bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–03–02
fifteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Sirtuin-1 Regulates Mitochondrial Calcium Uptake Through Mitochondrial Calcium Uptake 1 (MICU1).
  2. ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
  3. SenSkin™: a human skin-specific cellular senescence gene set.
  4. Cellular Senescence in Health, Disease, and Lens Aging.
  5. Resistance exercise training in older men reduces ATF4-activated and senescence-associated mRNAs in skeletal muscle.
  6. Cancer treatments accelerate ageing.
  7. Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
  8. Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
  9. Oleuropein supplementation increases resting skeletal muscle fractional PDH activity but does not influence whole-body metabolism: A randomized, double-blind, placebo-controlled trial in healthy, older males.
  10. Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
  11. Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.
  12. Peripheral fat mobilization and mitochondrial fat metabolism: Fueling the energy demands of liver regeneration.
  13. How quickly are you ageing? What molecular 'clocks' can tell you about your health.
  14. A framework of biomarkers for skeletal muscle aging: a consensus statement by the Aging Biomarker Consortium.
  15. Monitoring Cellular Energy Balance in Single Cells Using Fluorescent Biosensors for AMPK.
  1. Life (Basel). 2025 Jan 25. pii: 174. [Epub ahead of print]15(2):
    Sirtuin-1 Regulates Mitochondrial Calcium Uptake Through Mitochondrial Calcium Uptake 1 (MICU1).
    Xinyi Zhang, Shuhu Liu, Yanshan Su, Ling Zhang, Ting Guo, Xuemin Wang.
      Mitochondria play a central role in cell biological processes, functioning not only as producers of ATP but also as regulators of Ca2+ signaling. Mitochondrial calcium uptake occurs primarily through the mitochondrial calcium uniporter channel (mtCU), with the mitochondrial calcium uptake subunits 1, 2, and 3 (MICU1, MICU2, and MICU3) serving as the main regulatory components. Dysregulated mitochondrial calcium uptake is a hallmark of cellular degeneration. Sirtuin 1 (SIRT1), a key regulator of cellular metabolism, plays a critical role in aging and various neurodegenerative conditions. By blocking SIRT1 using EX527 or shSIRT1, we observed mitochondrial structural fragmentation as well as intensified and prolonged mitochondrial calcium overload. Our study revealed a direct interaction between SIRT1 and MICU1. Notably, SIRT1 inhibition resulted in reduced MICU1 expression, hence led to mitochondrial calcium overload, illustrating the unconventional role of SIRT1 in governing mitochondrial function.
    Keywords:  MICU1; SIRT1; Sirtuin 1; calcium uptake; mitochondria; mitochondrial calcium uptake 1
    DOI:  https://doi.org/10.3390/life15020174
  2. Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00036-4. [Epub ahead of print]
    ER-mitochondria contact sites: a refuge for mitochondrial mRNAs under ER stress.
    Philippe Pihán, Lisa M Ellerby, Claudio Hetz.
      Tight mitochondria-endoplasmic reticulum (ER) contacts (MERCS) play essential roles in cellular homeostasis. Brar et al. reveal a novel mechanism where mitochondrial mRNAs escape global translational repression at novel context-specific MERCS during ER stress, uncovering spatially regulated translation as a critical adaptive strategy to cope with cellular stress.
    Keywords:  ATAD3A; PERK; endoplasmic reticulum stress; mitochondria–ER contact sites (MERCS); spatial translation regulation
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.002
  3. Geroscience. 2025 Feb 25.
    SenSkin™: a human skin-specific cellular senescence gene set.
    Saranya P Wyles, Grace T Yu, Clarisse Ganier, Tamar Tchkonia, Magnus D Lynch, George A Kuchel, James L Kirkland.
      Cellular senescence gene sets have been leveraged to overcome the inadequate sensitivity or specificity of single markers. However, growing evidence of heterogeneity among tissues in senescent cell phenotypes and gene expression profiles has highlighted the need for tissue-specific gene sets. SenSkin™ was curated by an expert review of literature on cellular senescence in the skin and characterized with pathway analysis. To validate SenSkin™, it was evaluated for enrichment with chronological aging in a bulk RNA-sequencing (RNA-seq) dataset and a pseudobulk RNA-seq dataset. Further, changes to SenSkin™ in different skin cell types with photoaging were evaluated in two single-cell RNA-seq datasets. SenSkin™ predominantly included genes related to the senescence-associated secretory phenotype (SASP), which were associated with metabolism and multiple aspects of immune responses. SenSkin™ was more enriched in chronologically aged skin than other commonly used cellular senescence and aging gene sets. In scRNA-seq, SenSkin™ displayed significant upregulation due to photoaging in ten skin cell types. In conclusion, SenSkin™ is a human skin-specific senescence gene set validated in chronological aging and photoaging, which may be more effective at detecting senescent cells in the skin than non-tissue-specific gene sets.
    Keywords:  Bioinformatics; Cellular senescence; Skin
    DOI:  https://doi.org/10.1007/s11357-025-01568-y
  4. Pharmaceuticals (Basel). 2025 Feb 12. pii: 244. [Epub ahead of print]18(2):
    Cellular Senescence in Health, Disease, and Lens Aging.
    Ying Qin, Haoxin Liu, Hongli Wu.
      Background: Cellular senescence is a state of irreversible cell cycle arrest that serves as a critical regulator of tissue homeostasis, aging, and disease. While transient senescence contributes to development, wound healing, and tumor suppression, chronic senescence drives inflammation, tissue dysfunction, and age-related pathologies, including cataracts. Lens epithelial cells (LECs), essential for maintaining lens transparency, are particularly vulnerable to oxidative stress-induced senescence, which accelerates lens aging and cataract formation. This review examines the dual role of senescence in LEC function and its implications for age-related cataractogenesis, alongside emerging senotherapeutic interventions. Methods: This review synthesizes findings on the molecular mechanisms of senescence, focusing on oxidative stress, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). It explores evidence linking LEC senescence to cataract formation, highlighting key studies on stress responses, DNA damage, and antioxidant defense. Recent advances in senotherapeutics, including senolytics and senomorphics, are analyzed for their potential to mitigate LEC senescence and delay cataract progression. Conclusions: LEC senescence is driven by oxidative damage, mitochondrial dysfunction, and impaired redox homeostasis. These factors activate senescence path-ways, including p53/p21 and p16/Rb, resulting in cell cycle arrest and SASP-mediated inflammation. The accumulation of senescent LECs reduces regenerative capacity, disrupts lens homeostasis, and contributes to cataractogenesis. Emerging senotherapeutics, such as dasatinib, quercetin, and metformin, show promise in reducing the senescent cell burden and modulating the SASP to preserve lens transparency.
    Keywords:  cataractogenesis; cellular senescence; lens epithelial cells; oxidative stress; senescence-associated secretory phenotype; senotherapeutics
    DOI:  https://doi.org/10.3390/ph18020244
  5. Geroscience. 2025 Feb 27.
    Resistance exercise training in older men reduces ATF4-activated and senescence-associated mRNAs in skeletal muscle.
    Zachary D Von Ruff, Matthew J Miller, Tatiana Moro, Paul T Reidy, Scott M Ebert, Elena Volpi, Christopher M Adams, Blake B Rasmussen.
      Sarcopenia increases the risk of frailty, morbidity, and mortality in older adults. Resistance exercise training improves muscle size and function; however, the response to exercise training is variable in older adults. The objective of our study was to determine both the age-independent and age-dependent changes to the transcriptome following progressive resistance exercise training. Skeletal muscle biopsies were obtained before and after 12 weeks of resistance exercise training in 8 young (24 ± 3.3 years) and 10 older (72 ± 4.9 years) men. RNA was extracted from each biopsy and prepared for analysis via RNA sequencing. We performed differential mRNA expression, gene ontology, and gene set enrichment analyses. We report that when comparing post-training vs pre-training 226 mRNAs and 959 mRNAs were differentially expressed in the skeletal muscle of young and older men, respectively. Additionally, 94 mRNAs increased, and 17 mRNAs decreased in both young and old, indicating limited overlap in response to resistance exercise training. Furthermore, the differential gene expression was larger in older skeletal muscle. Finally, we report three novel findings: 1) resistance exercise training decreased the abundance of ATF4-activated and senescence-associated skeletal muscle mRNAs in older men; 2) resistance exercise-induced increases in lean mass correlate with increased mRNAs encoding mitochondrial proteins; and 3) increases in muscle strength following resistance exercise positively correlate with increased mRNAs involved in translation, rRNA processing, and polyamine metabolism. We conclude that resistance exercise training elicits a differential gene expression response in young and old skeletal muscle, including reduced ATF-4 activated and senescence-associated gene expression.
    Keywords:  ATF4; Aging; Resistance exercise; Senescence; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-025-01564-2
  6. Nat Rev Cancer. 2025 Feb 27.
    Cancer treatments accelerate ageing.
    Marco Demaria.
      
    DOI:  https://doi.org/10.1038/s41568-025-00801-2
  7. Trends Cell Biol. 2025 Feb 25. pii: S0962-8924(25)00038-8. [Epub ahead of print]
    Mitochondrial substrate oxidation regulates distinct cell differentiation outcomes.
    Woo Yong Park, Claudia Montufar, Elma Zaganjor.
      Mitochondrial metabolism, signaling, and dynamics are key regulators of cell fate. While glycolysis supports stemness, mitochondrial expansion and oxidative phosphorylation (OXPHOS) facilitate differentiation. This forum presents emerging evidence that the type of substrate, whether amino acids, carbohydrates, or fatty acids, oxidized by mitochondria significantly influences differentiation outcomes.
    Keywords:  OXPHOS; amino acids; differentiation; fatty acids; glucose; mitochondria
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.004
  8. Antioxidants (Basel). 2025 Jan 22. pii: 125. [Epub ahead of print]14(2):
    Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
    Szilvia Kiraly, Jack Stanley, Emily R Eden.
      The perception of lysosomes and mitochondria as entirely separate and independent entities that degrade material and produce ATP, respectively, has been challenged in recent years as not only more complex roles for both organelles, but also an unanticipated level of interdependence are being uncovered. Coupled lysosome and mitochondrial function and dysfunction involve complex crosstalk between the two organelles which goes beyond mitochondrial quality control and lysosome-mediated clearance of damaged mitochondria through mitophagy. Our understanding of crosstalk between these two essential metabolic organelles has been transformed by major advances in the field of membrane contact sites biology. We now know that membrane contact sites between lysosomes and mitochondria play central roles in inter-organelle communication. This importance of mitochondria-lysosome contacts (MLCs) in cellular homeostasis, evinced by the growing number of diseases that have been associated with their dysregulation, is starting to be appreciated. How MLCs are regulated and how their coordination with other pathways of lysosome-mitochondria crosstalk is achieved are the subjects of ongoing scrutiny, but this review explores the current understanding of the complex crosstalk governing the function of the two organelles and its impact on cellular stress and disease.
    Keywords:  crosstalk; lysosomes; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.3390/antiox14020125
  9. J Nutr. 2025 Feb 22. pii: S0022-3166(25)00098-7. [Epub ahead of print]
    Oleuropein supplementation increases resting skeletal muscle fractional PDH activity but does not influence whole-body metabolism: A randomized, double-blind, placebo-controlled trial in healthy, older males.
    Philippe Jm Pinckaers, Heather L Petrick, Astrid Mh Horstman, Alba Moreno-Asso, Umberto De Marchi, Floris K Hendriks, Lisa Me Kuin, Cas J Fuchs, Dominik Grathwohl, Lex B Verdijk, Antoine H Zorenc, Joan Mg Senden, Eugenia Migliavacca, Sylviane Metairon, Laure Poquet, Delphine Morin-Rivron, Leonidas G Karagounis, Graham P Holloway, Jerome N Feige, Luc Jc van Loon.
       BACKGROUND: The polyphenol oleuropein activates mitochondrial calcium import, which increases pyruvate dehydrogenase (PDH) activity. Preclinically, this increase in PDH activity following oleuropein supplementation resulted in improved mitochondrial bioenergetics and fatigue resistance.
    OBJECTIVE: This study aimed to examine the effects of acute and chronic oleuropein supplementation on muscle energy metabolism, whole-body substrate metabolism, strength, and fatigue resistance in older males.
    METHODS: In a randomized, double-blind, placebo-controlled trial, 40 healthy older males (60±5y) received either placebo (PLA) or 100mg oleuropein from olive leaf extract (OLE) supplementation daily for 36 days. On day 1 and 36, muscle and blood samples were collected, and indirect calorimetry was performed, before and up to 120min following supplement intake. Leg strength and fatigue were measured before and after 29 days of supplementation. Results were analyzed using ANCOVA or robust ANCOVA.
    RESULTS: OLE ingestion on day 1 and 36 increased plasma oleuropein metabolites (P<0.001). On day 1, no differences were observed in muscle PDH activity, mitochondrial respiration, or whole-body substrate metabolism 120min after acute OLE ingestion. RNA sequencing revealed upregulation of oxidative phosphorylation gene pathways (FDR<0.05), while PDH-Ser293-phosphorylation was higher after acute OLE vs PLA ingestion (P=0.015). Following chronic supplementation, fractional PDH activity was ∼25% greater in OLE vs PLA (49±14 vs 38±10%; P=0.016) with no differences in absolute PDH activity and PDH-Ser293-phosphorylation between groups. Mitochondrial respiration and protein content, whole-body substrate metabolism, leg strength and fatigue resistance, were not different between OLE vs PLA. Plasma LDL cholesterol was lower after chronic OLE vs PLA (P=0.043) with no differences in other blood metabolic markers.
    CONCLUSIONS: Chronic OLE supplementation resulted in higher skeletal muscle fractional PDH activity in healthy, older males, which may impact resting energy metabolism. Acute or chronic oleuropein supplementation do not modulate skeletal muscle mitochondrial respiration, muscle strength, muscle fatigue, or whole-body substrate metabolism.
    CLINICAL TRIAL REGISTRATION: Https://clinicaltrials.gov/study/NCT05217433. Registry: https://clinicaltrials.gov/study/NCT05217433.
    Keywords:  Body composition by MRI; Mitochondrial calcium uniporter; Mitochondrial respiration; Muscle strength; Olea europaea L.; Olive leaf extract; Pyruvate dehydrogenase; Whole-body substrate metabolism
    DOI:  https://doi.org/10.1016/j.tjnut.2025.02.015
  10. J Biol Chem. 2025 Feb 25. pii: S0021-9258(25)00198-X. [Epub ahead of print] 108349
    Methionine cycle inhibition disrupts antioxidant metabolism and reduces glioblastoma cell survival.
    Emma C Rowland, Matthew D'Antuono, Anna Jermakowicz, Nagi G Ayad.
      Glioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. Therefore, we must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY. We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and shifts the cellular metabolic profile towards oxidative stress and cell death. Mechanistically, MAT2a and AHCY regulate spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevent oxidative damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM. Significance We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM has the potential to reduce tumor growth and improve survival in patients.
    Keywords:  glioblastoma; lipid peroxidation; metabolism; metabolomics; methionine; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.jbc.2025.108349
  11. Nat Commun. 2025 Feb 24. 16(1): 1910
    Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.
    Alzheimer’s Disease Neuroimaging Initiative
      Impaired glucose uptake in the brain is an early presymptomatic manifestation of Alzheimer's disease (AD), with symptom-free periods of varying duration that likely reflect individual differences in metabolic resilience. We propose a systemic "bioenergetic capacity", the individual ability to maintain energy homeostasis under pathological conditions. Using fasting serum acylcarnitine profiles from the AD Neuroimaging Initiative as a blood-based readout for this capacity, we identified subgroups with distinct clinical and biomarker presentations of AD. Our data suggests that improving beta-oxidation efficiency can decelerate bioenergetic aging and disease progression. The estimated treatment effects of targeting the bioenergetic capacity were comparable to those of recently approved anti-amyloid therapies, particularly in individuals with specific mitochondrial genotypes linked to succinylcarnitine metabolism. Taken together, our findings provide evidence that therapeutically enhancing bioenergetic health may reduce the risk of symptomatic AD. Furthermore, monitoring the bioenergetic capacity via blood acylcarnitine measurements can be achieved using existing clinical assays.
    DOI:  https://doi.org/10.1038/s41467-025-57032-0
  12. J Hepatol. 2025 Feb 27. pii: S0168-8278(25)00071-6. [Epub ahead of print]
    Peripheral fat mobilization and mitochondrial fat metabolism: Fueling the energy demands of liver regeneration.
    Cornelius Engelmann.
      
    DOI:  https://doi.org/10.1016/j.jhep.2025.01.034
  13. Nature. 2025 Feb;638(8052): 874-876
    How quickly are you ageing? What molecular 'clocks' can tell you about your health.
    Heidi Ledford.
      
    Keywords:  Ageing; Epigenetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00566-6
  14. Life Med. 2024 Dec;3(6): lnaf001
    A framework of biomarkers for skeletal muscle aging: a consensus statement by the Aging Biomarker Consortium.
    Aging Biomarker Consortium
      The skeletal muscle is an important organ for movement and metabolism in human body, and its physiological aging underlies the occurrence of muscle atrophy and sarcopenia. China has the largest aging population in the world and is facing a grand challenge with how to prevent and treat skeletal muscle aging-related diseases. To address this difficult problem, the Aging Biomarker Consortium (ABC) of China has reached an expert consensus on biomarkers of skeletal muscle aging by synthesizing literatures and insights from scientists and clinicians. This consensus attempts to provide a comprehensive assessment of biomarkers associated with skeletal muscle aging, and proposes a systematic framework to classify them into three dimensions: functional, structural, and humoral. Within each dimension, the experts recommend clinically relevant biomarkers for skeletal muscle aging. This consensus aims to lay the foundation for future research on skeletal muscle aging, facilitating precise prediction, diagnosis, and treatment of skeletal muscle aging and sarcopenia. It is anticipated to make significant contributions to healthy aging of skeletal muscle in the elderly population in China and around the world as well.
    DOI:  https://doi.org/10.1093/lifemedi/lnaf001
  15. Methods Mol Biol. 2025 ;2882 47-79
    Monitoring Cellular Energy Balance in Single Cells Using Fluorescent Biosensors for AMPK.
    Nicholaus DeCuzzi, Nont Kosaisawe, Michael Pargett, Markhus Cabel, John G Albeck.
      5'-Adenosine monophosphate-activated protein kinase (AMPK) senses cellular metabolic status and reflects the balance between ATP production and ATP usage. This balance varies from cell to cell and changes over time, creating a need for methods that can capture cellular heterogeneity and temporal dynamics. Fluorescent biosensors for AMPK activity offer a unique approach to measure metabolic status nondestructively in single cells in real time. In this chapter, we provide a brief rationale for using live-cell biosensors to measure AMPK activity, survey the current AMPK biosensors, and discuss considerations for using this approach. We provide methodology for introducing AMPK biosensors into a cell line of choice, setting up experiments for live-cell fluorescent microscopy of AMPK activity, and calibrating the biosensors using immunoblot data.
    Keywords:  AMPKAR; Biosensors; Fluorescent protein reporters; Forster resonance energy transfer (FRET); Live-cell microscopy; Metabolic signaling; Single cell
    DOI:  https://doi.org/10.1007/978-1-0716-4284-9_3
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