bims-camemi 2025-12-07 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–12–07
forty-two papers selected by
Christian Frezza, Universität zu Köln

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.
Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
Decay of driver mutations shapes the landscape of intestinal transformation.
Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.
A guide to transcriptomic deconvolution in cancer.
Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation.
Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.
Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.
Fat sensory cues in early life program central response to food and obesity.
Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.
Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.
Digital twins for in vivo metabolic flux estimations in patients with brain cancer.
Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.
Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.
Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.
A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.
Renal PIEZO2 is an essential regulator of renin.
Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.
Membrane potential mediates the cellular response to mechanical pressure.
Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival.
A foundation for tomorrow's discoveries in cell biology.
The evolutionary role of mutational robustness: theoretical insights.
Renal and hepatic function is preserved following inducible knockout of kynurenine pathway enzymes KMO or QPRT in adult mice.
Drink Responsibly: Cancer Cells also Like Sugary Drinks.
Multiscale structure of chromatin condensates explains phase separation and material properties.
S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models.
Neural hijacking in cancer metabolism: from nutrients to organelles.
Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen.
Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.
Mapping heterogeneity in the tumor microenvironment of renal cell carcinoma through single-cell omics.
Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.
Toward the next 20 years of Cell Metabolism.
Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.
Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.
The return of metabolism: biochemistry and physiology of glycolysis.
Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.
Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.
Advancing small cell lung cancer metastasis research: innovations in preclinical mouse models.
MAVS oligomerization drives a faster and more efficient antiviral signaling activation at peroxisomes compared to mitochondria.
Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.
Standardized metrics for assessment and reproducibility of imaging-based spatial transcriptomics datasets.

Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1
Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00489-9. [Epub ahead of print]37(12): 2298-2300

Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.

Sébastien Ibanez, Olivier Feron.

Cancer cells experience multiple stresses within tumors, stemming from elevated metabolic activity, including nutrient shortage, waste buildup, hypoxia, and acidosis. According to Groessl et al.,1 acidosis is the dominant environmental factor offering metabolic flexibility to support tumor fitness and resilience to the other stresses by promoting mitochondria fusion and enhancing respiration capacity.

DOI: https://doi.org/10.1016/j.cmet.2025.11.005
Nature. 2025 Dec 03.

Decay of driver mutations shapes the landscape of intestinal transformation.

Filipe C Lourenço, Iannish D Sadien, Kim Wong, Sam Adler, Ashley Sawle, Leonor Schubert Santana, Lee Hazelwood, Giada Giavara, Anna M Nicholson, Matthew D Eldridge, Noori Maka, Gerard Lynch, Stephen T McSorley, Joanne Edwards, Richard Kemp, David J Adams, Douglas J Winton.

Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins1-4. Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.

DOI: https://doi.org/10.1038/s41586-025-09762-w
bioRxiv. 2025 Nov 17. pii: 2025.11.17.688927. [Epub ahead of print]

Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.

Kelley R McCutcheon, Josh Wu, Yasemin Ceyhan Ozdemir, Brock J McKinney, Sharan Srinivasan, Ayaha Itokawa, Oliver J Newsom, Anna Vigil, Douglas B Fox, Lucas B Sullivan, James V Alvarez.

Breast cancer recurrence remains a major clinical challenge, often associated with therapy resistance and altered metabolic states. To define metabolic vulnerabilities of recurrent disease, we performed a CRISPR knockout screen targeting 421 metabolic genes in paired primary and recurrent HER2-driven breast cancer cell lines. While both primary and recurrent tumors shared dependencies on core metabolic pathways, recurrent tumors exhibited selective essentiality for the de novo pyrimidine synthesis pathway, including Cad , Dhodh , and Ctps . Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant. BAY treatment robustly inhibited pyrimidine synthesis in all lines, but only recurrent cells underwent iron-dependent lipid peroxidation and ferroptotic cell death. Lipidomic profiling revealed enrichment of polyunsaturated ether phospholipids in recurrent cells, which may predispose them to ferroptosis. A sensitizer CRISPR screen in primary cells further identified nucleotide salvage and lipid metabolic pathways as modifiers of DHODH inhibitor sensitivity. Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28 / Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.

DOI: https://doi.org/10.1101/2025.11.17.688927
Nat Rev Cancer. 2025 Dec 02.

A guide to transcriptomic deconvolution in cancer.

Yaoyi Dai, Shuai Guo, Yidan Pan, Carla Castignani, Matthew D Montierth, Peter Van Loo, Wenyi Wang.

Cancer tissues are heterogeneous mixtures of tumour, stromal and immune cells, where each component comprises multiple distinct cell types and/or states. Mapping this heterogeneity and understanding the unique contributions of each cell type to the tumour transcriptome is crucial for advancing cancer biology, yet high-throughput expression profiles from tumour tissues only represent combined signals from all cellular sources. Computational deconvolution of these mixed signals has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns. Here, we provide a comprehensive guide to transcriptomic deconvolution, specifically tailored for cancer researchers, presenting a systematic framework for selecting and applying deconvolution methods, considering the unique complexities of tumour tissues, data availability and method assumptions. We detail 43 deconvolution methods and outline how different approaches serve distinctive applications in cancer research: from understanding tumour-immune surveillance to identifying cancer subtypes, discovering prognostic biomarkers and characterizing spatial tumour architecture. By examining the capabilities and limitations of these methods, we highlight emerging trends and future directions, particularly in addressing tumour cell plasticity and dynamic cell states.

DOI: https://doi.org/10.1038/s41568-025-00886-9
Mol Metab. 2025 Dec 02. pii: S2212-8778(25)00199-1. [Epub ahead of print] 102292

Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation.

Giulia Milan, Olga A Mareninova, Marco Fantuz, Martina Spacci, Carlotta Paoli, Jerik A Pineda, Roberta Noè, Beatrice Calciolari, Roberto Zoncu, Anna S Gukovskaya, Alessandro Carrer.

  Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive. Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells' lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of Acly ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage. Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both ex vivo and in vivo, in an mTORC1-dependent manner. These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.

Keywords:  acinar-to-ductal metaplasia (ADM); cholesterol; lysosome; mTORC1; pancreatitis

DOI:  https://doi.org/10.1016/j.molmet.2025.102292
Nat Commun. 2025 Dec 01. 16(1): 10817

Dietary lipid content modifies wah-1/AIFM1-associated phenotypes via LRK-1 and DRP-1 expression in C. elegans.

Mrityunjoy Mondal, Enzo Scifo, Rossella Erminia Ciliberti, Lena Wischhof, Tannaz Norizadeh Abbariki, Joshua Jackson, Ioanna-Maria Menegatou, Viktoria Zeisler-Diehl, Jan Riemer, Benjamin Jussila, Christopher E Hopkins, Sylwia Kierszniowska, Lukas Schreiber, Pierluigi Nicotera, Dan Ehninger, Daniele Bano.

Eukaryotic cells rely on mitochondria to fine-tune their metabolism in response to environmental and nutritional changes. However, how mitochondria adapt to nutrient availability and how diets impact mitochondrial disease progression, remain unclear. Here, we show that lipid-derived diets influence the survival of Caenorhabditis elegans carrying a hypomorphic wah-1/AIFM1 mutation that compromises mitochondrial Complex I assembly. Comparative proteomic and lipidomic analyses reveal that the overall metabolic profile of wah-1/AIFM1 mutants varies with bacterial diet. Specifically, high-lipid diets extend lifespan by promoting mitochondrial network maintenance and lipid accumulation, whereas low-lipid diets shorten animal survival via overactivation of LRK-1 and DRP-1. We demonstrate that LRK-1 inhibition downregulates DRP-1 expression, reduces mitochondrial network fragmentation, and attenuates excessive autophagy, thereby rescuing the survival defects of wah-1 mutants maintained on low-lipid diets. Together, these findings suggest that nutrition, and particularly lipid intake, may ameliorate certain disease phenotypes associated with an inherited mutation that disrupts mitochondrial bioenergetics.

DOI: https://doi.org/10.1038/s41467-025-66900-8
Cell. 2025 Nov 28. pii: S0092-8674(25)01251-6. [Epub ahead of print]

Innate immune and metabolic signals induce mitochondria-dependent membrane lysis via mitoxyperiosis.

Yaqiu Wang, Jianlin Lu, Alexandre F Carisey, Sangappa B Chadchan, Ha Won Lee, R K Subbarao Malireddi, Bhesh Raj Sharma, Nagakannan Pandian, Rebecca E Tweedell, Gustavo Palacios, Nathalie Becerra Mora, Camenzind G Robinson, Aaron Pitre, Peter Vogel, Taosheng Chen, Michael P Murphy, Thirumala-Devi Kanneganti.

  The combination of innate immune activation and metabolic disruption plays critical roles in many diseases, often leading to mitochondrial dysfunction and oxidative stress that drive pathogenesis. However, mechanistic regulation under these conditions remains poorly defined. Here, we report a distinct lytic cell death mechanism induced by innate immune signaling and metabolic disruption, independent of caspase activity and previously described pyroptosis, PANoptosis, necroptosis, ferroptosis, and oxeiptosis. Instead, mitochondria undergoing BAX/BAK1/BID-dependent oxidative stress maintained prolonged plasma membrane contact, leading to local oxidative damage, a process we termed mitoxyperiosis. This process then caused membrane lysis and cell death, termed mitoxyperilysis. mTORC2 regulated the cell death, and mTOR inhibition restored cytoskeletal activity for lamellipodia to retract and mobilize mitochondria away from the membrane, preserving integrity. Activating this pathway in vivo regressed tumors in an mTORC2-dependent manner. Overall, our results identify a lytic cell death modality in response to the synergism of innate immune signaling and metabolic disruption.

Keywords:  carbon starvation; cytokine; inflammasome; inflammatory cell death; innate immunity; mTOR; metabolism; mitochondria; oxidative damage; tumor

DOI:  https://doi.org/10.1016/j.cell.2025.11.002
Nat Metab. 2025 Dec 01.

Fat sensory cues in early life program central response to food and obesity.

Laura Casanueva Reimon, Ayden Gouveia, André Carvalho, Joscha N Schmehr, Mouna El Mehdi, Rolando D Moreira-Soto, Carlos G Ardanaz, Janice Bulk, Lionel Rigoux, Paul Klemm, Anna Lena Cremer, Frederik Dethloff, Yvonne Hinze, Heiko Backes, Patrick Giavalisco, Sophie M Steculorum.

Maternal obesity predisposes offspring to metabolic diseases. Here, we show that non-nutritive sensory components of a high-fat diet (HFD), beyond its hypercaloric, obesogenic effects, are sufficient to alter metabolic health in the offspring. To dissociate the caloric and sensory components of HFD, we fed dams a bacon-flavoured diet, isonutritional to a normal chow diet but enriched with fat-related odours. Offspring exposed to these fat-related odours during development display metabolic inflexibility and increased adiposity when fed HFD in adulthood independently of maternal metabolic health. Developmental exposure to fat-related odours shifts mesolimbic dopaminergic circuits and Agouti-related peptide (AgRP) hunger neurons' responses to phenocopy those of obese mice, including a desensitization of AgRP neurons to dietary fat. While neither neonatal optogenetic activation of sensory circuits nor passive exposure to fat-related odours is sufficient to alter metabolic responses to HFD, coupling optogenetic stimulation of sensory circuits with caloric intake exacerbates obesity. Collectively, we report that fat-related sensory cues during development act as signals that can prime central responses to food cues and whole-body metabolism regulation.

DOI: https://doi.org/10.1038/s42255-025-01405-8
Nat Commun. 2025 Dec 01.

Sprint interval exercise disrupts mitochondrial ultrastructure driving a unique mitochondrial stress response and remodelling in men.

J Botella, E Perri, N J Caruana, S López-Calcerrada, M Brischigliaro, N A Jamnick, V Oorschot, N J Saner, J Díaz-Lara, D F Taylor, A Garnham, E Fernández-Vizarra, C Ugalde, G Ramm, D A Stroud, M Lazarou, D J Bishop.

Exercise is a key lifestyle intervention for mitochondrial health, yet the molecular mechanisms by which different exercise prescriptions regulate mitochondrial remodeling remain unclear. We conducted an open-label counterbalanced randomized controlled trial (ACTRN12617001105336) and observed that sprint-interval exercise (SIE; n = 14), compared to moderate-intensity continuous exercise (MICE; n = 14), induces a mitochondrial stress signature and unfolded protein response (UPRmt). SIE triggers morphological and structural mitochondrial alterations along with activation of the integrated stress response (ISR) and mitochondrial quality control (MQC) pathways. Following eight weeks of training, moderate-intensity continuous training (MICT) increases mitochondrial content, complex I activity, and displays an enrichment of tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) proteins, while sprint-interval training (SIT) improves respiratory function and upregulates pathways involved in 1-carbon metabolism and protein quality control. We identify COX7A2L accumulating in III2 + IV1 supercomplexes only after SIT. These findings elucidate how exercise intensity shapes mitochondrial remodeling, informing tailored exercise prescriptions.

DOI: https://doi.org/10.1038/s41467-025-66625-8
Nat Metab. 2025 Dec 05.

Pathway coessentiality mapping reveals complex II is required for de novo purine biosynthesis in acute myeloid leukaemia.

Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, J Darren Stuart, Paul A Grimsrud, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.

Understanding how cellular pathways interact is crucial for treating complex diseases like cancer. Individual gene-gene interaction studies have provided valuable insights, but may miss pathways working together. Here we develop a multi-gene approach to pathway mapping which reveals that acute myeloid leukaemia (AML) depends on an unexpected link between complex II and purine metabolism. Through stable-isotope metabolomic tracing, we show that complex II directly supports de novo purine biosynthesis and that exogenous purines rescue AML cells from complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that complex II metabolizes to sustain purine synthesis. This connection translates into a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML cells to complex II inhibition. In a syngeneic AML mouse model, targeting complex II leads to rapid disease regression and extends survival. In individuals with AML, higher complex II gene expression correlates with resistance to BCL-2 inhibition and worse survival. These findings establish complex II as a central regulator of de novo purine biosynthesis and a promising therapeutic target in AML.

DOI: https://doi.org/10.1038/s42255-025-01410-x
Cell Metab. 2025 Dec 01. pii: S1550-4131(25)00482-6. [Epub ahead of print]

Digital twins for in vivo metabolic flux estimations in patients with brain cancer.

Baharan Meghdadi, Wajd N Al-Holou, Andrew J Scott, Anjali Mittal, Ningning Liang, Palavalasa Sravya, Abhinav Achreja, Alexandra O'Brien, Kathy Do, Zhe Wu, Jiane Feng, Nathan R Qi, Vijay Tarnal, Sriram Venneti, C Ryan Miller, Jann N Sarkaria, Weihua Zhou, Theodore S Lawrence, Costas A Lyssiotis, Daniel R Wahl, Deepak Nagrath.

  Recent advancements in metabolic flux estimations in vivo are limited to preclinical models, primarily due to challenges in tissue sampling, tumor microenvironment (TME) heterogeneity, and non-steady-state conditions. To address these limitations and enable flux estimation in human patients, we developed two machine learning-based frameworks. First, the digital twin framework (DTF) integrates first-principles stoichiometric and isotopic simulations with convolutional neural networks to estimate fluxes in patient bulk samples. Second, the single-cell metabolic flux analysis (13C-scMFA) framework combines patient single-cell RNA sequencing (scRNA-seq) data with 13C-isotope tracing, allowing single-cell-level flux quantification. These studies allow quantification of metabolic activity in neoplastic glioma cells, revealing frequently elevated purine synthesis and serine uptake, compared with non-malignant cells. Our models also identify metabolic heterogeneity among patients and mice with brain cancer, in turn predicting treatment responses to metabolic inhibitors. Our frameworks advance in vivo metabolic flux analysis, may lead to novel metabolic therapies, and identify biomarkers for metabolism-directed therapies in patients.

Keywords:  (13)C-single-cell metabolic flux analysis; cancer metabolism; glioblastoma; in vivo isotope tracing; in vivo metabolism; machine learning; purine metabolism; scRNA-seq; serine metabolism; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cmet.2025.10.022
bioRxiv. 2025 Nov 19. pii: 2025.11.19.688750. [Epub ahead of print]

Copper deficiency disrupts OXPHOS and mitochondrial dynamics through MTCH2-dependent copper trafficking in skeletal muscle.

Young-Seung Lee, Hee Soo Kim, Phuc L Nguyen, Junhyeong Lee, Dong-Il Kim, Jeongmin Lee, Changjong Moon, Kyoung-Oh Cho, Byung-Eun Kim, Jiyun Ahn, Timothy F Osborne, Taner Duysak, Jeong-Sun Kim, Chang Hwa Jung, Tae-Il Jeon.

Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.

DOI: https://doi.org/10.1101/2025.11.19.688750
Res Sq. 2025 Nov 17. pii: rs.3.rs-8077579. [Epub ahead of print]

Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.

Adam Antebi, Wenming Huang, Jonathan Kölschbach, Anna Loehrke, Hormos Dafsari, Emily Baum, Chun Kew, Ivan Dikic.

Spliceosomal dysfunction profoundly impacts cellular metabolism, yet mechanistic links between RNA splicing defects and metabolic rewiring remain limited. Here, we investigate Verheij syndrome (VRJS), a rare disease caused by mutations in the core splicing factor PUF60 . Using a Caenorhabditis elegans model, human cell lines, and patient-derived samples, we demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, culminating in impaired S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental and growth defects. Vitamin B12 (VB12) supplementation restores metabolic balance by reactivating SAM-dependent phospholipid remodelling and mTORC1 activity, effectively rescuing VRJS-like phenotypes. Similar metabolic responses arise from perturbations in other spliceosomal factors such as PRPF19/PRP-19, indicating a conserved mechanism across spliceosomopathies. Interestingly, we identify intron retention of the nhr-114/HNF4 transcription factor as a primary driver of growth defects, and restoring its splicing robustly suppresses these phenotypes. Our findings establish a mechanistic connection between RNA splicing and lipid metabolism, implicating VB12-dependent one-carbon metabolism as a metabolic modulator with broad implications for spliceosome-related diseases, and suggesting VB12 as a potential strategy to mitigate VRJS-related anomalies.

DOI: https://doi.org/10.21203/rs.3.rs-8077579/v1
Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2516288122

Oxidative pentose phosphate pathway is required for T cell activation and antitumor immunity.

Zihong Chen, Kellen L Olszewski, Rolf-Peter Ryseck, Xincheng Xu, Jacob A Boyer, Christian G Peace, Yihui Shen, Caroline R Bartman, Lydia Lynch, Joshua D Rabinowitz.

  Glucose is catabolized by two major metabolic pathways, glycolysis and the oxidative pentose phosphate pathway (oxPPP). The oxPPP generates nicotinamide adenine dinucleotide phosphate (NADPH) at two steps, glucose-6-phosphate dehydrogenase (G6PD), the most common enzyme deficiency in humans, and 6-phosphogluconate dehydrogenase (PGD). Previous literature suggests that G6PD supports but PGD limits T cell-mediated immunity. Here, we use T cell-specific knockout mouse models to show that both enzymes are required for antitumor immunity and response to immunotherapy. PGD knockout depletes mature T cells systemically, while G6PD loss does not reduce basal T cell populations but results in apoptosis upon activation. Such apoptosis is not reversed by major downstream products of the oxPPP, including antioxidants, nucleosides, or fatty acids. Instead, T cells are partially rescued by removal of media cystine, whose reduction requires NADPH. G6PD loss induces an oxidative stress response that upregulates cystine import, which together with low NADPH leads to fatal disulfide stress. Overall, these results highlight an essential role for the oxidative pentose phosphate pathway in cystine homeostasis and T cell-mediated immunity.

Keywords:  NADPH; T cell activation; T cell antitumor immunity; disulfide stress; oxidative pentose phosphate pathway

DOI:  https://doi.org/10.1073/pnas.2516288122
Sci Rep. 2025 Dec 01. 15(1): 42939

Mitochondrial glutathione transporter SLC25A40 regulates macrophage cytokine production.

Maureen Yin, Eva M Palsson-McDermott, Órlaith C Henry, Ziqian Ge, Juliana E Toller-Kawahisa, Yukun Min, Anne F McGettrick, Adam L Gordon, Stella B Heffernan, Laura Marrone, Bryan P Marzullo, Katherine L Eales, Sally A Clayton, Daniel A Tennant, Richard K Porter, Luke A J O'Neill.

  Mitochondrial glutathione (mtGSH) supports iron-sulfur cluster (ISC) stability in the electron transport chain (ETC). Here we have investigated the role of the mtGSH transporter SLC25A40 in macrophage activation. SLC25A40 is present in both murine and human macrophages and its expression was increased by LPS treatment. Reducing SLC25A40 expression using siRNA destabilized ISC-rich ETC proteins and elevated mitochondrial and cellular reactive oxygen species (ROS). It also induced expression of the genes Gclc and Gclm, which are involved in GSH biosynthesis. SLC25A40 deficiency also diminished IL-1β and IL-10 production at the transcriptional level in response to LPS. As a result, the production of mature IL-1β was decreased following activation of NLRP3 by nigericin or ATP, with no effect on pyroptosis. Depleting mtGSH with mitochondrially-targeted CDNB phenocopied these defects, whereas supplementation with a cell-permeable GSH ester partially restored pro-IL-1β production. Together, these data identify SLC25A40 as a key regulator that sustains ETC integrity to promote cytokine production, revealing a previously unrecognized role for the SLC25A40-mtGSH axis in coupling mitochondrial redox control to macrophage activation.

Keywords:  Cytokine; Electron transport chain (ETC); Glutathione (GSH); Macrophage immunometabolism; Mitochondria; SLC25A39/40

DOI:  https://doi.org/10.1038/s41598-025-30333-6
Cell. 2025 Dec 04. pii: S0092-8674(25)01310-8. [Epub ahead of print]

A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.

Svenja M Lorenz, Adam Wahida, Mark J Bostock, Tobias Seibt, André Santos Dias Mourão, Anastasia Levkina, Dietrich Trümbach, Mohamed Soudy, David Emler, Nicola Rothammer, Marcel S Woo, Jana K Sonner, Mariia Novikova, Bernhard Henkelmann, Maceler Aldrovandi, Daniel F Kaemena, Eikan Mishima, Perrine Vermonden, Zhi Zong, Deng Cheng, Toshitaka Nakamura, Junya Ito, Sebastian Doll, Bettina Proneth, Erika Bürkle, Francesca Rizzollo, Abril Escamilla Ayala, Valeria Napolitano, Marta Kolonko-Adamska, Stefan Gaussmann, Juliane Merl-Pham, Stefanie Hauck, Anna Pertek, Tanja Orschmann, Emily van San, Tom Vanden Berghe, Daniela Hass, Adriano Maida, Joris M Frenz, Lohans Pedrera, Amalia Dolga, Markus Kraiger, Martin Hrabé de Angelis, Helmut Fuchs, Gregor Ebert, Jerica Lenberg, Jennifer Friedman, Carolin Scale, Patrizia Agostinis, Annemarie Zimprich, Daniela Vogt-Weisenhorn, Lillian Garrett, Sabine M Hölter, Wolfgang Wurst, Enrico Glaab, Jan Lewerenz, Bastian Popper, Christian Sieben, Petra Steinacker, Hans Zischka, Ana J Garcia-Saez, Anna Tietze, Sanath Kumar Ramesh, Scott Ayton, Michelle Vincendeau, Manuel A Friese, Kristen Wigby, Michael Sattler, Matthias Mann, Irina Ingold, Ashok Kumar Jayavelu, Grzegorz M Popowicz, Marcus Conrad.

  Ferroptosis, driven by uncontrolled peroxidation of membrane phospholipids, is distinct from other cell death modalities because it lacks an initiating signal and is surveilled by endogenous antioxidant defenses. Glutathione peroxidase 4 (GPX4) is the guardian of ferroptosis, although its membrane-protective function remains poorly understood. Here, structural and functional analyses of a missense mutation in GPX4 (p.R152H), which causes early-onset neurodegeneration, revealed that this variant disrupts membrane anchoring without considerably impairing its catalytic activity. Spatiotemporal Gpx4 deletion or neuron-specific GPX4R152H expression in mice induced degeneration of cortical and cerebellar neurons, accompanied by progressive neuroinflammation. Patient induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids displayed increased ferroptotic vulnerability, mirroring key pathological features, and were sensitive to ferroptosis inhibition. Neuroproteomics revealed Alzheimer's-like signatures in affected brains. These findings highlight the necessity of proper GPX4 membrane anchoring, establish ferroptosis as a key driver of neurodegeneration, and provide the rationale for targeting ferroptosis as a therapeutic strategy in neurodegenerative disease.

Keywords:  Alzheimer’s disease; GPX4; SSMD; Sedaghatian type; cell death; ferroptosis; neurodegeneration; neuroinflammation; spondylometaphyseal dysplasia

DOI:  https://doi.org/10.1016/j.cell.2025.11.014
Cell. 2025 Dec 04. pii: S0092-8674(25)01309-1. [Epub ahead of print]

Renal PIEZO2 is an essential regulator of renin.

Rose Z Hill, Jonathan W Nelson, Georgina Gyarmati, Silvia Medrano, Sepenta Shirvan, James A McCormick, Sebastian Burquez, Jeanine Ahmed, Diana G Eng, Jan Wysocki, Adrienne E Dubin, M Rocio Servin-Vences, Arjun Lakshmanan, R Ariel Gomez, Maria Luisa S Sequeira-Lopez, Stuart J Shankland, Daniel Batlle, Jeffrey H Miner, Janos Peti-Peterdi, Ardem Patapoutian.

  Renin synthesis and release is the rate-limiting step of the renin-angiotensin-aldosterone system (RAAS) that controls fluid homeostasis. A major activator of the RAAS is a decrease in perfusion pressure within the kidneys, suggesting a link between renal mechanotransduction and renin. However, the identity of the mechanosensor(s) in the kidneys and their physiological significance to the RAAS remain unclear. We find that loss of the force-gated nonselective cation channel PIEZO2 in cells of renin lineage dysregulates the RAAS by elevating renin. We observe that PIEZO2 is expressed in renin-producing juxtaglomerular granular cells and is required for their calcium dynamics in vivo. PIEZO2 deficiency in cells of renin lineage drives renin-dependent and MAS-receptor-dependent glomerular hyperfiltration and regulates the RAAS during acute and chronic blood volume challenges. Collectively, our study identifies PIEZO2 as an essential regulator of juxtaglomerular granular cell calcium activity and renin in vivo.

Keywords:  PIEZO2; blood volume; calcium; ion channel; juxtaglomerular granular cell; kidney; mechanotransduction; mesangial cell; renin; renin-angiotensin-aldosterone system

DOI:  https://doi.org/10.1016/j.cell.2025.11.013
Res Sq. 2025 Nov 19. pii: rs.3.rs-7983397. [Epub ahead of print]

Dietary Polyunsaturated Fatty Acids Regulate Dendritic Cell Function via Nrf2-dependent Control of Ferroptosis.

Juan Cubillos-Ruiz, Deepika Awasthi, Erin McMinn, Camilla Salvagno, Sung-Min Hwang, Tito Sandoval, Chang-Suk Chae, Wiam Madani, Jacqueline Crater, Kaushik Sen, Daniel Min, Alexander Emmanuelli, Chen Tan, Andrew Dannenberg, Diana Morales, Evelyn Cantillo, Eloise Chapman-Davis, William Zhang, Suzanne Cloonan.

Dendritic cells (DCs) orchestrate adaptive immune responses to pathogens and tumors, yet how dietary lipids influence DC metabolism and function remains largely unexplored. Here we show that dietary polyunsaturated fatty acids (PUFAs) govern DC activity via Nuclear factor erythroid 2-like 2 (Nrf2)-dependent control of ferroptosis. In mice, an n-6 PUFA-enriched diet suppressed DC Nrf2 signaling, depleted glutathione, and induced lipid peroxidation and ferroptosis, thereby compromising antigen presentation. By contrast, dietary n-3 PUFAs enhanced Nrf2 signaling and redox homeostasis, preserving DC integrity and T cell priming. Pharmacologic Nrf2 activation or ferroptosis inhibition restored the function of DCs from n-6 PUFA-fed mice. Notably, adoptive immunotherapy with DCs conditioned by a diet rich in n-3 PUFAs-but not n-6 PUFAs-elicited durable, T cell-dependent control of metastatic ovarian cancer. These findings identify dietary PUFAs as key modulators of the Nrf2-glutathione-ferroptosis axis in DCs and reveal a redox-sensitive metabolic checkpoint that can be leveraged to improve cancer immunotherapy.

DOI: https://doi.org/10.21203/rs.3.rs-7983397/v1
Cell. 2025 Dec 02. pii: S0092-8674(25)01253-X. [Epub ahead of print]

Membrane potential mediates the cellular response to mechanical pressure.

Avik Mukherjee, Yanqing Huang, Jens Elgeti, Seungeun Oh, Jose G Abreu, Leander Ammar, Anjali R Neliat, Janik Schüttler, Dan-Dan Su, Christophe Dupre, Nina Catherine Benites, Xili Liu, Leonid Peshkin, Mihail Barboiu, Hugo Stocker, Marc W Kirschner, Markus Basan.

  Mechanical forces influence cellular decisions to grow, die, or differentiate, through largely mysterious mechanisms. Separately, changes in resting membrane potential have been observed in development, differentiation, regeneration, and cancer. We demonstrate that membrane potential is an important mediator of cellular response to mechanical pressure. We show that mechanical forces acting on the cell change cellular biomass density, which, in turn, alters membrane potential. Membrane potential then regulates cell number density in epithelia by controlling cell growth, proliferation, and cell elimination. Mechanistically, we show that changes in membrane potential control signaling through the Hippo and mitogen-activated protein kinase (MAPK) pathways and potentially other signaling pathways that originate at the cell membrane. While many molecular interactions are known to affect Hippo signaling, the upstream signal that activates the canonical Hippo pathway at the membrane has previously been elusive. Our results establish membrane potential as an important regulator of growth and tissue homeostasis.

Keywords:  Hippo; YAP; biomass density; growth control; mapk; mechanotransduction; membrane potential; tissue homeostasis

DOI:  https://doi.org/10.1016/j.cell.2025.11.004
PLoS Biol. 2025 Dec;23(12): e3003075

Distinct S-adenosylmethionine synthases link phosphatidylcholine to mitochondrial function and stress survival.

Athena L Munden, Arjamand Mushtaq, Dominique S Lui, Katherine M Edwards, Daniel P Higgins, Kasturi Biswas, Rachel M Walker, Leah H Crowley, Matthew J Fanelli, Thien-Kim Ngyuen, Maria Ericsson, Adwait A Godbole, John A Haley, Caroline A Lewis, Jessica B Spinelli, Benjamin Harrison, Daniel Raftery, Danijel Djukovic, Daniel E L Promislow, Dana L Miller, Amy K Walker.

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Humans and many other organisms express multiple SAM synthases. However, loss of different synthase activity can have distinct phenotypic effects. For instance, in Caenorhabditis elegans loss of sams-1 leads to enhanced heat shock survival and increased life span, but loss of sams-4 reduces heat stress survival. This provides a biological context to test the hypothesis that the enzymatic source of SAM impacts its function and to identify mechanistic connections. Here, we show that SAMS-1 contributes SAM to a variety of intermediary metabolic pathways, whereas SAMS-4 has a more limited role to support SAM-dependent protein transmethylation reactions. Mitochondria seem to be particularly impacted specifically by loss of sams-1; many mitochondrial metabolites are perturbed and there is an age-dependent decline of nuclear-encoded mitochondrial gene expression in these animals. We further demonstrate that reduced production of phosphatidylcholine in sams-1-deficient animals leads to mitochondrial fragmentation and subsequent loss of mitochondrial components. We propose that alterations in mitochondria are mechanistically linked to the increased survival in heat stress specific to sams-1-deficient animals.

DOI: https://doi.org/10.1371/journal.pbio.3003075
Nat Cell Biol. 2025 Dec 05.

A foundation for tomorrow's discoveries in cell biology.

Ruth R Cheng, Rebecca L Bradford.

DOI: https://doi.org/10.1038/s41556-025-01824-5
Trends Genet. 2025 Nov 28. pii: S0168-9525(25)00265-3. [Epub ahead of print]

The evolutionary role of mutational robustness: theoretical insights.

Ronja I Hulst, Sander K Govers, Jan Michiels, Kevin J Verstrepen, Pieter van den Berg.

  Mutational robustness, the ensemble of mechanisms that allow organisms to maintain a stable phenotype despite genetic mutations, affects adaptive evolution in several ways. Many models have attempted to explain how mutational robustness might evolve and shape adaptation, but the variety of approaches and assumptions complicates a clear synthesis. Here, we categorize and critically discuss the main approaches for modeling the evolutionary causes and consequences of mutational robustness. We discuss how robustness can emerge from aspects of biological organization (e.g., modularity, critical dynamics) and selection (e.g., stabilizing selection) and how robustness can both enhance and constrain evolvability [e.g., through cryptic genetic variation (CGV)]. We conclude by discussing challenges related to model complexity and computational cost and outline the foremost outstanding questions.

Keywords:  evolutionary model; fitness landscape; gene regulatory network; genetic interactions; genotype-to-phenotype map; mutational robustness

DOI:  https://doi.org/10.1016/j.tig.2025.10.011
PLoS One. 2025 ;20(12): e0335906

Renal and hepatic function is preserved following inducible knockout of kynurenine pathway enzymes KMO or QPRT in adult mice.

Benjamin S Summers, Luke Milham, Sonia Bustamante, Krishan Gondal, Peggy Rentsch, Gayathri Sundaram, Michael D Lovelace, Bryce Vissel, Bruce J Brew.

The kynurenine pathway (KP) is the canonical route by which tryptophan is metabolised, almost all of which occurs in the liver, with significant expression of its enzymes also known in the kidney. We generated two novel mouse models for inducible global knockout of midpoint KP enzyme kynurenine-3-monooxygenase (KMO) and endpoint enzyme quinolinate phosphoribosyltransferase (QPRT; converts known neurotoxic KP metabolite Quinolinic acid to nicotinamide adenine dinucleotide (NAD) precursor via the de novo synthesis pathway). The KP is dysregulated in many renal and hepatic disorders, but as an essential step prior to use in disease studies, we set out to characterise their basal KP metabolome and investigate any changes to their overall phenotype in the liver and kidney, free of exogenous inflammatory stimuli. Both enzyme knockouts caused rapid alterations in accumulation of blood metabolite levels upstream of the affected enzyme, although downstream metabolite concentrations were surprisingly unaffected. KMO knockout elevated kynurenine, kynurenic acid and anthranilic acid, while QPRT knockout elevated quinolinic acid. Regardless of these significant metabolic alterations, histological examination of liver and kidney tissues, standard clinical blood chemistry and gross animal observations indicated no evidence of pathological changes in both the renal and hepatic systems. Our findings suggest that in a timeframe of 1-5 weeks and without evoked inflammation, robust homeostatic mechanisms can accommodate substantial fluctuations in KP metabolite concentrations in knockout mice without affecting renal or hepatic structure or function.

DOI: https://doi.org/10.1371/journal.pone.0335906
Cancer Res. 2025 Dec 02.

Drink Responsibly: Cancer Cells also Like Sugary Drinks.

Fabio Zani, Julianna Blagih.

Sugar-sweetened beverages (SSBs), which contain both glucose and fructose, have been linked to an increased incidence of colorectal cancer (CRC). Their effects on CRC progression, however, are unclear. In their recent work, Feng and colleagues investigated how exposure to SSBs affects CRC metastasis. They discovered that several CRC cell lines showed enhanced migration when exposed to glucose and fructose together, compared to cells exposed to glucose or fructose alone. Similarly, in mouse models of CRC liver metastasis, mice fed with both glucose and fructose developed more liver metastases, suggesting that SSBs promote CRC spread. Leveraging on metabolomic analyses, they discovered that in the presence of both glucose and fructose, the enzyme SORD converts fructose to sorbitol, regenerating NAD⁺ from NADH. Deleting SORD reduced the NAD+/NADH ratio and CRC cell migration and metastasis. Restoring the NAD⁺/NADH ratio rescued migration, suggesting that SORD-driven NAD⁺ regeneration promotes metastatic behaviour. Furthermore, they demonstrated that increased NAD⁺/NADH levels have a profound effect on cell metabolism, supporting glycolysis, the TCA cycle, and the mevalonate pathway. Interestingly, pharmacologic inhibition of the mevalonate pathway with statins reduced cell migration and liver metastasis in mice consuming SSBs. Together, these findings demonstrate that SSBs enhance CRC metastasis through SORD-dependent metabolic reprogramming. By regenerating NAD⁺ and glycolysis and the mevalonate pathway, SORD links SSB consumption to increased tumor cell migration and metastatic potential.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-5296
Science. 2025 Dec 04. 390(6777): eadv6588

Multiscale structure of chromatin condensates explains phase separation and material properties.

Huabin Zhou, Jan Huertas, M Julia Maristany, Kieran Russell, June Ho Hwang, Run-Wen Yao, Nirnay Samanta, Joshua Hutchings, Ramya Billur, Momoko Shiozaki, Xiaowei Zhao, Lynda K Doolittle, Bryan A Gibson, Andrea Soranno, Margot Riggi, Jorge R Espinosa, Zhiheng Yu, Elizabeth Villa, Rosana Collepardo-Guevara, Michael K Rosen.

The structure and interaction networks of molecules within biomolecular condensates are poorly understood. Using cryo-electron tomography and molecular dynamics simulations, we elucidated the structure of phase-separated chromatin condensates across scales, from individual amino acids to network architecture. We found that internucleosomal DNA linker length controls nucleosome arrangement and histone tail interactions, shaping the structure of individual chromatin molecules within and outside condensates. This structural modulation determines the balance between intra- and intermolecular interactions, which governs the molecular network, thermodynamic stability, and material properties of chromatin condensates. Mammalian nuclei contain dense clusters of nucleosomes whose nonrandom organization is mirrored by the reconstituted condensates. Our work explains how the structure of individual chromatin molecules determines physical properties of chromatin condensates and cellular chromatin organization.

DOI: https://doi.org/10.1126/science.adv6588
J Clin Invest. 2025 Dec 01. pii: e188249. [Epub ahead of print]135(23):

S-acyl transferase ZDHHC13 modulates tumor microenvironment interactions to suppress metastasis in melanoma models.

Hongjin Li, Jianke Lyu, Yu Sun, Chengqian Yin, Yuewen Li, Weiqiang Chen, Suan-Sin Foo, Xianfang Wu, Colin R Goding, Shuyang Chen.

  The intratumor microenvironment shapes the metastatic potential of cancer cells and their susceptibility to any immune response. Yet, the nature of the signals within the microenvironment that control anticancer immunity and how they are regulated is poorly understood. Here, using melanoma as a model, we investigate the involvement in metastatic dissemination and the immune-modulatory microenvironment of Protein S-Acyl Transferases as an underexplored class of potential therapeutic targets. We find that ZDHHC13 suppresses metastatic dissemination by palmitoylation of CTNND1, leading to stabilization of E-cadherin. Importantly, ZDHHC13 also reshapes the tumor immune microenvironment by suppressing lysophosphatidylcholine (LPC) synthesis in melanoma cells, leading to inhibition of M2-like tumor-associated macrophages that we show degrade E-cadherin via MMP12 expression. Consequently, ZDHHC13 activity suppresses tumor growth and metastasis in immunocompetent mice. Our study highlights the therapeutic potential of targeting the ZDHHC13-E-cadherin axis and its downstream metabolic and immune-modulatory mechanisms, offering additional strategies to inhibit melanoma progression and metastasis.

Keywords:  Immunology; Immunotherapy; Molecular biology; Oncology; Skin cancer

DOI:  https://doi.org/10.1172/JCI188249
Trends Cancer. 2025 Nov 28. pii: S2405-8033(25)00280-8. [Epub ahead of print]

Neural hijacking in cancer metabolism: from nutrients to organelles.

Songhui Shin, Su Yeon Myoung, Hye Jin Cho, Seongjun Kim, Namgyu Lee, Sung Jin Park.

  Tumors dynamically interact with the central and peripheral nervous systems, hijacking neural plasticity and reprogramming metabolism in a bidirectional manner to drive cancer progression. Neural inputs reshape the metabolism of cancer cells and their microenvironment - glycolysis, oxidative phosphorylation, and lipid metabolism - while tumors exploit neuronal nutrients and mitochondria to thrive under metabolic stress. This review explores neurocancer metabolic crosstalk through multiple mechanisms by three principal modes of interaction, highlighting how targeting these metabolic interdependencies could disrupt tumor progression. By integrating cancer metabolism and neuroscience, it offers a conceptual framework for understanding neural-tumor metabolic circuits in malignancy and identifies potential therapeutic vulnerabilities.

Keywords:  cancer; crosstalk; metabolism; neuron; therapy

DOI:  https://doi.org/10.1016/j.trecan.2025.11.006
Mol Cell. 2025 Dec 01. pii: S1097-2765(25)00902-5. [Epub ahead of print]

Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen.

Alexander J Stuart, Kaori K Takai, Railia R Gabbasova, Henry Sanford, Ekaterina V Vinogradova, Titia de Lange.

  Replicative senescence is a powerful tumor suppressor pathway that curbs proliferation of human cells when a few critically-short telomeres activate the DNA damage response (DDR). We show that ATM is the sole DDR kinase responsible for the induction and maintenance of replicative senescence and that ATM inhibition can induce normal cell divisions in senescent cells. Compared to non-physiological atmospheric (∼20%) oxygen, primary fibroblast cells grown at physiological (3%) oxygen were more tolerant to critically short telomeres, explaining their extended replicative lifespan. We show that this tolerance is due to attenuation of the ATM response to double-strand breaks (DSBs) and unprotected telomeres. Our data indicate that the reduced ATM response to DSBs at 3% oxygen is due to increased ROS, which induces disulfide crosslinked ATM dimers that do not respond to DSBs. This regulation of cellular lifespan through attenuation of ATM at physiological oxygen has implications for tumor suppression through telomere shortening.

Keywords:  ATM; DDR; Hayflick; ROS; TRF2; cancer; hypoxia; oxygen; senescence; telomere

DOI:  https://doi.org/10.1016/j.molcel.2025.11.006
Nat Aging. 2025 Dec 03.

Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.

Bingjie Guan, Mantang Zhou, Weixing Dai, Jing Zhang, Bowen Xie, Yushuai Mi, Xin Zhang, Ping Wei, Youdong Liu, Shanbao Li, Haonan Guan, Xiaoming Zhang, Sanjun Cai, Dawei Li, Dongwang Yan, Senlin Zhao.

One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.

DOI: https://doi.org/10.1038/s43587-025-01023-9
Trends Cancer. 2025 Dec 02. pii: S2405-8033(25)00275-4. [Epub ahead of print]

Mapping heterogeneity in the tumor microenvironment of renal cell carcinoma through single-cell omics.

Betul Gok Yavuz, Narmina Khanmammadova, Zuhair Majeed, Mostafa I H Ali, Merve Hasanov, Mehmet Asim Bilen, Eric A Singer, Elshad Hasanov.

  Renal cell carcinoma (RCC) outcomes are shaped by a complex tumor microenvironment (TME), where malignant cells represent only a minority of the tissue. Recent advances in single-cell technologies - including single-cell RNA sequencing, single-nucleus RNA sequencing, single-cell assay for transposase-accessible chromatin sequencing, single-cell T-cell receptor sequencing, and imaging mass cytometry - have uncovered the cellular, regulatory, and spatial heterogeneity of RCC. Here, we synthesize insights from these approaches to define diverse CD8+ T-cell subsets and exhaustion trajectories, as well as the origins, phenotypic diversity, and functional states of other immune cells including tumor-associated macrophages, dendritic cells, natural killer cells and cancer-associated fibroblasts. Together, these findings highlight the transformative potential of single-cell technologies to unravel TME complexity, identify biomarkers of therapeutic response, and guide precision immunotherapy in RCC.

Keywords:  CAF; RCC; T cells; TAM; TME; lymphocytes; macrophages; scRNA sequencing; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2025.11.001
Nat Commun. 2025 Dec 04. 16(1): 10898

Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.

Tatiana N Tarasenko, Emily Warren, Bharati Singh, Amanda Fuchs, Jose Marin, Marten Szibor, Christopher King, Peter J McGuire.

T cell activation requires extensive metabolic reprogramming, but the specific requirement for mitochondrial respiration (MR) remains unresolved. While most studies have focused on aerobic glycolysis as the primary driver of proliferation and effector function, the role of MR has not been completely defined. To isolate MR from proton pumping by cytochrome c oxidase (COX), we expressed the non-proton-pumping alternative oxidase (AOX) in activated COX-deficient T cells. AOX restored electron flow, membrane potential, and mitochondrial ATP production, ultimately rescuing proliferation, effector and memory differentiation, and antiviral immunity. These improvements required upstream electron input, particularly from Complex I, with Complex II and DHODH contributing more modestly. Despite restored MR, glycolysis remained elevated, likely due to altered redox signaling. These findings demonstrate that MR, normally mediated by COX, is necessary and can be sufficient to support T cell activation and function, independent of proton translocation, provided upstream electron input is maintained.

DOI: https://doi.org/10.1038/s41467-025-65910-w
Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00488-7. [Epub ahead of print]37(12): 2295

Toward the next 20 years of Cell Metabolism.

Salvatore Fabbiano, Mari-Carmen Fernández-Agüera, Beste Mutlu, Patrick Schaefer, Yongmei Sun.

DOI: https://doi.org/10.1016/j.cmet.2025.11.004
Nat Metab. 2025 Dec 03.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy.

Olaya Santiago-Fernández, Luisa Coletto, Inmaculada Tasset, Susmita Kaushik, Axel R Concepcion, Rizwan Qaisar, Adrián Macho-González, Kristen Lindenau, Antonio Diaz, Rabia R Khawaja, Stefano Donega, Nirad Banskota, Ceereena Ubaida-Mohien, Gavin Pharaoh, Bumsoo Ahn, Lisa M Hartnell, Ignacio Ramírez-Pardo, Bhakti Chavda, Aiara Gazteluiturri, Michael Kinter, Luigi Ferrucci, Julie A Reisz, Angelo D'Alessandro, Holly Van Remmen, Pura Muñoz-Cánoves, Stefan Feske, Ana Maria Cuervo.

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise and tissue repair, but declines in ageing and obesity. Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

DOI: https://doi.org/10.1038/s42255-025-01412-9
Nat Metab. 2025 Dec 03.

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age.

Ignacio Ramírez-Pardo, Silvia Campanario, Bhakti Chavda, Olaya Santiago-Fernández, Marta Flández, Mercedes Grima-Terrén, Andrés Cisneros, Aina Calls-Cobos, Daniel N Itzhak, Bryan Ngo, Sudha Janaki-Raman, Edward D Kantz, Laura Ortet, Antonio Diaz, Kristen Lindenau, Julio Doménech-Fernández, Mari Carmen Gómez-Cabrera, Emilio Camafeita, Jesús Vázquez, Marta Martinez-Vicente, Antonio L Serrano, Eusebio Perdiguero, Joan Isern, Ana Maria Cuervo, Pura Muñoz-Cánoves.

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration. Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

DOI: https://doi.org/10.1038/s42255-025-01411-w
Biol Rev Camb Philos Soc. 2025 Nov 30.

The return of metabolism: biochemistry and physiology of glycolysis.

Nana-Maria Grüning, Federica Agostini, Camila Caldana, Johannes Hartl, Matthias Heinemann, Markus A Keller, Jan Lukas Krüsemann, Costanza Lamperti, Carole L Linster, Steffen N Lindner, Julia Muenzner, Jens Nielsen, Zoran Nikoloski, Bettina Siebers, Jacky L Snoep, Hezi Tenenboim, Bas Teusink, Spencer J Williams, Mirjam M C Wamelink, Markus Ralser.

  Glycolysis is a fundamental metabolic pathway central to the bioenergetics and physiology of virtually all living organisms. In this comprehensive review, we explore the intricate biochemical principles and evolutionary origins of glycolytic pathways, from the classical Embden-Meyerhof-Parnas (EMP) pathway in humans to various prokaryotic and alternative glycolytic routes. By examining glycolysis across the tree of life, we explore its presence and adaptation in prokaryotes, archaea, bacteria, animals and plants, and the extension of glycolysis into sulfosugar metabolism. Further, we discuss the role of unwanted side reactions, thermodynamic principles, and metabolic control principles that underpin glycolysis and the broader metabolic network, and summarise advanced methods for quantifying glycolytic activity, including new analytical methods, alongside kinetic, constraint-based, and machine-learning based modelling. With a focus on the Pasteur, Crabtree, and Warburg effects, this review further discusses the roles of glycolysis in health and disease, highlighting its impact on global metabolic operations, inborn errors, and various pathologies as well as its role in biotechnology and metabolic engineering.

Keywords:  Crabtree effect; Pasteur effect; Warburg effect; biochemical pathway; computational modelling; energy metabolism; glycolysis; metabolic diseases; metabolic regulation; thermodynamics

DOI:  https://doi.org/10.1111/brv.70104
Nat Commun. 2025 Dec 02.

Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.

NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group

We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.

DOI: https://doi.org/10.1038/s41467-025-65845-2
Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00905-0. [Epub ahead of print]

Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation.

Shashank Srivastava, Daniela Samaniego-Castruita, Shubhi Srivastava, Sakshi Khurana, Jalees Rehman, Vipul Shukla, Issam Ben-Sahra, Daniel R Foltz.

  Chromatin formation requires both an adequate nucleotide supply and histone availability. Newly synthesized histones are escorted by histone chaperones that mediate their orderly transfer from ribosomes to DNA. While nucleotide and histone synthesis are the two major biosynthetic processes required for chromatin assembly, how these processes are coordinated remains unknown. Phosphoribosyl pyrophosphate synthetases (PRPSs), which catalyze the first and rate-limiting step in nucleotide biosynthesis, form a complex with PRPS-associated proteins (PRPSAPs). Using a rapid degron system in multiple human cell lines, we show that PRPS enzymes, together with PRPSAPs, play a key role in early histone maturation independent of their nucleotide biosynthetic function. Depletion of either PRPS1 or PRPSAP1 limits histone availability and disrupts chromatin assembly. These findings reveal a previously unrecognized synchrony between nucleotide metabolism and chromatin regulation, providing insight into how nucleotide production and histone deposition are coordinated.

Keywords:  PRPS; PRPSAP; chromatin; chromatin assembly; histone chaperone; histone deposition; histone supply; metabolism; nucleotide metabolism

DOI:  https://doi.org/10.1016/j.molcel.2025.11.009
Cancer Metastasis Rev. 2025 Nov 29. 44(4): 86

Advancing small cell lung cancer metastasis research: innovations in preclinical mouse models.

Qiqi Zhao, Liang Hu, Hongbin Ji.

  Small cell lung cancer (SCLC) represents one of the most aggressive malignancies, featured with its extraordinary metastatic capacity. Preclinical mouse models have become indispensable systems for studying the molecular mechanisms underlying SCLC metastasis. This review summarizes recent advances in genetically engineered mouse models (GEMMs) and transplantation models for SCLC metastasis research, highlighting their unique advantages in investigating oncogenic drivers, tumor heterogeneity, immune interactions, and therapeutic responses. We further discuss emerging technologies capable of integrating with these models to advance both mechanistic and translational research. Lineage tracing and multi-omics approaches have provided unprecedented resolution in mapping clonal dynamics and phenotypic plasticity during SCLC metastasis. High-throughput in vivo screening has accelerated the systematic identification of novel metastasis regulators, and humanized mouse models offer clinically relevant systems for investigating human-specific tumor-immune interactions and supporting preclinical evaluation of immunotherapies. Collectively, these preclinical systems are reshaping our understanding of SCLC metastasis and providing powerful platforms to guide therapeutic discovery.

Keywords:  Allografts; Genetically engineered mouse models; Mouse models; Small cell lung cancer metastasis; Xenografts

DOI:  https://doi.org/10.1007/s10555-025-10301-2
FEBS J. 2025 Dec 05.

MAVS oligomerization drives a faster and more efficient antiviral signaling activation at peroxisomes compared to mitochondria.

Bruno Ramos, Jéssica Sarabando, Mariana Marques, Jonathan C Kagan, Daniela Ribeiro.

  Peroxisomes and mitochondria are important platforms for antiviral signal transduction, as detection of cytosolic viral RNA by retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) induces the activation of the mitochondrial antiviral signaling adaptor (MAVS) at both organelles. To decisively elucidate the mechanistic differences and similarities in kinetics and end products between these two pathways, we developed a doxycycline-inducible system that allows for precise control of MAVS expression and activation at either peroxisomes or mitochondria, in a timely manner, and across various cell types. Our findings demonstrate that both peroxisomal and mitochondrial MAVS induce type I and III interferon-dependent antiviral signaling and that the peroxisomal signaling occurs significantly faster than its mitochondrial counterpart. Importantly, using not only the doxycycline-inducible system but also the conventional activation of the MAVS pathway through direct stimulation of RIG-I-like receptors, we demonstrate that the rapid and robust antiviral response resulting from peroxisomal MAVS activation is mechanistically due to the faster oligomerization of MAVS at the membranes of this organelle, when compared to mitochondria. These data emphasize the versatility and speed of the peroxisome-dependent antiviral response and may lead to the identification of specific targets to develop novel host-directed antiviral strategies.

Keywords:  MAVS; MAVS oligomerization; antiviral signaling; mitochondria; peroxisomes

DOI:  https://doi.org/10.1111/febs.70360
Cell Metab. 2025 Dec 03. pii: S1550-4131(25)00486-3. [Epub ahead of print]

Excessive vigorous exercise impairs cognitive function through a muscle-derived mitochondrial pretender.

Yan Huang, Biao Hu, Ya Liu, Ling-Qi Xie, Yu Dai, Yu-Ze An, Xin-Yi Peng, Ya-Lun Cheng, Yi-Fan Guo, Wei-Hong Kuang, Yao Xiao, Xin Chen, Yong-Jun Zheng, Gen-Qing Xie, Jian-Ping Wang, Hui Peng, Xiang-Hang Luo.

  Excessive exercise impairs cognitive function, but the underlying mechanism remains unclear. Here, we show that excessive vigorous exercise-induced lactate accumulation stimulates muscles to secrete mitochondria-derived vesicles (MDVs), driving cognitive impairment. These MDVs (named otMDVs) are characterized by high mtDNA levels and the surface marker PAF. They tend to migrate into hippocampal neurons, substituting endogenous mitochondria and triggering a synaptic energy crisis. Mechanistically, otMDVs release mtDNA, which activates cGAS-STING-dependent inhibition of kinesin family member 5, preventing hippocampal mitochondria from transporting to synapses. Simultaneously, the otMDV marker PAF cooperates with syntaphilin to occupy mitochondrial anchoring sites, impairing synaptic energy supply. Blocking otMDVs migration into the hippocampus with a PAF-neutralizing antibody alleviates excessive vigorous exercise-induced synapse loss and cognitive dysfunction. Notably, human studies link high circulating otMDV levels to cognitive impairment. Together, our findings reveal that a unique muscle-derived MDV subpopulation, which displaces hippocampal mitochondria and disrupts their function, causes cognitive decline.

Keywords:  MDVs; cognitive decline; excessive vigorous exercise

DOI:  https://doi.org/10.1016/j.cmet.2025.11.002
Nat Biotechnol. 2025 Dec 03.

Standardized metrics for assessment and reproducibility of imaging-based spatial transcriptomics datasets.

Jasmine T Plummer, Felipe Segato Dezem, David P Cook, Jiwoon Park, Luke Zhang, Yutian Liu, Maycon Marção, Hannah DuBose, Arjumand Wani, Kellie Wise, Michael Roach, Kate Harvey, Taopeng Wang, Kirk B Jensen, Natalia Morosini, Roberto De Gregorio, Alicia Alonso, Shauna Lee Houlihan, Robert E Schwartz, Erika Hissong, Catherine Snopkowski, Jeffrey L Wrana, Natalie Ryan, Lisa M Butler, George Church, Alexander Swarbrick, Christopher E Mason, Luciano G Martelotto.

Spatial transcriptomics lacks standardized metrics for evaluating imaging-based in situ hybridization technologies across sites. In this study, we generated the Spatial Touchstone (ST) dataset from six tissue types across several global sites with centralized sectioning, analyzed on both Xenium and CosMx platforms. These platforms were selected for their widespread use and distinct chemistries. We assessed reproducibility, sensitivity, dynamic ranges, signal-to-noise ratio, false discovery rates, cell type annotation and congruence with single-cell profiling. This study offers ST standardized operating procedures (STSOPs) and an open-source software, SpatialQM, enabling evaluation of samples across all technical metrics and direct imputation of cell annotations. The generated imaging-based spatial transcriptomics data repository comprises 254 spatial profiles, incorporating both public and newly generated ST datasets in a web-based application, which enables analysis and comparison of user data against an extensive collection of imaging-based datasets. Finally, we establish best practices and metrics to evaluate and integrate imaging-based multi-omics data from single cells into spatial transcriptomics to spatial proteomics.

DOI: https://doi.org/10.1038/s41587-025-02811-9