bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2025–01–05
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Channels, Transporters, and Receptors at Membrane Contact Sites.
  2. Paradoxical link between senescent cell state and liver cancer resolved.
  3. Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.
  4. A brief report on biomarkers of cellular senescence associated with liver frailty and length of stay in liver transplantation.
  5. AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
  6. Broad repression of DNA repair genes in senescent cells identified by integration of transcriptomic data.
  7. Physiology of ageing skeletal muscle and the protective effects of exercise.
  8. Identifying ENO1 as a protein target of chlorogenic acid to inhibit cellular senescence and prevent skin photoaging in mice.
  9. Effect of 2-Aminoethoxydiphenyl Borate on the State of Skeletal Muscles in Dystrophin-Deficient mdx Mice.
  10. Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.
  1. Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241305593
    Channels, Transporters, and Receptors at Membrane Contact Sites.
    Maria Casas, Eamonn James Dickson.
      Membrane contact sites (MCSs) are specialized regions where two or more organelle membranes come into close apposition, typically separated by only 10-30 nm, while remaining distinct and unfused. These sites play crucial roles in cellular homeostasis, signaling, and metabolism. This review focuses on ion channels, transporters, and receptors localized to MCSs, with particular emphasis on those associated with the plasma membrane and endoplasmic reticulum (ER). We discuss the molecular composition and functional significance of these proteins in shaping both organelle and cellular functions, highlighting their importance in excitable cells and their influence on intracellular calcium signaling. Key MCSs examined include ER-plasma membrane, ER-mitochondria, and ER-lysosome contacts. This review addresses our current knowledge of the ion channels found within these contacts, the dynamic regulation of MCSs, their importance in various physiological processes, and their potential implications in pathological conditions.
    Keywords:  IP3 receptor; calcium (Ca2+); calcium-induced calcium release (CICR); endoplasmic reticulum (ER); ion channels; junctophilin (JPH); large conductance Ca2+-activated K+ channel (BKCa); membrane contact sites (MCS); neurodegeneration; niemann-Pick type C1 (NPC1); orai; ryanodine receptors (RyR); stromal interaction molecule (Stim); transient receptor potential cation channel subfamily M member 4 (TRPM4); voltage-gated calcium channel (CaV); voltage-gated potassium channel (KV)
    DOI:  https://doi.org/10.1177/25152564241305593
  2. Nature. 2025 Jan 01.
    Paradoxical link between senescent cell state and liver cancer resolved.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-04137-z
  3. Nat Commun. 2024 Dec 30. 15(1): 10786
    Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade.
    Qu Tian, Erin E Greig, Christos Davatzikos, Bennett A Landman, Susan M Resnick, Luigi Ferrucci.
      Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, kPCr) is associated with less ventricular enlargement and brain aging progression, and less atrophy in specific regions, notably primary sensorimotor cortex, temporal white and gray matter, thalamus, occipital areas, cingulate cortex, and cerebellum white matter. Higher kPCr is also associated with less microstructural integrity decline in white matter around cingulate, including superior longitudinal fasciculus, corpus callosum, and cingulum. Higher in vivo muscle oxidative capacity is associated with preserved brain structure up to over a decade, particularly in areas important for cognition, motor function, and sensorimotor integration.
    DOI:  https://doi.org/10.1038/s41467-024-55009-z
  4. Geroscience. 2024 Dec 30.
    A brief report on biomarkers of cellular senescence associated with liver frailty and length of stay in liver transplantation.
    William C Miller, Matthew J Yousefzadeh, Jessica Fisher, Heidi Sarumi, Varvara Kirchner, Laura J Niedernhofer, Timothy Pruett.
      The proportion of older individuals needing liver transplantation is growing, resulting in an increasingly frail patient population. Frailty constitutes a constellation of cognitive and physical symptoms associated with aging and increases the risk of morbidity and mortality. Senescence is a programmed cell fate in response to stress implicated in causing frailty, age-related diseases, and aging itself. This study explores the relationship between cellular senescence, physical frailty, and liver transplantation. Adults > 18 years old who underwent ambulatory liver transplantation at our center between September 1, 2022, and November 30, 2022, were included. Frailty assessments were performed using the Liver Frailty Index™, and blood was collected prior to transplantation. Expression of p16INK4a and p21CIP1 mRNA in T cells was measured by RT-qPCR, an established proxy for senescent cell burden, and plasma levels of senescence-associated secretory phenotype proteins were measured by multiplex ELISA. Patient outcomes were collected via electronic medical record. Univariate linear regression analysis demonstrated a statistically significant relationship between baseline patient frailty and p16INK4a and p21CIP1 (r2 = 0.5092, p-value = 0.0205; r2 = 0.5339, p-value = 0.0164, respectively). A similar correlation occurred between p16INK4a and p21CIP1 expression and length of hospitalization (r2 = 0.4960, p-value = 0.0230; r2 = 0.5868, p-value = 0.0098, respectively). This study revealed a potential association between biomarkers of cellular senescence, physical frailty, and length of hospitalization. This warrants further investigation as biomarkers to stratify patients are needed and therapeutics to reduce senescent cell burden exists and could be deployed to improve transplant outcomes.
    Keywords:  Cellular senescence; Frailty; Liver transplantation
    DOI:  https://doi.org/10.1007/s11357-024-01482-9
  5. Nat Cell Biol. 2025 Jan 02.
    AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
    Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li.
      Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
    DOI:  https://doi.org/10.1038/s41556-024-01549-x
  6. Nucleic Acids Res. 2024 Dec 31. pii: gkae1257. [Epub ahead of print]
    Broad repression of DNA repair genes in senescent cells identified by integration of transcriptomic data.
    Yann Frey, Majd Haj, Yael Ziv, Ran Elkon, Yosef Shiloh.
      Cellular senescence plays a significant role in tissue aging. Senescent cells, which resist apoptosis while remaining metabolically active, generate endogenous DNA-damaging agents, primarily reactive oxygen species. Efficient DNA repair is therefore crucial in these cells, especially when they undergo senescence escape, resuming DNA replication and cellular proliferation. To investigate whether senescent cell transcriptomes reflect adequate DNA repair capacity, we conducted a comprehensive meta-analysis of 60 transcriptomic datasets comparing senescent to proliferating cells. Our analysis revealed a striking downregulation of genes encoding essential components across DNA repair pathways in senescent cells. This includes pathways active in different cell cycle phases such as nucleotide excision repair, base excision repair, nonhomologous end joining and homologous recombination repair of double-strand breaks, mismatch repair and interstrand crosslink repair. The downregulation observed suggests a significant accumulation of DNA lesions. Experimental monitoring of DNA repair readouts in cells that underwent radiation-induced senescence supported this conclusion. This phenomenon was consistent across various senescence triggers and was also observed in primary cell lines from aging individuals. These findings highlight the potential of senescent cells as 'ticking bombs' in aging-related diseases and tumors recurring following therapy-induced senescence.
    DOI:  https://doi.org/10.1093/nar/gkae1257
  7. J Physiol. 2025 Jan 01.
    Physiology of ageing skeletal muscle and the protective effects of exercise.
    Christopher W Sundberg.
      
    Keywords:  ageing; contractile function; dynapenia; exercise; muscle metabolism; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1113/JP287926
  8. Aging Cell. 2024 Dec 31. e14433
    Identifying ENO1 as a protein target of chlorogenic acid to inhibit cellular senescence and prevent skin photoaging in mice.
    Xueling He, Chen Wang, Qianyu Zhang, Tong Yang, Qiuyan Guo, Yaxu Wang, Jiayue Guo, Pengjie Wang, Junzhe Zhang, Huan Tang, Yinhua Zhu, Jigang Wang.
      Cellular senescence plays a critical role in repeated ultraviolet (UV) exposure-induced skin photoaging. Currently, from the perspective of regulating senescent cells, potent compounds or reliable protein targets that could effectively prevent skin photoaging have not yet been reported. Herein, we demonstrated that chlorogenic acid (CGA) significantly inhibited UVA-induced senescence of human dermis skin fibroblasts (HDF) cells by screening the natural product library. The activity-based protein profiling (ABPP) result revealed that Enolase 1 (ENO1) is one of the direct targets of CGA in HDF cells. Further mechanism research indicated that CGA covalently binds to ENO1, and prevented UVA-induced cellular senescence by suppressing the activity of ENO1 protein to block the glycolytic pathway. Importantly, we found that CGA dose-dependently reduced the skin wrinkle score, alleviated skin pathological features and inhibited senescent characteristics in a photoaging mouse model. The proteomic analysis revealed that CGA treatment effectively inhibited senescence-associated secretory phenotype (SASP) secretion and glycolysis in skin samples of mice. Collectively, our study not only demonstrated that inhibiting cell senescence is an effective anti-skin photoaging strategy, but also revealed that ENO1 is a promising protein target to prevent photoaging.
    Keywords:  activity‐based protein profiling; chlorogenic acid; enolase 1; glycolysis; photoaging
    DOI:  https://doi.org/10.1111/acel.14433
  9. Front Biosci (Landmark Ed). 2024 Dec 25. 29(12): 428
    Effect of 2-Aminoethoxydiphenyl Borate on the State of Skeletal Muscles in Dystrophin-Deficient mdx Mice.
    Mikhail V Dubinin, Anastasia E Stepanova, Anastasia D Igoshkina, Irina B Mikheeva, Eugeny Yu Talanov, Alena A Cherepanova, Konstantin N Belosludtsev.
       OBJECTIVE: Ca2+ overload of muscle fibers is one of the factors that secondarily aggravate the development of Duchenne muscular dystrophy (DMD). The purpose of this study is to evaluate the effects of the Ca2+ channel modulator 2-aminoethoxydiphenyl borate (APB) on skeletal muscle pathology in dystrophin-deficient mdx mice.
    METHODS: Mice were randomly divided into six groups: wild type (WT), WT+3 mg/kg APB, WT+10 mg/kg APB, mdx, mdx+3 mg/kg APB, mdx+10 mg/kg APB. APB was administered intraperitoneally daily for 28 days. Finally, we assessed the grip strength and hanging time of mice, the histology and ultrastructure of the quadriceps, as well as the parameters reflecting quadricep mitochondrial function.
    RESULTS: 3 mg/kg APB was shown to reduce creatine kinase activity in the serum, intensity of degeneration and the level of fibrosis in the quadriceps of mdx mice, and improved tissue ultrastructure. However, this effect of APB was not sufficient to improve grip strength and hanging time of mdx mice. The effect of 3 mg/kg APB may be due to improve Ca2+ homeostasis in skeletal muscles, as evidenced by a trend toward decreased Ca2+ overload of quadricep mitochondria. High dose of APB (10 mg/kg body weight) showed less pronounced effect on the pathological phenotype of mdx mice. Moreover, 10 mg/kg APB disrupted the ultrastructure of the quadriceps and caused a decrease in grip strength in WT mice.
    CONCLUSIONS: APB is able to improve the phenotype in mdx mouse DMD model. However, the effect of APB is quite limited, which may be due to its multitargeting of Ca2+ channels in the membranes of muscle fibers and intracellular organelles, differentially expressed in DMD.
    Keywords:  2-aminoethoxydiphenyl borate; Duchenne muscular dystrophy; calcium; mdx mice; mitochondria; skeletal muscles
    DOI:  https://doi.org/10.31083/j.fbl2912428
  10. Nat Commun. 2025 Jan 02. 16(1): 122
    Effects of seven days' fasting on physical performance and metabolic adaptation during exercise in humans.
    Kristoffer J Kolnes, Emelie T F Nilsen, Steffen Brufladt, Allison M Meadows, Per B Jeppesen, Øyvind Skattebo, Egil I Johansen, Jesper B Birk, Kurt Højlund, Janne Hingst, Bjørn S Skålhegg, Rasmus Kjøbsted, Julian L Griffin, Anders J Kolnes, Stephen O'Rahilly, Jørgen F P Wojtaszewski, Jørgen Jensen.
      Humans have, throughout history, faced periods of starvation necessitating increased physical effort to gather food. To explore adaptations in muscle function, 13 participants (7 males and 6 females) fasted for seven days. They lost 4.6 ± 0.3 kg lean and 1.4 ± 0.1 kg fat mass. Maximal isometric and isokinetic strength remained unchanged, while peak oxygen uptake decreased by 13%. Muscle glycogen was halved, while expression of electron transport chain proteins was unchanged. Pyruvate dehydrogenase kinase 4 (PDK4) expression increased 13-fold, accompanied by inhibitory pyruvate dehydrogenase phosphorylation, reduced carbohydrate oxidation and decreased exercise endurance capacity. Fasting had no impact on 5' AMP-activated protein kinase (AMPK) activity, challenging its proposed role in muscle protein degradation. The participants maintained muscle strength and oxidative enzymes in skeletal muscle during fasting but carbohydrate oxidation and high-intensity endurance capacity were reduced.
    DOI:  https://doi.org/10.1038/s41467-024-55418-0
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