bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–10–27
ten papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Cyclophilin D plays a critical role in the survival of senescent cells.
  2. The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
  3. ERMCS Ca2+ transmission fuels cell division.
  4. The IP3 receptor-KRAP complex at the desmosomes: A new player in the apoptotic process.
  5. The double-edged sword of eliminating senescent cells.
  6. Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
  7. Mitochondrial pathways and sarcopenia in the geroscience era.
  8. Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).
  9. The Anti-Aging Effects of Collagen Type VII (COL7A1) as Longevity Mediator in Caenorhabditis elegans Healthspan Extension and Skin Collagen Synthesis.
  10. S-acylation of Ca2+ transport proteins in cancer.
  1. EMBO J. 2024 Oct 24.
    Cyclophilin D plays a critical role in the survival of senescent cells.
    Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.
      Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.
    Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering
    DOI:  https://doi.org/10.1038/s44318-024-00259-2
  2. Proc Natl Acad Sci U S A. 2024 Oct 29. 121(44): e2401218121
    The mitochondrial enzyme pyruvate carboxylase restricts pancreatic β-cell senescence by blocking p53 activation.
    Yumei Yang, Baomin Wang, Haoru Dong, Huige Lin, Melody Yuen-Man Ho, Ke Hu, Na Zhang, Jing Ma, Rong Xie, Kenneth King-Yip Cheng, Xiaomu Li.
      Defective glucose-stimulated insulin secretion (GSIS) and β-cell senescence are hallmarks in diabetes. The mitochondrial enzyme pyruvate carboxylase (PC) has been shown to promote GSIS and β-cell proliferation in the clonal β-cell lines, yet its physiological relevance remains unknown. Here, we provide animal and human data showing a role of PC in protecting β-cells against senescence and maintaining GSIS under different physiological and pathological conditions. β-cell-specific deletion of PC impaired GSIS and induced β-cell senescence in the mouse models under either a standard chow diet or prolonged high-fat diet feeding. Transcriptomic analysis indicated that p53-related senescence and cell cycle arrest are activated in PC-deficient islets. Overexpression of PC inhibited hyperglycemia- and aging-induced p53-related senescence in human and mouse islets as well as INS-1E β-cells, whereas knockdown of PC provoked senescence. Mechanistically, PC interacted with MDM2 to prevent its degradation via the MDM2 binding motif, which in turn restricts the p53-dependent senescent program in β-cells. On the contrary, the regulatory effects of PC on GSIS and the tricarboxylic acid (TCA) anaplerotic flux are p53-independent. We illuminate a function of PC in controlling β-cell senescence through the MDM2-p53 axis.
    Keywords:  MDM2; cellular senescence; diabetes; p53; pyruvate carboxylase
    DOI:  https://doi.org/10.1073/pnas.2401218121
  3. Trends Cell Biol. 2024 Oct 21. pii: S0962-8924(24)00208-3. [Epub ahead of print]
    ERMCS Ca2+ transmission fuels cell division.
    Muniswamy Madesh, Neelanjan Vishnu, Dhanendra Tomar.
      Mitosis is a cellular process that demands high energy, but it was previously unclear how this process is linked with mitochondrial ATP production. Zhao et al. describe how during mitosis, the lamin B receptor migrates to the ER membrane to enhance ER-mitochondria contact sites, coordinating Ca2+ surges that increase ATP production necessary for cell division.
    DOI:  https://doi.org/10.1016/j.tcb.2024.10.002
  4. Cell Calcium. 2024 Oct 18. pii: S0143-4160(24)00121-0. [Epub ahead of print]124 102963
    The IP3 receptor-KRAP complex at the desmosomes: A new player in the apoptotic process.
    Jan B Parys.
      The IP3 receptor (IP3R) is a ubiquitously expressed Ca2+-release channel located in the endoplasmic reticulum (ER). Ca2+ signals originating from the IP3R initiate or regulate a plethora of cellular events, including cell life and death processes, e.g. exaggerated Ca2+ release from the ER to the mitochondria is a trigger for apoptosis. Recently, Cho et al. (Current Biology, 2024, DOI: 10.1016/j.cub.2024.08.057) demonstrated that in epithelial monolayers a sustained [Ca2+] elevation caused by the IP3Rs is responsible for the extrusion of adjacent apoptotic cells out of the epithelial monolayer. Interestingly, the IP3Rs involved are associated with the desmosomes via K-Ras-induced actin-interacting protein (KRAP). This study not only highlight a novel role of the IP3R in apoptosis, but also shed a new light on how KRAP -and by extension KRAP-related proteins- contribute to the regulation of IP3R activity and, more broadly, underscores the crucial role of associated proteins in determining the function of IP3Rs.
    Keywords:  Apoptosis; Desmosome; Epithelium; IP(3) receptor; KRAP; Protein-protein interaction; TESPA1
    DOI:  https://doi.org/10.1016/j.ceca.2024.102963
  5. Nat Rev Mol Cell Biol. 2024 Oct 24.
    The double-edged sword of eliminating senescent cells.
    Eric Gilson.
      
    DOI:  https://doi.org/10.1038/s41580-024-00798-w
  6. Ageing Res Rev. 2024 Oct 19. pii: S1568-1637(24)00367-2. [Epub ahead of print]102 102549
    Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions.
    Luigi Ferrucci, Flora Guerra, Cecilia Bucci, Emanuele Marzetti, Anna Picca.
      Mitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal-lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal-lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations.
    Keywords:  Exosomes; Extracellular vesicles; Inflammaging; Mitochondrial DNA; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1016/j.arr.2024.102549
  7. J Nutr Health Aging. 2024 Oct 19. pii: S1279-7707(24)00485-8. [Epub ahead of print]28(12): 100397
    Mitochondrial pathways and sarcopenia in the geroscience era.
    Emanuele Marzetti, Riccardo Calvani, Helio José Coelho-Junior, Anna Picca.
      Sarcopenia is associated with structural, ultrastructural, and molecular abnormalities of skeletal muscle. Mitochondrial dysfunction is a pivotal factor involved in muscle aging and sarcopenia. Mitochondrial bioenergetics are significantly reduced in muscles of older adults which is associated with whole-body aerobic capacity, muscle strength, and physical performance. Transcriptional profiling of muscle samples from older adults also revealed inverse correlations between gene expression patterns of autophagy and mitophagy and muscle volume and physical performance. This is in line with the proposition that mitochondrial quality control (MQC) processes are key to organellar and tissue health. MQC encompasses mitochondrial biogenesis, dynamics, and mitophagy. The latter has recently been included among the hallmarks of aging and alterations in MQC have been associated with chronic sterile inflammation as well as muscle atrophy and dysfunction. Several biomarkers spanning MQC, inflammation, metabolism, intercellular communication, and gut microbiota have been linked to sarcopenia. Findings from these initial studies hold promise to inform geroscience-based research in the field of sarcopenia by offering a plausible biological framework for developing gerotherapeutics and monitoring their effects.
    Keywords:  Biology of aging; Extracellular vesicles; Inflammaging; Mitochondrial quality control; Multi-Marker; Omics
    DOI:  https://doi.org/10.1016/j.jnha.2024.100397
  8. Geroscience. 2024 Oct 22.
    Sex differences in the association between skeletal muscle energetics and perceived physical fatigability: the Study of Muscle, Mobility and Aging (SOMMA).
    Emma L Gay, Paul M Coen, Stephanie Harrison, Reagan E Garcia, Yujia Susanna Qiao, Bret H Goodpaster, Daniel E Forman, Frederico G S Toledo, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Anthony J A Molina, Barbara J Nicklas, Steven R Cummings, Peggy M Cawthon, Russell T Hepple, Anne B Newman, Nancy W Glynn.
      Greater perceived physical fatigability and lower skeletal muscle energetics are both predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher = greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher = greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N = 873) were 76.3 ± 5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo) were associated with lower perceived physical fatigability, all p < 0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE Fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS ≥ 25, RPE Fatigability ≥ 12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p < 0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the ex vivo measures (p < 0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.
    Keywords:  Aging; Epidemiology; Fatigue; Mitochondria; Oxidative phosphorylation
    DOI:  https://doi.org/10.1007/s11357-024-01373-z
  9. Biomol Ther (Seoul). 2024 Oct 21.
    The Anti-Aging Effects of Collagen Type VII (COL7A1) as Longevity Mediator in Caenorhabditis elegans Healthspan Extension and Skin Collagen Synthesis.
    Juewon Kim, Hyeryung Kim, Woo-Young Seo, Eunji Lee, Donghyun Cho.
      Longevity genes and senescence-related signaling proteins are crucial targets in aging research, which aims to enhance the healthy period and quality of life. Identifying these target proteins remains challenging because of the need for precise categorization and validation methods. Our multifaceted approach combined bioinformatics with transcriptomic data to identify collagen as a key element associated with the lifespan of the model organism, Caenorhabditis elegans. By analyzing transcriptomic data from long-lived mutants that involved mechanisms such as antioxidation, dietary restriction, and genetic background, we identified collagen as a common longevity-associated gene. We validated these findings by confirming that collagen peptides positively affect lifespan, thereby strengthening the validity of the target. Further verification through healthspan factors in C. elegans and functional assays in skin fibroblasts provided additional evidence of the role of collagen in organismal aging. Specifically, our study revealed that collagen type VII is a significant target protein for mitigating age-related decline. By validating these findings across different aging models and cell-based studies, we present compelling evidence for the anti-aging effects of collagen type VII, highlighting its potential as a target for promoting healthy aging. This study proposes that collagen not only serves as an indicative marker of organismal longevity across various senescence-related signaling pathways, but also offers a mechanistic understanding of skin degeneration. Consequently, collagen is an effective target for interventions aimed at mitigating skin aging. This study underscores the potential of collagen type VII (bonding collagen T7) as a therapeutic target for enhancing skin health and overall longevity.
    Keywords:  Bonding collagen; C. elegans; Collagen VII; Healthspan; Skin aging
    DOI:  https://doi.org/10.4062/biomolther.2024.127
  10. Chronic Dis Transl Med. 2024 Dec;10(4): 263-280
    S-acylation of Ca2+ transport proteins in cancer.
    Sana Kouba, Nicolas Demaurex.
      Alterations in cellular calcium (Ca2+) signals have been causally associated with the development and progression of human cancers. Cellular Ca2+ signals are generated by channels, pumps, and exchangers that move Ca2+ ions across membranes and are decoded by effector proteins in the cytosol or in organelles. S-acylation, the reversible addition of 16-carbon fatty acids to proteins, modulates the activity of Ca2+ transporters by altering their affinity for lipids, and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers. Here, we compile studies reporting an association between Ca2+ transporters or S-acylation enzymes with specific cancers, as well as studies reporting or predicting the S-acylation of Ca2+ transporters. We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca2+ transport proteins involved in cancer.
    Keywords:  Ca2+ signaling; Ca2+ transport proteins; S‐acylation; S‐palmitoylation; cancer
    DOI:  https://doi.org/10.1002/cdt3.146
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