bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–10–12
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Translating cellular senescence research into clinical practice for metabolic disease.
  2. Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
  3. Acidosis orchestrates adaptations of energy metabolism in tumors.
  4. Heterogeneity of Cellular Senescence: Subtype-Specific Mechanisms and the Emerging Role of Plasma Membrane Damage.
  5. Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
  6. Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
  7. Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.
  8. Longevity steps on the cGAS.
  9. Human Cell Aging Transcriptome Atlas (HCATA): a single-cell atlas of age-associated transcriptomic alterations across human tissues.
  10. Seeking ghosts.
  1. Nat Rev Endocrinol. 2025 Oct 06.
    Translating cellular senescence research into clinical practice for metabolic disease.
    Selim Chaib, Allyson K Palmer, Saranya P Wyles, Nicolas Musi, James L Kirkland, Tamara Tchkonia.
      Translational research on cellular senescence has led to numerous early-phase clinical trials targeting senescent cells to treat, prevent or alleviate multiple disorders and diseases, including metabolic diseases and their comorbidities. Cellular senescence is a cell fate that occurs in response to stressors, including metabolic disruptions, and is one of the hallmarks (or pillars) of ageing. In their senescent state, cells cease proliferation and can develop a senescence-associated secretory and metabolic phenotype that contributes to the pathogenesis of metabolic dysfunction associated with obesity and ageing. Metabolic stress, which is central to the development of metabolic diseases, can trigger cellular senescence, thereby enabling a vicious cycle that exacerbates metabolic dysfunction. Therapies targeting senescent cells (senotherapeutics), either alone or in combination with other gerotherapies or lifestyle interventions, hold great promise for addressing the ongoing obesity epidemic and the need for improved therapies to prevent and treat metabolic diseases and their complications and comorbidities. In this Review, we discuss novel senotherapeutics, including challenges related to the translation of these therapies and the need to establish gerodiagnostic biomarkers to track the elimination of senescent cells, define eligibility and measure efficacy, as well as considerations for clinical trial design and execution.
    DOI:  https://doi.org/10.1038/s41574-025-01187-9
  2. Cell Metab. 2025 Oct 07. pii: S1550-4131(25)00390-0. [Epub ahead of print]37(10): 1927-1928
    Mitochondrial sodium-calcium exchange-Can TMEM65 do it alone?
    Joanne F Garbincius, John W Elrod.
      The mechanisms mediating calcium transport into and out of the mitochondrial matrix have critical implications for signaling, bioenergetics, and cell death. Zhang et al.1 propose that the protein TMEM65, recently identified as a key component of the mitochondrial calcium efflux machinery, functions as the mitochondrial sodium/calcium exchanger. Their report encourages critical re-examination of the components required for mitochondrial calcium handling.
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.005
  3. Science. 2025 Oct 09. 390(6769): eadp7603
    Acidosis orchestrates adaptations of energy metabolism in tumors.
    Sven Groessl, Robert Kalis, Marteinn T Snaebjornsson, Leon Wambach, Jakob Haider, Florian Andersch, Almut Schulze, Wilhelm Palm, Johannes Zuber.
      Malignant tumors are characterized by diverse metabolic stresses, including nutrient shortages, hypoxia, and buildup of metabolic by-products. To understand how cancer cells adapt to such challenges, we conducted sequential CRISPR screens to identify genes that affect cellular fitness under specific metabolic stress conditions in cell culture and to then probe their relevance in pancreatic tumors. Comparative analyses of hundreds of fitness genes revealed that cancer metabolism in vivo was shaped by bioenergetic adaptations to tumor acidosis. Mechanistically, acidosis suppressed cytoplasmic activity of extracellular signal-regulated kinase (ERK), thereby preventing oncogene-induced mitochondrial fragmentation and promoting fused mitochondria. The resulting boost in mitochondrial respiration supported cancer cell adaptations to various metabolic stresses. Thus, acidosis is an environmental factor that alters energy metabolism to promote stress resilience in cancer.
    DOI:  https://doi.org/10.1126/science.adp7603
  4. Cancer Sci. 2025 Oct 11.
    Heterogeneity of Cellular Senescence: Subtype-Specific Mechanisms and the Emerging Role of Plasma Membrane Damage.
    Enaam Alghamdi, Keiko Kono.
      Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age-related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context-dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro-tumorigenic and pro-aging effects.
    Keywords:  cellular senescence; oncogene‐induced senescence; p16; p53; plasma membrane damage
    DOI:  https://doi.org/10.1111/cas.70223
  5. Nat Commun. 2025 Oct 10. 16(1): 9053
    Quantitative cellular characterization of extracellular mitochondria uptake and delivery.
    Zahra Al Amir Dache, Maud Chevé, Julia Dancourt, Grégory Lavieu.
      Mitochondria are essential intracellular organelles responsible for energy production. Over the past two decades, unconventional intercellular mitochondrial transfer has been reported, but the nature of the transport intermediates, the efficiency of the process, and the cellular mechanisms involved in their uptake and putative integration by acceptor cells remain poorly understood. This gap in knowledge is especially significant given the potential therapeutic applications of mitochondrial transplantation. In this study, we use quantifiable cell biology and biochemical approaches to assess intercellular mitochondria exchange. Our findings suggest that low amount of free mitochondria can be released into conditioned media and subsequently internalized by recipient cells, primarily via fluid-phase uptake, although alternative or concurrent endocytic pathways may also contribute. Notably, we show that a subset of internalized mitochondria escapes the endosomal compartment, reaches the cytosol, and may integrate into the host cell's pre-existing mitochondrial network.
    DOI:  https://doi.org/10.1038/s41467-025-64147-x
  6. Nat Commun. 2025 Oct 08. 16(1): 8952
    Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells.
    Vidhi Pareek, Stephen Benkovic.
      Cancer cells have the unique capability to upregulate the de novo nucleotide biosynthesis supporting cell survival under nucleotide deprivation. We probe the role of metabolic channeling and membrane-less metabolic compartmentalization by mitochondria-proximal dynamic de novo pyrimidine and purine biosynthesis metabolons, the pyrimidinosome and the purinosome, respectively. We designed in-cell stable isotope label incorporation assays (13C6 glucose, 15N2 glutamine) for detection of metabolic channeling, revealing the function and enzymatic composition of these complexes. Moreover, we discovered that the mitochondrially compartmentalized GOT2 dependent generation of aspartic acid feeds the channeled nucleotide synthesis instead of the bulk cytosolic pool or the GOT1 activity. While a low flux diffusive pathway generates the pathway intermediates in an accumulative process, it's the channeled pathway that successfully generates the end product nucleotides. Our results demonstrate how metabolic channeling and efficient de novo nucleotide biosynthesis is fueled by coordination of mitochondrially compartmentalized metabolic events with cytosolic metabolons in cancer cells.
    DOI:  https://doi.org/10.1038/s41467-025-64013-w
  7. FEBS Open Bio. 2025 Oct 10.
    Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.
    Viet Bui, Maryline Santerre, Natalia Shcherbik, Bassel E Sawaya.
      Mitochondria-associated membranes (MAMs) are specialized contact sites between the endoplasmic reticulum (ER) and mitochondria that maintain cellular homeostasis through precisely orchestrated molecular mechanisms. These dynamic interfaces are maintained at 10-50 nm distances by complex tethering proteins, including the core IP3R-GRP7 5-VDAC1 complex and regulatory proteins, such as the sigma-1 receptor. MAMs coordinate multiple essential cellular processes: lipid synthesis and transfer, calcium signaling, metabolic regulation, and quality control through autophagy and mitophagy. Recent advances in super-resolution microscopy and proteomics have revealed that MAM dysfunction drives pathogenesis across various diseases. In Alzheimer's disease, disrupted MAM spacing directly affects Aβ production and mitochondrial function, while in Parkinson's disease, α-synuclein accumulation at MAMs impairs phosphatidylserine metabolism and mitochondrial dynamics. Beyond neurodegeneration, MAMs play crucial roles in metabolic disorders, cancer progression, and viral infections. This review provides mechanistic insights into MAM biology, from molecular organization to disease pathogenesis, integrating structural analyses with dynamic visualization approaches. We examine emerging therapeutic strategies targeting MAM-associated pathways and highlight their potential in treating complex diseases.
    Keywords:  ER–mitochondria contact sites; calcium signaling; cellular stress responses; lipid metabolism; mitochondria‐associated membranes; neurodegeneration
    DOI:  https://doi.org/10.1002/2211-5463.70121
  8. Science. 2025 Oct 09. 390(6769): 126-127
    Longevity steps on the cGAS.
    John C Martinez, Andrei Seluanov, Vera Gorbunova.
      A DNA repair function in a cytosolic sensor demonstrates a potential role in naked mole-rat longevity.
    DOI:  https://doi.org/10.1126/science.aeb6125
  9. Commun Biol. 2025 Oct 09. 8(1): 1450
    Human Cell Aging Transcriptome Atlas (HCATA): a single-cell atlas of age-associated transcriptomic alterations across human tissues.
    Josh Bartz, Xiao Ma, Lei Zhang, Xiao Dong.
      Biological aging is associated with progressively more severe genetic and epigenetic alterations. While these changes are expected to affect the transcriptional profile of cells, the magnitude of that effect is unknown as the aging transcriptome is still poorly understood. Understanding the aging transcriptional landscape will give us greater insight into how cells are affected by and/or respond to the aging process. To facilitate the large-scale exploration of the aging transcriptome, we report the development of the Human Cell Aging Transcriptome Atlas (HCATA). HCATA, contains single-cell RNA-sequencing datasets from 76 publications totaling 92 million cells and 3,475 tissue-level samples across more than 50 tissue types with ages ranging from 0 to 103 years. HCATA includes a genome browser that allows users to interactively explore age-related differential expression, as well as functions to explore related pathways at the tissue and cell-type level. HCATA is publicly accessible at http://hcata-xiaodonglab.org:3304 .
    DOI:  https://doi.org/10.1038/s42003-025-08845-8
  10. Science. 2025 Oct 09. 390(6769): 122-125
    Seeking ghosts.
    Dennis Normile.
      A Japanese botanist is revealing the secrets of plants that have given up photosynthesis.
    DOI:  https://doi.org/10.1126/science.aec8710
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