bims-miptne 2026-10-18 papers

Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2627551123

Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.

Calcium ion (Ca2+) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi, the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome-mitochondrion contact sites (LMCs) that enable direct Ca2+ transfer. TcPiezo2 triggers Ca2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca2+ uniporter complex. Disruption of TcPiezo2-dependent Ca2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca2+ transfer and mitochondrial bioenergetics.

Keywords: Piezo channel; calcium; lysosomes; membrane contact sites; mitochondria

DOI: https://doi.org/10.1073/pnas.2627551123

Nat Commun. 2026 09 10. pii: 10690. [Epub ahead of print]17(1):

ATAD-3 couples plasma membrane injury to mitochondrial Ca2+ signaling.

Shiqi Xu, Yi Peng, Hengda Zhou, Xuecong Ren, Xin Wang, Zhenguang Ying, Meijiao Li, Yujie Sun, Bing Yang, Mao Zhang, Chonglin Yang, Weirui Ma, Suhong Xu.

Mitochondrial Ca2+ uptake couples cellular Ca2+ signals to mitochondrial metabolism and stress responses and is primarily mediated by the mitochondrial Ca2+ uniporter (MCU). Here, we identify an ATAD-3-dependent mechanism that promotes mitochondrial Ca2+ uptake following plasma membrane injury in C. elegans. Living imaging reveals robust, albeit delayed, mitochondrial Ca2+ influx following injury in mcu-1 mutants, indicating the existence of a compensatory Ca2+ uptake mechanism. RNAi screen identifies the conserved AAA+ ATPase ATAD-3 as an essential regulator of this pathway, whereas MICU-3 acts as a negative regulator. Wounding induces ATAD-3 oligomerization and mitochondrial enrichment, which are enhanced in mcu-1 mutants. Disrupting ATAD-3 oligomerization or expression of disease-associated ATAD-3 variants abolishes wounding-induced mitochondrial Ca2+ uptake. Structure modeling predicts that oligomeric ATAD-3 adopts a channel-like architecture. These findings uncover ATAD-3 as a context-dependent regulator of mitochondrial Ca2+ homeostasis during cellular stress and provide insight into how this process may be disrupted in disease.

DOI: https://doi.org/10.1038/s41467-026-77690-y

Sci Adv. 2026 Oct 16. 12(42): eaef3522

SPRIZ (CCDC127) protein conserved in deuterostome animals is a rigid OMM-IMM tether that locally sets mitochondrial IMS volume.

Raman Shulinski, Roman Loban, Danny Farhat, Benjamín Cartes-Saavedra, Matthew J Magda, Pavel Kotchetkov, Victoria Caminiti, Linda David, Yuri I Wolf, Conor O'Dwyer, Morgan Fullerton, Yan Burelle, Jyh-Yeuan Eric Lee, Andrea Raimondi, Eugene V Koonin, György Hajnóczky, Mary-Ellen Harper, Luca Pellegrini.

The double-membrane nature of mitochondria generates an intermembrane volume through which ions, reactive oxygen species, and metabolites must flux to reach the matrix or cytosol, but whether this volume is a genetically specified structure remains unknown. We identify SPRIZ (spatial regulator of the intermembrane zone), the product of Ccdc127, a gene conserved across deuterostome animals. SPRIZ assembles into an ∼18-nanometer homodimeric tether anchored in the outer mitochondrial membrane (OMM) and inserted into the inner mitochondrial membrane (IMM) through vertebrate-specific hydrophobic loops, physically spacing the two membranes and setting local intermembrane volume. Cryo-electron tomography of native mitochondria revealed rod-like densities spanning the intermembrane space (IMS), consistent with SPRIZ's predicted rigid coiled-coil architecture and membrane-spanning topology. In mouse liver, two-dimensional morphometry measured ∼3-fold expansion of IMS area with SPRIZ and ∼5.5-fold with lengthened mitochondrial artificial increaser of the IMS (MARTINI); 3D electron tomography confirmed MARTINI's greater OMM-IMM separation and normalized IMS volume. This expansion was functionally validated by increased 14C-mannitol accessibility to the IMS and by impaired mitochondrial Ca2+ uptake. Constitutive Ccdc127/SPRIZ knockout produced viable mice and, in liver mitochondria, preserved overall ultrastructure but caused modest IMS expansion, consistent with loss of local OMM-IMM constraints that stabilize membrane geometry at discrete sites. We therefore identify IMS volume as a genetically encoded and tunable architectural parameter of vertebrate mitochondria. In this model, SPRIZ is a molecular spacing system that locally sets OMM-IMM separation, shaping the environment through which metabolites, ions, and signals diffuse and establishing local gradients within the IMS.

DOI: https://doi.org/10.1126/sciadv.aef3522

Nat Methods. 2026 Oct 14.

MassNet: billion-scale AI-ready mass spectral corpus empowering scalable deep learning in proteomics.

Jun A, Xiang Zhang, Xiaofan Zhang, Jiaqi Wei, Te Zhang, Yamin Deng, Pu Liu, Zongxiang Nie, Yiwen Yu, Yi Chen, Nanqing Dong, Zhiqiang Gao, Siqi Sun, Tiannan Guo.

Here we present MassNet, inspired by large-scale data corpora of text and images; MassNet is an artificial intelligence (AI)-ready data corpus for mass spectrometry (MS)-based proteomics. The corpus contains 1.5 billion tandem MS spectra from high-quality data-dependent acquisition (DDA) MS data across 35 species. Approximately 1.7 million peptide precursors are from human samples. We further present an AI-ready DDA data format called Mass Spectrometry DDA Tensor (MSDT) for compact and standardized storage, curation and reuse of data from multiple sources, which can be optionally converted to a Lightning Memory-Mapped Database for accelerated input/output in deep learning. On the basis of MassNet, we develop XuanjiNovo, a nonautoregressive transformer model that leverages a curriculum learning strategy for de novo peptide sequencing. XuanjiNovo achieves 38.35-143.57% improvement over state-of-the-art methods on human Astral data. MassNet also supports additional downstream tasks, including retention time prediction and PSM rescoring. MassNet represents a foundational MS-based proteomics data resource, marking a critical milestone for AI proteomics research.

DOI: https://doi.org/10.1038/s41592-026-03247-y

Nat Biomed Eng. 2026 Oct 13.

Interpretable AI model reveals spatial codes of cell recruitment in tissues.

Understanding which molecular signals recruit specific cells to precise tissue locations is fundamental to tissue biology, immunity and disease. Existing computational tools for spatially resolved transcriptomics (SRT) describe where cells reside but cannot explain why. Here we introduce SPACER, a fully interpretable multi-instance learning framework that decodes gene-level recruitment rules directly from SRT data. Applied to 37 SRT datasets spanning multiple human tumour types and mouse heart, SPACER achieved 4-21-fold improvement over existing methods in various tasks of recovering biologically meaningful recruitment signals. SPACER revealed (1) that tumour-expressed mucins are associated with physical barriers to T cell engagement, which predicts resistance to immune checkpoint inhibitors and patient prognosis, (2) that local antigen presentation is the dominant correlate of T cell engagement across cancer types and (3) that Cd4+ T cells are the dominant functional effectors in severe immune checkpoint inhibitor-induced myocarditis. These findings establish SPACER as a discovery engine for cellular recruitment biology with direct translational applications.

DOI: https://doi.org/10.1038/s41551-026-01804-6

EMBO Mol Med. 2026 Oct 14.

RMND1 dysfunction causes OXPHOS deficiency and alters mitoribosomal protein homeostasis in vivo.

Alba Pesini, Maria J Sanchez-Quintero, Carlos Lopez-Gomez, Eliana Barriocanal-Casado, Agustin Hidalgo-Gutierrez, Eva Nyvltova, Joanna Rorbach, Giulio Kleiner, May T Ting, Christian Garcia, Lucia Dec-Prat, Kurenai Tanji, Christopher B Damoci, Robert McFarland, Robert W Taylor, Michal Minczuk, Antoni Barrientos, Catarina M Quinzii.

Pathogenic, bi-allelic variants in RMND1 typically manifest as an early-onset multisystemic mitochondrial disease, yet the consequences of RMND1 dysfunction in vivo remain poorly understood. To answer this question, we generated and characterized the first in vivo model of RMND1-related disease, carrying the recurrent p.(Asn238Ser) variant. Homozygous Rmnd1N238S mice exhibit growth defect, premature mortality, and a multisystem phenotype marked by widespread tissue-dependent defects in oxidative phosphorylation assembly and activity. Quantitative proteomic analysis of Rmnd1N238S heart revealed extensive metabolic remodeling, with significant alterations in the abundance of mitoribosomal proteins and factors associated with mitoribosome maturation. Selected changes in mitoribosomal protein abundance were also observed in Rmnd1N238S liver, and RMND1 mutant and depleted human cells. Despite these changes, sucrose-gradient sedimentation did not reveal a gross alteration in mtSSU, mtLSU, or 55S distribution, suggesting that RMND1 dysfunction perturbs mitoribosomal protein homeostasis that could affect late-assembly stages of the mitochondrial ribosome large subunit. Together, our findings establish Rmnd1N238S mice as a robust in vivo model of RMND1-related disease and provide a framework for understanding how RMND1 supports mitochondrial gene expression.

DOI: https://doi.org/10.1038/s44321-026-00534-1