bims-cesemi 2026-03-22 papers

Issue of 2026–03–22
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor

Endocrinol Metab (Seoul). 2026 Mar 13.

Cellular Senescence in Skeletal Muscle Aging.

Cellular senescence is increasingly recognized as a pivotal mechanism driving skeletal muscle aging and the development of sarcopenia, a condition characterized by the progressive loss of muscle mass, strength, and function. This review synthesizes recent evidence detailing the accumulation of senescent cells in aged skeletal muscle, including muscle stem cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, endothelial cells, and even post-mitotic myofibers. Senescence in these cell types impairs regenerative signaling, disrupts niche homeostasis, and propagates chronic inflammation. Emerging therapeutic strategies, termed senotherapeutics, aim to counteract these effects through senolytics (which eliminate senescent cells) and senomorphics (which modulate the senescence-associated secretory phenotype), as promising interventions to restore muscle function and delay sarcopenia. We will also discuss the remaining challenges and future directions for studying senescence in skeletal muscle.

Keywords: Aging; Cellular senescence; Senotherapy; Skeletal muscle

DOI: https://doi.org/10.3803/EnM.2025.2816

Nature. 2026 Mar 19.

Masked mitochondria slip into cells to treat disease in mice.

Edward Chen.

Keywords: Cell biology; Gene therapy; Medical research; Metabolism

DOI: https://doi.org/10.1038/d41586-026-00869-2

Open Biol. 2026 Mar 18. pii: 250220. [Epub ahead of print]16(3):

STIM1 and endoplasmic reticulum-plasma membrane contact sites oscillate independently of calcium-induced calcium release.

Ding Xiong, Cheesan Tong, Suet Yin Sarah Fung, Samantha McClellan, Yang Yang, Jeffery Yong, Min Wu.

Calcium (Ca²+) release from intracellular stores, Ca²+ entry across the plasma membrane and their coordination via store-operated Ca²+ entry (SOCE) are critical for receptor-activated Ca²+ oscillations. However, the precise mechanism of Ca²+ oscillations and whether their control loop resides at the plasma membrane or intracellularly remains unresolved. By examining the dynamics of stromal interaction molecule 1 (STIM1), an endoplasmic reticulum (ER)-localized Ca²+ sensor that activates the Orai1 channel on the plasma membrane for SOCE, in mast cells, we found that a significant proportion of cells exhibited STIM1 oscillations with the same periodicity as Ca²+ oscillations. These cortical oscillations, shared with ER-plasma membrane (ER-PM) contact site proteins, were only detectable using total internal reflection fluorescence microscopy. Notably, STIM1 oscillations could occur independently of Ca²+ oscillations. Simultaneous imaging of cytoplasmic Ca²+ and ER Ca²+ with CEPIA1er revealed that receptor activation does not deplete ER Ca²+, whereas receptor activation without extracellular Ca²+ influx induces cyclic ER Ca²+ depletion. However, under such non-physiological conditions, cyclic ER Ca²+ oscillations lead to sustained STIM1 recruitment, indicating that oscillatory Ca²+ release is neither necessary nor sufficient for STIM1 oscillations. Using optogenetic tools to manipulate ER-PM contact site dynamics, we found that persistent ER-PM contact sites reduced the amplitude of Ca²+ oscillations without alteration of oscillation frequency. Together, these findings suggest an active cortical mechanism governs the rapid dissociation of ER-PM contact sites, thereby controlling amplitude of oscillatory Ca²+ dynamics during receptor-induced Ca²+ oscillations.

Keywords: calcium oscillations; dynamical systems; endoplasmic reticulum calcium imaging; optogenetics

DOI: https://doi.org/10.1098/rsob.250220

Trends Endocrinol Metab. 2026 Mar 17. pii: S1043-2760(26)00013-5. [Epub ahead of print]

Do metabolic fluxes change with age?

Sebastian J Hofer, Anna Katharina Simon, Frank Madeo.

Metabolomes change with age. Yet, fluxomics points to a contradiction: Jankowski et al. in Cell Metabolism report shifts in metabolite concentrations in aged mice, alongside largely preserved metabolite fluxes, evoking important questions on the nature of age-related metabolic disturbances. We discuss how this might recalibrate our understanding of aging metabolism.

Keywords: age-associated diseases; aging; autophagy; geroscience; metabolism

DOI: https://doi.org/10.1016/j.tem.2026.01.013

Cell Rep. 2026 Mar 15. pii: S2211-1247(26)00190-7. [Epub ahead of print]45(3): 117112

Mitochondria acidify lysosomes through membrane contacts.

Zhiqi Tian, Rui Chen, Guiqian Fang, Kangqiang Qiu, Weijun Wu, Xintian Shao, Daili Liu, Huilin Que, Xueqian Wang, Ji Gao, Jianyu Zhang, Bidyut Kundu, Qixin Chen, Jun-Lin Guan, Yueguang Rong, Ben Zhong Tang, Kai Li, Yujie Sun, Jiajie Diao.

The acidic environment within the lysosome lumen is essential for its digestive function. However, the source of protons responsible for acidification has remained elusive. Here, using a molecular probe to monitor lysosomal digestion, we discovered enhanced lysosome content degradation at mitochondria-lysosome contact (MLC) sites, which was caused by lysosomal acidification. Using a mitochondrial probe, we observed a proton flux from mitochondria to lysosomes at these MLC sites. Furthermore, we found that physically bringing mitochondria and lysosomes into close proximity can increase lysosome acidification to enhance content digestion under disease conditions. These findings unveil a crucial physiological role of MLCs in cellular functions.

Keywords: CP: cell biology; lysosome acidification; mitochondria-lysosome contact; proton flux

DOI: https://doi.org/10.1016/j.celrep.2026.117112

Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2521256123

Microglial fructose metabolism is essential for glioblastoma growth.

Glioblastoma (GBM) remains one of the most aggressive and treatment-resistant brain tumors in adults. Its immune microenvironment is dominated by tumor-associated macrophages, including both infiltrating monocytes and brain-resident microglia. While metabolic rewiring of infiltrating myeloid cells has been shown to support tumor progression, the role of microglial metabolism in GBM remains incompletely understood. Here, we demonstrate that microglia uniquely express the fructose transporter GLUT5 and are the only immune cells in the GBM microenvironment capable of metabolizing fructose. Using murine orthotopic glioma and Replication-Competent Avian sarcoma leuko virus Splice acceptor (RCAS)-derived tumor models, we show that global deletion of GLUT5 confers profound resistance to tumor growth. This effect is driven by loss of fructose metabolism in microglia and occurs independently of contributions from peripheral immune compartments. In GLUT5-deficient mice, tumors exhibit increased infiltration and activation of both innate and adaptive immunity, including enhanced antigen presentation, clonal expansion of CD8+ T cells, and increased cytokine production. Depletion of B-cells or CD8+ T cells abrogated survival phenotypes in knockout mice, demonstrating that GLUT5 suppresses adaptive immunity. These findings identify microglial fructose metabolism as a critical regulator of immune suppression in GBM and suggest that targeting this pathway may improve immunotherapeutic responses.

Keywords: fructose metabolism; glioblastoma; microglia; redox homeostasis

DOI: https://doi.org/10.1073/pnas.2521256123

Cell Rep. 2026 Mar 13. pii: S2211-1247(26)00174-9. [Epub ahead of print]45(3): 117096

Radiation-induced autophagy regulates fibroblast mitochondrial metabolism and crosstalk with triple-negative breast cancer cells.

Kevin C Corn, Shannon E Martello, Vinay K Menon, Lucy S Britto, Kara M Simmons, Youssef K Mohamed, Yoanna I Ivanova, Abtin A Ghelmansaraei, Sara A Weidenbach, Tian Zhu, Evan S Krystofiak, Jamey D Young, Vivian Gama, Marjan Rafat.

Patients with triple-negative breast cancer (TNBC) experience high recurrence rates despite current interventions, which include radiation therapy (RT). Tumor cells thought to be involved in recurrence may survive in part due to their interactions with irradiated fibroblasts following treatment. How fibroblasts metabolically respond to RT and influence the behavior of TNBC cells is poorly understood. In this study, we demonstrate that irradiated fibroblasts undergo dynamic mitochondrial changes that are regulated by autophagy, resulting in a metabolic profile characterized by high levels of mitochondrial respiration and fatty acid oxidation. These metabolic adaptations lead to a secretory profile that induces an aggressive phenotype in TNBC cells that is mitigated when fibroblast autophagy is blocked. Our work reveals a burgeoning link between post-RT metabolic adaptations in fibroblasts and crosstalk with TNBC cells that promotes a microenvironment conducive to recurrence.

Keywords: CP: cancer; CP: metabolism; autophagy; fatty acid oxidation; fibroblasts; lipid metabolism; mitochondrial elongation; mitochondrial fusion; mitochondrial respiration; radiation therapy; recurrence; triple-negative breast cancer

DOI: https://doi.org/10.1016/j.celrep.2026.117096