bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–10–20
fifteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. MICU1 and MICU2, two peas in a pod or entirely different fruits?
  2. MICUs protect the heart by regulating mitochondrial calcium.
  3. Mitophagy as a guardian against cellular aging.
  4. A simulation study on the role of mitochondria-sarcoplasmic reticulum Ca2+ interaction in cardiomyocyte energetics during exercise.
  5. Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
  6. Molecular tools for analysing in vivo senescence.
  7. Senolytic therapy combining Dasatinib and Quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro-anabolic mediators.
  8. Targeted apoptosis of senescent cells by valproic acid alleviates therapy-induced cellular senescence and lung aging.
  9. IDO1-mediated kynurenine production inhibits IGFBP5 signaling to promote 5-fluorouracil-induced senescence escape and chemoresistance in colorectal cancer.
  10. Goodbye, senescent cells: CAR-T cells unleashed to fight ageing.
  11. An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.
  12. Glucose has a surprise role in directing cell fate and migration.
  13. IL-11 as a master regulator of ageing.
  14. Quantification of nutrient fluxes during acute exercise in mice.
  15. Gene therapy for fat-1 prevents obesity-induced metabolic dysfunction, cellular senescence, and osteoarthritis.
  1. Cell Calcium. 2024 Oct 08. pii: S0143-4160(24)00117-9. [Epub ahead of print]124 102959
    MICU1 and MICU2, two peas in a pod or entirely different fruits?
    Jiuzhou Huo, Jeffery D Molkentin.
      Fluctuations in mitochondrial matrix Ca2+ plays a critical role in matching energy production to cellular demand through direct effects on oxidative phosphorylation and ATP production. Disruption in mitochondrial Ca2+ homeostasis, particularly under pathological conditions such as ischemia or heart failure, can lead to mitochondrial dysfunction, energy deficit, and eventually death of cardiomyocytes. The primary channel regulating acute mitochondrial Ca2+ influx is the mitochondrial Ca2+ uniporter (mtCU), which is regulated by the mitochondrial Ca2+ uptake (MICU) proteins that were examined here.
    DOI:  https://doi.org/10.1016/j.ceca.2024.102959
  2. Trends Pharmacol Sci. 2024 Oct 14. pii: S0165-6147(24)00209-8. [Epub ahead of print]
    MICUs protect the heart by regulating mitochondrial calcium.
    Ulas Ozkurede, Shanmugasundaram Pakkiriswami, Julia C Liu.
      Regulation of mitochondrial calcium uptake by the mitochondrial calcium uniporter (mtCU) complex is crucial for heart function. In a recent study, Hasan et al. demonstrated that mitochondrial calcium uptake (MICU)1 and MICU2, regulatory subunits of the complex, help maintain calcium homeostasis in cardiac mitochondria, providing potential targets for therapies aimed at improving mitochondrial function in heart disease.
    Keywords:  EMRE; MCU; MICU1; MICU2; calcium; heart; mitochondria
    DOI:  https://doi.org/10.1016/j.tips.2024.09.010
  3. Autophagy. 2024 Oct 14. 1-3
    Mitophagy as a guardian against cellular aging.
    Tetsushi Kataura, Niall Wilson, Gailing Ma, Viktor I Korolchuk.
      Mitophagy, the selective autophagic clearance of damaged mitochondria, is considered vital for maintaining mitochondrial quality and cellular homeostasis; however, its molecular mechanisms, particularly under basal conditions, and its role in cellular physiology remain poorly characterized. We recently demonstrated that basal mitophagy is a key feature of primary human cells and is downregulated by immortalization, suggesting its dependence on the primary cell state. Mechanistically, we demonstrated that the PINK1-PRKN-SQSTM1 pathway regulates basal mitophagy, with SQSTM1 sensing superoxide-enriched mitochondria through its redox-sensitive cysteine residues, which mediate SQSTM1 oligomerization and mitophagy activation. We developed STOCK1N-57534, a small molecule that targets and promotes this SQSTM1 activation mechanism. Treatment with STOCK1N-57534 reactivates mitophagy downregulated in senescent and naturally aged donor-derived primary cells, improving cellular senescence(-like) phenotypes. Our findings highlight that basal mitophagy is protective against cellular senescence and aging, positioning its pharmacological reactivation as a promising anti-aging strategy.Abbreviation: IR: ionizing radiation; ROS: reactive oxygen species; SARs: selective autophagy receptors.
    Keywords:  Aging; SQSTM1/p62; autophagy; mitochondria; mitophagy; senescence
    DOI:  https://doi.org/10.1080/15548627.2024.2414461
  4. J Physiol. 2024 Oct 10.
    A simulation study on the role of mitochondria-sarcoplasmic reticulum Ca2+ interaction in cardiomyocyte energetics during exercise.
    Ayako Takeuchi, Satoshi Matsuoka.
      Previous studies demonstrated that the mitochondrial Ca2+ uniporter MCU and the Na+-Ca2+ exchanger NCLX exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca2+ pump SERCA, respectively, creating a mitochondria-SR Ca2+ interaction. However, the physiological relevance of the mitochondria-SR Ca2+ interaction has remained unsolved. Furthermore, although mitochondrial Ca2+ has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases, the contribution of the Ca2+-dependent regulatory mechanisms to cellular functions under physiological conditions has been controversial. In this study, we constructed a new integrated model of human ventricular myocyte with excitation-contraction-energetics coupling and investigated systematically the contribution of mitochondria-SR Ca2+ interaction, especially focusing on cardiac energetics during dynamic workload transitions in exercise. Simulation analyses revealed that the spatial coupling of mitochondria and SR, particularly via mitochondrial Ca2+ uniport activity-RyR, was the primary determinant of mitochondrial Ca2+ concentration, and that the Ca2+-dependent regulatory mechanism facilitated mitochondrial NADH recovery during exercise and contributed to the stability of NADH in the workload transition by about 40%, while oxygen consumption rate and cytoplasmic ATP level were not influenced. We concluded that the mitochondria-SR Ca2+ interaction, created via the uneven distribution of Ca2+ handling proteins, optimizes the contribution of the mitochondrial Ca2+-dependent regulatory mechanism to stabilizing NADH during exercise. KEY POINTS: The mitochondrial Ca2+ uniporter protein MCU and the Na+-Ca2+ exchanger protein NCLX are reported to exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca2+ pump SERCA, respectively, creating a mitochondria-SR Ca2+ interaction in cardiomyocytes. Mitochondrial Ca2+ (Ca2+ mit) has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases. Here we constructed an integrated model of a human ventricular myocyte with excitation-contraction-energetics coupling and investigated the role of the mitochondria-SR Ca2+ interaction in cardiac energetics during exercise. Simulation analyses revealed that the spatial coupling particularly via mitochondrial Ca2+ uniport activity-RyR is the primary determinant of Ca2+ mit concentration, and that the activation of NADH-producing dehydrogenases by Ca2+ mit contributes to NADH stability during exercise. The mitochondria-SR Ca2+ interaction optimizes the contribution of Ca2+ mit to the activation of NADH-producing dehydrogenases.
    Keywords:  energetics; exercise; heart; mathematical modelling; mitochondria; sarcoplasmic reticulum
    DOI:  https://doi.org/10.1113/JP286054
  5. Adv Biol (Weinh). 2024 Oct 16. e2400235
    Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.
    Xin Zhang, Suchan Liao, Lingling Huang, Jinhua Wang.
      Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.
    Keywords:  Aging; mechanism; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1002/adbi.202400235
  6. Nat Rev Mol Cell Biol. 2024 Oct 14.
    Molecular tools for analysing in vivo senescence.
    Allison B Herman, Myriam Gorospe.
      
    DOI:  https://doi.org/10.1038/s41580-024-00790-4
  7. Aging Cell. 2024 Oct 14. e14361
    Senolytic therapy combining Dasatinib and Quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro-anabolic mediators.
    Svenja Maurer, Valeria Kirsch, Leonie Ruths, Rolf E Brenner, Jana Riegger.
      Cellular senescence is associated with various age-related disorders and is assumed to play a major role in the pathogenesis of osteoarthritis (OA). Based on this, we tested a senolytic combination therapy using Dasatinib (D) and Quercetin (Q) on aged isolated human articular chondrocytes (hACs), as well as in OA-affected cartilage tissue (OARSI grade 1-2). Stimulation with D + Q selectively eliminated senescent cells in both, cartilage explants and isolated hAC. Furthermore, the therapy significantly promoted chondroanabolism, as demonstrated by increased gene expression levels of COL2A1, ACAN, and SOX9, as well as elevated collagen type II and glycosaminoglycan biosynthesis. Additionally, D + Q treatment significantly reduced the release of SASP factors (IL6, CXCL1). RNA sequencing analysis revealed an upregulation of the anabolic factors, inter alia, FGF18, IGF1, and TGFB2, as well as inhibitory effects on cytokines and the YAP-1 signaling pathway, explaining the underlying mechanism of the chondroanabolic promotion upon senolytic treatment. Accordingly, stimulation of untreated hAC with conditioned medium of D + Q-treated cells similarly induced the expression of chondrogenic markers. Detailed analyses demonstrated that chondroanabolic effects could be mainly attributed to Dasatinib, while monotherapeutical application of Quercetin or Navitoclax did not promote the chondroanabolism. Overall, D + Q therapy restored the chondrogenic phenotype in OA hAC most likely by creating a pro-chondroanabolic environment through the reduction of SASP factors and upregulation of growth factors. This senolytic approach could therefore be a promising candidate for further testing as a disease-modifying osteoarthritis drug.
    Keywords:  Dasatinib; Quercetin; chondrocytes; osteoarthritis; senescence; senolytic therapy
    DOI:  https://doi.org/10.1111/acel.14361
  8. Phytomedicine. 2024 Oct 05. pii: S0944-7113(24)00788-8. [Epub ahead of print]135 156131
    Targeted apoptosis of senescent cells by valproic acid alleviates therapy-induced cellular senescence and lung aging.
    Wentao Sun, Yue Gao, Yubing Wu, Wei Wu, Chaofan Wang, JiaXiao Chen, Changjiao Luan, Ming Hua, Weili Liu, Weijuan Gong, Xingjie Ma.
       BACKGROUND: Accumulation of senescent cells in tissues and their downstream effect programs have emerged as key drivers of aging and age-associated pathologies. Recent progresses in senotherapeutics indicated that either selectively killing senescent cells with senolytics or suppressing the senescence-associated secretory phenotype (SASP) secretion using senomorphics contributes to extending of the healthy lifespan and alleviating numerous age-related disorders in mice.
    PURPOSE: However, the potential side-effects and long-term cytotoxicity of the above novel compounds have not yet been determined. Therefore, it seems to be more efficient to explore new senotherapeutical functions from approved drugs.
    METHODS: The effects of valproic acid (VPA), a derivative of valine, in cellular senescence were evaluated by senescence-associated β galactosidase (SA-β-Gal) staining, flow cytometry and western blot (WB). The cell viability was tested using CCK-8 kits. Cell apoptosis was detected by Annexin V-EGFP/PI apoptosis detection kit. Cell autophagy was checked using GFP-RFP-LC3 ratiometric plasmid. The roles of VPA in lung aging were investigated by in vivo experiments using H&E and Masson staining, WB, as well as electronic microscope strategies.
    RESULTS: Here we identified VPA was able to induce an over-accumulation of reactive oxygen species (ROS) (>1.5 times increasing) and apoptosis (>2 times increasing) of senescent cells. Mechanistically, VPA activated the phospholipid modifying enzyme membrane-bound O-acyltransferase domain-containing protein 1 (MBOAT1), which was repressed during senescence, then promoted mitochondrial autophagy and apoptosis. In addition, VPA was also found to alleviate therapy induced abnormal mitochondria and lung aging phenotype (>1.5 times decreasing of lung fibrosis markers and >2.5 times increasing of naïve/memory CD4+ or CD8+ T cells) in vivo.
    CONCLUSION: Taken together, our study demonstrated that VPA was able to selectively kill senescent cells both in vitro and in vivo, and thus shedding light on new functions and novel potential application of VPA in anti-aging and anti-age-associated diseases.
    Keywords:  Cellular senescence; Mitochondria; ROS; SASP
    DOI:  https://doi.org/10.1016/j.phymed.2024.156131
  9. Am J Cancer Res. 2024 ;14(9): 4551-4566
    IDO1-mediated kynurenine production inhibits IGFBP5 signaling to promote 5-fluorouracil-induced senescence escape and chemoresistance in colorectal cancer.
    Yu Li, Chao Li, Xufeng Yao, Junjie Lv, Wenjun Li, Rong Fu, Mengyang Chen, Peng Yang, Qian Dai, Wei Wei, Zongwei Li.
      Cellular senescence is an irreversible state of growth arrest, and induction of senescence is considered a potential therapeutic strategy against cancer. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme catabolizing L-tryptophan into kynurenine, plays a key role in tumor immune tolerance. However, the roles of IDO1 in cellular senescence and chemoresistance remain elusive. Herein, we observed a significant elevation of IDO1 expression in colorectal cancer (CRC) tissues compared to non-neoplastic controls, based on both the GEPIA database and mouse model. Functionally, ectopic expression of IDO1 blunted 5-fluorouracil (5-FU)-induced cell senescence and rendered CRC cells more refractory towards 5-FU treatment, whereas IDO1 silencing resulted in opposing effects. Further studies demonstrated that IDO1 overexpression decreased the levels of senescent-related proteins, including p16, p21, p53, and cyclin D1. Mechanistically, the kynurenine released from IDO1-expressing CRC cells inhibited the IGFBP5/p53 signaling pathway, accounting for IDO1-mediated suppression of cell senescence and induction of chemoresistance. Collectively, these data revealed an unrecognized role of IDO1 in senescence escape and chemoresistance via releasing its catabolite kynurenine, implicating that therapeutically targeting IDO1 or IGFBP5/p53 signaling pathway holds great promise for CRC treatment.
    Keywords:  IDO1; cell senescence; chemoresistance; colorectal cancer; kynurenine
    DOI:  https://doi.org/10.62347/XTRC3347
  10. Nat Rev Mol Cell Biol. 2024 Oct 16.
    Goodbye, senescent cells: CAR-T cells unleashed to fight ageing.
    Raffaella Di Micco.
      
    DOI:  https://doi.org/10.1038/s41580-024-00792-2
  11. EMBO J. 2024 Oct 17.
    An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.
    Nan Zhao, Antonio Michelucci, Laura Pietrangelo, Sundeep Malik, Linda Groom, Jennifer Leigh, Thomas N O'Connor, Takahiro Takano, Paul D Kingsley, James Palis, Simona Boncompagni, Feliciano Protasi, Robert T Dirksen.
      Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.
    Keywords:  Calcium Signaling; Mitochondria; Muscle Disease; ORAI1; Proteomics
    DOI:  https://doi.org/10.1038/s44318-024-00273-4
  12. Nature. 2024 Oct 16.
    Glucose has a surprise role in directing cell fate and migration.
    Christian Schröter.
      
    Keywords:  Developmental biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03284-7
  13. Nat Rev Mol Cell Biol. 2024 Oct 16.
    IL-11 as a master regulator of ageing.
    Ana O'Loghlen.
      
    DOI:  https://doi.org/10.1038/s41580-024-00793-1
  14. Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]
    Quantification of nutrient fluxes during acute exercise in mice.
    Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany.
      Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.
    Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
  15. Proc Natl Acad Sci U S A. 2024 Oct 22. 121(43): e2402954121
    Gene therapy for fat-1 prevents obesity-induced metabolic dysfunction, cellular senescence, and osteoarthritis.
    Ruhang Tang, Natalia S Harasymowicz, Chia-Lung Wu, Yun-Rak Choi, Kristin Lenz, Sara J Oswald, Farshid Guilak.
      Obesity is one of the primary risk factors for osteoarthritis (OA), acting through cross talk among altered biomechanics, metabolism, adipokines, and dietary free fatty acid (FA) composition. Obesity and aging have been linked to cellular senescence in various tissues, resulting in increased local and systemic inflammation and immune dysfunction. We hypothesized that obesity and joint injury lead to cellular senescence that is typically associated with increased OA severity or with aging and that the ratio of omega-6 (ω-6) to omega-3 (ω-3) FAs regulates these pathologic effects. Mice were placed on an ω-6-rich high-fat diet or a lean control diet and underwent destabilization of the medial meniscus to induce OA. Obesity and joint injury significantly increased cellular senescence in subcutaneous and visceral fat as well as joint tissues such as synovium and cartilage. Using adeno-associated virus (AAV) gene therapy for fat-1, a fatty acid desaturase that converts ω-6 to ω-3 FAs, decreasing the serum ω-6:ω-3 FA ratio had a strong senomorphic and therapeutic effect, mitigating metabolic dysfunction, cellular senescence, and joint degeneration. In vitro coculture of bone marrow-derived macrophages and chondrocytes from control and AAV8-fat1-treated mice were used to examine the roles of various FA mediators in regulating chondrocyte senescence. Our results suggest that obesity and joint injury result in a premature "aging" of the joint as measured by senescence markers, and these changes can be ameliorated by altering FA composition using fat-1 gene therapy. These findings support the potential for fat-1 gene therapy to treat obesity- and/or injury-induced OA clinically.
    Keywords:  AAV; gene therapy; obesity; osteoarthritis; senescence
    DOI:  https://doi.org/10.1073/pnas.2402954121
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