bims-celmim 2026-09-20 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–09–20
seventeen papers selected by
Marc Segarra Mondejar, AINA

Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.
Cysteine excess triggers a mitochondrial iron-dependent cell death.
Metabolic regulation of tumor angiogenesis in colorectal cancer: mechanisms and therapeutic opportunities.
Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.
Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.
Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming in non-small cell lung cancer cells.
Tubular ACSM3 controls fatty acid metabolism and safeguards against acute kidney injury in male mice.
Metabolic reprogramming-mediated therapeutic resistance in renal cell carcinoma: Mechanisms and targeted intervention strategies.
DFCP1-containing ER microdomains mediate lysosomal membrane repair.
Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.
Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.
Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues.
Ferroptosis as a target mechanism in heart and kidney disease.
ATP synthase subunits e and g are essential for Ca2+ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.

Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):

Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.

Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.

Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.

DOI: https://doi.org/10.1038/s41467-026-77423-1
Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):

Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.

Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-76619-9
Elife. 2026 Sep 18. pii: RP104055. [Epub ahead of print]13

Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.

Grzegorz Walkiewicz, Siyu Chen, Chienhui Lo, Jingyu Zhao, Zhiquan Liu, Biao Wang, Qing Wang, Tia J Kowal, Benjamin Lawson, Yang Sun.

  Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an Ocrl knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, our findings support a model in which OCRL deficiency is associated with mitochondrial dysfunction, increased oxidative stress, altered neural lineage balance, and reduced Hedgehog pathway activity, providing a framework for understanding these interconnected phenotypes.

Keywords:  Lowe syndrome; ROS; cell biology; cilia formation; human; mitochondria; mouse; neuronal differentiation; oxidative stress; zebrafish

DOI:  https://doi.org/10.7554/eLife.104055
Nat Metab. 2026 Sep 15.

Cysteine excess triggers a mitochondrial iron-dependent cell death.

Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.

Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.

DOI: https://doi.org/10.1038/s42255-026-01616-7
Biochim Biophys Acta Rev Cancer. 2026 Sep 12. pii: S0304-419X(26)00185-X. [Epub ahead of print]1881(6): 189713

Metabolic regulation of tumor angiogenesis in colorectal cancer: mechanisms and therapeutic opportunities.

Donghao Tang, Qijie Li, Costanza Tacchi, Marta Banchi, Guido Bocci.

  Colorectal cancer (CRC) progression is closely linked to abnormal vascular remodeling. Tumor vessels are structurally disorganized and poorly perfused, creating spatially heterogeneous regions of hypoxia and nutrient deprivation. These conditions reshape tumor metabolism by increasing glycolysis, glutamine utilization, and lipid metabolic plasticity. Metabolic changes, in turn, alter endothelial function and the surrounding tumor microenvironment through lactate accumulation, lipid-derived mediators, amino acid metabolism, and extracellular vesicle-mediated signaling. This reciprocal interaction contributes to vascular instability, impaired drug delivery, immune suppression, and treatment resistance. The VEGF pathway remains the principal therapeutic target in CRC angiogenesis. However, the benefits of anti-VEGF agents are often temporary because tumors activate alternative vascular programs and adapt metabolically to reduced blood supply. Hypoxia-induced HIF signaling is central to this response, but resistance also involves enhanced glycolysis, redox adaptation, lipid remodeling, amino acid metabolism, and communication among tumor, endothelial, stromal, and immune cells.In this review, we examine how metabolic reprogramming regulates angiogenesis in CRC and how vascular dysfunction, in turn, shapes tumor metabolism. We focus on endothelial metabolism, the glycolysis-lactate axis, amino acid and lipid metabolism, vitamin- and cofactor-dependent pathways, and exosomal non-coding RNAs. We also discuss how these mechanisms contribute to resistance to anti-angiogenic therapy and assess the rationale for combining vascular and metabolic interventions. A better understanding of this metabolic-vascular interaction may help identify more durable therapeutic strategies for CRC.

Keywords:  Anti-angiogenic therapy; Colorectal cancer; HIF-1α; Metabolic reprogramming; Tumor angiogenesis; VEGF

DOI:  https://doi.org/10.1016/j.bbcan.2026.189713
Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2616684123

Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.

Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.

  Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.

Keywords:  SREBP; de novo lipogenesis; lysosomal enzyme transport; protein myristoylation; proximity labeling

DOI:  https://doi.org/10.1073/pnas.2616684123
PLoS Biol. 2026 Sep 18. 24(9): e3003555

Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation.

Mona Nazemi, Bian Yanes, Eric Vancauwenberghe, Ifeoluwa Oyelade, Heather Walker, Elena Rainero.

Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the (LAT1)-4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1-4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.

DOI: https://doi.org/10.1371/journal.pbio.3003555
iScience. 2026 Sep 18. 29(9): 117336

Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming in non-small cell lung cancer cells.

Yimin Chen, Yuxi Liu, Zhenyun Zhu, Anqi Ding, Yuying Suo, Cheng Wang, Xiongjun Wang, Hu Zhou, Qiyu Fang, Qian Liu.

  Methionine adenosyltransferase 2A (MAT2A) links metabolic reprogramming to epigenetic regulation via S-adenosylmethionine (SAM) production, but its role in non-small cell lung cancer (NSCLC) remains unclear, and current inhibitors require combination strategies. Using proteomics and metabolomics in NSCLC cells treated with MAT2A-targeting siRNA or the inhibitor AG-270, we characterized MAT2A-driven metabolic rewiring. In fatty acid biosynthesis, MAT2A regulates FASN and SCD; exogenous palmitic acid reverses AG-270-induced growth inhibition, supporting combination with the FASN inhibitor TVB-2640. In cholesterol metabolism, MAT2A modulates biosynthesis and efflux, and an LXR agonist promoting cholesterol efflux enhances AG-270 efficacy. In energy metabolism, MAT2A governs glycolysis via HIF1A, and a GLUT1 inhibitor synergizes with AG-270. In the transsulfuration pathway, MAT2A transcriptionally regulates CBS and shows synergy with inhibitors of PHGDH (producing serine for cysteine biosynthesis) and SLC7A11 (mediating cysteine uptake). Collectively, our findings establish MAT2A as a central metabolic regulator in NSCLC and propose rational combination strategies.

Keywords:  MAT2A; metabolic reprogramming; metabolomics; non-small cell lung cancer; proteomics

DOI:  https://doi.org/10.1016/j.isci.2026.117336
Nat Commun. 2026 Aug 14. pii: 9782. [Epub ahead of print]17(1):

Tubular ACSM3 controls fatty acid metabolism and safeguards against acute kidney injury in male mice.

Fengping Zhang, Li Feng, Ting Xiang, Jinxi Li, Qimei Wu, Fan Guo, Lingzhi Li, Zhouke Tan, Ping Zhou, Lin Lin, Liang Ma, Ping Fu.

Kidney tubular epithelial cells exceptionally exhibit high energy demands and preferentially metabolize long-chain fatty acids via fatty acid oxidation (FAO), where the impairment of FAO represents a hallmark of acute kidney injury (AKI). However, the role of medium-chain fatty acid metabolism in kidney injury remains unexplored. Here, we identify that tubular acyl-CoA synthetase medium-chain family member 3 (ACSM3), the key enzyme responsible for medium-chain fatty acid activation, is significantly down-regulated in damaged kidneys of distinct AKI male mouse models and acute tubular necrosis patients. Unexpectedly, tubule-specific ACSM3 deletion improves renal dysfunction, pathological damage, and metabolic disturbances in AKI male mice. Mechanistically, tubular ACSM3 deficiency preserves free fatty acid pool and reduces medium-chain fatty acids utilization, where these unused medium-chain fatty acids as ligands can activate peroxisome proliferator-activated receptor alpha (PPARα) and further upregulate PPARα-associated fatty acid metabolic genes to repair injured kidneys. Notably, dietary supplementation of medium-chain fatty acids confers protective effects against AKI in male mice. Our findings highlight tubular ACSM3 as a potential therapeutic target to control renal fatty acid metabolism and provide preclinical evidence that medium-chain fatty acid supplementation safeguards against AKI.

DOI: https://doi.org/10.1038/s41467-026-76637-7
iScience. 2026 Sep 18. 29(9): 117279

Metabolic reprogramming-mediated therapeutic resistance in renal cell carcinoma: Mechanisms and targeted intervention strategies.

Han Wu, Xinxin Gan, Siyi Wang, Ruoyao Wang, Jiatao Hu, Linhui Wang, Jiazi Shi.

  Renal cell carcinoma (RCC) is one of the most frequent urological tumors and exhibits metabolic reprogramming alongside genetic mutations. RCC cells reprogram pathways involved in glucose, lipid, and amino acid metabolism to meet their energy and anabolic demands. In recent years, targeted drugs, immunotherapy, and radiotherapy have significantly improved the prognosis of patients with metastatic RCC. Nevertheless, the development of resistance remains a major cause of treatment failure and disease progression in metastatic RCC. A deeper understanding of the metabolic mechanisms underlying therapy resistance is critical for refining therapeutic strategies. The molecular mechanism of metabolic reprogramming involved in therapy resistance is comprehensively discussed. Novel strategies for overcoming therapy resistance of RCC are proposed, including the development of new drugs targeting metabolism, nanoparticles co-loaded with anti-tumor drugs, the application of combination therapies, and personalized medicine approaches. In conclusion, this review provides a thorough overview of metabolic alterations in RCC and their role in therapy resistance, highlighting the potential for developing new treatments for RCC.

Keywords:  drug resistance; metabolic reprogramming; minimally invasive surgery; renal cell carcinoma; therapy

DOI:  https://doi.org/10.1016/j.isci.2026.117279
Nat Cell Biol. 2026 Sep 15.

DFCP1-containing ER microdomains mediate lysosomal membrane repair.

Maja Radulovic, Sascha Pust, Athanasios Kournoutis, Di Chen, M Isabel Giner, Qijian Liang, Santosh Phuyal, Thomas J Böddeker, Katy McCarron, Eric Herrmann, Kevin Rose, Sebastian W Schultz, Andreas Brech, James H Hurley, Claudio Bussi, Luis Bonet-Ponce, Maximiliano G Gutierrez, Camilla Raiborg, Harald Stenmark.

Lysosomal membrane integrity is essential for preserving cellular homeostasis in response to different stressors. Upon lysosomal membrane permeabilization, cells activate several mechanisms for lysosomal membrane repair, including ESCRT proteins, phosphatidylinositol 4-phosphate (PI4P)-dependent lipid transfer from the endoplasmic reticulum (ER) and conjugation of ATG8 family proteins to single membranes (CASM). The interplay between these pathways and the regulation of the lipid transfer machinery remain incompletely understood. Here we show that phosphatidylinositol 3-phosphate (PI3P)-containing ER domains play a major role in lysosomal membrane repair. PI3P is formed on lysosome-proximal ER domains by the phosphatidylinositol 3-kinase PIK3C3/VPS34 in response to membrane damage, and inhibition or depletion of PIK3C3 inhibits lysosome repair. Mechanistically, the ATPase DFCP1/ZFYVE1 accumulates on lysosome-proximal ER domains by its PI3P binding, triggered by Ca2+ efflux from lysosomes and requiring the ULK1 kinase complex and ER proteins of the VAP family. Downstream of CASM, PI4P, ESCRTs and PI3P, DFCP1 promotes focal accumulation of the lipid channel VPS13C on ER domains proximal to damaged lysosomes to promote their repair. The function and dynamics of DFCP1 depend on its ability to bind and hydrolyse ATP, and absence of DFCP1 compromises cellular resistance to vacuolar damage induced by Listeria monocytogenes. We conclude that DFCP1 mediates concentration of the ER-associated lipid transport machinery at damaged lysosomes to promote their sealing in response to Ca2+ flux and PIK3C3 activation.

DOI: https://doi.org/10.1038/s41556-026-02062-z
Nat Commun. 2026 Aug 15. pii: 9805. [Epub ahead of print]17(1):

Macrophage trained immunity requires a mitochondrial glutamine-restriction checkpoint for antitumor protection in mice.

Ya Chun Yu, Yulseung Sung, Seonghun Lim, Jeong Ah Kwon, Min Ju Lee, Hyeong Yun Kim, Sunghoon Kim, Kuglae Kim, Do Sik Min, Hee Chan Yoo, Jung Min Han.

Trained immunity enables innate immune cells to acquire memory-like responses, offering a strategy to enhance antitumor immunity. However, the metabolic‒epigenetic mechanisms underlying this process remain poorly defined. Here, we show that lipopolysaccharide-induced macrophage training is encoded by a mitochondrial metabolic checkpoint. Integrated transcriptomic, metabolomic, and epigenomic profiling reveals that TLR4-NF-κB signaling represses SLC1A5_var, a mitochondrial glutamine transporter, limiting glutaminolysis and reducing α-ketoglutarate availability. This metabolic restriction limits removal of the activating histone mark histone H3 lysine 4 trimethylation by KDM5B, thereby maintaining inflammatory gene accessibility. Functionally, pharmacological inhibition or myeloid-specific knockdown of SLC1A5_var potentiates macrophage training and improves tumor control in murine cancer models, whereas enforced SLC1A5_var expression or α-ketoglutarate supplementation abrogates these effects. These findings define an SLC1A5_var-α-ketoglutarate-KDM5B metabolic-epigenetic axis that programs macrophage trained immunity and illustrate how targeted metabolic restriction can be leveraged to enhance innate immune responses against cancer.

DOI: https://doi.org/10.1038/s41467-026-76757-0
Cell. 2026 Sep 15. pii: S0092-8674(26)01010-X. [Epub ahead of print]

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer.

  The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an alternative function. GAA accumulates in GAA N-methyltransferase (GAMT) deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

Keywords:  GABA; GAMT deficiency; cancer metabolism; cancer neuroscience; creatine; glioma; guanidinoacetate; inborn error of metabolism; metabolite signaling

DOI:  https://doi.org/10.1016/j.cell.2026.08.037
Sci Immunol. 2026 Sep 18. 11(123): eaea4179

In vivo CRISPR screens identify the glutamine transporter SLC1A5 as a metabolic barrier to antitumor immunity.

Wenlong Jia, Guanxing Yu, Shenqi Han, Zhibo Ma, Junnan Liang, Wei Yan, Xinling Zhang, Chenglong Zeng, Lin Xue, Feng Xia, Ganxun Li, Ran Tao, Peixiang Lan, Wei Yan, Wanguang Zhang, Huifang Liang, Xiaoping Chen, Zhao Huang, Bixiang Zhang.

Tumor cells often evade immune pressure via metabolic reprogramming, yet the key metabolic regulators orchestrating this process remain incompletely defined. Here, using in vivo metabolic CRISPR screening under distinct immune pressures, we identified tumor cell-intrinsic solute carrier family 1 member 5 (SLC1A5) as a metabolic node that sustains an immunosuppressive tumor microenvironment. SLC1A5-mediated glutamine metabolism in tumor cells modulated CD8 T cell infiltration and effector function, reshaping tumor responses to immune checkpoint blockade therapy. Glucose deprivation up-regulated SLC1A5 isoforms in tumor cells, enhancing glutamine uptake and glutathione synthesis. This adaptation limited mitochondrial oxidative stress and cytosolic mitochondrial DNA release, thereby suppressing cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation, interferon-β production, and CD8 T cell antitumor responses. These findings define a glutamine-fueled metabolic program as a barrier to tumor immunogenicity, positioning SLC1A5 as a tumor-intrinsic metabolic regulator with potential therapeutic relevance.

DOI: https://doi.org/10.1126/sciimmunol.aea4179
Science. 2026 Sep 17. 393(6817): eady6372

Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues.

Raghabendra Adhikari, Alexander Hillsley, Alana Dowdell Johnson, Shihong Max Gao, Isabel Espinosa-Medina, Jan Funke, Daniel Feliciano.

Cell-state diversity drives tissue adaptability, repair, and disease resilience, but capturing this complexity is a challenge. Current approaches rely on transcriptional profiling and overlook organelle structure, a key indicator of metabolism and stress. We developed spatial Organellomics (sOrganellomics), an imaging workflow that integrates automated segmentation with machine learning to classify and spatially map cell states from multi-organelle signatures. In liver and pancreas, these signatures distinguished broad cellular classes. In liver, sOrganellomics revealed that zonal position did not fully explain organelle-defined hepatocyte categories. Instead, hepatocytes formed intermixed communities within canonical zones, supporting a refined subzonal diversity model. Nutritional stress reshaped this organization. Intravital imaging linked fasting-induced organelle remodeling with altered mitochondrial membrane potential in vivo, supporting multi-organelle architecture as a structural readout of tissue adaptation.

DOI: https://doi.org/10.1126/science.ady6372
J Clin Invest. 2026 Sep 15. pii: e202823. [Epub ahead of print]136(18):

Ferroptosis as a target mechanism in heart and kidney disease.

Simar J Singh, Baljash Cheema, Hossein Ardehali.

Ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation and redox imbalance. Since its formal recognition in 2012, ferroptosis has emerged as a central pathway linking metabolic stress and oxidative injury to both physiologic and pathologic processes. Its functions extend from tissue sculpting during embryogenesis and tumor suppression to pathologic contributions in neurodegeneration, cardiovascular disease, liver and kidney injury, cancer, and inflammatory disorders. Despite these advances in our understanding of ferroptosis, critical questions remain regarding its precise regulation, context-specific consequences, and interactions with other cell death pathways. Continued progress in identifying biomarkers, defining context-specific roles, and developing selective modulators will be essential to translate ferroptosis biology into clinical therapies with broad impact. Here, we describe the current state of our understanding of the role of ferroptosis in physiology and its potential as a target mechanism in heart and kidney disease.

DOI: https://doi.org/10.1172/JCI202823
Cell Death Differ. 2026 Sep 15.

ATP synthase subunits e and g are essential for Ca2+ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.

Elena Frigo, Manuela Santalla, Michele Brischigliaro, Federica Boscolo Nata, Ludovica Tommasin, Michela Rossini, Denis Komarov, Stefania Ferro, Diana Pendin, Oriano Marin, Rodolfo Costa, Michela Carraro, Paolo Bernardi.

Beyond its roles in ATP production and shaping cristae architecture, mitochondrial ATP synthase has been implicated in generating the permeability transition pore (PTP), a Ca2+-activated, high-conductance channel that leads to matrix swelling and cell death in mammalian cells. In Drosophila melanogaster, the PTP homolog rather forms a selective Ca2+-induced Ca2+-release (CICR) channel whose physiological relevance at the organism level remains poorly understood. Here, we down-regulated Drosophila subunits e and g, which are essential for PTP formation in yeast and mammalian cells. Ubiquitous down-regulation of either subunit caused larval developmental arrest, whereas tissue-specific suppression in muscle or neurons led to severe locomotor impairment. Dimerization was markedly reduced, altering mitochondrial ultrastructure while leaving respiratory capacity largely preserved. Strikingly, mitochondria from both knockdown animals accumulated larger Ca2+ loads, consistent with an impaired CICR. This was accompanied by near-complete loss of ecdysone, the Ca2+-dependent master hormone of metamorphosis. Neuron-specific knockdown flies displayed defective mitochondrial Ca2+ efflux and altered synaptic organization at the neuromuscular junction. Altogether, our findings establish that ATP synthase functions as a CICR channel controlling Ca2+ homeostasis, endocrine signaling and development in Drosophila.

DOI: https://doi.org/10.1038/s41418-026-01869-5