bims-cesemi 2026-09-20 papers

Issue of 2026–09–20
seven papers selected by
Julio Cesar Cardenas, Universidad Mayor

Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):

Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.

Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-76619-9

Mech Ageing Dev. 2026 Sep 14. pii: S0047-6374(26)00094-1. [Epub ahead of print] 112242

Loss of Ca2+ Signaling Fidelity During Aging: Mitochondrial Dysfunction, Senescence, and Cognitive-Motor Decline.

Sergio Linsambarth, Alejandra Lopez-Moroni, Cesar Casanova, Simon Alarcon, Loreto Araos, Andrea Puebla-Huerta, Fabian Jaña, Alenka Lovy, Carlos Villalobos, J Cesar Cárdenas.

Aging is characterized by a progressive decline in cellular homeostasis that ultimately compromises tissue integrity, regenerative capacity, and organismal function. Among the molecular processes increasingly recognized as central regulators of aging, intracellular Ca2+ signaling has emerged as a major determinant of metabolic adaptation, stress responses, inflammation, and cell fate. Ca2+ controls essential biological functions in virtually every tissue. Importantly, the remarkable versatility of Ca2+ signaling depends on the precise spatial and temporal coordination of channels, pumps, exchangers, buffering proteins, and organelle contact sites that together generate highly organized intracellular Ca2+ microdomains. During aging, the quality of this signaling progressively deteriorates. Altered activity of plasma membrane channels, defective endoplasmic reticulum (ER) Ca2+ handling, impaired mitochondrial buffering, oxidative stress, and chronic inflammation collectively destabilize intracellular Ca2+ homeostasis. These alterations converge on mitochondrial dysfunction, one of the central hallmarks of aging, leading to bioenergetic decline, excessive reactive oxygen species production, cellular senescence, and impaired tissue adaptation. In the nervous system, disrupted Ca2+ signaling contributes to synaptic dysfunction, neuroinflammation, and neuronal vulnerability associated with cognitive decline and neurodegenerative disease. In skeletal muscle, defective Ca2+ handling impairs excitation-contraction coupling, mitochondrial metabolism, and regenerative capacity, thereby promoting sarcopenia and motor decline. In this review, we discuss how aging remodels the cellular Ca2+ signaling toolkit across neuronal and muscular systems, with particular emphasis on mitochondrial dysfunction, senescence and inter-organelle communication. Finally, we examine therapeutic strategies aimed at restoring Ca2+ signaling fidelity as potential interventions to preserve tissue function and extend healthspan.

Keywords: Channels; MERCs; mitochondria; neurodegeneration; sarcopenia

DOI: https://doi.org/10.1016/j.mad.2026.112242

Aging Cell. 2026 Sep;25(9): e70719

Rethinking Senescence Hallmarks in the Brain: Lessons From Peripheral Tissues and Challenges in Defining Neuronal Senescence.

Miraj Ud Din Momand, Kristina Macova, Dominika Fricova.

Cellular senescence is increasingly recognized as a fundamental driver of aging and age-related diseases. Studies in peripheral tissues have revealed that senescence is not a uniform cellular state, but a highly heterogeneous phenotype shaped by distinct combinations of DNA damage, mitochondrial dysfunction, chromatin remodeling, impaired proteostasis, and diverse senescence-associated secretory phenotype. This heterogeneity critically influences both the identification and therapeutic targeting of senescent cells. As senescent cells accumulate with age, they contribute to chronic low-grade inflammation and tissue dysfunction, while their selective elimination can improve health span, establishing senescence as both a pathogenic mechanism and a therapeutic target in systemic aging. Emerging evidence now suggests that post-mitotic neurons and other neural cell types can acquire senescence-like states during aging and neurodegeneration. However, the direct application of canonical peripheral senescence markers to the nervous system remains conceptually and experimentally problematic, raising the risk of inconsistent or misleading interpretations across models and studies. In this review, we integrate insights from peripheral senescence biology to examine how cell type, inducing stressor, and experimental context shape senescence-associated phenotypes across neural systems, including in vitro models, physiologically aged brains, and models of Alzheimer's and Parkinson's disease. By critically evaluating where canonical senescence hallmarks translate and where they fail to translate to post-mitotic neurons, we propose that a refined, neuron-centered framework is essential for moving the field beyond descriptive observations and for rigorously testing the causal contribution of senescent neural cells to neurodegeneration.

Keywords: Alzheimer's disease; Parkinson's disease; alpha‐synuclein; cellular senescence; markers; models; neurodegeneration; neuronal senescence; tau

DOI: https://doi.org/10.1111/acel.70719

Cell. 2026 Sep 15. pii: S0092-8674(26)01010-X. [Epub ahead of print]

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer.

The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an alternative function. GAA accumulates in GAA N-methyltransferase (GAMT) deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

Keywords: GABA; GAMT deficiency; cancer metabolism; cancer neuroscience; creatine; glioma; guanidinoacetate; inborn error of metabolism; metabolite signaling

DOI: https://doi.org/10.1016/j.cell.2026.08.037

Adv Sci (Weinh). 2026 Sep 16. e77818

Lactylation-Driven PROS1-TYRO3-CARF Signaling Promotes Therapy-Induced Senescence Escape and Radioresistance in Meningioma.

Zhuohang Wang, Qixiang Zhang, Keman Liao, Xiaoyu Liu, Hongchi Zhang, Yunsheng Chen, Yuxiao Ma, Yikui Liu, Aoqian Xu, Yuhao Sun, Jiayi Chen, Liuguan Bian, Baofeng Wang.

Radiotherapy is a major treatment for meningioma, but radioresistance remains a key obstacle to durable disease control. Here, we show that escape from therapy-induced senescence (TIS) is a hallmark of radioresistant meningioma cells and identify a novel glycolysis-H3K27 lactylation-PROS1-TYRO3-CARF axis underlying this phenotype. Using photon-derived radioresistant meningioma models established from two independent meningioma cell lines, combined with multi-omics, CUT&Tag, dual‑luciferase reporter assays, immunoprecipitation-mass spectrometry, and in vivo xenograft analyses, we found that radioresistant cells display enhanced glycolysis, lactate accumulation, and increased H3K27 lactylation. H3K27la promotes PROS1 transcription, leading to PROS1 secretion and TYRO3 activation. Activated TYRO3 in turn promotes phosphorylation of CARF at tyrosine 8 and triggers its proteasomal degradation, relieving CDKN2A/p53-associated senescence, and permitting cell cycle re-entry. Disruption of PROS1 signaling or inhibition of CARF phosphorylation restores senescence-associated phenotypes and enhances radiosensitivity in vivo. Together, these findings establish a metabolic-epigenetic-signaling mechanism that couples glycolytic reprogramming to TIS escape in meningioma and highlight the PROS1-TYRO3-CARF axis as a potential radiosensitizing target.

Keywords: CARF; PROS1; TYRO3; cellular senescence; histone lactylation; meningioma; radioresistance

DOI: https://doi.org/10.1002/advs.77818

Nature. 2026 Sep 17.

How fast are you ageing? Ask AI.

Heidi Ledford.

Keywords: Ageing; Machine learning

DOI: https://doi.org/10.1038/d41586-026-02913-7