bims-cesemi 2026-09-27 papers

Issue of 2026–09–27
five papers selected by
Julio Cesar Cardenas, Universidad Mayor

Cell Calcium. 2026 Sep 22. pii: S0143-4160(26)00090-4. [Epub ahead of print]138 103197

TPC2-mediated lysosomal Ca2+ release puts the brakes on store-operated Ca2+ entry.

Qianru Mu, Sandip Patel, David Yule, Siddhi Shetty.

Lysosomal Ca2+ release can trigger endoplasmic reticulum (ER) Ca2+ mobilisation, which would be expected to activate store-operated Ca2+ entry (SOCE). Recent work by Lee et al. reveals that activation of the lysosomal two-pore channel TPC2 instead suppresses SOCE despite ER Ca2+ depletion. TPC2-derived Ca2+ signals recruit calmodulin to promote STIM1 inactivation, imparing STIM oligomerisation and coupling to Orai1. These findings identify a lysosomal feedback pathway that restrains Ca2+ influx and expand the role of TPC2 from an initiator of intracellular Ca2+ release to a brake on SOCE.

Keywords: Calcium signalling; Lysosome; STIM1; Store-operated Ca(2+) entry; TPC2

DOI: https://doi.org/10.1016/j.ceca.2026.103197

Cell Rep. 2026 Sep 24. pii: S2211-1247(26)01114-9. [Epub ahead of print]45(10): 118036

MCUB restricts mitochondrial calcium to support metabolic adaptation and homeostasis in glioblastoma.

The refractory nature of glioblastoma (GBM) is largely attributed to metabolic plasticity and stress adaptation. However, the role of precise mitochondrial calcium (mCa2+) flux gating in this context remains elusive. Here, we identify MCUB as a key gatekeeper upregulated in GBM, establishing a restricted mCa2+ threshold associated with malignancy. Mechanistically, MCUB limits mCa2+ uptake, attenuating pyruvate dehydrogenase activity and enforcing a glycolytic shift. MCUB deficiency triggers mCa2+ overload and reactive oxygen species bursts, sensitizing GBM cells to oxidative stress and radiotherapy. Moreover, hypoxia drives this adaptation via HIF-1α, which upregulates MCUB and reinforces its interaction with MCU to tune mCa2+ flux. Through high-throughput screening, we identify TF-PPAO as a compound interfering with the MCUB-MCU interaction. TF-PPAO exerts antitumor and radiosensitizing effects in xenografts, patient-derived xenografts (PDXs), and GBM organoids. Our findings reveal MCUB-mediated mCa2+ restriction as a mechanism of GBM metabolic adaptation and mitochondrial homeostasis, highlighting MCUB as a therapeutic target.

Keywords: CP: cancer; MCUB; glioblastoma; metabolic reprogramming; mitochondrial calcium; mitochondrial homeostasis; radiosensitization

DOI: https://doi.org/10.1016/j.celrep.2026.118036

Nat Commun. 2026 Aug 21. pii: 10042. [Epub ahead of print]17(1):

Metabolic licensing of quiescent glioblastoma activation and immune evasion via astrocyte-mitochondria shuttle.

Hongrui Zhu, Li Wang, Qi Wu, Yanwei Yu, Mengmeng Yang, Youqiong Ye, Wenchao Zhou, Jiabei Wang, Xuedan Sun, Sheng Wang, Qingsong Hu.

Reactivating quiescent tumor cells at the invasive margin are either eliminated by immune surveillance or expand through immune escape. The mechanisms underpinning phenotypic plasticity driving expansion leading to therapeutic resistance, dissemination, and recurrence remain elusive. Here we establish a metabolic licensing paradigm wherein reactive astrocytes awaken dormant glioblastoma cells and simultaneously confer immune evasion through intercellular mitochondrial transfer. Astrocyte-derived mitochondria, enriched with the one carbon metabolism enzyme SHMT2, deliver functional metabolic units that reprogram recipient glioma cells. This shuttled cargo fuels S adenosylmethionine production, driving m⁶A RNA methylation and release of paused RNA polymerase II over a specific set of genes. Ribosome biogenesis and focal adhesion pathways are selectively upregulated consequently, which enables rapid proliferation and immune resistance of tumour cells. Genetic ablation of astrocytic Shmt2 or pharmacological blockade of mitochondrial transfer suppresses quiescent cell reactivation and delays tumor progression. Our findings thus establish the astrocyte-mitochondria shuttle as a core vulnerability in glioblastomas, linking metabolic crosstalk to epitranscriptomic control of reactivation and immune escape.

DOI: https://doi.org/10.1038/s41467-026-76828-2

Cell Rep. 2026 Sep 23. pii: S2211-1247(26)01130-7. [Epub ahead of print]45(10): 118052

Dietary α-ketoglutarate modulates lung adenocarcinoma growth and epigenetic remodeling in a sex-dependent fashion.

Martín Alcaraz, Aparamita Pandey, Mia Santiago, Camelia Dumitras, Leilani Pradis, Estefany Gomez, Adriana Soto, Pasquale Saggese, Abigail S Krall, Bin Liu, Heather R Christofk, Steven M Dubinett, Xue Li, Claudio Scafoglio.

Lung adenocarcinoma (LUAD) is the most common form of lung cancer and a leading cause of cancer-related mortality, underscoring the need for new chemopreventive strategies. α-Ketoglutarate (αKG), a tricarboxylic acid cycle metabolite and dioxygenase cofactor, links cellular metabolism to chromatin regulation. Here, we demonstrate that dietary calcium αKG (Ca-αKG) is associated with remodeling of LUAD in a sex-dependent manner. In female mice, Ca-αKG is associated with reduced tumor area, decreased repressive histone marks (H3K27me3 and H3K9me3), and upregulated TBX5 and myogenesis-associated genes. In male mice, Ca-αKG is associated with increased tumor area and elevated H3K27me3. Analysis of human LUAD revealed that TBX5 expression is enriched in female tumors and associated with improved survival, suggesting it may serve as a marker of favorable outcome. Together, these findings support Ca-αKG as an epigenetic modulator with potential chemopreventive activity in lung cancer and highlight the importance of incorporating sex as a biological variable in preclinical studies.

Keywords: CP: cancer; Tbx5; chemoprevention; dietary supplement; differentiation; epigenetics; histone methylation; lung cancer; metabolism; sexual dimorphism; α-ketoglutarate

DOI: https://doi.org/10.1016/j.celrep.2026.118052

J Aging Res. 2026 ;2026 4970524

β-Nicotinamide Mononucleotide Inhibits Cellular Senescence in Mouse C2C12 Skeletal Muscle Cells.

Jing Mi, Chenxin Wang, Hongfei Gu, Mengxuan Wang, Weihua Zhang, Qiangqiang Zhou, Yuejiao Zhang, Jie Pan, Liming Yu.

β-Nicotinamide mononucleotide (NMN), as the precursor of nicotinamide adenine dinucleotide (NAD+), has remarkable therapeutic potential in aging-associated diseases. Skeletal muscle exhibits not only reduced mass but also impaired strength and function during aging. However, the protective effects of NMN against skeletal muscle cell senescence remain to be fully elucidated. In this study, we used D-galactose (D-gal) to establish a senescence model in C2C12 cells. Our results demonstrate that aging C2C12 cells displayed a significant impairment in differentiation capacity, an effect that was ameliorated by NMN treatment, as indicated by an increase in myotube formation and elevated myosin heavy chain (MHC) expression. NMN significantly decreased reactive oxygen species (ROS) levels in both aged C2C12 myoblasts and myotubes. NMN treatment downregulated the mRNA expression of aging-associated markers, including tumor protein p53 (Trp53), poly (ADP-ribose) polymerases (PARPs), and interleukin-1α (IL-1α) in aged C2C12 myotubes. Immunofluorescence staining revealed that the expressions of p53 and interleukin-1β (IL-1β) were significantly upregulated in aged C2C12 myotubes, while NMN treatment significantly attenuated this elevation. Collectively, the present study demonstrates that NMN treatment attenuates D-gal-induced ROS accumulation, enhances myotube formation, and downregulates several senescence-associated molecules. Therefore, our findings suggest that NMN represents a promising therapeutic agent for mitigating skeletal muscle cell aging.

Keywords: D-galactose; cellular senescence; nicotinamide adenine dinucleotide; β-nicotinamide mononucleotide

DOI: https://doi.org/10.1155/jare/4970524