bims-camemi 2025-07-13 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–07–13
forty-five papers selected by
Christian Frezza, Universität zu Köln

Polyamines buffer labile iron to suppress ferroptosis.
Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.
Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.
Macrophage respiratory complex III governs immune evasion.
Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.
An unexpected career in cancer metabolism.
Purinosomes and Lysosomes Interact to Maintain the Purine Pools.
Organelles share the load.
Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.
Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion.
The role of metabolism in shaping enzyme structures over 400 million years.
Precise metabolic dependencies of cancer through deep learning and validations.
MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.
ANGPTL3 orchestrates hepatic fructose sensing and metabolism.
Stress is wrecking your health: how can science help?
Sideroflexins enable mitochondrial transport of polar neutral amino acids.
Kynurenine pathway dysregulation via loss of QPRT drives declines in activity and altered metabolism in mice.
A noncanonical cGAS-STING pathway drives cellular and organismal aging.
Super-resolution microscopy of mitochondrial mRNAs.
Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.
Nutrients activate distinct patterns of small-intestinal enteric neurons.
A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.
Serine ADPr on histones and PARP1 is a cellular target of ester-linked ubiquitylation.
The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes.
Oxidative Phosphorylation in Uncoupled Mitochondria.
Mitochondrial ATP-Sensitive K+ Channels (MitoKATP) Regulate Brown Adipocyte Differentiation and Metabolism.
Adaptations of lipid metabolism in low-grade clear cell renal cell carcinoma are linked to cholesteryl ester accumulation.
White Paper on Nutrition Sensing and Ageing.
Evolution of growth factor signaling to the TSC complex to regulate mTORC1.
Nucleosome spacing can fine-tune higher-order chromatin assembly.
Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.
ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.
HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.
Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP.
Aging impairs peroxisome biogenesis in human B cells.
Selective remodelling of the adipose niche in obesity and weight loss.
Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers.
Immunogenicity of autologous and allogeneic human primary cholangiocyte organoid cellular therapies.
Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy.
Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity.
CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure.
Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease.
GDF15: from biomarker to target in cancer cachexia.
Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.
Glycogen metabolism: not just a one-trick pony.

bioRxiv. 2025 Jul 02. pii: 2025.06.30.662349. [Epub ahead of print]

Polyamines buffer labile iron to suppress ferroptosis.

Pushkal Sharma, Heather R Keys, Sebastian Müller, Ivan S Pires, Ryan Mansell, Shinya Imada, Tenzin Kunchok, Millenia Waite, Christalyn Ausler, Bingbing Yuan, Amy Deik, Paula T Hammond, Raphaël Rodriguez, Whitney Henry, Ankur Jain.

Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines function as endogenous buffers of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using genome-wide CRISPR screens, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, GPX4. Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.

DOI: https://doi.org/10.1101/2025.06.30.662349
Sci Adv. 2025 Jul 11. 11(28): eadw1883

Sensing of extracellular l-proline availability by the integrated stress response determines the outcome of cell competition.

Shruthi Krishnan, Ana Lima, Sizhe Tan, Ying Thong Low, Salvador Perez Montero, Aida Di Gregorio, Adrian Perez Barreto, Sarah Bowling, Karen Vousden, Tristan A Rodriguez.

Cell competition is a conserved fitness quality control that eliminates cells that are less fit than their neighbors. How winner cells induce the elimination of losers is poorly understood. We tackle this question by studying the onset of embryonic differentiation in mice, where cell competition eliminates 35% of embryonic cells. These loser cells have mitochondrial dysfunction, which we show causes amino acid deprivation and activation of the integrated stress response (ISR), a pathway essential for their survival. We demonstrate that l-proline is a key amino acid sensed by the ISR and that proline represses the ISR and drives their elimination. These results indicate that cell competition acts as a previously unidentified tissue-sparing mechanism, regulated by the availability of extracellular amino acids, that allows for the elimination of dysfunctional cells when amino acids are plentiful but ensures their survival in nutrient-poor environments.

DOI: https://doi.org/10.1126/sciadv.adw1883
PLoS Genet. 2025 Jul 07. 21(7): e1011773

Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions.

Leonor Miller-Fleming, Wing Hei Au, Laura Raik, Pedro Rebelo-Guiomar, Jasper Schmitz, Ha Yoon Cho, Aron Czako, Alexander J Whitworth.

Mitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that the Drosophila melanogaster and Saccharomyces cerevisiae Clu/Clu1 proteins form dynamic, membraneless, mRNA-containing granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial proteins by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggest that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.

DOI: https://doi.org/10.1371/journal.pgen.1011773
Immunometabolism (Cobham). 2025 Jul;7(3): e00065

Macrophage respiratory complex III governs immune evasion.

Marie Anne-Catherine Neumann, Christian Frezza.

  The intricate interplay between cellular metabolism and immune function has emerged as a pivotal area of research in immunology. Macrophages, as central players in the innate immune system, exhibit remarkable metabolic flexibility that influences their activation states and functional outputs, with important implications for the pathophysiology of inflammatory diseases and cancer. A recent study by Zotta and colleagues provides new insights into the role of mitochondrial complex III (CIII) in regulating the anti-inflammatory cytokine interleukin-10 (IL-10) and its implications for tumor immunity.

Keywords:  IL-10; ROS; immune evasion; inflammation; metabolism; mitochondria

DOI:  https://doi.org/10.1097/IN9.0000000000000065
Cell Immunol. 2025 Jun 28. pii: S0008-8749(25)00086-3. [Epub ahead of print]414 105000

Acetyl-CoA subcellular compartmentalization regulates T cell adaptation.

Annefien Tiggeler, Paul J Coffer.

  Upon activation, naïve T cells undergo rapid proliferation and differentiation, giving rise to clonally expanded populations specifically tailored for an effective immune response. To meet the heightened bioenergetic and biosynthetic demands associated with activation, T cells adapt and reprogram both their metabolism and transcriptome. Beyond this, T cells are also able to dynamically adapt to fluctuations in the microenvironmental nutrient levels. While the adaptability of T cells is a well-established hallmark of their functionality, the molecular mechanisms by which metabolic responses underpin this flexibility remain incompletely defined. Acetyl-CoA, with its role as a central metabolite in mitochondrial ATP production, and a substrate for nuclear histone acetylation reactions, emerges as a key player in a metabolic-epigenetic axis. Recent evidence indicates that enzymes responsible for generating acetyl-CoA can translocate to the nucleus, supporting sub-cellular local acetyl-CoA production. Here, we explore the impact of acetyl-CoA metabolism on T cell functionality within different subcellular compartments and highlight the potential for intervention in acetyl-CoA metabolic pathways in T cell-driven autoimmune diseases and cancers.

Keywords:  Acetyl-CoA; Epigenetic remodelling; Metabolic reprogramming; Nuclear metabolism; T cells

DOI:  https://doi.org/10.1016/j.cellimm.2025.105000
Nat Cancer. 2025 Jul 08.

An unexpected career in cancer metabolism.

Ralph J DeBerardinis.

DOI: https://doi.org/10.1038/s43018-025-01017-x
Int J Biochem Cell Biol. 2025 Jul 05. pii: S1357-2725(25)00098-6. [Epub ahead of print] 106830

Purinosomes and Lysosomes Interact to Maintain the Purine Pools.

Yubing Liu, Vidhi Pareek, Dipankar Bhowmik, Xin Zhang, Stephen J Benkovic.

  Purines are the building blocks of DNA/RNA and hence essential metabolites. While the contributions of external purine salvage as well as the de novo purine biosynthesis (DNPB) have been widely studied, the contribution of lysosome mediated DNA/RNA digestion and external reabsorption into the cytosol remains unknown. Here, we address that question as well as the role of lysosome-mediated purine recycling and its coordination with DNPB in maintaining total purine pools in human cancer cell lines. By combining in-cell stable isotope incorporation assay with quantitative metabolomics we show: cellular uptake of external purines and their internal generation are equivalent; an upregulation in lysosome biogenesis that functions in response to purine deficiency caused by methotrexate (MTX) and lometrexol (LTX) treatment. This leads to increased RNA digestion as visualized by a newly developed intracellular RNA-FRET oligo assay. Interestingly, downregulation of lysosomal RNase activity through knockdown of RNAseT2 increased RNA accumulation and a compensating increase in DNPB.

Keywords:  RNASET2; de novo purine biosynthesis; lysosome; mTORC1; purine salvage; purinosome

DOI:  https://doi.org/10.1016/j.biocel.2025.106830
Science. 2025 Jul 10. 389(6756): 130-131

Organelles share the load.

Marc Fransen.

Peroxisome-mitochondria contact sites manage mitochondrial oxidative stress.

DOI: https://doi.org/10.1126/science.adz0109
Nature. 2025 Jul 09.

Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.

Guangbin Shi, Claire Miller, Sota Kuno, Alejandro G Rey Hipolito, Salsabiel El Nagar, Giulietta M Riboldi, Megan Korn, Wyatt C Tran, Zixuan Wang, Lia Ficaro, Tao Lin, Quentin Spillier, Begoña Gamallo-Lana, Drew R Jones, Matija Snuderl, Soomin C Song, Adam C Mar, Alexandra L Joyner, Roy V Sillitoe, Robert S Banh, Michael E Pacold.

Decreased brain levels of coenzyme Q10 (CoQ10), an endogenously synthesized lipophilic antioxidant1,2, underpin encephalopathy in primary CoQ10 deficiencies3,4 and are associated with common neurodegenerative diseases and the ageing process5,6. CoQ10 supplementation does not increase CoQ10 pools in the brain or in other tissues. The recent discovery of the mammalian CoQ10 headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ10 headgroup precursor 4-hydroxybenzoate (4-HB)7, offers an opportunity to pharmacologically restore CoQ10 synthesis and mechanistically treat CoQ10 deficiencies. To test whether 4-HMA or 4-HB supplementation promotes CoQ10 headgroup synthesis in vivo, here we administered 4-HMA and 4-HB to Hpdl-/- mice, which model an ultra-rare, lethal mitochondrial encephalopathy in humans. Both 4-HMA and 4-HB were incorporated into CoQ9 and CoQ10 in the brains of Hpdl-/- mice. Oral treatment of Hpdl-/- pups with 4-HMA or 4-HB enabled 90-100% of Hpdl-/- mice to live to adulthood. Furthermore, 4-HB treatment stabilized and improved the neurological symptoms of a patient with progressive spasticity due to biallelic HPDL variants. Our work shows that 4-HMA and 4-HB can modify the course of mitochondrial encephalopathy driven by HPDL variants and demonstrates that CoQ10 headgroup intermediates can restore CoQ10 synthesis in vivo.

DOI: https://doi.org/10.1038/s41586-025-09246-x
J Clin Invest. 2025 Jul 10. pii: e191855. [Epub ahead of print]

Somatic mutations in TBX3 promote hepatic clonal expansion by accelerating VLDL secretion.

Gregory Mannino, Gabriella Quinn, Min Zhu, Zixi Wang, Xun Wang, Boyuan Li, Meng-Hsiung Hsieh, Thomas Mathews, Lauren Zacharias, Wen Gu, Purva Gopal, Natalia Brzozowska, Peter Campbell, Matt Hoare, Glen Liszczak, Hao Zhu.

  Somatic mutations that increase clone fitness or resist disease are positively selected, but the impact of these mutations on organismal health remains unclear. We previously showed that Tbx3 deletion increases hepatocyte fitness within fatty livers. Here, we detected TBX3 somatic mutations in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In mice, Tbx3 deletion protected against, whereas Tbx3 overexpression exacerbated MASLD. Tbx3 deletion reduced lipid overload by accelerating VLDL secretion. Choline deficient diets, which block VLDL secretion, abrogated this protective effect. TBX3 transcriptionally suppressed the conventional secretory pathway and cholesterol biosynthesis. Hdlbp is a direct target of TBX3 that is responsible for the altered VLDL secretion. In contrast to wild-type TBX3, the TBX3 I155S and A280S mutations found in patients failed to suppress VLDL secretion. In conclusion, TBX3 mutant clones expand during MASLD through increased lipid disposal, demonstrating that clonal fitness can benefit the liver at the cost of hyperlipidemia.

Keywords:  Cell biology; Gastroenterology; Hepatitis

DOI:  https://doi.org/10.1172/JCI191855
Nature. 2025 Jul 09.

The role of metabolism in shaping enzyme structures over 400 million years.

Oliver Lemke, Benjamin Murray Heineike, Sandra Viknander, Nir Cohen, Feiran Li, Jacob Lucas Steenwyk, Leonard Spranger, Federica Agostini, Cory Thomas Lee, Simran Kaur Aulakh, Judith Berman, Antonis Rokas, Jens Nielsen, Toni Ingolf Gossmann, Aleksej Zelezniak, Markus Ralser.

Advances in deep learning and AlphaFold2 have enabled the large-scale prediction of protein structures across species, opening avenues for studying protein function and evolution1. Here we analyse 11,269 predicted and experimentally determined enzyme structures that catalyse 361 metabolic reactions across 225 pathways to investigate metabolic evolution over 400 million years in the Saccharomycotina subphylum2. By linking sequence divergence in structurally conserved regions to a variety of metabolic properties of the enzymes, we reveal that metabolism shapes structural evolution across multiple scales, from species-wide metabolic specialization to network organization and the molecular properties of the enzymes. Although positively selected residues are distributed across various structural elements, enzyme evolution is constrained by reaction mechanisms, interactions with metal ions and inhibitors, metabolic flux variability and biosynthetic cost. Our findings uncover hierarchical patterns of structural evolution, in which structural context dictates amino acid substitution rates, with surface residues evolving most rapidly and small-molecule-binding sites evolving under selective constraints without cost optimization. By integrating structural biology with evolutionary genomics, we establish a model in which enzyme evolution is intrinsically governed by catalytic function and shaped by metabolic niche, network architecture, cost and molecular interactions.

DOI: https://doi.org/10.1038/s41586-025-09205-6
Cell Rep. 2025 Jul 03. pii: S2211-1247(25)00716-8. [Epub ahead of print]44(7): 115945

Precise metabolic dependencies of cancer through deep learning and validations.

Tao Wu, Xiangyu Zhao, Yu Zhang, Die Qiu, Kaixuan Diao, Dongliang Xu, Weiliang Wang, Xiaopeng Xiong, Xinxiang Li, Xue-Song Liu.

  Cancer cells exhibit metabolic reprogramming to sustain proliferation, creating metabolic vulnerabilities absent in normal cells. While prior studies identified specific metabolic dependencies, systematic insights remain limited. Here, we build a graph deep learning-based metabolic vulnerability prediction model, "DeepMeta," which can accurately predict the dependent metabolic genes for cancer samples based on transcriptome and metabolic network information. The performance of DeepMeta has been extensively validated with independent datasets. The metabolic vulnerability of "undruggable" cancer-driving alterations has been systematically explored using The Cancer Genome Atlas (TCGA) dataset. Notably, CTNNB1 T41A-activating mutations showed experimentally confirmed vulnerability to purine/pyrimidine metabolism inhibition. TCGA patients with the predicted pyrimidine metabolism dependency show a dramatically improved clinical response to chemotherapeutic drugs that block this pyrimidine metabolism pathway. This study systematically uncovers the metabolic dependency of cancer cells and provides metabolic targets for cancers driven by genetic alterations that are originally undruggable on their own.

Keywords:  CP: Cancer; CP: Metabolism; CTNNB1; GAT; cancer metabolism; drug target; graph attention network; metabolic dependency; nucleotide metabolism; undruggable

DOI:  https://doi.org/10.1016/j.celrep.2025.115945
J Cell Sci. 2025 Jul 01. pii: jcs263701. [Epub ahead of print]138(13):

MitoRUSH as a tool to study the efficiency of mitochondrial import in complex I-deficient cells.

Michal Wasilewski, Karthik Mohanraj, Maciej Zakrzewski, Remigiusz A Serwa, Agnieszka Chacinska.

  Most mitochondrial proteins are imported through the actions of the presequence translocase of the inner membrane, the TIM23 complex, which requires energy in the form of the electrochemical potential of the inner membrane and ATP. Conversions of energy in mitochondria are disturbed in mitochondrial disorders that affect oxidative phosphorylation. Despite the widely accepted dependence of protein import into mitochondria on mitochondrial bioenergetics, effects of mitochondrial disorders on biogenesis of the mitochondrial proteome are poorly characterized. Here, we describe molecular tools that can be used to explore mitochondrial protein import in intact cells, the mitoRUSH assay, and a novel method based on labeling of nascent proteins with an amino acid analog and click chemistry. Using these orthogonal approaches, we discovered that defects in the electron transport chain and manipulating the expression of TIMM23, as well as the TIMM17A or TIMM17B paralogs, in human cells are associated with a decrease in protein import into mitochondria. We postulate that in the absence of a functional electron transfer chain, the mechanisms that support electrochemical potential of the inner membrane and ATP production are insufficient to sustain the import of proteins to mitochondria.

Keywords:  Bioenergetics; Mitochondria; Mitochondrial diseases; Protein import; TIM23; Translocase; mitoRUSH

DOI:  https://doi.org/10.1242/jcs.263701
Cell Rep. 2025 Jul 09. pii: S2211-1247(25)00733-8. [Epub ahead of print]44(7): 115962

ANGPTL3 orchestrates hepatic fructose sensing and metabolism.

Meng Zhao, Karen Y Linde-Garelli, Zeyuan Zhang, David Toomer, Saranya C Reghupaty, John Isaiah Jimenez, Laetitia Coassolo, Lianna W Wat, Daniel Fernandez, Katrin J Svensson.

  Fructose metabolism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the regulatory mechanisms governing fructose uptake remain poorly understood. Here, we demonstrate that MASLD livers exhibit increased uptake of fructose-derived carbons compared to healthy livers and identify that the MASLD hepatocyte secretome can increase fructose metabolism. By performing fractionation and untargeted proteomics, we uncover a role for Angiopoietin-like 3 (ANGPTL3) as a regulator of hepatic fructose metabolism, independent of its role as a lipoprotein lipase (LPL) inhibitor. Circulating ANGPTL3 levels increase in response to fructose exposure, consistent with an action as a fructose sensor. Angptl3 knockdown in the liver resulted in a significant reduction in the uptake of hepatic fructose metabolites in vivo and downregulation of the facilitative hepatic fructose transporter slc2a8 (GLUT8) and fructolysis enzymes. This work demonstrates the existence of extracellular control of hepatic fructose metabolism through ANGPTL3.

Keywords:  ANGPTL3; CP: Metabolism; MASLD; fructolysis; fructose

DOI:  https://doi.org/10.1016/j.celrep.2025.115962
Nature. 2025 Jul;643(8071): 318-320

Stress is wrecking your health: how can science help?

Lynne Peeples.



Keywords:  Ageing; Physiology; Psychology; Public health; Therapeutics

DOI:  https://doi.org/10.1038/d41586-025-02066-z
bioRxiv. 2025 Jul 02. pii: 2025.06.18.660357. [Epub ahead of print]

Sideroflexins enable mitochondrial transport of polar neutral amino acids.

Samuel Block, Fangtao Chi, Paul C Rosen, S Sebastian Pineda, Alicia M Darnell, Keene L Abbott, Izabella A Pena, Myriam Heiman, Ömer H Yilmaz, Nora Kory, Matthew G Vander Heiden.

Mitochondria contribute to compartmentalized metabolism in eukaryotic cells, supporting key enzymatic reactions for cell function and energy homeostasis. However, this compartmentalization necessitates regulated metabolite transport across mitochondrial membranes. Although many transport proteins have been identified, several mitochondrial amino acid transporters remain largely uncharacterized. Using CRISPR-Cas9-mediated candidate transporter knockouts coupled with assessment of metabolite transport via a mitochondrial swelling assay, we identify SFXN1, previously characterized for its role in mitochondrial serine transport, as a protein that mediates mitochondrial transport of a range of other polar neutral amino acids including proline, glycine, threonine, taurine, hypotaurine, β-alanine, and γ-aminobutyric acid (GABA). Furthermore, the SFXN1 paralogues SFXN2 and SFXN3 partially complement loss of SFXN1 to enable glycine transport, while SFXN2 and SFXN5 partially complement loss of SFXN1 to enable GABA transport. Altogether, these data suggest that sideroflexins facilitate the transport of polar neutral amino acids across the inner mitochondrial membrane.

DOI: https://doi.org/10.1101/2025.06.18.660357
Geroscience. 2025 Jul 10.

Kynurenine pathway dysregulation via loss of QPRT drives declines in activity and altered metabolism in mice.

Reyhan Westbrook, Vinal Menon, Joy Cagmat, Timothy Garrett, Robert Schwarcz, Jeremy Walston, Peter M Abadir, Tae Chung.

  Chronic inflammatory pathway activation increases with age and is epidemiologically linked to multiple aging-related pathophysiological processes, phenotypes such as physical frailty and sarcopenia and early healthspan declines in aging organisms. Despite this, molecular mechanisms that directly connect chronic inflammation to these conditions remain poorly characterized. We hypothesize that chronic inflammation contributes to the development of age-related phenotypes by increasing the degradation of dietary tryptophan into multiple metabolites with unique physiological properties, called kynurenines, via the 'kynurenine pathway' (KP). To understand the impact of elevated KP metabolites on mammalian healthspan we utilized the quinolinate phosphoribosyltransferase knock-out (QPRT-/-) mouse which lacks the terminal enzyme of the KP and thus develops increased levels of downstream kynurenines. We tested the effects of this mutation on glucose handling, spontaneous motor activity, body composition and metabolism using indirect calorimetry, in male and female, young, middle aged and older mice. QPRT - / - mice had significantly altered levels of numerous KP metabolites and nicotinamide. Phenotypic characteristics varied in a sex-specific manner with decreased activity, lean mass and VO2, and impaired glucose clearance as early as 12 months seen in female QPRT-/- compared to age and sex-matched mice. Male QPRT-/- mice developed reduced lean mass by middle age and had altered respiration and food intake. This data indicates that KP dysregulation can drive declines in activity and alter metabolism in mammals and is a potential target to intervene on frailty and functional decline.

Keywords:  Indirect calorimetry; Kynurenine; Metabolism; Mice; Nicotinamide; Quinolinic acid

DOI:  https://doi.org/10.1007/s11357-025-01735-1
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2424666122

A noncanonical cGAS-STING pathway drives cellular and organismal aging.

Rafael Cancado de Faria, Lilian N D Silva, Barbara Teodoro-Castro, Kyle S McCommis, Elena V Shashkova, Susana Gonzalo.

  Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson-Gilford progeria syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the nonconventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype and the interferon response, in a cGAS and STING-dependent manner, revealing a noncanonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the noncanonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a noncanonical pathway that drives senescence/aging phenotypes.

Keywords:  aging; cGAS; cytosolic DNA; senescence-associated secretory phenotype; stimulator of interferon genes

DOI:  https://doi.org/10.1073/pnas.2424666122
Nat Commun. 2025 Jul 10. 16(1): 6391

Super-resolution microscopy of mitochondrial mRNAs.

Stefan Stoldt, Frederike Maass, Michael Weber, Sven Dennerlein, Peter Ilgen, Jutta Gärtner, Aysenur Canfes, Sarah V Schweighofer, Daniel C Jans, Peter Rehling, Stefan Jakobs.

Mitochondria contain their own DNA (mtDNA) and a dedicated gene expression machinery. As the mitochondrial dimensions are close to the diffraction limit of classical light microscopy, the spatial distribution of mitochondrial proteins and in particular of mitochondrial mRNAs remains underexplored. Here, we establish single-molecule fluorescence in situ hybridization (smFISH) combined with STED and MINFLUX super-resolution microscopy (nanoscopy) to visualize individual mitochondrial mRNA molecules and associated proteins. STED nanoscopy reveals the spatial relationships between distinct mRNA species and proteins such as the RNA granule marker GRSF1, demonstrating adaptive changes in mRNA distribution and quantity in challenged mammalian cells and patient-derived cell lines. Notably, STED-smFISH shows the release of mRNAs during apoptosis, while MINFLUX reveals the folding of the mRNAs into variable shapes, as well as their spatial proximity to mitochondrial ribosomes. These protocols are transferable to various cell types and open new avenues for understanding mitochondrial gene regulation in health and disease.

DOI: https://doi.org/10.1038/s41467-025-61577-5
Cell Rep. 2025 Jul 01. pii: S2211-1247(25)00693-X. [Epub ahead of print] 115922

Controlling mitochondrial membrane architecture via MIC60 determines viral replication to promote anti-viral immunity.

Ichiro Katahira, Nina Liebrand, Michal Gorzkiewicz, Niklas Paul Klahm, Džiuljeta Abromavičiūtė, Julia Werner, Karina Stephanie Krings, Sarah Orywol, Tobias Lautwein, Karl Köhrer, Diran Herebian, Ertan Mayatepek, Max Anstötz, Ann Kathrin Bergmann, Arun Kumar Kondadi, Haifeng C Xu, Aleksandra A Pandyra, Takumi Kobayashi, Dirk Brenner, Thomas Floss, Ulrich Kalinke, Andreas S Reichert, Philipp A Lang.

  Virus-infected cells often exhibit dramatic cellular changes accompanied by altered mitochondrial function. The contribution of factors shaping the inner mitochondrial membrane (IMM) and cristae architecture to viral replication is insufficiently understood. Single-cell transcriptomics applying vesicular stomatitis virus infection suggests involvement of factors determining IMM architecture following infection. Consistently, inhibition of the F1FO adenosine triphosphate (ATP) synthase reduces viral replication, which is associated with oligomerization of this complex and altered IMM structure. Moreover, deletion of mitochondrial contact site and cristae organizing system (MICOS) complex by targeting MIC60 results in reduced viral replication. Generation of Mic60inv/invCD11c-Cre+ mice uncovers reduced crista junctions and viral replication in bone marrow-derived dendritic cells. Consequently, reduced viral replication in CD11c-expressing cells limits prolonged immune activation. Altogether, by linking the F1FO ATP synthase and the MICOS complex to viral replication and immune activation, we describe links between the mitochondrial structure-metabolism and the immune response against viral infection.

Keywords:  BMDC; CP: Cell biology; CP: Microbiology; MIC60; MICOS; immunometabolism; innate immunity; inner mitochondrial membrane; itaconate; mitochondria; viral infection

DOI:  https://doi.org/10.1016/j.celrep.2025.115922
Nature. 2025 Jul 09.

Nutrients activate distinct patterns of small-intestinal enteric neurons.

Candice Fung, Tom Venneman, Amy M Holland, Tobie Martens, Milvia I Alata, Marlene M Hao, Ceyhun Alar, Yuuki Obata, Jan Tack, Alejandro Sifrim, Vassilis Pachnis, Werend Boesmans, Pieter Vanden Berghe.

The ability to detect and respond appropriately to ingested nutrients is essential for an organism's survival and to ensure its metabolic demands are met. Nutrient signals from the gut lumen trigger local intestinal reflexes in the enteric nervous system (ENS) to facilitate digestion and absorption1-4, but the precise cellular pathways that are involved in the initial neuronal sensory process remain unclear. The extent to which the ENS is capable of discerning different luminal chemicals is also unknown. Here we use calcium imaging to identify specific enteric pathways that are activated in response to luminal nutrients applied to mouse jejunum. Notably, we show that different nutrients activate neurochemically defined ensembles of myenteric and submucosal neurons. Furthermore, we find that enteric neurons are not directly sensitive to nutrients but detect different luminal chemicals through the epithelium, mainly via a serotonin signalling pathway. Finally, our data reveal a spatial distribution of luminal information along the radial axis of the intestine, whereby some signals that originate from the villus epithelium are transmitted first to the myenteric plexus, and then back to the submucosal plexus, which is closer to the lumen.

DOI: https://doi.org/10.1038/s41586-025-09228-z
FEBS J. 2025 Jul 07.

A guide to characterizing the dynamic mitochondria-endoplasmic reticulum contact sites.

Antigoni Diokmetzidou, Luca Scorrano.

  Organelles were once regarded as discrete entities, but it is now established that they interact through specialized membrane contacts maintained by protein tethers and lipid interactions. Among these, mitochondria-endoplasmic reticulum contact sites (MERCS) emerged as hubs for calcium signaling, lipid metabolism, and mitochondrial dynamics. Here, we critically appraise current methodologies for MERC visualization and quantification, survey the molecular toolbox for their selective perturbation, and highlight common experimental pitfalls. We also discuss key conceptual issues-defining MERCs on structural and functional grounds, addressing redundancy among tethering factors, and distinguishing primary MERC-mediated effects from secondary cellular responses. Finally, we propose that an integrative strategy combining imaging, precise biochemical isolation, proteomics, and functional assays will be essential to resolve outstanding questions about MERC dynamics in physiology and pathology.

Keywords:  endoplasmic reticulum; imaging; membrane contact sites; mitochondria; mitochondria–ER contact sites

DOI:  https://doi.org/10.1111/febs.70184
Nat Chem Biol. 2025 Jul 09.

Serine ADPr on histones and PARP1 is a cellular target of ester-linked ubiquitylation.

Andreas Kolvenbach, Maria Dilia Palumbieri, Thomas Colby, Diyaraj Nadarajan, Remo Bode, Ivan Matić.

ADP-ribosylation and ubiquitylation regulate various cellular processes, with the complexity of their interplay becoming increasingly clear, as illustrated by ADP-ribosylation-dependent ubiquitylation mediated by Legionella. Biochemical studies have reported ester-linked ubiquitylation of ADP-ribose by DELTEX ubiquitin ligases, yet the modification sites on cellular targets remain unknown. Here, our search for interactors of RNF114 revealed DNA-damage-induced serine mono-ADP-ribosylation as a cellular target for ester-linked ubiquitylation. By developing proteomics strategies tailored to the chemical features of this composite modification, combined with an enrichment method using the zfDi19 and ubiquitin interaction motif domain (ZUD) of RNF114 and specific chemical elution, we identified ADP-ribosyl-linked serine ubiquitylation sites in cells, including on histones and poly(ADP-ribose) polymerase 1. Engineering ZUD into a modular reagent enabled the detection of this dual modification by immunoblotting. We establish ADP-ribosyl-ubiquitylation as an endogenous serine post-translational modification and propose that our multifaceted, tailored methodology will uncover its widespread occurrence, along with other conjugation chemistries, across diverse signaling pathways.

DOI: https://doi.org/10.1038/s41589-025-01974-5
bioRxiv. 2025 Apr 11. pii: 2025.04.09.647991. [Epub ahead of print]

The mitochondrial NAD transporter SLC25A51 is a modulator of beta cell senescence and type 2 diabetes.

Byung Soo Kong, Sehi L'Yi, Erika Gabriela Ramirez-Hernandez, Serin Hong, Rosa Weidenspointner, Suyeon Song, Chase Caserta, Young Min Cho, Nora Kory.

Nicotinamide adenine dinucleotide (NAD + ) is an essential redox cofactor and signaling molecule linked to age-dependent metabolic decline, with its compartmentalization regulated by the mitochondrial carrier SLC25A51. The mechanisms contributing to declining NAD + levels during aging and the consequences of altered NAD + homeostasis across tissues are poorly understood. Here, we show that SLC25A51 is upregulated in aging and aging-associated conditions, particularly in senescent cells. In a mouse model of beta-cell senescence, upregulated SLC25A51 was associated with beta-cell identity loss, senescence progression, and a reduced NAD + /NADH ratio. SLC25A51 was elevated following p16 INK4a -, replicative-, irradiation-, and H 2 O 2 -induced senescence, with NRF2 implicated as a potential transcriptional regulator. Overexpression of SLC25A51, but not a transport-dead mutant, induced senescence factors, while its deletion prevented this effect. Beta-cell-specific deletion of SLC25A51 lowered p16 INK4a levels in pancreatic islets, circulating insulin, and glucose levels, improving insulin sensitivity and indicating its role in cellular senescence and the metabolic control of beta-cell function.

DOI: https://doi.org/10.1101/2025.04.09.647991
Bioessays. 2025 Jul 06. e70038

Oxidative Phosphorylation in Uncoupled Mitochondria.

Henver S Brunetta, Marcelo A Mori, Alexander Bartelt.

  Mitochondrial membrane potential is highly dependent on coupled as well as uncoupled respiration. While brown adipose tissue (BAT) mediates non-shivering thermogenesis (NST), a highly adaptive bioenergetic process critical for energy metabolism, the relationship of coupled and uncoupled respiration in thermogenic adipocytes remains complicated. Uncoupling protein 1 (UCP1)-mediated proton leak is the primary driver of NST, but recent studies have shown that oxidative phosphorylation may be an underappreciated contributor to UCP1-dependent NST. Here, we highlight the role of ATP synthase for BAT thermogenesis and discuss the implications of fine-tuning adrenergic signaling in brown adipocytes by the protein inhibitory factor 1 (IF1). We conclude by hypothesizing future directions for mitochondrial research, such as investigating the potential role of IF1 for mitochondrial substrate preference, structural dynamics, as well as its role in cell fate decision and differentiation.

Keywords:  UCP1; adipocytes; bioenergetics; metabolism; mitochondria; obesity; thermogenesis

DOI:  https://doi.org/10.1002/bies.70038
Am J Physiol Cell Physiol. 2025 Jul 11.

Mitochondrial ATP-Sensitive K+ Channels (MitoKATP) Regulate Brown Adipocyte Differentiation and Metabolism.

Osvaldo Rodrigues Pereira, Julian D C Serna, Camille C Caldeira da Silva, Henrique Camara, Sean D Kodani, William T Festuccia, Yu-Hua Tseng, Alicia J Kowaltowski.

  Brown adipose tissue (BAT) plays a central role in mammalian non-shivering thermogenesis, dissipating mitochondrial membrane potentials through the activity of uncoupling protein UCP1 to release heat. Inner membranes of mitochondria are known to be permeable to potassium ions (K+), which enter the matrix either through ATP-sensitive channels (MitoKATP) or leakage across the bilayer driven by inner membrane potentials. Mitochondrial K+ influx is associated with increased osmotic pressure, promoting water influx and increasing matrix volume. Since BAT mitochondria have lower inner membrane potentials due to uncoupling protein 1 (UCP1) activity, we hypothesized this could involve compensatory changes in MitoKATP activity, and thus tested MitoKATP involvement in brown adipocyte activities under basal and stimulated conditions. We find that cold exposure and adrenergic stimulation in mice modulate BAT MitoK levels, the channel portion of MitoKATP. Genetic ablation of the gene that codes for the pore-forming subunit of MitoKATP in human pre-adipocytes decreased cellular respiration and proliferation, compromising differentiation into mature adipocytes. In mouse cell lines, the absence of the protein limited cellular oxygen consumption in the precursor stage, but not in mature adipocytes. Interestingly, inhibition of MitoKATP in mature adipocytes increased adrenergic-stimulated oxygen consumption, indicating that shutdown of this pathway is important for full BAT thermogenesis. Similarly, MitoKATP inhibition increased oxygen consumption in BAT mitochondria isolated from mice treated with beta 3 adrenergic receptor agonist CL316,243. Overall, our results suggest that the activity of MitoKATP regulates differentiation and metabolism of brown adipocytes, impacting on thermogenesis.

Keywords:  K+ transport; brown adipose tissue; mitochondria; thermogenesis; uncoupling

DOI:  https://doi.org/10.1152/ajpcell.00070.2025
Sci Rep. 2025 Jul 09. 15(1): 24762

Adaptations of lipid metabolism in low-grade clear cell renal cell carcinoma are linked to cholesteryl ester accumulation.

Olatz Fresnedo, Jose Antonio Lopez-Gomez, Carlos Ceniceros, Gorka Larrinaga, Alberto Saiz, Lorena Mosteiro, Hiart Navarro-Imaz, Yuri Rueda.

  Clear cell renal cell carcinoma (ccRCC) is characterized by the accumulation of high quantities of lipids in cytoplasmic lipid droplets. Owing to the tissue heterogeneity of ccRCC, adjacent biopsies from a tumor can diverge substantially in molecular characteristics. To elucidate metabolic alterations leading to extensive lipidomic changes in grade 2 human nephrectomies, we applied a dual lipidome-transcriptome analytical procedure that allows performing correlational studies of the two datasets. Linked to the mean 100 fold increase of esterified cholesterol (ChE) in ccRCC we found multiple significant correlations between ChE and the main membrane lipids that might be mediated by an increased capacity for lipid hydrolysis linked to lysosomes and the endoplasmic reticulum.Our results suggest that the accumulation of ChE from extracellular sources might be a determinant metabolic flux in low-grade ccRCC. ChE mobilization by non-canonical hydrolytic systems might confer increased metabolic flexibility to obtain free cholesterol and fatty acids. Based on correlations between lipidome and lipometabolic transcriptome, this study provides new perspectives for evaluating pharmacological lipid management as a future therapeutic approach for low-grade ccRCC treatment.

Keywords:  AADAC; Cholesteryl ester accumulation; Kidney; Lipidomics; Lysosomal acid lipase; ccRCC

DOI:  https://doi.org/10.1038/s41598-025-09664-x
Nutr Bull. 2025 Jul 09.

White Paper on Nutrition Sensing and Ageing.

Aygul Dagbasi, Adrian Holliday, Bernadette Carroll, Chiara de Lucia, Oliver M Shannon, John Mathers, John McLaughlin, Chloe French, Aylin Hanyaloglu, Sorrel Burden, Douglas Morrison, Viktor Korolchuk, Gary Frost.

  Ageing, which is defined as the progressive deterioration of physiological functions, is an inevitable part of the lifecycle. Nevertheless, its progress is believed to be influenced by modifiable factors, one of the most important being dietary intake. Like many other systems within the human body, detection of nutrients (defined as nutrition sensing), their metabolism, and the body's response to nutrients may change with ageing. There is compelling evidence to suggest that nutrition sensing mechanisms can become dysregulated in certain ageing adults, which can lead to increased morbidity and mortality. However, there is still much to unravel in nutrition sensing and its impact on ageing on multiple levels from molecular signalling to the food environment. We hypothesise that nutrition sensing mechanisms play an important role in the ageing process. To this end, we formed the Ageing and Nutrition Sensing Network to bring together leading multi-disciplinary researchers and early career researchers with expertise across ageing, cell biology, nutrition, epidemiology, and policy. The network aims to address the priority area of health span and quality of life in older age. As a consortium, we defined nutrition sensing and identified five key challenges to be addressed to advance the field of nutrition sensing and ageing. This resulted in the development of four main projects, each one embracing multidisciplinary working and investigating nutrition sensing and ageing from different perspectives. Here we describe our network, our projects, and how we plan to incorporate our findings to promote healthy ageing from science and industry to policy.

Keywords:  ageing; healthy ageing; network; nutrition; nutrition sensing

DOI:  https://doi.org/10.1111/nbu.70020
Sci Signal. 2025 Jul 08. 18(894): eadw4165

Evolution of growth factor signaling to the TSC complex to regulate mTORC1.

Kun Wang, Sophie E Lockwood, Brendan D Manning.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates signals from factors that both stimulate (exogenous growth factors) and are essential for (intracellular nutrients and energy) cellular growth. Activation of the protein kinase mTOR within mTORC1 results in the phosphorylation of downstream substrates that collectively stimulate biomass accumulation to drive cell growth. Many upstream signals, especially growth factors, regulate mTORC1 by inducing the phosphorylation of the tuberous sclerosis complex 2 (TSC2) subunit of the TSC protein complex, a conserved brake on mTORC1 activation and its promotion of cell growth. Cryo-electron microscopy studies of the TSC protein complex have revealed that this phosphoregulation of TSC2 occurs almost exclusively on residues in loops that are outside of the evolutionarily conserved core structural elements and that did not resolve in these structures. These phosphorylation-rich unstructured loops evolved with metazoans, suggesting that the regulation of mTORC1 by diverse growth factors likely evolved with the emergence of complex body plans and diverse cell types to coordinate cell growth and metabolism within and across distinct tissues. Unlike the core structure of TSC2, these loops lack disease-associated missense mutations. These features suggest that the regulatory loops on TSC2 are more amenable to evolutionary changes that enable diverse signals to converge on the TSC protein complex to regulate mTORC1.

DOI: https://doi.org/10.1126/scisignal.adw4165
Nat Commun. 2025 Jul 09. 16(1): 6315

Nucleosome spacing can fine-tune higher-order chromatin assembly.

Lifeng Chen, M Julia Maristany, Stephen E Farr, Jinyue Luo, Bryan A Gibson, Lynda K Doolittle, Jorge R Espinosa, Jan Huertas, Sy Redding, Rosana Collepardo-Guevara, Michael K Rosen.

Cellular chromatin displays heterogeneous structure and dynamics, properties that control diverse nuclear processes. Models invoke phase separation of conformational ensembles of chromatin fibers as a mechanism regulating chromatin organization in vivo. Here we combine biochemistry and molecular dynamics simulations to examine, at single base-pair resolution, how nucleosome spacing controls chromatin phase separation. We show that as DNA linkers extend from 25 bp to 30 bp, as exemplars of 10 N + 5 and 10 N (integer N) bp lengths, chromatin condensates become less thermodynamically stable and nucleosome mobility increases. Simulations reveal that this is due to trade-offs between inter- and intramolecular nucleosome stacking, favored by rigid 10 N + 5 and 10 N bp linkers, respectively. A remodeler can induce or inhibit phase separation by moving nucleosomes, changing the balance between intra- and intermolecular stacking. The intrinsic phase separation capacity of chromatin enables fine tuning of compaction and dynamics, likely contributing to heterogeneous chromatin organization in vivo.

DOI: https://doi.org/10.1038/s41467-025-61482-x
J Biol Chem. 2025 Jul 08. pii: S0021-9258(25)02314-2. [Epub ahead of print] 110464

Leber's hereditary optic neuropathy-associated ND1 3733G> C mutation ameliorates the mitochondrial quality control and cellular homeostasis.

Meiheriayi Yasheng, Yanchun Ji, Yunfan He, Qiuzi Yi, Huanhuan Zhang, Wenqi Shan, Kai Wang, Juanjuan Zhang, Ya Li, Feilong Meng, Minglian Zhang, Jun Qin Mo, Shihui Wei, Min-Xin Guan.

Leber's hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy due to mitochondrial DNA (mtDNA) mutations. However, the mechanism underlying LHON-linked mtDNA mutations, especially their impact on mitochondrial and cellular integrity, is not well understood. Recently, the ND1 3733G>C (p.E143Q) mutation was identified in three Chinese pedigrees with suggestively maternal inheritance of LHON. In this study, we investigated the pathogenic mechanism of m.3733G>C mutation using cybrids generated by fusing mtDNA-less ρ0 cells with enucleated cells from a Chinese patient carrying the m.3733G>C mutation and control subject. Molecular dynamics simulations showed that p.E143Q mutation destabilized these interactions between residues E143 and S110/Y114, or between S141 and W290 in the ND1. Its impact of ND1 structure and function was further evidenced by reduced levels of ND1 in mutant cells. The m.3733G>C mutation caused defective assembly and activity of complex I, respiratory deficiency, diminished mitochondrial ATP production, and increased production of mitochondrial ROS in the mutant cybrids carrying the m.3733G>C mutation. These mitochondrial dysfunctions regulated mitochondrial quality control via mitochondrial dynamics and mitophagy. The m.3733G>C mutation-induced dysfunction yielded elevating mitochondrial localization of DRP1, decreasing network connectivity and increasing fission with abnormal morphologies. Furthermore, the m.3733G>C mutation downregulated ubiquitin-dependent mitophagy pathway, evidenced by decreasing the levels of Parkin and Pink, but not ubiquitin-independent mitophagy pathway. The m.3733G>C mutation-induced deficiencies reshaped the cellular homeostasis via impairing autophagy process and promoting intrinsic apoptosis. Our findings provide new insights into pathophysiology of LHON arising from the m.3733G>C mutation-induced mitochondrial dysfunctions and reprograming organellular and cellular homeostasis.

DOI: https://doi.org/10.1016/j.jbc.2025.110464
Science. 2025 Jul 10. 389(6756): 157-162

ROS transfer at peroxisome-mitochondria contact regulates mitochondrial redox.

Laura F DiGiovanni, Prabhsimran K Khroud, Ruth E Carmichael, Tina A Schrader, Shivneet K Gill, Kyla Germain, Robert Y Jomphe, Christoph Wiesinger, Maxime Boutry, Maki Kamoshita, Daniel Snider, Garret Stubbings, Rong Hua, Noel Garber, Christian Hacker, Andrew D Rutenberg, Roman A Melnyk, Johannes Berger, Michael Schrader, Brian Raught, Peter K Kim.

Maintenance of mitochondrial redox homeostasis is of fundamental importance to cellular health. Mitochondria harbor a host of intrinsic antioxidant defenses, but the contribution of extrinsic, nonmitochondrial antioxidant mechanisms is less well understood. We found a direct role for peroxisomes in maintaining mitochondrial redox homeostasis through contact-mediated reactive oxygen species (ROS) transfer. We found that ACBD5 and PTPIP51 form a contact between peroxisomes and mitochondria. The percentage of these contacts increased during mitochondrial oxidative stress and helped to maintain mitochondrial health through the transfer of mitochondrial ROS to the peroxisome lumen. Our findings reveal a multiorganelle layer of mitochondrial antioxidant defense-suggesting a direct mechanism by which peroxisomes contribute to mitochondrial health-and broaden the scope of known membrane contact site functions.

DOI: https://doi.org/10.1126/science.adn2804
Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2504080122

HIF1α mediates circadian regulation of skeletal muscle metabolism and substrate preference in response to time-of-day exercise.

Amy M Ehrlich, Kirstin A MacGregor, Stephen P Ashcroft, Lewin Small, Ali Altıntaş, Alexander V Chibalin, Matthias Anagho-Mattanovich, Ben Stocks, Thomas Moritz, Jonas T Treebak, Juleen R Zierath.

  The regulation of metabolism in peripheral tissues is intricately linked to circadian rhythms, with hypoxia-inducible factor-1α (HIF1α) implicated in modulating time-of-day-specific exercise responses. To investigate this relationship, we generated a skeletal muscle-specific HIF1α knockout (KO) mouse model and performed extensive metabolic phenotyping and transcriptomic profiling under both basal conditions and following acute exercise during early rest (ZT3) and active (ZT15) phases. Our findings reveal that HIF1α drives a more robust transcriptional and glycolytic response to exercise at ZT3, promoting glucose oxidation and mannose-6-phosphate production while potentially sparing fatty acid oxidation. In the absence of HIF1α, skeletal muscle metabolism shifts toward oxidative pathways at ZT3, with notable alterations in glucose fate. These results establish HIF1α as an important regulator of time-of-day-specific metabolic adaptations, integrating circadian and energetic signals to optimize substrate utilization. This work highlights the broader significance of HIF1α in coordinating circadian influences on metabolic health and exercise performance.

Keywords:  circadian; energy metabolism; exercise; metabolism; transcription factor

DOI:  https://doi.org/10.1073/pnas.2504080122
bioRxiv. 2025 Jul 02. pii: 2025.06.30.662346. [Epub ahead of print]

Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP.

Bohdana M Rovenko, Kari Moisio, Cornelia Biehler, Mykhailo Girych, Atte Hallasaari, Onur Deniz, Sarah Bluhm, Arto Viitanen, Krista Kokki, Gaia Fabris, Yi Yang, Valentin Cracan, Irene Miguel-Aliaga, Ville Hietakangas.

Enteroendocrine (EE) cells monitor the intestinal nutrient composition and consequently control organismal physiology through hormonal signaling. In addition to the immediate effects on hormone secretion, nutrients influence EE cell abundance by affecting the determination and maintenance of cell fate. EE cells are known to import and respond to dietary sugars, but how the sugar-induced changes in the intracellular metabolic state are sensed to control the immediate and long-term responses of EE cells, remains poorly understood. We report that the NADH binding transcriptional cofactor C-terminal binding protein (CtBP) acts at the interface between nutrient sensing and fate regulation of Drosophila larval EE cells, thus controlling organismal energy metabolism and survival on a high sugar diet. CtBP dimerization in EE cells is regulated through the redox balance of nicotinamide cofactors controlled by glycolysis and pentose phosphate pathway, allowing EE cells sense their internal metabolic state in response to sugar catabolism. CtBP interacts with the EE cell fate determining transcription factor Prospero through a conserved binding motif and binds to genomic targets controlling EE cell fate and size, such as components of Notch and insulin/mTOR pathways. Collectively, our findings uncover a modality where changes in intracellular redox state serve as an instructive signal to control EE cell function to globally control organismal homeostasis.
GRAPHICAL ABSTRACT:

DOI: https://doi.org/10.1101/2025.06.30.662346
J Gerontol A Biol Sci Med Sci. 2025 Jul 09. pii: glaf148. [Epub ahead of print]

Aging impairs peroxisome biogenesis in human B cells.

Jacinta Correia, Promit Sinha Roy, Kaitlyn G Holden, Marian L Kohut, Hua Bai.

  Emerging evidence highlights the critical role of cellular metabolism in immune cell activation, development, and function. Peroxisomes, key metabolic organelles, maintain metabolic homeostasis, yet their role in immune cells remains underexplored. While animal studies show age-related declines in peroxisome biogenesis, this process is unconfirmed in human aging. We investigated peroxisome biogenesis in human peripheral blood mononuclear cells (PBMCs) and found a significant decline in aged CD19+ B cells compared to CD4+ T cells, CD8+ T cells, and CD14+ monocytes. B cell aging also reduces peroxisomal matrix enzyme import, evidenced by decreased SKL-containing enzymes and mature ACOX1, alongside downregulation of PEX19 and E3 ubiquitin ligases PEX2, PEX10, and PEX12. These findings confirm an evolutionarily conserved and age-related decline in peroxisome biogenesis. Further, our work unveils cell type-specific changes in aging human PBMCs, and provides new insights into peroxisome-mediated immunometabolism and B cell aging.

Keywords:  B cell aging; B cell metabolism; Peroxisomal enzyme import; Peroxisome biogenesis

DOI:  https://doi.org/10.1093/gerona/glaf148
Nature. 2025 Jul 09.

Selective remodelling of the adipose niche in obesity and weight loss.

Antonio M A Miranda, Liam McAllan, Guianfranco Mazzei, Ivan Andrew, Iona Davies, Meryem Ertugrul, Julia Kenkre, Hiromi Kudo, Joana Carrelha, Bhavik Patel, Sophie Newton, Weihua Zhang, Alice Pollard, Amy Cross, Oliver McCallion, Mikyung Jang, Ka Lok Choi, Scarlett Brown, Yasmin Rasool, Marco Adamo, Mohamed Elkalaawy, Andrew Jenkinson, Borzoueh Mohammadi, Majid Hashemi, Robert Goldin, Laurence Game, Joanna Hester, Fadi Issa, Dylan G Ryan, Patricia Ortega, Ahmed R Ahmed, Rachel L Batterham, John C Chambers, Jaspal S Kooner, Damir Baranasic, Michela Noseda, Tricia Tan, William R Scott.

Weight loss significantly improves metabolic and cardiovascular health in people with obesity1-3. The remodelling of adipose tissue (AT) is central to these varied and important clinical effects4. However, surprisingly little is known about the underlying mechanisms, presenting a barrier to treatment advances. Here we report a spatially resolved single-nucleus atlas (comprising 171,247 cells from 70 people) investigating the cell types, molecular events and regulatory factors that reshape human AT, and thus metabolic health, in obesity and therapeutic weight loss. We discover selective vulnerability to senescence in metabolic, precursor and vascular cells and reveal that senescence is potently reversed by weight loss. We define gene regulatory mechanisms and tissue signals that may drive a degenerative cycle of senescence, tissue injury and metabolic dysfunction. We find that weight loss reduces adipocyte hypertrophy and biomechanical constraint pathways, activating global metabolic flux and bioenergetic substrate cycles that may mediate systemic improvements in metabolic health. In the immune compartment, we demonstrate that weight loss represses obesity-induced macrophage infiltration but does not completely reverse activation, leaving these cells primed to trigger potential weight regain and worsen metabolic dysfunction. Throughout, we map cells to tissue niches to understand the collective determinants of tissue injury and recovery. Overall, our complementary single-nucleus and spatial datasets offer unprecedented insights into the basis of obese AT dysfunction and its reversal by weight loss and are a key resource for mechanistic and therapeutic exploration.

DOI: https://doi.org/10.1038/s41586-025-09233-2
EMBO Rep. 2025 Jul 07.

Inhibition of the minor spliceosome restricts the growth of a broad spectrum of cancers.

Karen Doggett, Kimberly J Morgan, Anouk M Olthof, Stephen Mieruszynski, Benjamin B Williams, Alexandra L Garnham, Michael J G Milevskiy, Lachlan Whitehead, Janine Coates, Michael Buchert, Robert J J O'Donoghue, Thomas E Hall, Tracy L Putoczki, Matthias Ernst, Kate D Sutherland, Rahul N Kanadia, Joan K Heath.

  Minor splicing is an under-appreciated splicing system required for the correct expression of ~700 genes in the human genome. This small subset of genes (0.35%) harbours introns containing non-canonical splicing sequences that are recognised uniquely by the minor spliceosome and cannot be processed by the major spliceosome. Using in vivo zebrafish and mouse cancer models, we show that heterozygous expression of Rnpc3, encoding a unique protein component of the minor spliceosome, restricts the growth and survival of liver, lung and gastric tumours without impacting healthy cells. RNPC3 knockdown in human lung cancer-derived A549 cells also impairs cell proliferation and RNA-seq analysis reveals a robust and selective disruption to minor intron splicing and transcription-wide effects on gene expression. We further demonstrate that these perturbations are accompanied by DNA replication stress, DNA damage, accumulation of TP53 protein and activation of a Tp53-dependent transcriptional program that induces cell cycle arrest and apoptosis. Together our data reveal a vulnerability of cancer cells to minor splicing inhibition that restricts tumour growth.

Keywords:  Cancer; DNA Damage; Minor Splicing; RNA Processing; RNPC3

DOI:  https://doi.org/10.1038/s44319-025-00511-8
Cell Rep Med. 2025 Jul 07. pii: S2666-3791(25)00278-2. [Epub ahead of print] 102205

Immunogenicity of autologous and allogeneic human primary cholangiocyte organoid cellular therapies.

Sandra Petrus-Reurer, Winnie Lei, Olivia Tysoe, Maelle Mairesse, Adrian Baez-Ortega, Julia Jones, Thomas Tan, Sylvia Rehakova, Krishnaa T Mahbubani, Cara Brodie, Namshik Han, Inigo Martincorena, Catherine Betts, Ludovic Vallier, Kourosh Saeb-Parsy.

  Primary human cells cultured in long-term expandable 3D organoid format have great promise as potential regenerative cellular therapies, but their immunogenicity has not yet been fully characterized. In this study, we use in vitro co-cultures and in vivo humanized mouse experimental models to examine autologous and allogeneic immune response to human primary cholangiocyte organoids (PCOs) as treatment for bile duct disorders. Our data demonstrate that PCOs upregulate the expression of human leukocyte antigen (HLA)-I and HLA-II in inflammatory conditions. The allogeneic immune response to PCOs is driven by both HLA-I and HLA-II and is substantially ameliorated by donor-recipient HLA matching. While allogeneic cells display evolving stages of immune rejection in vivo, autologous PCOs induce a low-level immune infiltration into the graft site possibly influenced by acquired mutations in culture, cell viability, and culture matrix. Our findings have important implications for the design and clinical translation of autologous and allogeneic organoid cellular therapies.

Keywords:  NanoSeq; autologous and allogeneic immunogenicity; cell therapies; cholangiocyte; human primary organoids; humanized mouse model; spatial transcriptomics; transplantation immunology

DOI:  https://doi.org/10.1016/j.xcrm.2025.102205
Cell. 2025 Jul 04. pii: S0092-8674(25)00684-1. [Epub ahead of print]

Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy.

Catherine M Phelps, Nathaniel B Willis, Tingting Duan, Amanda H Lee, Yue Zhang, Daphne M Rodriguez J, Surya P Pandey, Colin R Laughlin, Aaron B I Rosen, Alex C McPherson, Jake H Shapira, Simran K Randhawa, Lee Hedden, Tanner G Richie, Hallie M Wiechman, Mackenzie J Bender, Ina Nemet, Patrick A Zöhrer, Rachel A Gottschalk, Kathryn H Schmitz, Steven J Mullett, Stacy L Gelhaus, Diwakar Davar, Hassane M Zarour, Reinhard Hinterleitner, Thomas Mossington, Jonathan H Badger, Richard R Rodrigues, John A McCulloch, Sonny T M Lee, Karl-Heinz Wagner, Maria G Winter, Sebastian E Winter, Jishnu Das, Joseph F Pierre, Giorgio Trinchieri, Marlies Meisel.

  Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers such as melanoma; however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we identify that the gut microbiota plays a critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances cytotoxic CD8 T cell (Tc1)-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identify the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we uncover human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity, supporting its functional role in melanoma suppression.

Keywords:  CD8 T cells; FMT; Nrf2; exercise; formate; immune checkpoint inhibitor; melanoma; microbiota; microbiota metabolite

DOI:  https://doi.org/10.1016/j.cell.2025.06.018
bioRxiv. 2025 Jul 06. pii: 2025.07.04.663231. [Epub ahead of print]

Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity.

Eric Greene, Richard Muniz, Hiroki Yamamura, Samuel E Hoff, Priyanka Bajaj, D John Lee, Erin M Thompson, Angelika Arada, Gyun Min Lee, Massimiliano Bonomi, Justin M Kollman, James S Fraser.

To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a composite binding site formed at the filament interface by the product, glutamine. Time-resolved cryo-electron microscopy (cryo-EM) confirms that glutamine binding stabilizes these filaments, which in turn exhibit reduced catalytic specificity for ammonia at physiological concentrations. This inhibition appears induced by a conformational change that remodulates the active site loop ensemble gating substrate entry. Metadynamics ensemble refinement revealed >10 Å conformational range for the active site loop and that the loop is stabilized by transient contacts. This disorder is significant, as we show that the transient contacts which stabilize this loop in a closed conformation are essential for catalysis both in vitro and in cells. We propose that GS filament formation constitutes a negative-feedback mechanism, directly linking product concentration to the structural and functional remodeling of the enzyme.

DOI: https://doi.org/10.1101/2025.07.04.663231
Nat Metab. 2025 Jul 08.

CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure.

Julie Mie Jacobsen, Jens Frey Halling, Ida Blom, Jaime Moreno Martinez, Bjørn Hald, Kent Pedersen, Johannes Josef Fels, Søren Snitker, Anna Secher, Sofia Lundh, Carel W le Roux, Kirsten Raun, Marc L Reitman, Rune Ehrenreich Kuhre.

CagriSema is a combination of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide) analogues being developed for weight management. Here, we show that CagriSema blunts metabolic adaptation in rats. Quantifying CagriSema's action on energy intake and expenditure in rats we observe 12% weight loss with a 39% reduction in food intake. By contrast, pair-feeding causes less-pronounced weight loss, while weight matching requires a 51% decrease in food intake. Therefore, approximately one-third of CagriSema's weight loss efficacy arises from an effect on energy expenditure, the blunting of metabolic adaptation, which contributes to the successful treatment of obesity.

DOI: https://doi.org/10.1038/s42255-025-01324-8
bioRxiv. 2025 Jul 04. pii: 2025.06.30.662363. [Epub ahead of print]

Crosstalk Between ALPK1 and STING: A Synergistic Axis in Innate Immune Activation and Human Inflammatory Disease.

Chong-Shan Shi, Christina Kozycki, Ning-Na Huang, Il-Young Hwang, Dima A Hammoud, Daniel L Kastner, John H Kehrl.

Alpha kinase 1 (ALPK1) is a cytosolic sensor of microbial sugar metabolites that activates NF-κB signaling through phosphorylation of the adaptor protein TIFA. Although canonically linked to NF-κB, individuals with gain-of-function ALPK1 mutations also show features of interferon-driven inflammation. Here, we show that ALPK1 activation enhances multiple outputs of the stimulator of interferon genes (STING) pathway, including both canonical and noncanonical responses such as STING proton channel-dependent LC3B lipidation and NLRP3 inflammasome activation. Furthermore, ALPK1 signaling activates eIF2α, an effector of the integrated stress response. Conversely, STING activation increases ALPK1 protein expression and triggers TIFA-Threonine 9 phosphorylation. Clinically, individuals with ALPK1-mediated disease exhibit premature intracranial mineralization and elevated cerebrospinal fluid neopterin, both associated with dysregulated interferon signaling. These findings support a model of bidirectional signaling between ALPK1 and STING, in which microbial and nucleic acid sensing pathways can amplify one another. This crosstalk provides a mechanistic framework for understanding innate immune signaling relevant to both homeostasis and disease.

DOI: https://doi.org/10.1101/2025.06.30.662363
Trends Cancer. 2025 Jul 09. pii: S2405-8033(25)00150-5. [Epub ahead of print]

GDF15: from biomarker to target in cancer cachexia.

Max Hüllwegen, Maximilian Kleinert, Stephan von Haehling, Andreas Fischer.

  Most patients with advanced cancer suffer from cachexia, a complex metabolic disorder characterized by unintentional body weight loss that diminishes their quality of life and reduces the effectiveness of therapies. Currently, effective treatments for cachexia remain elusive. Growth differentiation factor 15 (GDF15) is a nonspecific blood biomarker of cancer, hyperemesis gravidarum, and various chronic diseases. GDF15 acts through GDNF family receptor α-like (GFRAL) receptors in the hindbrain to influence food intake, nausea, body weight, and insulin sensitivity. In this review we synthesize the current literature on the role of GDF15 in regulating metabolism and immunosuppression, and elucidate how these processes impact on cancer progression. We highlight recent clinical trials demonstrating that targeting GDF15 can overcome resistance to immunotherapy and increase physical activity, appetite, and weight gain in cancer patients.

Keywords:  GDF15; biomarker; cachexia; cancer; immunosuppression; metabolism

DOI:  https://doi.org/10.1016/j.trecan.2025.06.007
EMBO Rep. 2025 Jul 07.

Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer.

Hao Li, Yohei Kanamori, Akihiro Nita, Ayato Maeda, Tianli Zhang, Kenta Kikuchi, Hiroyuki Yamada, Touya Toyomoto, Mohamed Fathi Saleh, Mayumi Niimura, Hironori Hinokuma, Mayuko Shimoda, Koei Ikeda, Makoto Suzuki, Yoshihiro Komohara, Daisuke Kurotaki, Tomohiro Sawa, Toshiro Moroishi.

  Recent advances in single-cell technologies have uncovered significant cellular diversity in tumors, influencing cancer progression and treatment outcomes. The Hippo pathway controls cell proliferation through its downstream effectors: yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Our analysis of human lung adenocarcinoma and murine models revealed that cancer cells display heterogeneous YAP/TAZ activation levels within tumors. Murine lung cancer cells with high YAP/TAZ activity grow rapidly but are sensitive to ferroptosis, a cell death induced by lipid peroxidation. In contrast, cells with low YAP/TAZ activity grow slowly but resist ferroptosis. Moreover, they protect neighbouring cells from ferroptosis, creating a protective microenvironment that enhances the tumor's resistance to ferroptosis. Mechanistically, inhibiting YAP/TAZ upregulates GTP cyclohydrolase 1 (GCH1), an enzyme critical for the biosynthesis of tetrahydrobiopterin (BH4), which functions as a secretory antioxidant to prevent lipid peroxidation. Pharmacological inhibition of GCH1 sensitizes lung cancer cells to ferroptosis inducers, suggesting a potential therapeutic approach. Our data highlights the non-cell-autonomous roles of the Hippo pathway in creating a ferroptosis-resistant tumor microenvironment.

Keywords:  Biopterin; Cell Communication; Ferroptosis; Hippo Pathway; Lung Cancer

DOI:  https://doi.org/10.1038/s44319-025-00515-4
Nat Rev Endocrinol. 2025 Jul 08.

Glycogen metabolism: not just a one-trick pony.

Dipsikha Biswas.

DOI: https://doi.org/10.1038/s41574-025-01152-6