This article identifies the small GTPase RHOA as a critical controller of mitochondria-endoplasmic reticulum contact sites (MERCS). Through a genome-wide screen, scientists discovered that RHOA facilitates organelle communication by directly binding to the ER protein VAPB, which stabilizes its interaction with the mitochondrial protein PTPIP51. The study demonstrates that manipulating RHOA levels—either through its degradation via the CUL3 pathway or through pharmacological means—directly impacts essential functions like calcium transfer and metabolic remodeling. Furthermore, the authors reveal that disease-related mutations in these proteins disrupt this tethering mechanism, potentially contributing to cancer, hypertension, and neurodegenerative disorders like ALS. Ultimately, the findings establish RHOA as a molecular switch that tunes inter-organellar proximity, offering new insights into cellular health and potential therapeutic targets.

References:

• Yang Z, Nakajima S, Chen H, et al. RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether[J]. Nature Communications, 2025.

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The paper introduces PhenoProfiler, a sophisticated deep learning framework designed to revolutionize image-based drug discovery by analyzing how cells respond to chemical treatments. Unlike traditional methods that require complex preprocessing and image segmentation, this end-to-end system directly converts high-content microscopy images into compact, biologically meaningful representations. The model utilizes a unique multi-objective learning strategy—combining classification, regression, and contrastive learning—to ensure high accuracy and robustness against technical noise. Extensive testing on hundreds of thousands of images proves that PhenoProfiler significantly outperforms existing tools in identifying drug mechanisms and generalizing across different cell lines. Furthermore, its specialized phenotype correction strategy enhances the detection of subtle biological signals, making it a scalable solution for AI-driven pharmaceutical research. This innovation facilitates a more precise, interpretable understanding of cellular behavior to accelerate the identification of new therapeutic targets.

References:

• Li B, Zhang B, Zhang C, et al. PhenoProfiler: advancing phenotypic learning for image-based drug discovery[J]. Nature Communications, 2025.

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This research utilizes large-scale electron microscopy datasets to establish quantitative rules governing the morphology and spatial positioning of mitochondria within neural circuits. By analyzing thousands of neurons in both Drosophila and mice, researchers discovered that mitochondrial shapes are so cell-type specific they can act as "fingerprints" to identify specific neurons and neurotransmitter identities. The study demonstrates that these organelles are positioned with high precision relative to synapses and branch points, with their distribution correlating strongly to regional brain activity. In the fly's mushroom body, mitochondrial presence varies across functional compartments, suggesting that cells strategically allocate metabolic resources to support specific synaptic connections. Ultimately, these findings reveal that mitochondria are not merely generic powerhouses but are precisely organized components that link subcellular architecture to broader brain connectivity and function.

References:

• Sager G, Pfeiffer P, Wu H, et al. Spatial and morphological organization of mitochondria in neurons across a connectome[J]. Science, 2025: eads6674.

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This article focuses on mTORC2, a protein kinase complex critical for diverse cellular functions, including growth, metabolism, and proliferation, whose dysregulation is implicated in various diseases like cancer. The authors aimed to determine the structural basis for how mTORC2 selectively recognizes and phosphorylates its substrates, particularly Akt, a crucial signaling protein. Using a combination of cryo-electron microscopy (cryo-EM), chemical semisynthesis, and cross-linking mass spectrometry, the study details two key structural interfaces between Akt and the mTORC2 subunit mSin1, showing that the recognition relies on the Akt protein's three-dimensional structure, not merely its linear sequence. These findings clarify the molecular mechanism of mTORC2's high substrate specificity and provide a foundation for designing selective mTORC2 inhibitors to improve the clinical utility of current treatments.

References:

• Taylor M S, Chen M, Hancock M, et al. Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2[J]. Science, 2025: eadv7111.

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This paper presents a research article that investigates the conflicts between different levels of biological organization-specifically, how plasmids (extrachromosomal, self-replicating genetic elements) experience competition both within their host cell (within-cell) and between different host cells (between-cell). The authors use a novel experimental system involving synthetic plasmid dimers, which can be split to initiate balanced within-cell competition, and microfluidic devices (mother machines) to isolate and measure these intracellular dynamics. Key findings show that plasmid transcriptional activity imposes a within-cell fitness cost, favoring gene loss, while regulatory mechanisms like hemimethylation can prolong the coexistence of competing plasmids, and the translational strength of genes on the plasmid modulates the interplay between within- and between-cell selection, impacting how efficiently beneficial traits (like antibiotic resistance) fix in the bacterial population. These results highlight the complex, non-trivial evolutionary dynamics that govern the spread of plasmids, including those carrying antibiotic resistance genes.

References:

• Rossine F, Sanchez C, Eaton D, et al. Intracellular competition shapes plasmid population dynamics[J]. bioRxiv, 2025.

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The multi-institutional study investigates the presence and biological significance of microbial elements within primary and metastatic brain tumors (gliomas and brain metastases). Researchers utilized rigorous, orthogonal methods, including fluorescence in situ hybridization (FISH), immunohistochemistry, and spatial molecular imaging (SMI), on 243 tissue samples to validate the presence of intracellular bacterial 16S rRNA and lipopolysaccharides localized to tumor, immune, and stromal cells. Although standard culture methods failed to grow cultivable bacteria, sequencing workflows identified distinct bacterial taxa, some of which showed sequence overlap with oral and gut microbiota, suggesting a distant source. Furthermore, spatial analysis demonstrated that tumor regions with high bacterial signals were enriched for antimicrobial and immunometabolic signatures, suggesting a complex host-response interaction within the tumor microenvironment.

References:

• Morad G, Damania A V, Melendez B, et al. Microbial signals in primary and metastatic brain tumors[J]. Nature Medicine, 2025, 31(11): 3675-3688.

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This article investigates the neural mechanisms underlying specific food preferences, focusing on high-fat diets (HFD) and high-sugar diets (HSD). The research identifies two distinct populations of neurons in the paraventricular thalamus (PVT) that selectively mediate the intake of HFD or HSD, respectively. Crucially, the study identifies the histamine H3 receptor (H3R) as a defining molecular marker for the PVT neurons that regulate fat consumption, particularly in response to orosensory cues like food texture. Functional experiments demonstrate that the H3R-G12/13 signaling axis specifically regulates the excitability of PVT HFD neurons, suggesting a potential therapeutic target for the precise management of fat consumption and obesity.

References:

• Zheng Y, Liao J, Fang Z, et al. Biased histamine signaling selectively gates fat preference[J]. Neuron, 2025.

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This article presents research demonstrating that protective Apolipoprotein E (ApoE) variants, specifically ApoE2 and ApoE3 Christchurch, support neuronal health by actively effluxing oxidized phospholipids from neurons, a process mediated by the ABCA7 transporter. This mechanism reduces the toxic burden of oxidized lipids, thereby rescuing lysosomal function and protecting neurons from a form of programmed cell death called ferroptosis. Conversely, the Alzheimer's disease risk factor ApoE4 exacerbates the accumulation of these toxic lipids, leading to lysosomal dysfunction and impaired neuronal activity in hippocampal tissue, effects that can be restored by the protective ApoE particles. The study provides detailed lipidomic and functional evidence showing how the protective isoforms mitigate neurodegeneration-associated lipid toxicity.

References:

• Ralhan I, Do A D, Bae J Y, et al. Protective ApoE variants support neuronal function by effluxing oxidized phospholipids[J]. Neuron, 2025.

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The paper details an article and associated research focusing on the molecular and functional diversity of sympathetic postganglionic neurons within the celiac-superior mesenteric ganglia (CG-SMG) complex. Through single-cell transcriptomics and functional assays like chemogenetics and optogenetics, the study identifies two genetically distinct subpopulations of CG-SMG neurons: Calb2-positive neurons and Nxph4-positive neurons. The research establishes that these distinct genetic identities correlate with specific anatomical projections and physiological roles, with Calb2-positive neurons acting as sympathetic visceromotor units regulating gut motility, and Nxph4-positive neurons functioning as visceral vasoconstrictor units controlling organ blood flow. This work suggests the sympathetic nervous system employs a labeled line logic for precise control of visceral organ physiology, challenging older views of sympathetic action as monolithic.

References:

• Wei Y, Ma Z, Zhang B, et al. Sympathetic functional units encoded by genetically defined postganglionic neurons[J]. Neuron, 2025.

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The paper focuses on the dynamics of fluid transport and immunity within the central nervous system (CNS). Authored by a large, collaborative group of international experts, the article synthesizes recent advancements in understanding the glymphatic system, the brain's waste clearance mechanism, and the role of meningeal lymphatic vessels in connecting the brain to the peripheral immune system. Key areas of discussion include the anatomical pathways of cerebrospinal fluid (CSF) flow, the importance of physiological factors like sleep and vascular pulsation in driving clearance, and the complex neuroimmune interactions occurring at the brain borders. The review also addresses ongoing scientific debates, contrasts findings between rodent models and human studies, and highlights emerging noninvasive imaging strategies for assessing fluid dynamics in clinical settings.

References:

• Kipnis J, Benveniste H, Eichmann A, et al. Resolving the mysteries of brain clearance and immune surveillance[J]. Neuron, 2025.

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