functions via the exchange of lipids, Ca2+, and reactive oxygen species (ROS) in various cell-types/tissues. Genetic deletion of mitofusin 2 (Mfn2), one of the key components of ER-Mito tethering, in cardiomyocytes (CMs) in vivo revealed the importance of the microdomains between mitochondria and sarcoplasmic reticulum (SR), a differentiated form of ER in muscle cells, for maintaining normal mitochondrial Ca2+ (mtCa2+) handling and bioenergetics in the adult heart. However, key questions remain to be answered: 1) What tethering proteins sustain SR-Mito contact site structure in SR-Mito contact sites in the adult ventricular CMs (AVCMs), the predominant cell type in adult heart; 2) Which MERC proteins operate in AVCMs to mediate specific microdomain functions under physiological conditions; 3) How is the MERC protein expression profile and function altered in cardiac pathophysiology. In this review, we summarize current knowledge regarding the structure, function, and regulation of SR-Mito microdomains in the heart, with particular focus on AVCMs, which display unique membrane organization and Ca2+ handling compared to other cell types. We further explore molecular mechanisms underpinning microdomain dysfunction in cardiac diseases and highlight the emerging roles of MERC proteins in the development and progression of cardiac pathology.
    Keywords:  IP3 receptor; calcium; cardiac myocyte; mitochondria-associated membrane; ryanodine receptor
    DOI:  https://doi.org/10.1152/ajpcell.00435.2025
  4. Smart Mol. 2025 Mar;3(1): e20240062
    A β-galactosidase activated near-infrared fluorescent probe for tracking cellular senescence in vitro and in vivo.
    Tian Su, Ruijun Shen, Dengchu Tu, Xiaoyue Han, Xianzhu Luo, Fabiao Yu.
      Cellular senescence is a steady state of cell cycle arrest necessary to maintain homeostasis in organisms. However, senescent cells may cause senescence in neighboring healthy cells, inducing the onset of several diseases, such as inflammation, neurological disorders, and atherosclerosis. Therefore, early detection of cellular senescence is extremely important. β-Galactosidase (β-gal), as a critical marker of cellular senescence, can be monitored to facilitate early diagnosis of aging-related diseases. Furthermore, β-gal is mainly found in lysosomes, which have a pH value of about 4.5-5.5. Here, we developed a near-infrared fluorescent probe (QMOH-Gal) for tracking cell senescence in vitro and in vivo via the detection of β-gal. In addition, the probe displayed high sensitivity and specificity for β-gal with good fluorescence signal in the acidity range. Subsequently, this QMOH-Gal probe was successfully employed to differentiate between normal cells and senescent cells by monitoring β-gal. Furthermore, the probe not only realized the monitoring of β-gal in zebrafish but also the tracking of β-gal in palbociclib-induced breast tumor senescence. Overall, the probe shows great promise as an effective tool for imaging β-gal in vivo for studying the biology of aging in organisms.
    Keywords:  cellular senescence; fluorescent probe; lysosomes; near‐infrared; β‐gal
    DOI:  https://doi.org/10.1002/smo.20240062
  5. Elife. 2025 Jul 07. pii: RP101984. [Epub ahead of print]13
    The ESCRT protein CHMP5 restricts bone formation by controlling endolysosome-mitochondrion-mediated cell senescence.
    Fan Zhang, Yuan Wang, Luyang Zhang, Chunjie Wang, Deping Chen, Haibo Liu, Ren Xu, Cole M Haynes, Jae-Hyuck Shim, Xianpeng Ge.
      The dysfunction of the cellular endolysosomal pathway, such as in lysosomal storage diseases, can cause severe musculoskeletal disorders. However, how endolysosomal dysfunction causes musculoskeletal abnormalities remains poorly understood, limiting therapeutic options. Here, we report that CHMP5, a member of the endosomal sorting complex required for transport (ESCRT)-III protein family, is essential to maintain the endolysosomal pathway and regulate bone formation in osteogenic lineage cells. Genetic ablation of Chmp5 in mouse osteogenic cells increases bone formation in vivo and in vitro. Mechanistically, Chmp5 deletion causes endolysosomal dysfunction by decreasing the VPS4A protein, and CHMP5 overexpression is sufficient to increase the VPS4A protein. Subsequently, endolysosomal dysfunction disturbs mitochondrial functions and increases mitochondrial ROS, ultimately resulting in skeletal cell senescence. Senescent skeletal cells cause abnormal bone formation by combining cell-autonomous and paracrine actions. Importantly, the elimination of senescent cells using senolytic drugs can alleviate musculoskeletal abnormalities in Chmp5 conditional knockout mice. Therefore, our results show that cell senescence represents an underpinning mechanism and a therapeutic target for musculoskeletal disorders caused by the aberrant endolysosomal pathway, such as in lysosomal storage diseases. These results also uncover the function and mechanism of CHMP5 in the regulation of cell senescence by affecting the endolysosomal-mitochondrial pathway.
    Keywords:  CHMP5; bone; cell biology; cell senescence; endolysosomal pathway; medicine; mouse; musculoskeletal disease; skeletal stem cell
    DOI:  https://doi.org/10.7554/eLife.101984
  6. Nat Commun. 2025 Jul 05. 16(1): 6207
    Multiomics and cellular senescence profiling of aging human skeletal muscle uncovers Maraviroc as a senotherapeutic approach for sarcopenia.
    Yang Li, Chuhan Li, Qin Zhou, Xingyuan Liu, Yulong Qiao, Ting Xie, Hao Sun, Michael Tim-Yun Ong, Huating Wang.
      Cellular senescence is a hallmark of organismal aging but how it drives aging in human tissues is not fully understood. Here we leverage single nucleus multiomics to profile senescence in mononucleated cells of human skeletal muscle and provide the first senescence atlas. We demonstrate the intra- and inter-populational transcriptomic and epigenomic heterogeneity and dynamics of cellular senescence. We also identify commonalities and variations in senescence-associated secretory phenotypes (SASPs) among the cells and elucidate SASP mediated cellular interactions and niche deregulation. Furthermore, we identify targetable SASPs and demonstrate the possibility of using Maraviroc as a pharmacological senotherapeutic for treating age-associated sarcopenia. Lastly, we define transcription factors that govern senescence state and SASP induction in aging muscle and elucidate the key function and mechanism of JUNB in SASP activation. Altogether, our findings demonstrate the prevalence and function of cellular senescence in skeletal muscle and identify a novel pharmacological intervention for sarcopenia.
    DOI:  https://doi.org/10.1038/s41467-025-61403-y
  7. Nat Commun. 2025 Jul 09. 16(1): 6328
    Early-life exercise extends healthspan but not lifespan in mice.
    Mengya Feng, Min Li, Jing Lou, Guiling Wu, Tian Gao, Fangqin Wu, Yanzhen Tan, Nini Zhang, Yong Zhao, Lin Zhao, Jia Li, Changhong Shi, Xing Zhang, Jiankang Liu, Feng Gao.
      It is well-known that physical activity exerts health benefits, yet the potential impacts of early-life regular exercise on later-life health and lifespan remains poorly understood. Here, we demonstrate that 3 months of early-life exercise in mice results in lasting health benefits, extending healthspan, but not lifespan. C57BL/6J mice underwent swimming exercise from 1 to 4 months of age, followed by detraining for the remainder of their lives. While early-life exercise did not extend the overall lifespan, it significantly improved healthspan in both male and female mice, as evidenced by enhanced systemic metabolism, cardiovascular function, and muscle strength, as well as reduced systemic inflammation and frailty in aged mice. Multiple-organ transcriptome analyses identified enhanced fatty acid metabolism in skeletal muscles as a major feature in aged mice that underwent early-life exercise. These findings reveal the enduring long-term health benefits of early-life exercise, highlighting its pivotal role in improving healthspan.
    DOI:  https://doi.org/10.1038/s41467-025-61443-4
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