bims-cesemi 2025-06-01 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–06–01
nine papers selected by
Julio Cesar Cardenas, Universidad Mayor

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.
Agonist-Triggered Ca2+ Release From Functionally Connected Endoplasmic Reticulum and Lysosomal Ca2+ Stores in bEND.3 Endothelial Cells.
The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
Emerging role of mitochondrial calcium levels in cellular senescence and in switching cell fates.
Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches.
Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.
Postbiotic Parabacteroides Distasonis Supplementation Enhances Intestinal and Skeletal Muscle Function in Aged Mice.
Citrinin delays muscle aging and extends lifespan in C. elegans and prevents senescence in C2C12 through SKN-1/Nrf2 activation.

Nat Commun. 2025 May 27. 16(1): 4909

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.

Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

DOI: https://doi.org/10.1038/s41467-025-60196-4
Sci Adv. 2025 May 30. 11(22): eadu9512

Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.

Nicole M Marsh, Melissa J S MacEwen, Jane Chea, Heidi L Kenerson, Albert A Kwong, Timothy M Locke, Francisco Javier Miralles, Tanmay Sapre, Natasha Gozali, Madeleine L Hart, Theo K Bammler, James W MacDonald, Lucas B Sullivan, G Ekin Atilla-Gokcumen, Shao-En Ong, John D Scott, Raymond S Yeung, Yasemin Sancak.

Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss and gain of function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, the uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism.

DOI: https://doi.org/10.1126/sciadv.adu9512
Physiol Res. 2025 Apr 30. 74(2): 249-254

Agonist-Triggered Ca2+ Release From Functionally Connected Endoplasmic Reticulum and Lysosomal Ca2+ Stores in bEND.3 Endothelial Cells.

Cing-Yu Chen, Yu-Jen Chen, Cheng-An Wang, Chen-Hsiu Lin, Jong-Shiuan Yeh, Paul Chan, Lian-Ru Shiao, Yuk-Man Leung.

Endoplasmic reticulum (ER) and lysosomes are physiologically active, physically and functionally connected intracellular Ca2+ stores. In this study we investigated agonist-triggered Ca2+ release from these two stores in mouse microvascular endothelial bEND.3 cells. Addition of nigericin to discharge lysosomal Ca2+ did not affect endoplasmic reticulum Ca2+ release induced by cyclopiazonic acid (CPA) and vice versa, suggesting lysosomes and ER were separate Ca2+ stores whose Ca2+ content was not readily reduced by depletion of the counterpart. ATP triggered Ca2+ release was partially inhibited by Ned-19 (lysosomal two-pore channel inhibitor) or xestospongin C (inositol 1,4,5-trisphosphate receptor-channel inhibitor), suggesting ATP mobilized Ca2+ from both ER and lysosomes. Whilst ATP-triggered Ca2+ release did not affect subsequent CPA- or nigericin-induced Ca2+ discharge, pretreatment with either CPA or nigericin abolished subsequent ATP-triggered Ca2+ release. Thus, the empty state of ER suppressed lysosomal Ca2+ release elicited by ATP, and vice versa, the empty state of lysosome inhibited ATP triggered Ca2+ release from ER. These data suggest cross-talk of the two organelles on the Ca2+ filling state to regulate agonist-stimulated Ca2+ release of each other.
Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00073-0. [Epub ahead of print]95 102535

The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.

Jason C Casler, Laura L Lackner.

The continuous remodeling of the mitochondrial network through fusion, fission, transport, and turnover events, collectively known as mitochondrial dynamics, is essential for the maintenance of mitochondrial metabolic and genomic health. While the primary molecular machines that mediate these processes were discovered decades ago, the regulation of mitochondrial dynamics clearly involves additional factors. A major breakthrough came from the discovery that sites of close apposition between organelles, known as membrane contact sites (MCSs), serve as critical regulators of organelle function. MCSs between mitochondria and the ER are now universally recognized as important regulatory hubs of mitochondrial dynamics. Despite this, there are still many unknowns pertaining to the mechanisms by which MCSs influence mitochondrial dynamics. In this review, we describe recent progress identifying novel protein and lipid components that regulate mitochondrial dynamics and emphasize clear gaps in our understanding of how mitochondrial dynamics are coordinated at MCSs. Finally, we conclude by discussing progress towards defining the highly biomedically relevant, but enigmatic, role of mitochondrial dynamics in the preservation of mitochondrial DNA integrity.

DOI: https://doi.org/10.1016/j.ceb.2025.102535
Nat Aging. 2025 May 26.

Emerging role of mitochondrial calcium levels in cellular senescence and in switching cell fates.

Céline Margand, Pablo Morgado-Cáceres, Ulises Ahumada-Castro, J César Cárdenas, Nadine Martin, David Bernard.

DOI: https://doi.org/10.1038/s43587-025-00887-1
Aging Cell. 2025 May 28. e70114

Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches.

Kevin O Murray, Sophia A Mahoney, Katelyn R Ludwig, Jill H Miyamoto-Ditmon, Nicholas S VanDongen, Nirad Banskota, Allison B Herman, Douglas R Seals, Robert T Mankowski, Matthew J Rossman, Zachary S Clayton.

  Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice. The improvements in frailty and grip strength in old mice were accompanied by favorable modulation of the skeletal muscle transcriptome, including lower abundance of cellular senescence-related genes (e.g., Cdkn1a and Ddit4). Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic-based clearance of excess p16+ senescent cells and treatment with ABT-263. Taken together, our findings provide proof-of-concept support for fisetin as a senolytic strategy to improve physical function with aging.

Keywords:  flavonoid; motor function; natural senolytic; senescence associated secretory phenotype; skeletal muscle senescence; transcriptome

DOI:  https://doi.org/10.1111/acel.70114
Sci Rep. 2025 May 28. 15(1): 18736

Metabolic flux analysis of glioblastoma neural stem cells reveals distinctive metabolic phenotypes in ketogenic conditions.

Anna Rushin, Aleezeh Shaikh, Callie Hardin, Loic P Deleyrolle, Matthew E Merritt.

  Glioblastomas (GBM) are the most prevalent primary brain tumors, affecting 5 in every 100,000 people. GBMs optimize proliferation through adaptive cellular metabolism, frequently exploiting the Warburg effect by increasing aerobic glycolysis and glucose utilization to facilitate rapid cell growth. This disproportionate reliance on glucose has driven interest in using the ketogenic diet (KD) as a treatment for GBM. In this study, we explored metabolic flux in three primary human GBM cell samples using a media simulating a KD. Flux analysis using a detailed metabolic modeling approach revealed three unique metabolic phenotypes in the patient GBMs that correlated with cell viability. Notably, these phenotypes are apparent in the flux modeling, but were not evidenced by changes in the metabolite pool sizes. This variability in metabolic flux may underlie the inconsistent results observed in preclinical and clinical studies using the KD as a treatment paradigm.

Keywords:  Cancer biology; Glioblastoma; Isotopic analysis; Ketogenesis; Metabolism

DOI:  https://doi.org/10.1038/s41598-025-02124-6
Aging Dis. 2025 May 15.

Postbiotic Parabacteroides Distasonis Supplementation Enhances Intestinal and Skeletal Muscle Function in Aged Mice.

Pablo Morgado-Cáceres, Hernán Huerta, Cristian Bergman, Reinaldo Figueroa, Paula Farias, Gabriel Quiroz, Ute Woehlbier, Karen Mella, Osmán Díaz-Rivera, Sergio Linsambarth, Paulina Calderón-Romero, Felipe A Court, Denisse Sepulveda, Daniela Sauma, Patricia Luz-Crawford, Anibal A Vargas, Catalina Gonzalez-Seguel, J César Cárdenas, Alenka Lovy.

Parabacteroides distasonis (Pd), a core member of the human gut microbiota, is enriched in centenarians, suggesting a potential role in promoting organismal resilience. While Pd supplementation has been shown to alleviate cancer and inflammatory diseases, its ability to mitigate the decline associated with aging remains unexplored. Here, we demonstrate that postbiotic Pd supplementation induces multiple beneficial effects in 18- and 26-month-old mice following three months of treatment. Pd-treated mice exhibit lower blood glucose levels and increased ketone body production. In the gut, Pd reduces colon shortening observed in aged control mice and decreases the inflammatory mediator NFκB, in the colonic mucosa. Microbiome analysis further reveals enhanced gut microbiota diversity in Pd-supplemented mice. Additionally, FITC-dextran permeability assays indicate improved intestinal barrier function. Cell culture experiments in HCT116 colon cell line show that Pd reduces oxygen consumption and promotes mitochondrial networking, accompanied by upregulation of PGC1α and CHOP, suggesting a mitohormetic response. Beyond metabolic and gut-related benefits, Pd supplementation enhances skeletal muscle strength in both 18- and 26-month-old mice. Proteomic analysis of gastrocnemius muscle reveals that Pd increases the expression of mitochondrial proteins associated with mitochondrial fitness and survival. Notably, Pd-supplemented mice challenged with a high-fat diet gain weight at a slower rate, while maintaining better skeletal muscle coordination and strength. In summary, our findings suggest that postbiotic Pd supplementation enhances metabolic health, reduces inflammation, improves mitochondrial function, and preserves muscle strength in aged mice. These results position Pd as a promising therapeutic tool for promoting healthy aging and combating aging-related diseases.

DOI: https://doi.org/10.14336/AD.2025.0188
Geroscience. 2025 May 30.

Citrinin delays muscle aging and extends lifespan in C. elegans and prevents senescence in C2C12 through SKN-1/Nrf2 activation.

Yejin Cho, Woo Jin Lee, Hee Soo Kim, Hyo-Deok Seo, Chang Hwa Jung, Jiyun Ahn, Hong-Seok Son, Jeong-Hoon Hahm.

  Sarcopenia, a condition characterized by the loss of muscle mass and function with aging, is linked to various health issues including diabetes and increased risk of falls and fractures. Currently, there is no FDA-approved treatment exists for sarcopenia. Citrinin, a natural compound present in daily dietary sources such as grains, has not been well characterized for its biological effects on muscle aging. Here, we found that citrinin exhibits beneficial effects in delaying muscle aging in both Caenorhabditis elegans (C. elegans) and mouse muscle cells (C2C12). Citrinin attenuated the decline of muscle activities in aged C. elegans, including pharyngeal pumping, body bending, maximum velocity, and locomotor abilities. It also prevented myosin protein loss in C. elegans muscle cells. Citrinin activated SKN-1 (the C. elegans ortholog of mammalian Nrf2), which mediated the prevention of myosin protein loss and the decline in muscle activities. Additionally, citrinin extended the median lifespan of C. elegans via SKN-1. Furthermore, we found that IRE-1 mediated the effects of citrinin on SKN-1 activation and that citrinin delayed aging through the IRE-1/SKN-1 pathway. However, citrinin prevented muscle aging in a UPRER (unfolded protein response of the endoplasmic reticulum) independent manner. In addition, in C2C12 cells, citrinin reduced the number of β-galactosidase-positive stained cells, prevented nuclear expansion, and decreased p21 expression under etoposide-induced senescence conditions, while also activating Nrf2. These findings suggest that citrinin is a potential candidate compound for preventing muscle aging by inducing well-conserved stress response mechanisms from C. elegans to humans. Thus, we propose that citrinin may have positive effects on promoting healthy aging in humans.

Keywords:   C. elegans ; Citrinin; IRE-1; Lifespan; Mouse muscle cells; Muscle aging; SKN-1

DOI:  https://doi.org/10.1007/s11357-025-01713-7