bims-miptne 2026-08-09 papers

Exp Mol Med. 2026 Aug 05.

Asymmetric distribution of mitochondrial Ca2+ regulators specifies compartment-specific mitochondrial function and neuronal development.

Dong Cheol Jang, Su Yeon Kim, Won Seok Kim, In Young Choi, Eunsu Jang, Hyunsu Jung, Changuk Chung, Seokyoung Bang, Hong Nam Kim, Hae Woong Choi, Kihoon Han, Yongcheol Cho, Seok-Kyu Kwon.

Neuronal polarization is essential for functional compartmentalization, enabling dendritic synaptic integration and axonal action potential generation. Although structural differences in mitochondria across compartments have been identified, their functional distinctions remain unclear. Here, we uncovered compartment-specific mitochondrial Ca2+ dynamics and their molecular determinants. In axonal mitochondria, Ca2+ uptake through mitochondrial Ca2+ uniporter occurs independently of ER-stored Ca2+ release, with faster matrix Ca2+ clearance than dendritic mitochondria, where Ca2+ uptake predominantly originates from ER Ca2+. The ER-independent mitochondrial Ca2+ uptake in axonal mitochondria is associated with enriched mitochondrial Ca2+ uniporter-regulating proteins, MICU1 and MICU2, whereas higher NCLX expression facilitates rapid Ca2+ clearance. Moreover, NCLX knockdown, which functionally mimics a mental retardation-associated mutation, caused more significant developmental defects of axons than dendrites in vivo, aligning with its enrichment in axons. These findings highlight fundamental Ca2+-modulating features and developmental importance of neuronal mitochondria in a compartment-specific manner and reveal the key underlying molecular determinants.

DOI: https://doi.org/10.1038/s12276-026-01803-2

Biochim Biophys Acta Mol Cell Res. 2026 Aug 03. pii: S0167-4889(26)00101-1. [Epub ahead of print] 120202

The ubiquitin-activating enzyme inhibitor TAK-243 activates store-operated Ca2+ channels independently of endoplasmic reticulum Ca2+ stores and enhances mitochondrial Ca2+ buffering capacity in DU-145 human prostate cancer cells.

Marie Perrier, J Cory Benson, Marie-Odile Fauvarque, Mohamed Trebak, Alexandre Bouron.

TAK-243, an inhibitor of the ubiquitin-activating enzyme UBA1, impairs the ubiquitination of proteins. We investigated its effects on the intracellular Ca2+ dynamics of human prostate cancer cells DU-145. Live-cell Ca2+ imaging with Fura2 showed that DU-145 cells exhibited spontaneous Ca2+ transients that were largely independent of the activity of the Na+/Ca2+ exchanger but were abolished by extracellular Ca2+ removal, La3+, Gd3+, BTP2 (Orai channel blocker), and thapsigargin (which depletes endoplasmic reticulum -ER- Ca2+ stores). They were also sensitive to U73122 (a phospholipase C inhibitor) and dantrolene (a ryanodine receptor blocker), suggesting the contribution of both store-operated Ca2+ channels and intracellular Ca2+ release pathways in the generation and maintenance of these Ca2+ spikes. At 0.2 μM, TAK-243 augmented the cytosolic concentration of Ca2+ ([Ca2+]i), boosted the Ca2+ spiking activity, whereas at 10 μM it caused a constitutive Ca2+ entry through BTP2-sensitive Ca2+ channels, which further augmented [Ca2+]i but reduced the number of spontaneously active cells. Experiments conducted with the genetically encoded Ca2+ dye CEPIA1er showed that TAK-243 did not empty the ER Ca2+ stores. Moreover, Förster resonance energy transfer (FRET) experiments on HEK-293 cells transfected with Orai1-CFP and STIM1-YFP indicated that it caused the relocalization of STIM1 and its coupling with Orai1. TAK-243 also increased the membrane potential and the Ca2+ buffering capacities of mitochondria. Taken together, treating DU-145 cells with TAK-243 to prevent the ubiquitination of proteins activates the entry of Ca2+ through store-operated Ca2+ channels independently of the ER Ca2+ stores and alters mitochondrial functions.

Keywords: Calcium imaging; Calcium intracellular release; Calcium release-activated calcium channel protein 1 (ORAI1); Calcium transport; Prostate cancer; Ubiquitination

DOI: https://doi.org/10.1016/j.bbamcr.2026.120202

Nature. 2026 Aug 05.

ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.

Phenotypic plasticity is a hallmark of cancer1; however the molecular switches required for cell-fate reprogramming are poorly understood. During intestinal wound-healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth2-10. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC11-15, is a pivotal stress-responsive orchestrator of dynamic dedifferentiation. In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, ZFP36L2 binds to stress-associated mRNAs that contain AU-rich 3' untranslated regions, which induces the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response. Together, these data show that ZFP36L2 acts as an important molecular switch that couples stress sensing with phenotypic plasticity. This in turn drives cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2-deficient CRC, the inability to re-enter the LGR5+ state during metastatic outgrowth promotes non-canonical lineage plasticity, which is associated with poor clinical outcomes.

DOI: https://doi.org/10.1038/s41586-026-10890-0

Nat Nanotechnol. 2026 Aug 06.

Spectral biophysical cytometry with nanosensors reveals remodelling of immune cells in atherosclerosis.

Cenk O Gurdap, Dunya Aydos, Luca A Andronico, Gábor Tóth, Tugce Ceker, John Cowgill, Irem Muge Akbulut Koyuncu, Neslihan Basak, Jaromir Mikes, Andrey S Klymchenko, Federico Pietrocola, Petter Brodin, Ingela Lanekoff, Verda Ceylan Bitirim, Erdinc Sezgin.

The biophysical properties of cells determine cellular physiology. Leveraging these properties for biomedical applications demands the ability to measure multiple parameters simultaneously across millions of cells and diverse cell types. However, current technologies are limited by throughput and low dimensionality. Here we introduce spectral biophysical cytometry (SBC), a high-throughput platform that integrates environment-sensitive nanosensors with spectral flow cytometry to resolve multiparametric biophysical properties of immune cells at single-cell resolution. By using fluorescent nanosensors that report membrane order, mitochondrial potential and membrane potential, SBC enables simultaneous quantification of key cellular physical states across diverse immune cell populations. When applied to peripheral blood mononuclear cells, SBC reveals cell-type-specific biophysical heterogeneity and identifies distinct remodelling signatures associated with atherosclerosis. In particular, T-cell subsets exhibit substantial alterations in membrane order and mitochondrial depolarization, reflecting coordinated changes in lipid composition and metabolic pathways. Integration with lipidomics and transcriptomics demonstrates that the nanosensors can detect biophysical shifts that correlate with dysregulated lipid metabolism and mitochondrial function, providing mechanistic insight into immune dysfunction in disease. Importantly, SBC achieves rapid, label-efficient profiling using commercially available instrumentation, enabling scalable biomarker discovery directly from blood samples and establishing a powerful strategy for linking biophysical phenotypes to immune cell function.

DOI: https://doi.org/10.1038/s41565-026-02236-8

Proc Natl Acad Sci U S A. 2026 Aug 11. 123(32): e2535979123

AI-driven PROTAC design overcomes oncogenic resilience by eliminating the CLIP1-LTK fusion protein.

Shicheng Chen, Haiting Duan, Sheng Zhong, Jingxuan Ge, Huifeng Zhao, Yuanyi Ye, Huiyong Sun, Dan Li, Yu Kang, Xiaowu Dong, Jinxin Che, Tingjun Hou, Peichen Pan.

The discovery of CAP-Gly domain-containing linker protein 1(CLIP1)-Leukocyte tyrosine kinase (LTK) as an oncogenic fusion reveals a unique dependency not only on LTK kinase activity but also on CLIP1-mediated multimerization, a noncatalytic function that drives oncogenic signaling. While this fusion is currently targeted with anaplastic lymphoma kinase inhibitors, their exclusive focus on kinase inhibition leaves the scaffolding function intact, necessitating a complete protein clearance strategy. Here, we report the AI-guided development of a first-in-class proteolysis-targeting chimera (PROTAC) designed to selectively degrade the CLIP1-LTK fusion protein. By integrating deep learning models for ternary complex prediction with structure-based molecular optimization, we designed DCL05, an orally bioavailable degrader of CLIP1-LTK fusion protein, achieving picomolar degradation potency (DC50 = 40 pM) and robust antitumor activity. DCL05 consistently outperformed existing kinase inhibitors across a broad spectrum of LTK resistance-associated mutations, both in vitro and in vivo. Collectively, our study explores resistance-associated contexts of LTK and establishes a structure-guided PROTAC development pipeline, providing a promising therapeutic strategy for overcoming acquired resistance in kinase-driven cancers.

Keywords: AlphaFold3; CLIP1–LTK; PROTAC; drug resistance; oncology

DOI: https://doi.org/10.1073/pnas.2535979123

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