bims-cesemi 2026-08-23 papers

iScience. 2026 Aug 21. 29(8): 116955

Specialized cortical ER architecture modulates Ca2+ signaling dynamics.

Raphael J Courjaret, Lloyd Lee, Hana Mohamed, Fang Yu, Lama Assaf, Melanie Fisher, David I Yule, Mark Terasaki, James Sneyd, Khaled Machaca.

Ca2+ signaling is ubiquitous and supports a multitude of cellular events. Specificity in Ca2+ signaling is encoded in its spatial and temporal dynamics. Ca2+ tunneling regulates the dynamics of Ca2+ signals downstream of store operated Ca2+ entry (SOCE). Here, we describe a novel cortical ER (cER) architectural feature, that we call the cER-basket, which underpins Ca2+ tunneling. We discovered the cER-basket through a combination of 3D reconstructions of the cortical ER at the ultrastructural level coupled to mathematical modeling of Ca2+ tunneling. Using insights from the modeling to inform experimental approaches and vice versa, we show that the detailed structural features of the cER-basket support Ca2+ tunneling. Therefore, we report a specific cortical ER structure, the cER-basket, which modulates cellular Ca2+ dynamics.

Keywords: ER structure; calcium signaling; calcium tunneling; mathematical modeling; store-operated calcium entry

DOI: https://doi.org/10.1016/j.isci.2026.116955

Biochim Biophys Acta Mol Basis Dis. 2026 Aug 20. pii: S0925-4439(26)00284-X. [Epub ahead of print] 168421

From protection to progression: How CCT/TRiC shapes therapy-induced senescence in Glioblastoma multiforme.

Maria Antonella Augello, Maciej Wnuk, Celeste Caruso Bavisotto, Francesco Cappello, Federica Scalia.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor despite maximal resection, radiotherapy, and temozolomide. Growing evidence indicates that standard therapies drive many GBM cells into therapy-induced senescence (TIS), marked by permanent proliferation arrest, high metabolic activity, and secretion of the senescence-associated secretory phenotype (SASP). Although senescent cells may initially limit growth, their persistence can fuel recurrence by altering the microenvironment while driving immunosuppression and stem-like traits. GBM is also "chaperone dependent," relying on proteostasis networks for rapid growth, invasion, and treatment resistance. The eukaryotic chaperonin CCT/TRiC, an ATP-dependent complex of eight subunits (CCT1-CCT8), is essential for folding actin and tubulin and for the maturation of multiple oncogenic clients. We review recent findings on CCT/TRiC subunit dysregulation in GBM and propose a mechanistic link between chaperonin activity and senescence, integrating p53/p21 and p16INK4a/Rb signaling, EGFR-driven survival, hypoxia/HIF-mediated metabolic reprogramming, and immune infiltration in high-SASP tumors. We discuss how CCT/TRiC is probably involved in maintaining glioma stem cell (GSC) proteostasis by modulating EGFR, TGF-β, mTOR, Wnt/β-catenin, and Notch pathways, thereby supporting GSC survival, self-renewal, and invasiveness. We also propose how CCT/TRiC inhibition can lead to impaired macroautophagy by disrupting mTOR signaling-both crucial for sustaining senescence and SASP-thereby compromising proteostasis and autophagic flux. Finally, we outline possible therapeutic strategies based on this axis, including novel combinations of senolytics, immunotherapy potentiators, and CCT/TRiC-targeted agents to prevent SASP-driven progression and relapse.

Keywords: CCT/TRiC; Cellular senescence; EGFR; Glioblastoma; Hypoxia; Proteostasis; SASP; Senolytics; Therapy-induced senescence

DOI: https://doi.org/10.1016/j.bbadis.2026.168421

Nat Aging. 2026 Aug 20.

Inhibiting cyclin D1-CDK6 suppresses senescence-associated inflammatory gene expression and age-related functional decline.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the senescence-associated secretory phenotype (SASP), including interferon-stimulated genes (ISGs). Here we confirm and extend previous observations that cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated across models of nonproliferating senescent cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments that activate pro-inflammatory cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the clinical grade CDK4/6 inhibitor palbociclib reduces DNA damage and ISGs in aged mouse liver. Further, palbociclib suppresses frailty and improves physical performance of aged mice. These findings demonstrate a role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising target for therapeutic repurposing.

DOI: https://doi.org/10.1038/s43587-026-01196-x

bioRxiv. 2026 Aug 07. pii: 2026.08.06.743365. [Epub ahead of print]

NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM.

Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.

DOI: https://doi.org/10.64898/2026.08.06.743365

J Gen Physiol. 2026 Sep 07. pii: e202413564. [Epub ahead of print]158(5):

A ratiometric ER calcium sensor for quantitative comparisons across cell types and subcellular regions.

Ryan J Farrell, S Thomas Hennigan, Kirsten G Bredvik, Michael B Hoppa, Timothy A Brown, Timothy A Ryan.

The ER is an important regulator of Ca2+ in cells and dysregulation of ER Ca2+ homeostasis can lead to numerous pathologies. Understanding how various pharmacological and genetic perturbations of ER Ca2+ homeostasis impact cellular physiology would be facilitated by quantitative measurements of ER Ca2+ levels that allow for robust comparisons across conditions. To achieve this, we enhanced our original high dynamic range ER Ca2+ indicator, ER-GCaMP6-150, by fusing it to the HaloTag protein, which when bound to Janelia Fluor (JF) dyes creates a ratiometric ER Ca2+ probe. This probe (ER-Halo-GCaMP6-150) displayed minimal changes to the Ca2+-binding properties compared with our original ER Ca2+ probe as shown through in vitro and in cell Ca2+ calibrations. We describe a method to use this ratiometric probe for quantitative comparisons of ER Ca2+ concentrations and leverage this technique to compare ER Ca2+ levels across cell types and subcellular compartments. Using this approach, we show that the resting concentration of ER Ca2+ in primary dissociated neurons does not differ between excitatory and inhibitory subtypes nor between axonal and somatodendritic compartments. However, resting ER Ca2+ levels in neuronal somas are substantially lower than that measured in embryonic fibroblasts. The ER-Halo-GCaMP6-150 provides a robust tool to directly measure ER Ca2+ levels for studies of ER physiology across cell types and compartments.

DOI: https://doi.org/10.1085/jgp.202413564

Nat Metab. 2026 Aug 20.

The hallmarks of skeletal muscle health.

Anna Vainshtein, Bert Blaauw, Katrien De Bock, Pura Munoz-Canoves, Eric N Olson, Coen A C Ottenheijm, Erik A Richter, Jorge L Ruas, Laurent Schaffer, Bruce Spiegelman, Marco Sandri.

Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.

DOI: https://doi.org/10.1038/s42255-026-01595-9