bims-cesemi 2026-08-09 papers

Cell Chem Biol. 2026 Aug 03. pii: S2451-9456(26)00244-8. [Epub ahead of print]

The BAX/BAK apoptotic checkpoint polices entry to therapy-induced senescence.

Aislinn Gallagher Aldave, Vaishnavi Venugopalan, Gokhan Gunay, Seren Hamsici, Ronaldo Rodrigues Ribeiro, Aoife Costigan, Anna Gabrielyan, Hande Efe-Cicek, Seamus J Martin.

Cytotoxic chemotherapy is intended to eliminate transformed cells but can also provoke therapy-induced senescence, a persistent and pro-inflammatory cell state that can promote tumor progression. The molecular mechanisms that govern the apoptosis-senescence fate decision remain incompletely understood. Here, we show that the mitochondrial pore-forming proteins BAX and BAK function as a critical checkpoint that restricts entry to therapy-induced senescence. Genetic ablation of BAX and BAK markedly enhanced entry to senescence in response to multiple DNA-damaging agents, whereas loss of the BAX/BAK antagonists Bcl-xL or Mcl-1 suppressed entry to senescence and promoted cell death. Mechanistically, genotoxic stress induced BH3-only proteins, including Noxa, Bid, and Puma, creating a dependence on Bcl-xL and Mcl-1 to restrain BAX/BAK activation and maintain survival. These findings identify the Bcl-2 family network as a central regulator of entry to therapy-induced senescence, a pro-inflammatory cell state that goes beyond the mere avoidance of apoptosis.

Keywords: BAK; BAX; Bcl-2 family; DNA damage; apoptosis; cell death; chemotherapy; mitochondria; senescence; senolysis

DOI: https://doi.org/10.1016/j.chembiol.2026.07.002

Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923

Mitochondria with (distinct) personality.

Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.

Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.

DOI: https://doi.org/10.1016/j.molcel.2026.06.044

Cell Mol Gastroenterol Hepatol. 2026 Aug 05. pii: S2352-345X(26)00133-5. [Epub ahead of print] 101855

The SenKiller Mouse: Enabling Cell Type-Specific Ablation of Senescent Cells.

Xuerui Wu, Eric L Waite, Mark Tigue, Benjamin Glaser, Dana Avrahami, Klaus H Kaestner.

DOI: https://doi.org/10.1016/j.jcmgh.2026.101855

Biochim Biophys Acta Rev Cancer. 2026 Aug 03. pii: S0304-419X(26)00145-9. [Epub ahead of print]1881(5): 189673

Rethinking glioma-associated senescence: Drivers of heterogeneity and therapeutic resistance.

Yuting Yan, Boxiang Zhang, Shuyang Chen, Yongqing Sun, Jinhai Huang, Guangyu Li.

Cellular senescence, traditionally defined as a stress-induced irreversible cell-cycle arrest program with tumor-suppressive functions in normal somatic cells, exhibits remarkable heterogeneity in malignant gliomas, particularly in glioblastoma (GBM, WHO grade IV). Glioma-associated senescence represents a dynamic and context-dependent cellular state rather than a uniform endpoint and can be broadly categorized into therapy-induced senescence (TIS) and spontaneous senescence (SS) based on induction mechanisms. The phenotypic and functional heterogeneity of glioma-associated senescence is a key driver of intratumoral complexity, adaptive tumor survival, and resistance to conventional glioma therapies, and engages in bidirectional crosstalk with the brain tumor microenvironment to modulate disease progression. In this review, we rethink the current understanding of the core characteristics and multi-dimensional heterogeneity of glioma-associated senescence, including phenotypic, functional, spatial and temporal heterogeneity. We further elaborate on the critical molecular drivers underlying glioma-associated senescence heterogeneity, encompassing alterations in core cell-cycle regulatory pathways, dysregulation of oncogenic signaling including epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-AKT), and mitogen-activated protein kinase (MAPK) pathways, epigenetic modifications, metabolic reprogramming, and the regulatory role of the tumor microenvironment. We also discuss the senescence-associated secretory phenotype (SASP) as a core functional feature of senescent or senescence-like glioma cells, its composition and functional heterogeneity, and its pivotal role in remodeling the glioma microenvironment and mediating non-cell-autonomous effects in therapy resistance. Additionally, we analyze the dual role of TIS in glioma treatment and the mechanisms by which TIS-associated senescence-like states may contribute to tumor recurrence. Finally, we outline emerging senescence-targeted therapeutic strategies, including senolytics and senomorphics, as well as optimized combination regimens with conventional therapies, and highlight the challenges and future perspectives in translating these strategies into clinical practice. This review aims to provide a comprehensive framework for understanding the biological significance of glioma-associated senescence heterogeneity and to guide the development of innovative precision interventions to overcome therapy resistance and improve clinical outcomes for glioma patients.

DOI: https://doi.org/10.1016/j.bbcan.2026.189673

EMBO J. 2026 Aug 07.

Allosteric switching of Ca2+ permeability in the lysosomal ion channel TPC2 underpins biased agonist activation.

Ion channels possess selectivity filters that are hardwired to ensure the selective passage of ions. Lysosomal two-pore channels are unusual as they are able to switch their cation selectivity in an agonist-specific manner, allowing differential control of organellar activity. TPC2 is permeable to Ca2+ when activated by the calcium-mobilizing messenger NAADP, but largely Na+-selective when activated by the signaling lipid PI(3,5)P2. Co-stimulation increases Ca2+ but not Na+ permeability; however, the molecular basis for these specificity switches is not well understood. Here we show that mutation of TPC2 residues within the distal cytosolic linker, which connects the first voltage-sensing-like domain to the pore, rendered TPC2 largely unable to discriminate its agonists and highly calcium-permeable, even in the presence of PI(3,5)P2. This mutation induced a co-activated-like state by disrupting a network of residues that connects the linker to the activation gate. Such deregulated agonist action increased lysosomal Ca2+ flux and compromised locomotion and viability when expressed in C. elegans. A proximal disease-linked mutation perturbed agonist action in a similar way both in vitro and in vivo. Biased signaling through TPC2 thus proceeds through molecular determinants that are remote from the selectivity filter, affecting Ca2+ permeability, endo-lysosomal integrity and disease.

DOI: https://doi.org/10.1038/s44318-026-00882-1