bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–12–28
eleven papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A gut-to-brain pathway that limits protein intake.
  2. TMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.
  3. Tissue maps in motion.
  4. Cryo-EM structure of TMEM164 reveals distinct phospholipid remodeling mechanisms with anti-ferroptotic potential.
  5. Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
  6. A stationary phase-specific bacterial green light sensor for enhancing metabolite production.
  7. Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.
  8. SREBP1-mediated lipogenesis promotes dedifferentiation and senescence of vascular smooth muscle cells through epigenetic remodeling.
  9. IL-33 expands plasma cells, disrupts germinal centers, and increases autoantibody production in mice.
  10. Tracking cell ancestry and spatial gene expression with high resolution.
  11. 4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila.
  1. Cell. 2025 Dec 24. pii: S0092-8674(25)01363-7. [Epub ahead of print]188(26): 7333-7334
    A gut-to-brain pathway that limits protein intake.
    Marito Hayashi.
      In this issue of Cell, Jaschke and Luchsinger et al. uncover a gut-to-brain signaling mechanism that dynamically shapes protein intake. During recovery from extreme fasting, ammonia derived from the metabolism of specific dietary amino acids is detected by Trpa1-expressing intestinal epithelial cells, leading to the activation of a protein aversion pathway.
    DOI:  https://doi.org/10.1016/j.cell.2025.11.028
  2. Nat Commun. 2025 Dec 21.
    TMEM120A maintains adipose tissue lipid homeostasis through ER CoA channeling.
    Yoon Keun Cho, Junhyuck Lee, Yujin L Jeong, Minki Shim, Xuan Linh Mai, Chang Seomoon, Cheol Woon Jung, Yoon Ha Choi, Sik Namgoong, Young-Suk Jung, Sung Won Kwon, Juyong Lee, Je Kyung Seong, Sunghyouk Park, Emilio P Mottillo, James G Granneman, Dong-Kyu Lee, Jong Kyoung Kim, Yun-Hee Lee.
      Efficient fatty acid (FA) re-esterification is essential for lipid homeostasis in adipocytes, yet the mechanisms coordinating Coenzyme A (CoA) availability at the endoplasmic reticulum (ER)-a major site of lipid synthesis-remain unclear. Here, we identify TMEM120A as an ER-resident CoA-binding protein that regulates intracellular FA metabolism. TMEM120A interacts with the ER-localized acyl-CoA synthetase ACSL1 and ACSL3 to promote long-chain acyl-CoA synthesis and channeling into the ER, thereby facilitating FA re-esterification and lipid cycling during lipolysis. By relieving acyl-CoA-mediated feedback inhibition of lipolysis, TMEM120A enhances lipid turnover while protecting against ER stress and lipotoxicity. Adipocyte-specific deletion of Tmem120a in mice impairs lipolysis-induced energy expenditure and exacerbates inflammation and metabolic dysfunction under high-fat diet conditions. These findings establish TMEM120A as a critical regulator of ER CoA handling and lipid flux, revealing a previously unrecognized mechanism that links intracellular CoA dynamics to systemic energy balance and metabolic health.
    DOI:  https://doi.org/10.1038/s41467-025-67870-7
  3. Nat Methods. 2025 Dec 24.
    Tissue maps in motion.
    Miriam Osterfield.
      
    DOI:  https://doi.org/10.1038/s41592-025-02950-6
  4. Nat Commun. 2025 Dec 20.
    Cryo-EM structure of TMEM164 reveals distinct phospholipid remodeling mechanisms with anti-ferroptotic potential.
    Minjing Ke, Yuanyue Shan, Ziwei Zhai, Guoqiang Yao, Xinyi Guo, Xiaoxi Li, Zichao Wu, Huifeng Chen, Mengmeng Zhang, Meiyu Chen, Ying Li, Chengchen Zhao, Bo Wang, Micky D Tortorella, Xiaodong Shu, Mingfeng Zhang, Junqi Kuang, Duanqing Pei.
      Phospholipids in cell membrane provide both regulatory and structural function of a cell. How lipid remodeling regulates cell fate remains less explored. Here we report the cryo-electron microscopy structure of TMEM164 identified by genome-wide CRISPR screen as an anti-ferroptotic factor. The overall architecture reveals a dimer of two 7 transmembrane domain monomers and a metal ion catalytic center with phospholipid substrate in a distinct polyunsaturated fatty acyl (PUFA)-C123 intermediate state. Both loss and gain of its function result in the decline of PUFA-ePE and elevation of C16/18:1-ePE, consequently confer resistance to GPX4 inhibitor RSL3 induced ferroptosis. Mutagenesis studies further validate critical residues for the catalytic center (C123) and the chelates center (E106, Y177 and H181). Through virtual screen and rational design, we identify and test candidate inhibitors for TMEM164, including activity for Montelukast S-enantiomer with 4 order of magnitude higher affinity. Our works not only demonstrates TMEM164 as a membrane lipid remodeler that controls the ferroptotic fate, but also highlights the power of integrating multi-scale platforms to unravel distinct mechanisms and functions.
    DOI:  https://doi.org/10.1038/s41467-025-67651-2
  5. Cell Rep. 2025 Dec 18. pii: S2211-1247(25)01499-8. [Epub ahead of print]45(1): 116727
    Mitochondrial contact site and cristae organizing system promotes modular assembly of cytochrome c oxidase.
    Lilia Colina-Tenorio, Patrick Horten, Enzo Scifo, Susanne E Horvath, Rhena F U Klar, Chantal Priesnitz, Fabian den Brave, Martin van der Laan, Thomas Becker, Kuo Song, Heike Rampelt.
      Mitochondrial cytochrome c oxidase, complex IV (CIV) of the respiratory chain, is assembled in a modular fashion from mitochondrial as well as nuclear-encoded subunits, guided by numerous assembly factors. This intricate process is further complicated by the characteristic architecture of the inner mitochondrial membrane. The mitochondrial contact site and cristae organizing system (MICOS) maintains the stability of crista junctions that connect the cristae, the site of mitochondrial respiration, with the inner boundary membrane, where newly imported respiratory subunits first arrive. Here, we report that MICOS facilitates specific assembly steps of CIV and associates with intermediates of the Cox1 and Cox3 modules. Moreover, MICOS recruits a variety of assembly factors even in the absence of ongoing CIV biogenesis, directly or via the mitochondrial multifunctional assembly (MIMAS). Our results establish MICOS as an important agent in efficient respiratory chain assembly that promotes CIV biogenesis within the compartmentalized inner membrane architecture.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; MIMAS; Mic60; cristae; cytochrome c oxidase; mitochondria; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2025.116727
  6. Nat Commun. 2025 Dec 24.
    A stationary phase-specific bacterial green light sensor for enhancing metabolite production.
    John T Lazar, Daniel J Haller, Abbas Ghaddar, Jae J Kim, Kevin Yang, Sebastián M Castillo-Hair, Andrew R Gilmour, Ross Thyer, Jeffrey J Tabor.
      Genetically-encoded sensors are used to control protein and metabolite production in bacterial fermentations. However, these sensors are generally optimized for exponential growth rather than stationary phase where production occurs. Here, we find that our previously engineered E. coli green light sensor CcaSR, which functions robustly in exponential phase, fails in stationary phase due to spontaneous loss of an engineered chromophore biosynthetic pathway and accumulation of CcaS and CcaR. We optimize the genetic context and expression determinants of each component, resulting in a stable system named CcaSRstat that imposes little metabolic burden, exhibits low leakiness and an 80-fold green light response, and functions exclusively in stationary phase. We combine CcaSRstat-driven enzyme expression with varied static and periodic illumination patterns to achieve high titers of the industrially-relevant phenylpropanoid p-Coumaric acid and demonstrate that these optimizations scale to benchtop bioreactor conditions. Finally, we use CcaSRstat to optimize the expression level of a co-transcribed multi-enzyme metabolic pathway encoding production of plant-derived betaxanthin family pigments. Stationary phase-optimized bacterial sensors should enhance fermentation productivity by enabling rapid interrogation of the impact of enzyme expression level and induction dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-67829-8
  7. Nat Commun. 2025 Dec 23.
    Leveraging engineered mitochondria through intercellular communication network for accelerated transport and delivery.
    Yiwei Peng, Datong Gao, Yiliang Yang, Yitian Du, Zhenzhen Yang, Jiajia Li, Meng Lin, Yanxia Zhou, Xinru Li, Xianrong Qi.
      Inspired by the non-transmembrane transfer of mitochondria in cell-to-cell communications, herein, we report an original exploration to accelerate mitochondrial intercellular transport, and its application to exogenous cargo delivery. We discover that deliberate PINK1-targeted mitophagy downregulation elevates mitochondrial transit capacity via multifaceted drivers-morphological adaptation, metabolic reprogramming, and respiratory enhancement. Capitalizing on this, we engineer high-speed mitochondrial vehicles for photosensitizer hitchhiking, with spatiotemporal tracking elucidating its dynamic intercellular transit and physiological impacts. Through mitochondria's communication network-tunneling nanotubes (TNTs), the mitochondria-photosensitizer cotransporter achieves reinforced intercellular delivery, thereby inducing deep tumor penetration and enhanced photodynamic killing. Our work establishes a transformative mitochondria-hitchhiking platform for overcoming biological barriers in drug delivery and provides mechanistic insights into manipulating intercellular organelle transport for therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-025-67837-8
  8. Nat Commun. 2025 Dec 26.
    SREBP1-mediated lipogenesis promotes dedifferentiation and senescence of vascular smooth muscle cells through epigenetic remodeling.
    Bowen Li, Kaixiang Zhou, Anan Yin, Yonghong Liu, Xichen Wang, Yujia Cui, Fangfang Liu, Qiurong Liu, Hongjing Zheng, Zhiqiang Mu, Kun Chen, Yuanming Wu, Yaoming Chang, Junxiang Bao.
      Real or simulated microgravity induces a senescence-like modification of carotid artery in both human and animal observations, with the mechanisms not fully elucidated. Here, we aim to elucidate the role of sterol regulatory element-binding protein 1 (SREBP1, encoded by Srebf1) mediated lipogenesis in the process. Pharmacological activation of SREBP1 directly triggers senescence-like transformation in vascular smooth muscle cells (VSMC), while silencing Srebf1 exerts an opposite effect. Mechanistically, SREBP1-mediated lipogenesis upregulates acetyl-CoA pool to increase histone acetylation, modifying the chromatin accessibility which limiting recruitment of SRF/myocardin complexes to CArG boxes of contractile genes and opening the chromatin accessibility of aging genes. Srebf1 knockdown and local delivery of lentivirus or AAV-mediated VSMC specific expressing sh-Srebf1 significantly attenuates the senescence-like transformation of VSMC both in vitro and in vivo. Our findings reveal a previously unrecognized feature of SREBP1-mediated lipogenesis in vascular biology and SM-induced carotid artery remodeling.
    DOI:  https://doi.org/10.1038/s41467-025-67534-6
  9. Nat Commun. 2025 Dec 23.
    IL-33 expands plasma cells, disrupts germinal centers, and increases autoantibody production in mice.
    Eva Conde, Seblewongel Asrat, Andrea Vecchione, Kaitlyn Gayvert, Paulina Pedraza, Carley Tasker, Sharon Huang, Dmitry Yarilin, Dylan Birchard, Li-Hong Ben, Wei Keat Lim, Andrew J Murphy, Matthew A Sleeman, Andre Limnander, Jamie M Orengo.
      IL-33 is an inflammatory cytokine contributing to asthma, Chronic Obstructive Pulmonary Disease (COPD), and autoimmune diseases. Although recent studies suggest that IL-33 can induce the generation of autoantibodies, the role of IL-33 on B cell maturation and tolerance is poorly understood. Here, by inducing systemic overexpression of IL-33 in mice, we show that this cytokine induces the IL-5 and CD4 T cell-dependent accumulation of plasmablasts and plasma cells of all isotypes in the spleen, and leads to an increased antibody production. IL-33 also disrupts splenic architecture and elevates autoantibody production, indicating a break in peripheral tolerance. Consistently, elevated levels of IL-33 exacerbate autoantibody production, kidney damage, and decrease survival in a mouse model of lupus. Additionally, intranasal delivery of IL-33 in mice exposed to house dust mite extract (HDM) increases autoantibodies in the lung. Notably, blocking IL-33 reduced the autoantibodies generated during HDM exposure, indicating that HDM-induced autoantibody production is IL-33 dependent. Thus, our findings implicate IL-33 in the break of peripheral B cell tolerance, opening new therapeutic avenues for the treatment of infection, COPD and autoimmune conditions.
    DOI:  https://doi.org/10.1038/s41467-025-67867-2
  10. Nat Methods. 2025 Dec 22.
    Tracking cell ancestry and spatial gene expression with high resolution.
      
    DOI:  https://doi.org/10.1038/s41592-025-02964-0
  11. Nat Commun. 2025 Dec 23.
    4EHP and NELF-E regulate physiological ATF4 induction and proteostasis in disease models of Drosophila.
    Kristoffer Walsh, Hidetaka Katow, Hannah Junn, Deepika Vasudevan, Christoph Dieterich, Hyung Don Ryoo.
      Cells adapt to proteostatic and metabolic stresses, in part, through stress activated eIF2α kinases that stimulate the translation of ATF4. Stress-induced ATF4 translation is regulated through elements at ATF4 mRNA's 5' leader. In addition to eIF2α kinases, ATF4 induction requires other regulators that remain poorly understood. Here, we report an ATF4 regulatory network consisting of eIF4E-Homologous Protein (4EHP), NELF-E, the 40S ribosome, and eIF3 subunits. Specifically, we found that the mRNA cap-binding protein, 4EHP, was required for ATF4 signaling in the Drosophila larval fat body and in disease models associated with abnormal ATF4 signaling. NELF-E mRNA, encoding a regulator of pol II-mediated transcription, was identified as a top interactor of 4EHP in a TRIBE (Targets of RNA Binding through Editing) screen. Quantitative proteomics analysis revealed that the knockdown of NELF-E or 4EHP commonly reduced several subunits of the 40S ribosome (RpS) and the eIF3 translation initiation factor. Moreover, reduction of NELF-E, 4EHP, RpS12, eIF3l, or eIF3h suppressed the expression of ATF4 and its target genes. These results uncover a previously unrecognized ATF4 regulatory network consisting of 4EHP and NELF-E that impacts proteostasis during normal development and in disease models.
    DOI:  https://doi.org/10.1038/s41467-025-67357-5
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