bims-cesemi 2024-12-29 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–12–29
thirteen papers selected by
Julio Cesar Cardenas, Universidad Mayor

Muscle mitochondrial bioenergetic capacities is associated with multimorbidity burden in older adults: the Study of Muscle, Mobility and Aging (SOMMA).
Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.
Targeting senescent cells for the treatment of age-associated diseases.
TRPC1 links calcium signaling to cellular senescence in the protection against post-traumatic osteoarthritis.
How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.
Arachidonoylethanolamide promotes cellular senescence in a human glioblastoma cell line.
Mitonuclear Communication in Stem Cell Function.
Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites.
Inhibiting glioblastoma stem cells by targeting pyruvate carboxylase: A novel therapeutic strategy with both opportunities and challenges.
Melodinines J Induces Apoptosis in Temozolomide-Resistant Glioma Cells by Disrupting TMX1-Dependent Homeostasis of Endoplasmic Reticulum-Mitochondria-Associated Membrane Contacts.
Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog.
High p16INK4A expression in glioblastoma is associated with senescence phenotype and better prognosis.
Effects of Aging on Glucose and Lipid Metabolism in Mice.

medRxiv. 2023 Nov 07. pii: 2023.11.06.23298175. [Epub ahead of print]

Muscle mitochondrial bioenergetic capacities is associated with multimorbidity burden in older adults: the Study of Muscle, Mobility and Aging (SOMMA).

Theresa Mau, Terri L Blackwell, Peggy M Cawthon, Anthony J A Molina, Paul M Coen, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Daniel E Forman, Bret H Goodpaster, Frederico G S Toledo, Kate A Duchowny, Lauren M Sparks, Anne B Newman, Stephen B Kritchevsky, Steven R Cummings.

   Background: The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity.
Methods: The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age =76.4, 56.5% women, 85.9% non-Hispanic white) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95%CI]) for the likelihood of greater multimorbidity (four levels: 0 conditions, N=332; 1 condition, N=299; 2 conditions, N=98; or 3+ conditions, N=35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions.
Results: Lower oxidative phosphorylation supported by fatty acids and/or complex-I and -II linked carbohydrates (e.g., Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR=1.32[1.13,1.54]) and separately with diabetes mellitus (OR=1.62[1.26,2.09]), depressive symptoms (OR=1.45[1.04,2.00]) and possibly chronic kidney disease (OR=1.57[0.98,2.52]) but not significantly with other conditions (e.g., cardiac arrhythmia, chronic obstructive pulmonary disease).
Conclusions: Lower muscle mitochondrial bioenergetic capacities was associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and is more strongly related to some conditions than others.

Keywords:  aging muscle; bioenergetics; mitochondria; multimorbidity

DOI:  https://doi.org/10.1101/2023.11.06.23298175
Cell Death Differ. 2024 Dec 21.

Senolysis by ABT-263 is associated with inherent apoptotic dependence of cancer cells derived from the non-senescent state.

Fleur Jochems, Chrysiida Baltira, Julie A MacDonald, Veerle Daniels, Abhijeet Mathur, Mark C de Gooijer, Olaf van Tellingen, Anthony Letai, René Bernards.

Cellular senescence is a stress response that cells can employ to resist cell death. Senescent cells rely on anti-apoptotic signaling for their survival, which can be targeted by senolytic agents, like the BCL-XL, BCL-2, BCL-W inhibitor ABT-263. However, the response to ABT-263 of senescent cancer cells ranges from highly sensitive to refractory. Using BH3 profiling, we identify here apoptotic blocks in cancer cells that are resistant to this senolytic treatment and discover a correlation between mitochondrial apoptotic priming and cellular sensitivity to ABT-263 in senescence. Intriguingly, ABT-263 sensitivity correlates with overall mitochondrial apoptotic priming, not only in senescence but also in the parental state. Moreover, we confirm that ABT-263 exposure increases dependency on MCL-1, which is most enhanced in ABT-263 sensitive cells. ABT-263 resistant cells however upregulate MCL-1, while sensitive cells exhibit low levels of this anti-apoptotic protein. Overall, our data indicate that the response of senescent cells to ABT-263 is predetermined by the mitochondrial apoptotic priming state of the parental cells, which could serve as a predictive biomarker for response to senolytic therapy.

DOI: https://doi.org/10.1038/s41418-024-01439-7
J Biochem. 2024 Dec 27. pii: mvae091. [Epub ahead of print]

Targeting senescent cells for the treatment of age-associated diseases.

Masayoshi Suda, Tamar Tchkonia, James L Kirkland, Tohru Minamino.

  Cellular senescence, which entails cellular dysfunction and inflammatory factor release-the senescence-associated secretory phenotype (SASP)-is a key contributor to multiple disorders, diseases, and the geriatric syndromes. Targeting senescent cells using senolytics has emerged as a promising therapeutic strategy for these conditions. Among senolytics, the combination of dasatinib and quercetin (D + Q) was the earliest and one of the most successful so far. D + Q delays, prevents, alleviates, or treats multiple senescence-associated diseases and disorders with improvements in healthspan across various preclinical models. While early senolytic therapies have demonstrated promise, ongoing research is crucial to refine them and address such challenges as off-target effects. Recent advances in senolytics include new drugs and therapies that target senescent cells more effectively. The identification of senescence-associated antigens-cell surface molecules on senescent cells-pointed to another promising means for developing novel therapies and identifying biomarkers of senescent cell abundance.

Keywords:  Cell surface proteins; Cellular senescence; Immunotherapy; Seno-antigens; Senolytics

DOI:  https://doi.org/10.1093/jb/mvae091
JCI Insight. 2024 Dec 24. pii: e182103. [Epub ahead of print]

TRPC1 links calcium signaling to cellular senescence in the protection against post-traumatic osteoarthritis.

Meike Sambale, Starlee Lively, Osvaldo Espin-Garcia, Pratibha Potla, Chiara Pastrello, Sarah Bödecker, Linda Wessendorf, Simon Kleimann, Peter Paruzel, Rojiar Asgarian, Alexandra Tosun, Johanna Intemann, Jessica Bertrand, Francesco Dell'Accio, Mohit Kapoor, Thomas Pap, Joanna Sherwood.

  Transient receptor potential channel 1 (TRPC1) is a widely expressed mechanosensitive ion channel located within the endoplasmic reticulum membrane, crucial for refilling depleted internal calcium stores during activation of calcium-dependent signaling pathways. Here, we demonstrate that TRPC1 activity is protective within cartilage homeostasis in the prevention of cellular senescence associated cartilage breakdown during mechanical and inflammatory challenge. We reveal that TRPC1 loss is associated with early stages of osteoarthritis (OA) and plays a non-redundant role in calcium signaling in chondrocytes. Trpc1-/- mice subjected to destabilization of the medial meniscus induced OA developed a more severe OA phenotype than wild type controls. During early OA development, Trpc1-/- mice displayed an increased chondrocyte survival rate, however remaining cells displayed features of senescence including p16INK4a expression and decreased Sox9. RNA sequencing identified differentially expressed genes related to cell number, apoptosis and extracellular matrix organization. Trpc1-/-chondrocytes exhibited accelerated dedifferentiation, while demonstrating an increased susceptibility to cellular senescence. Targeting the mechanism of Trpc1 activation may be a promising therapeutic strategy in osteoarthritis prevention.

Keywords:  Bone biology; Calcium channels; Cell biology; Cellular senescence; Osteoarthritis

DOI:  https://doi.org/10.1172/jci.insight.182103
Exp Eye Res. 2024 Dec 22. pii: S0014-4835(24)00441-X. [Epub ahead of print]251 110219

How crosstalk between mitochondria, lysosomes, and other organelles can prevent or promote dry age-related macular degeneration.

Aparna Lakkaraju, Patricia Boya, Marie Csete, Deborah A Ferrington, James B Hurley, Alfredo A Sadun, Peng Shang, Ruchi Sharma, Debasish Sinha, Marius Ueffing, Susan E Brockerhoff.

  Organelles such as mitochondria, lysosomes, peroxisomes, and the endoplasmic reticulum form highly dynamic cellular networks and exchange information through sites of physical contact. While each organelle performs unique functions, this inter-organelle crosstalk helps maintain cell homeostasis. Age-related macular degeneration (AMD) is a devastating blinding disease strongly associated with mitochondrial dysfunction, oxidative stress, and decreased clearance of cellular debris in the retinal pigment epithelium (RPE). However, how these occur, and how they relate to organelle function both with the RPE and potentially the photoreceptors are fundamental, unresolved questions in AMD biology. Here, we report the discussions of the "Mitochondria, Lysosomes, and other Organelle Interactions" task group of the 2024 Ryan Initiative for Macular Research (RIMR). Our group focused on understanding the interplay between cellular organelles in maintaining homeostasis in the RPE and photoreceptors, how this could be derailed to promote AMD, and identifying where these pathways could potentially be targeted therapeutically.

Keywords:  Bioenergetics; Oxidative stress; Photoreceptors; Retinal pigment epithelium; Therapeutics

DOI:  https://doi.org/10.1016/j.exer.2024.110219
Biochem Biophys Res Commun. 2024 Dec 24. pii: S0006-291X(24)01771-6. [Epub ahead of print]745 151235

Arachidonoylethanolamide promotes cellular senescence in a human glioblastoma cell line.

Luis A Zapi-Colín, Jorge E Dotor-Hernández, Irazú Contreras, José A Estrada.

  Glioblastomas are the most common and deadly primary brain tumors, with high mortality rates despite aggressive therapies. Cellular senescence is important for cancer development, as it limits tumor progression; however, it may also stimulate inflammation at the tumor microenvironment, promoting tumor development. Hence, modulation of senescence is an important target for cancer therapy. Endocannabinoids modulate energy metabolism and the functions of the immune and nervous systems and have shown significant anti-tumor effects in experimental conditions, inhibiting cell growth and proliferation, while promoting apoptosis. Altered endocannabinoid concentrations are related to development of different types of cancer, and recent studies have shown that endocannabinoids and their synthetic analogs are capable of modulating senescence in multiple tissues, affecting cell proliferation and survival. Nonetheless, their effects on cellular senescence in cancer have not been defined. This study explored the effect of the endocannabinoid arachidonoylethanolamide on the induction of cellular senescence in human glioblastoma cell line U-87MG. Our results show that direct supplementation of AEA decreases cell cycle progression, while increasing beta-galactosidase activity and expression of p21, in U-87MG cells, in a dose- and time-dependent manner. Our data suggest that arachidonoylethanolamide may be useful for the modulation of glioblastoma senescence and should be explored further as an adjuvant for cancer therapy.

Keywords:  Beta-galactosidase; Cell cycle; Endocannabinoids; Glioblastoma; Senescence; p21

DOI:  https://doi.org/10.1016/j.bbrc.2024.151235
Cell Prolif. 2024 Dec 26. e13796

Mitonuclear Communication in Stem Cell Function.

Baozhou Peng, Yaning Wang, Hongbo Zhang.

  Mitochondria perform multiple functions within the cell, including the production of ATP and a great deal of metabolic intermediates, while also contributing to the cellular stress response. The majority of mitochondrial proteins are encoded by nuclear genomes, highlighting the importance of mitonuclear communication for sustaining mitochondrial homeostasis and functional. As a crucial part of the intracellular signalling network, mitochondria can impact stem cell fate determinations. Considering the essential function of stem cells in tissue maintenance, regeneration and aging, it is important to understand how mitochondria influence stem cell fate. This review explores the significant roles of mitonuclear communication and mitochondrial proteostasis, highlighting their influence on stem cells. We also examine how mitonuclear interactions contribute to cellular homeostasis, stem cell therapies, and the potential for extending lifespan.

Keywords:  aging; fate determination; metabolism; mitochondria; mitochondrial stress; mitonuclear communication; stem cell

DOI:  https://doi.org/10.1111/cpr.13796
Cell. 2024 Dec 18. pii: S0092-8674(24)01345-X. [Epub ahead of print]

Periodic ER-plasma membrane junctions support long-range Ca2+ signal integration in dendrites.

Lorena Benedetti, Ruolin Fan, Aubrey V Weigel, Andrew S Moore, Patrick R Houlihan, Mark Kittisopikul, Grace Park, Alyson Petruncio, Philip M Hubbard, Song Pang, C Shan Xu, Harald F Hess, Stephan Saalfeld, Vidhya Rangaraju, David E Clapham, Pietro De Camilli, Timothy A Ryan, Jennifer Lippincott-Schwartz.

  Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca2+ channels and ER Ca2+-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca2+ homeostasis, and local activation of the Ca2+/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca2+ modulatory machinery, facilitating signal transmission and ryanodine-receptor-dependent Ca2+ release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca2+ release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.

Keywords:  Ca(2+)/calmodulin-dependent protein kinase II; CaMKII; Drosophila melanogaster; ER-PM junctions; Junctophilin; RyRs; VGCC; endoplasmic reticulum; hippocampal neurons; ryanodine receptors; voltage-gated calcium channels; volume electron microscopy

DOI:  https://doi.org/10.1016/j.cell.2024.11.029
Neuro Oncol. 2024 Dec 26. pii: noae250. [Epub ahead of print]

Inhibiting glioblastoma stem cells by targeting pyruvate carboxylase: A novel therapeutic strategy with both opportunities and challenges.

Ophélie Renoult, Mélanie Laurent-Blond, Claire Pecqueur.

DOI: https://doi.org/10.1093/neuonc/noae250
Phytother Res. 2024 Dec 23.

Melodinines J Induces Apoptosis in Temozolomide-Resistant Glioma Cells by Disrupting TMX1-Dependent Homeostasis of Endoplasmic Reticulum-Mitochondria-Associated Membrane Contacts.

Fanfan Chen, Weiwei Cao, Xuejuan Li, Zebin Chen, Guoxu Ma, Sicen Wang, Zongyang Li, Lei Chen, Weiping Li, Xiangbao Meng, Guodong Huang, Ping Cui.

  Glioma is recognized as one of the most lethal and aggressive brain tumors. Although the standard-of-care treatment for glioblastoma (GBM) involves maximal surgical resection and temozolomide (TMZ) chemotherapy, the discovery of novel anti-tumor agents from nature sources is an effective strategy for glioma treatment. In this study, we conducted a screening process to identify the bisindole alkaloid melodinine J (MDJ) from Melodinus tenuicaudatus. We assessed its potency in overcoming TMZ resistance in patient-derived recurrent glioma strains, TMZ-resistant cell lines, and nude mouse tumor models of glioma cells. Our results first indicated that MDJ effectively inhibited malignancy and stimulated apoptosis in glioma. Mechanistic studies revealed that MDJ triggered deadly mitochondrial dysfunction and apoptosis by disrupting cross-organellar communication between the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). We also showed that high levels of TMX1 may promote malignancy of glioma by ER-mitochondria communications, bioenergetics efficiency, and tumor growth. Overall, our study proved that MDJ interfered the function of TMX1-mediated MAM networks, thereby overcoming the proliferation and chemo-resistance of glioma cells.

Keywords:  ER and mitochondria‐associated membranes; TMX1; chemotherapy resistance; glioma; melodinine J

DOI:  https://doi.org/10.1002/ptr.8396
Nat Aging. 2024 Dec 27.

Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog.

Sophia Magkouta, Dimitris Veroutis, Angelos Papaspyropoulos, Maria Georgiou, Nikolaos Lougiakis, Natassa Pippa, Sophia Havaki, Anastasia Palaiologou, Dimitris-Foivos Thanos, Konstantinos Kambas, Nefeli Lagopati, Nikos Boukos, Nicole Pouli, Panagiotis Marakos, Athanassios Kotsinas, Dimitris Thanos, Konstantinos Evangelou, Fotios Sampaziotis, Constantin Tamvakopoulos, Stergios Pispas, Russell Petty, Nicholas Kotopoulos, Vassilis G Gorgoulis.

The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond. As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.

DOI: https://doi.org/10.1038/s43587-024-00747-4
Neoplasia. 2024 Dec 25. pii: S1476-5586(24)00157-X. [Epub ahead of print]60 101116

High p16INK4A expression in glioblastoma is associated with senescence phenotype and better prognosis.

Soon Sang Park, Tae Hoon Roh, Yoshiaki Tanaka, Young Hwa Kim, So Hyun Park, Tae-Gyu Kim, So Yeong Eom, Tae Jun Park, In-Hyun Park, Se-Hyuk Kim, Jang-Hee Kim.

  Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (GBM), is the most malignant brain tumor in adults, with limited therapeutic intervention. Previous studies have identified a few prognostic markers for GBM, including the methylation status of O6-methylguanine-DNA methyltransferase (MGMT) promoter, TERT promoter mutation, EGFR amplification, and CDKN2A/2B deletion. However, the classification of GBM remains incomplete, necessitating a comprehensive analysis. In this study, we investigated the impact of p16INK4A expression in GBM and found that p16INK4A-high GBM exhibits distinct characteristics compared to p16INK4A-low GBM. Specifically, tumor cells with p16INK4A-high expression display a senescent phenotype and are correlated with higher intra-tumoral immune cell infiltration. Furthermore, an association was observed between elevated p16INK4A expression in GBM and extended overall survival of patients. Our in vivo and in vitro studies revealed that CCL13 is predominantly expressed by p16INK4A-high GBM cells. The released CCL13 enhances the infiltration of T cells within the tumor, potentially contributing to the improved prognosis observed in patients with high p16INK4A expression. These findings suggest that tumor cells with a senescence phenotype in GBM, through the secretion of chemokines such as CCL13, may augment immune cell infiltration and potentially enhance patient outcomes by creating a more immunologically active tumor microenvironment.

Keywords:  CCL13; GBM IDH-wildtype; Glioblastoma; Senescence; Senescent tumor cells

DOI:  https://doi.org/10.1016/j.neo.2024.101116
Aging Cell. 2024 Dec 27. e14462

Effects of Aging on Glucose and Lipid Metabolism in Mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

  Aging is accompanied by multiple molecular changes that contribute to aging associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part, because mitochondria are central to cellular metabolism. Moreover, the cofactor NAD+, which is reported to decline across multiple tissues during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and diversity outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of upregulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. These data suggest that NAD+-generating lipid metabolism reactions may help to maintain the NAD+/NADH ratio during healthy aging.

Keywords:  NAD; aging; metabolic rate; mice

DOI:  https://doi.org/10.1111/acel.14462