bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–06–22
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Fumarate hits the brakes on mitophagy.
  2. The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
  3. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  4. Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.
  5. ATR promotes mTORC1 activity via de novo cholesterol synthesis.
  6. Transcription arrest induces formation of RNA granules in mitochondria.
  7. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
  8. Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.
  9. ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.
  10. Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
  11. Shaping the composition of the mitochondrial outer membrane.
  12. Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
  13. Rewriting cancer's code: A micropeptide's mitochondrial mission.
  14. Cysteine Signalling in Plant Pathogen Response.
  15. GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.
  16. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
  17. Organelle conversations drive ferroptosis.
  18. Dysfunctional mitochondria trap proteins in the intermembrane space.
  19. The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5.
  20. USP37 prevents premature disassembly of stressed replisomes by TRAIP.
  21. Cancer gene identification from RNA variant allelic frequencies using RVdriver.
  22. The molecular landscape of cellular metal ion biology.
  23. Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
  24. Iron and the immune system.
  25. The redox landscape of pyruvate:ferredoxin oxidoreductases reveals often conserved Fe-S cluster potentials.
  26. Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
  27. The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine.
  28. Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis.
  29. Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.
  30. SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
  31. Multiple roles for a mitochondrial enzyme.
  32. Senescence Cell Induction Methods Display Diverse Metabolic Reprogramming and Reveal an Underpinning Serine/Taurine Reductive Metabolic Phenotype.
  33. Gut sulfide metabolism modulates behavior and brain bioenergetics.
  34. ILC3s sense gut microbiota through STING to initiate immune tolerance.
  35. pDCs drive immunopathology by sensing oxidized mitochondrial DNA.
  36. PUMA reduces FASN ubiquitination to promote lipid accumulation and tumor progression in human clear cell renal cell carcinoma.
  37. Thermodynamic free energy map for the non-oxidative glycolysis pathways.
  38. Bivalent chromatin instructs lineage specification during hematopoiesis.
  39. A unified pan-cancer proteome atlas.
  40. Reframing the role of the objective function in its proper context for metabolic network modeling.
  41. Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.
  42. ALDH9A1 deficiency as a source of endogenous DNA damage that requires repair by the Fanconi anemia pathway.
  43. LKB1 regulates ILC3 postnatal development and effector function through metabolic programming.
  44. Neuro-immune cross-talk in cancer.
  45. Grow up, beta cells.
  46. Quantitative measurement of phenotype dynamics during cancer drug resistance evolution using genetic barcoding.
  1. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00471-X. [Epub ahead of print]85(12): 2261-2263
    Fumarate hits the brakes on mitophagy.
    Ana Paula Magalhães Rebelo, Christian Frezza.
      In this issue of Molecular Cell, Ham et al.1 demonstrate that the metabolite fumarate, when accumulated in cells, can influence mitochondrial quality control by inhibiting Parkin translocation to mitochondria and blocking its E3 ligase activity via the fumarate-dependent post-translational modification called succination.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.032
  2. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]
    The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
    Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.
      Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.
    Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
  3. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00659-X. [Epub ahead of print]44(7): 115888
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs over glucose. Here, we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FAs under cold conditions.
    Keywords:  CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115888
  4. Nat Cell Biol. 2025 Jun;27(6): 902-917
    Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.
    Maria Livia Sassano, Yulia Y Tyurina, Antigoni Diometzidou, Ellen Vervoort, Vladimir A Tyurin, Sanket More, Rita La Rovere, Francesca Giordano, Geert Bultynck, Benjamin Pavie, Johan V Swinnen, Hülya Bayir, Valerian E Kagan, Luca Scorrano, Patrizia Agostinis.
      The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level. Here we show that EMCSs expand minutes after localized PL peroxides are formed and secondarily spread to mitochondria, promoting mitochondrial reactive oxygen species and fission. Oxidative lipidomics unravels that EMCSs host distinct proferroptotic polyunsaturated-PLs, including doubly proferroptotic polyunsaturated-acylated PLs, demonstrating their high propensity to undergo PL peroxidation. Endoplasmic reticulum-mitochondria untethering blunts PL peroxidation and ferroptosis, while EMCS stabilization enhances them. Consistently, distancing EMCSs protects the ferroptosis-susceptible triple-negative breast cancer subtype, harbouring high EMCS-related gene expression and basal PL peroxide levels. Conversely, in insensitive triple-negative breast cancer subtypes, bolstering EMCSs sensitizes them to ferroptosis. Our data unveil endoplasmic reticulum-mitochondria appositions as initial hubs of PL peroxide formation and posit that empowering EMCSs endorses ferroptosis in cancer cells.
    DOI:  https://doi.org/10.1038/s41556-025-01668-z
  5. EMBO Rep. 2025 Jun 13.
    ATR promotes mTORC1 activity via de novo cholesterol synthesis.
    Naveen Kumar Tangudu, Alexandra N Grumet, Richard Fang, Raquel Buj, Aidan R Cole, Apoorva Uboveja, Amandine Amalric, Baixue Yang, Zhentai Huang, Cassandra Happe, Mai Sun, Stacy L Gelhaus, Matthew L MacDonald, Nadine Hempel, Nathaniel W Snyder, Katarzyna M Kedziora, Alexander J Valvezan, Katherine M Aird.
      DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback. Key mediators of these pathways include ATR and mTORC1, respectively. Previous studies established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. We demonstrate that ATR promotes mTORC1 activity across various human cancer cells and both human and mouse normal cells under basal conditions. This effect is enhanced in human cancer cells (SKMEL28, RPMI-7951, HeLa) following knockdown of p16, a cell cycle inhibitor that we have previously found increases mTORC1 activity and here found increases ATR activity. Mechanistically, ATR promotes de novo cholesterol synthesis and mTORC1 activation through the phosphorylation and upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Interestingly, this pathway is distinct from the regulation of mTORC1 by ATM and may be specific to cancer cells. Finally, ATR-mediated increased cholesterol correlates with enhanced localization of mTOR to lysosomes. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.
    Keywords:  Cholesterol; Lanosterol Synthase; Lysosome; Metabolism; p16
    DOI:  https://doi.org/10.1038/s44319-025-00451-3
  6. Life Sci Alliance. 2025 Sep;pii: e202403082. [Epub ahead of print]8(9):
    Transcription arrest induces formation of RNA granules in mitochondria.
    Katja G Hansen, Autum Baxter-Koenigs, Caroline Am Weiss, Erik McShane, L Stirling Churchman.
      Mitochondrial gene expression regulation is required for the biogenesis of oxidative phosphorylation (OXPHOS) complexes, yet the spatial organization of mitochondrial RNAs (mt-RNAs) remains unknown. Here, we investigated the spatial distribution of mt-RNAs during various cellular stresses using single-molecule RNA-FISH. We discovered that transcription inhibition leads to the formation of distinct RNA granules within mitochondria, which we term inhibition granules. These structures differ from canonical mitochondrial RNA granules and form in response to multiple transcription arrest conditions, including ethidium bromide treatment, specific inhibition or stalling of the mitochondrial RNA polymerase, and depletion of the SUV3 helicase. Inhibition granules appear to stabilize certain mt-mRNAs during prolonged transcription inhibition. This phenomenon coincides with an imbalance in OXPHOS complex expression, where mitochondrial-encoded transcripts decrease while nuclear-encoded subunits remain stable. We found that cells recover from transcription inhibition via resolving the granules, restarting transcription, and repopulating the mitochondrial network with mt-mRNAs within hours. We suggest that inhibition granules may act as a reservoir to help overcome OXPHOS imbalance during recovery from transcription arrest.
    DOI:  https://doi.org/10.26508/lsa.202403082
  7. Nat Commun. 2025 Jun 20. 16(1): 5355
    Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
    Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  8. Mol Cell. 2025 Jun 11. pii: S1097-2765(25)00469-1. [Epub ahead of print]
    Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.
    Christopher Nardone, Jingjing Gao, Hyuk-Soo Seo, Julian Mintseris, Lucy Ort, Matthew C J Yip, Milen Negasi, Anna K Besschetnova, Nolan Kamitaki, Steven P Gygi, Sirano Dhe-Paganon, Nikhil C Munshi, Mariateresa Fulciniti, Michael E Greenberg, Sichen Shao, Stephen J Elledge, Xin Gu.
      The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome complex, revealing how established proteasomal components are repurposed to enable a unique form of proteolysis. While the proteasomal subunit PSMD2/Rpn1 binds to ubiquitinated or ubiquitin-like (Ubl) proteins, we discover that it also interacts with the midnolin nuclear localization sequence, elucidating how midnolin's activity is confined to the nucleus. Likewise, PSMD14/Rpn11, an enzyme that normally cleaves ubiquitin chains, surprisingly functions non-enzymatically as a receptor for the midnolin Ubl domain, positioning the substrate-binding Catch domain directly above the proteasomal entry site to guide substrates into the proteasome. Moreover, we demonstrate that midnolin downregulation is critical for the survival of myeloma cells by stabilizing the transcription factor substrate IRF4. Our findings uncover the mechanisms underlying the midnolin-proteasome pathway and midnolin downregulation as a driver of multiple myeloma.
    Keywords:  IRF4; PSMD14/Rpn11; PSMD2/Rpn1; midnolin; myeloma; proteasome; ubiquitin-independent
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.030
  9. Nat Struct Mol Biol. 2025 Jun 19.
    ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism.
    Edrees H Rashan, Abigail K Bartlett, Daven B Khana, Jingying Zhang, Raghav Jain, Gina Wade, Luciano A Abriata, Andrew J Smith, Zakery N Baker, Taylor Cook, Alana Caldwell, Autumn R Chevalier, Patrick Forny, Brian F Pfleger, Matteo Dal Peraro, Peng Yuan, Daniel Amador-Noguez, Judith A Simcox, David J Pagliarini.
      Fatty acid β-oxidation is a central catabolic pathway with broad health implications. However, various fatty acids, including 4-hydroxy acids (4-HAs), are largely incompatible with β-oxidation machinery before being modified. Here we reveal that two atypical acyl-CoA dehydrogenases, ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains that phosphorylate the 4-hydroxy position as a requisite step in converting 4-hydroxyacyl-CoAs into conventional 2-enoyl-CoAs. Through cryo-electron microscopy and molecular modeling, we identified an atypical dehydrogenase binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma and females are susceptible to body weight and fat gain, concurrent with decreased adipocyte differentiation and adipokine expression. Collectively, we present that ACAD10 and ACAD11 are the primary gatekeepers of mammalian 4-HA catabolism.
    DOI:  https://doi.org/10.1038/s41594-025-01596-4
  10. Cancer Res. 2025 Jun 20.
    Ceramide-Induced Metabolic Stress Depletes Fumarate and Drives Mitophagy to Mediate Tumor Suppression.
    Natalia V Oleinik, Firdevs Cansu Atilgan, Mohamed Faisal Kassir, Han Gyul Lee, Alhaji H Janneh, Wyatt Wofford, Chase Walton, Zdzislaw M Szulc, Elizabeth G Hill, Alexander V Alekseyenko, Huseyin Cimen, Jessica H Hartman, Christina Voelkel-Johnson, Michael B Lilly, John J Lemasters, Norma Frizzell, Xue-Zhong Yu, Shikhar Mehrotra, Besim Ogretmen.
      Bioactive ceramide induces cell death in part by promoting mitophagy. C18-ceramide levels are commonly reduced in head and neck squamous cell carcinoma (HNSCC), which correlates with poor prognosis, suggesting the potential of harnessing ceramide for cancer treatment. Here, we evaluated the ability of the ceramide analog LCL768 to induce mitophagy and metabolic stress in HNSCC. Mechanistically, LCL768 induced CerS1-mediated endogenous C18-ceramide accumulation in mitochondria to mediate mitophagy, which did not require the CerS1 transporter p17/PERMIT but was dependent on DRP1 activation via nitrosylation at C644. DRP1 facilitated anchoring of the endoplasmic reticulum (ER) and mitochondrial membranes by promoting the association between phosphatidylethanolamine in the ER and cardiolipin in mitochondrial membranes. Mutations of Drp1 that prevented its binding to ER and mitochondrial membranes blocked CerS1/C18-ceramide mitochondrial accumulation, inhibiting LCL768-mediated mitophagy. In addition, LCL768-driven mitophagy altered mitochondrial metabolism, resulting in fumarate depletion and leading to tumor suppression in vivo. Exogenous fumarate supplementation prevented LCL768-mediated mitophagy, mitochondrial trafficking of CerS1, ER-mitochondrial tethering, and tumor suppression in mice. Fumarate metabolism was associated with PARKIN succination at a catalytic cysteine (Cys431), inhibiting its association with PINK1 and ubiquitin and thereby preventing mitophagy. LCL768-induced fumarate depletion attenuated PARKIN succination to promote PARKIN activation and mitophagy, indicating a feed-forward mechanism that regulates mitophagy and fumarate metabolism through PARKIN succination. These data provide a mechanism whereby LCL768/CerS1-C18-ceramide-mediated mitophagy and tumor suppression are regulated by Drp1 nitrosylation, fumarate depletion, and PARKIN succination, providing a metabolic stress signature for lethal mitophagy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4042
  11. Nat Cell Biol. 2025 Jun;27(6): 890-901
    Shaping the composition of the mitochondrial outer membrane.
    Gayathri Muthukumar, Jonathan S Weissman.
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  12. Nat Commun. 2025 Jun 17. 16(1): 5328
    Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.
    Prince Saforo Amponsah, Jan-Eric Bökenkamp, Olha Kurpa, Svenja Lenhard, Anna Myronova, Daniel Osmar Vega Velazquez, Celina Hirschelmann, Christian Behrends, Johannes M Herrmann, Markus Räschle, Zuzana Storchová.
      Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-60857-4
  13. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00473-3. [Epub ahead of print]85(12): 2263-2264
    Rewriting cancer's code: A micropeptide's mitochondrial mission.
    George A Calin, Tanvi H Visal.
      In this issue of Molecular Cell, Zhu et al.1 uncover a lncRNA-derived micropeptide that disrupts mitochondrial RNA processing, revealing a new layer of metabolic vulnerability in hepatocellular carcinoma (HCC).
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.034
  14. Plant Cell Environ. 2025 Jun 16.
    Cysteine Signalling in Plant Pathogen Response.
    Jannis Moormann, Björn Heinemann, Cecile Angermann, Anna Koprivova, Ute Armbruster, Stanislav Kopriva, Tatjana M Hildebrandt.
      The amino acid cysteine is the precursor for a wide range of sulfur-containing functional molecules in plants, including enzyme cofactors and defence compounds. Due to its redox active thiol group cysteine is highly reactive. Synthesis and degradation pathways are present in several subcellular compartments to adjust the intracellular cysteine concentration. However, stress conditions can lead to a transient increase in local cysteine levels. Here we investigate links between cysteine homeostasis and metabolic signalling in Arabidopsis thaliana. The systemic proteome response to cysteine feeding strongly suggests that Arabidopsis seedlings interpret accumulation of cysteine above a certain threshold as a signal for a biotic threat. Cysteine supplementation of Arabidopsis plants via the roots increases their resistance to the hemibiotrophic bacterium Pseudomonas syringae confirming the protective function of the cysteine induced defence pathways. Analysis of mutant plants reveals that the balance of cysteine synthesis between the cytosol and organelles is crucial during Arabidopsis immune response to Pseudomonas syringae. The induction profile of pathogen responsive proteins by cysteine provides insight into potential modes of action. Our results highlight the role of cysteine as a metabolic signal in the plant immune response and add evidence to the emerging concept of intracellular organelles as important players in plant stress signalling.
    Keywords:  amino acid metabolism; immunometabolism; infochemicals; mitochondria; proteomics; sulfur signalling
    DOI:  https://doi.org/10.1111/pce.70017
  15. Mol Cell Oncol. 2025 ;12(1): 2518773
    GSTP1 knockdown induces metabolic changes affecting energy production and lipid balance in pancreatic cancer cells.
    Jenna N Duttenhefner, Katie M Reindl.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options, underscoring the need for novel therapeutic targets. Metabolic reprogramming is a hallmark of PDAC, enabling tumor cells to sustain rapid proliferation and survive under nutrient-deprived conditions. While glutathione S-transferase pi 1 (GSTP1) is a known regulator of redox homeostasis in PDAC, its role in metabolic adaptation remains unclear. Here, we show that GSTP1 knockdown disrupts PDAC metabolism, leading to downregulation of key metabolic enzymes (ALDH7A1, CPT1A, SLC2A3, PGM1), ATP depletion, mitochondrial dysfunction, and phospholipid remodeling. Phospholipid remodeling, including an increase in phosphatidylcholine (PC) levels, further suggests a compensatory response to metabolic stress. Importantly, GSTP1 knockdown led to elevated lipid peroxidation, increasing 4-hydroxynonenal (4-HNE) accumulation. Treatment with the antioxidant N-acetyl cysteine (NAC) partially restored metabolic gene expression, reinforcing GSTP1's role in the interplay between redox regulation and metabolism in PDAC. By disrupting multiple metabolic pathways, GSTP1 depletion creates potential therapeutic vulnerabilities that could be targeted through metabolic and oxidative stress-inducing therapies to enhance treatment efficacy.
    Keywords:  Pancreatic ductal adenocarcinoma; glutathione S-transferase pi 1 (GSTP1); metabolic reprogramming; metabolomics; therapeutic targeting
    DOI:  https://doi.org/10.1080/23723556.2025.2518773
  16. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
    FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
    Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  17. Nat Cell Biol. 2025 Jun 19.
    Organelle conversations drive ferroptosis.
    Ancély Ferreira Dos Santos, José Pedro Friedmann Angeli.
      
    DOI:  https://doi.org/10.1038/s41556-025-01694-x
  18. EMBO J. 2025 Jun 16.
    Dysfunctional mitochondria trap proteins in the intermembrane space.
    Tamara Flohr, Markus Räschle, Johannes M Herrmann.
      The accumulation of mitochondrial precursor proteins in the cytosol due to mitochondrial dysfunction compromises cellular proteostasis and is a hallmark of diseases. Why non-imported precursors are toxic and how eukaryotic cells prevent their accumulation in the cytosol is still poorly understood. Using a proximity labeling-based assay to globally monitor the intramitochondrial location of proteins, we show that, upon mitochondrial dysfunction, many mitochondrial matrix proteins are sequestered in the intermembrane space (IMS); something we refer to as "mitochondrial triage of precursor proteins" (MitoTraP). MitoTraP is not simply the result of a general translocation block at the level of the inner membrane, but specifically directs a subgroup of matrix proteins into the IMS, many of which are constituents of the mitochondrial ribosome. Using the mitoribosomal protein Mrp17 (bS6m) as a model, we found that IMS sequestration prevents its mistargeting to the nucleus, potentially averting interference with assembly of cytosolic ribosomes. Thus, MitoTraP represents a novel, so far unknown mechanism of the eukaryotic quality control system that protects the cellular proteome against the toxic effects of non-imported mitochondrial precursor proteins.
    Keywords:  Intermembrane Space; Mitochondria; Nucleolus; Protein Targeting; Ribosome
    DOI:  https://doi.org/10.1038/s44318-025-00486-1
  19. Sci Adv. 2025 Jun 20. 11(25): eadv2417
    The RNA demethylase FTO promotes glutamine metabolism in clear cell renal cell carcinoma through the regulation of SLC1A5.
    Man Zhao, Dalin Zhang, Haowen Jiang, Nishanth Kuganesan, Suchitra Natarajan, Leighton Pu, Kaushik N Thakkar, Hongjuan Zhao, Quynh Thu Le, Amato J Giaccia, James D Brooks, Donna M Peehl, Jiangbin Ye, Erinn B Rankin.
      Glutamine reprogramming plays a crucial role in the growth and survival of clear cell renal cell carcinoma (ccRCC), although the mechanisms governing its regulation are still not fully understood. We demonstrate that the RNA demethylase fat mass and obesity-associated gene (FTO) drives glutamine reprogramming to support ccRCC growth and survival. Genetic and pharmacologic inhibition of FTO in ccRCC cells impaired glutamine-derived reductive carboxylation, depleted pyrimidines, and increased reactive oxygen species. This led to increased DNA damage and reduced survival, which could be rescued by pyrimidine nucleobases or the antioxidant N-acetylcysteine. Mechanistically, FTO demethylates the glutamine transporter solute carrier family 1 member 5 (SLC1A5) messenger RNA to promote its expression. Restoration of SLC1A5 expression in FTO-knockdown cells rescued metabolic and survival defects. FTO inhibition reduced ccRCC tumor xenograft and PDX growth under the renal capsule. Our findings indicate that FTO is an epitranscriptomic regulator of ccRCC glutamine reprogramming and highlight the therapeutic potential of targeting FTO for the treatment of ccRCC.
    DOI:  https://doi.org/10.1126/sciadv.adv2417
  20. Nat Commun. 2025 Jun 18. 16(1): 5333
    USP37 prevents premature disassembly of stressed replisomes by TRAIP.
    Olga V Kochenova, Giuseppina D'Alessandro, Domenic Pilger, Ernst Schmid, Sean L Richards, Marcos Rios Garcia, Satpal S Jhujh, Andrea Voigt, Vipul Gupta, Christopher J Carnie, R Alex Wu, Nadia Gueorguieva, Simon Lam, Grant S Stewart, Johannes C Walter, Stephen P Jackson.
      The eukaryotic replisome, which consists of the CDC45-MCM2-7-GINS (CMG) helicase, replicative polymerases, and several accessory factors, sometimes encounters proteinaceous obstacles that threaten genome integrity. These obstacles are targeted for removal or proteolysis by the E3 ubiquitin ligase TRAIP, which associates with the replisome. However, TRAIP must be carefully regulated to avoid inappropriate ubiquitylation and disassembly of the replisome. Here, we demonstrate that human cells lacking the de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons and other replication stress-inducing agents. Furthermore, TRAIP loss rescues the hypersensitivity of USP37 knockout cells to topoisomerase inhibitors. In Xenopus egg extracts depleted of USP37, TRAIP promotes premature CMG ubiquitylation and disassembly when converging replisomes stall. Finally, guided by AlphaFold-Multimer, we discovered that binding to CDC45 mediates USP37's response to topological stress. We propose that USP37 protects genome stability by preventing TRAIP-dependent CMG unloading when replication stress impedes timely termination.
    DOI:  https://doi.org/10.1038/s41467-025-60139-z
  21. Genome Biol. 2025 Jun 13. 26(1): 165
    Cancer gene identification from RNA variant allelic frequencies using RVdriver.
    James R M Black, Thomas P Jones, Carlos Martínez-Ruiz, Maria Litovchenko, Clare Puttick, Charles Swanton, Nicholas McGranahan.
      Existing approaches to identifying cancer genes rely overwhelmingly on DNA sequencing data. Here, we introduce RVdriver, a computational tool that leverages paired bulk genomic and transcriptomic data to classify RNA variant allele frequencies (VAFs) of non-synonymous mutations relative to a synonymous mutation background. We analyze 7882 paired exomes and transcriptomes from 31 cancer types and identify novel, as well as known, cancer genes, complementing other DNA-based approaches. Furthermore, RNA VAFs of individual mutations are able to distinguish "driver" from "passenger" mutations within established cancer genes. This approach highlights the value of multi-omic approaches for cancer gene discovery.
    DOI:  https://doi.org/10.1186/s13059-025-03557-y
  22. Cell Syst. 2025 Jun 10. pii: S2405-4712(25)00152-8. [Epub ahead of print] 101319
    The molecular landscape of cellular metal ion biology.
    Simran Kaur Aulakh, Oliver Lemke, Lukasz Szyrwiel, Stephan Kamrad, Yu Chen, Johannes Hartl, Michael Mülleder, Jens Nielsen, Markus Ralser.
      Metal ions have crucial roles in cells, but the impact of their availability on biological networks is underexplored. We systematically quantified yeast cell growth and the corresponding metallomic, proteomic, and genetic responses to perturbations in metal availability along concentration gradients of all growth-essential metal ions. We report a remarkable metal concentration dependency of cellular networks, with around half of the proteome, and most signaling pathways such as target of rapamycin (TOR), being metal responsive. Although the biological response to each metal is distinct, our data reveal common properties of metal responsiveness, such as concentration interdependencies and metal homeostasis. Furthermore, our resource indicates that many understudied proteins have functions related to metal biology and reveals that metalloenzymes occupy central nodes in metabolic networks. This work provides a framework for understanding the critical role of metal ions in cellular function, with broader implications for manipulating metal homeostasis in biotechnology and medicine.
    Keywords:  calcium poorly characterized proteins; copper; gene function prediction; iron; metabolism; metal ion biology; metal responsiveness; metal signaling; zinc
    DOI:  https://doi.org/10.1016/j.cels.2025.101319
  23. Cell Rep. 2025 Jun 17. pii: S2211-1247(25)00580-7. [Epub ahead of print]44(6): 115809
    Hexokinase 2 interacts with PINK1 to facilitate mitophagy in astrocytes and restrain inflammation-induced neurotoxicity.
    Jack H Howden, Hanna Hakansson, Manuela Nieto-Rostro, Robyn McAdam, Charles Arber, Nicholas J Brandon, Josef T Kittler.
      Mitochondria are essential for ATP production, calcium buffering, and apoptotic signaling, with mitophagy playing a critical role in removing dysfunctional mitochondria. This study demonstrates that PINK1-dependent mitophagy occurs more rapidly and is less spatially restricted in astrocytes compared to neurons. We identified hexokinase 2 (HK2) as a key regulator of mitophagy in astrocytes, forming a glucose-dependent complex with PINK1 in response to mitochondrial damage. Additionally, exposure to neuroinflammatory stimuli enhances PINK1/HK2-dependent mitophagy, providing neuroprotection. These findings contribute to our understanding of mitophagy mechanisms in astrocytes and underscore the importance of PINK1 in cellular health and function within the context of neurodegenerative diseases.
    Keywords:  CP: Metabolism; CP: Neuroscience; PINK1; Parkinson’s disease; astrocyte; hexokinase; inflammation; metabolism; mitochondria; mitophagy; neurodegeneration
    DOI:  https://doi.org/10.1016/j.celrep.2025.115809
  24. Nat Rev Immunol. 2025 Jun 16.
    Iron and the immune system.
    Joe N Frost, Hal Drakesmith.
      Iron is a cofactor for hundreds of enzymes and biochemical processes that support cellular metabolism across the kingdoms of life. Because of this, the host and pathogen compete for iron as a vital resource. Moreover, research has shown that iron acquisition and iron trafficking have substantial effects on the immune system. This is especially important because iron-related disorders - both deficiency and overload - are common worldwide. In this Review, we describe how immune cells acquire and use iron, which branches of the immune system are most affected by iron and how changes in iron availability can affect infectious diseases, autoinflammatory disorders and antitumour immunity. We also discuss key unanswered questions and potential therapeutic opportunities to manipulate immunity by controlling iron trafficking.
    DOI:  https://doi.org/10.1038/s41577-025-01193-y
  25. J Biol Chem. 2025 Jun 16. pii: S0021-9258(25)02230-6. [Epub ahead of print] 110380
    The redox landscape of pyruvate:ferredoxin oxidoreductases reveals often conserved Fe-S cluster potentials.
    Sheila C Bonitatibus, Ryan V Pham, Andrew C Weitz, Madeline M Lopéz-Muñoz, Bin Li, William W Metcalf, Satish K Nair, Sean J Elliott.
      Here we investigate the thermodynamic driving force of internal electron transfer (ET) of pyruvate:ferredoxin oxidoreductases (PFORs), by comparing the redox properties of a series of PFORs from Chlorobaculum tepidum (Ct), Magnetococcus marinus (Mm), Methanosarccina acetivorans (Ma), as well as revisiting the single historical precedent, the enzyme from Desulfovibrio africanus. These enzymes require a thiamine pyrophosphate (TPP) cofactor, three [4Fe-4S] clusters, and Coenzyme A (CoA) for activity and are found within anaerobic organisms that utilize the reverse tricarboxylic acid (TCA cycle), or other reductive pathways, performing CO2 reduction and pyruvate synthesis. Yet, PFOR is often invoked as an oxidative enzyme responsible for generating reducing equivalents in the form of the redox carrier ferredoxin. Previous efforts to understand the mechanism of PFOR have relied upon a prior report of the iron-sulfur redox potentials derived from an incomplete redox titration. Here we use direct protein film electrochemistry (PFE) to provide a side-by-comparison of four PFOR enzymes, providing a new assessment of the iron-sulfur cluster redox potentials. As the Ma PFOR is comprised of multiple polypeptides, our investigation of the recombinant PorD sub-unit allows us to construct a model where the revised redox-potentials are mapped to specific iron-sulfur clusters.
    Keywords:  Iron-sulfur protein; electron-transfer; enzymes; redox chemistry
    DOI:  https://doi.org/10.1016/j.jbc.2025.110380
  26. Nat Immunol. 2025 Jun 17.
    Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
    Hongxu Xian, Kosuke Watari, Masafumi Ohira, Jonathan S Brito, Peng He, Janset Onyuru, Elina I Zuniga, Hal M Hoffman, Michael Karin.
      Stress-induced oxidized mitochondrial DNA (Ox-mtDNA) fragments enter the cytoplasm, activating the NLRP3 inflammasome and caspase-1 and enabling gasdermin-D-mediated circulatory release of mtDNA. Elevated amounts of circulating mtDNA, presumably oxidized, have been detected in older individuals and patients with metabolic or autoimmune disorders. Here we show that sustained Ox-mtDNA release, triggered by a prototypical NLRP3 inflammasome activator, induces autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells, are elicited by in vitro-generated Ox-mtDNA, but not by non-oxidized mtDNA. Although both mtDNA forms are internalized by pDCs and induce interferon-α, only Ox-mtDNA stimulates autocrine interleukin (IL)-1β signaling that induces co-stimulatory molecules and IL-21, which enable mouse and human pDCs to induce functional TFH differentiation, supportive of autoantibody production. These findings underscore the role of pDC-generated IL-1β in autoantibody production and highlight Ox-mtDNA as an important autoimmune trigger, suggesting potential therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41590-025-02179-7
  27. Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2425364122
    The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine.
    Lyubomyr Burtnyak, Yifeng Yuan, Erwina Stojek, Xiaobei Pan, Lankani Gunaratne, Gabriel Silveira d'Almeida, Claire Fergus, Maria Martinelli, Colbie J Reed, Jessie Fernandez, Bhargesh Indravadan Patel, Isaac Marquez, Ann E Ehrenhofer-Murray, Manal A Swairjo, Juan D Alfonzo, Brian D Green, Vincent P Kelly, Valérie de Crécy-Lagard.
      The nucleobase queuine (q) and its nucleoside queuosine (Q) are micronutrients derived from bacteria that are acquired from the gut microbiome and/or diet in humans. Following cellular uptake, Q is incorporated at the wobble base (position 34) of tRNAs that decode histidine, tyrosine, aspartate, and asparagine codons, which is important for efficient translation. Early studies suggested that cytosolic uptake of queuine is mediated by a selective transporter that is regulated by mitogenic signals, but the identity of this transporter has remained elusive. Here, through a cross-species bioinformatic search and genetic validation, we have identified the solute carrier family member SLC35F2 as a unique transporter for both queuine and queuosine in Schizosaccharomyces pombe and Trypanosoma brucei. Furthermore, gene disruption in human HeLa cells revealed that SLC35F2 is the sole transporter for queuosine (Km 174 nM) and a high-affinity transporter for the queuine nucleobase (Km 67 nM), with the additional presence of second low-affinity queuine transporter (Km 259 nM). Ectopic expression of labeled SLC35F2 reveals localization to the cell membrane and Golgi apparatus via immunofluorescence. Competition uptake studies show that SLC35F2 is not a general transporter for other canonical ribonucleobases or ribonucleosides but selectively imports q and Q. The identification of SLC35F2, an oncogene, as the transporter of both q and Q advances our understanding of how intracellular levels of queuine and queuosine are regulated and how their deficiency contributes to a variety of pathophysiological conditions, including neurological disorders and cancer.
    Keywords:  Qtp1; SPCC320.08; tRNA modification
    DOI:  https://doi.org/10.1073/pnas.2425364122
  28. Dis Model Mech. 2025 Jun 01. pii: dmm052313. [Epub ahead of print]18(6):
    Epigenetic reprogramming induced by key metabolite depletion is an evolutionarily ancient path to tumorigenesis.
    Zhe Chen, Xiaomeng Zhang, Mingxi Deng, Chongyang Li, Thi Thuy Nguyen, Min Liu, Kun Dou, Toyotaka Ishibashi, Jiguang Wang, Yan Yan.
      Tumor growth is a challenge for multicellular life forms. Contrary to human tumors, which take years to form, tumors in short-living species can arise within days without accumulating multiple mutations, raising the question whether the paths to tumorigenesis in diverse species have any commonalities. In a fly tumor model caused by loss of cell polarity genes, we identified two key metabolic changes: first, systemic depletion of acetyl-CoA leading to a reduction in histone acetylation levels and stochastic silencing of actively transcribed genes; and second, defects in the methionine cycle causing systemic depletion of S-adenosyl methionine, which further reduces histone methylation levels and causes stochastic activation of transposons. Perturbation of the methionine metabolic process inhibits tumor growth. To understand the evolutionary origin of tumorigenesis, we performed comparative studies of fly and human tumors and found that human tumors with metabolic signatures similar to those of fly tumors have a lower mutational load, younger patient age and lower DNA methylation levels. This study indicates that depletion of key metabolites is an evolutionarily ancient driving force for tumorigenesis.
    Keywords:   Drosophila melanogaster ; Acetyl-CoA; Epigenetics; Invertebrate tumor model; Metabolism; S-Adenosyl methionine
    DOI:  https://doi.org/10.1242/dmm.052313
  29. Aging Cell. 2025 Jun 16. e70135
    Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.
    Claudia C S Chini, Laura Colman, Eduardo Palmieri, Jessica L Strange, Sonu Kashyap, Bing Han, Andres Benitez-Rosendo, Gina L Ciccio Lopez, Sara Peixoto Rabelo, Shreyartha Mukherjee, Gustavo H de Souza, John Varga, Ralph G Meyer, Mirella L Meyer-Ficca, Eduardo N Chini.
      Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7-14 days of NAM depletion, despite NAD+ levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon-dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage-dependent anion channel 1 (VDAC1), which activated the cGAS-STING signaling pathway. Inhibition of VDAC oligomerization with VBIT-4, STING signaling with H-151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC-mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.
    DOI:  https://doi.org/10.1111/acel.70135
  30. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00464-2. [Epub ahead of print]85(12): 2390-2408.e6
    SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
    Khoa A Tran, Michael Gilbert, Berta N Vazquez, Alessandro Ianni, Benjamin A Garcia, Alejandro Vaquero, Shelley L Berger.
      Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12. We identified the transcription factor nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) as an interactor of SIRT7 and found NUCKS1 recruitment onto chromatin during senescence mediated by SIRT7 loss, correlating with increased NUCKS1 acetylation. NUCKS1 depletion delayed senescence, leading to reduced inflammatory gene expression associated with transcription factors RELA and CEBPβ. In Sirt7 knockout and aged mouse livers, NUCKS1 was bound at the promoters and enhancers of age-related genes, and these regulatory regions gained accessibility during aging. Overall, our results uncover NUCKS1 as an interactor of SIRT7 and indicate that proteasomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.
    Keywords:  NUCKS1; SIRT7; acetylation; aging; post-translation modification; protein regulation; senescence; sirtuins
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.025
  31. Elife. 2025 Jun 16. pii: e107882. [Epub ahead of print]14
    Multiple roles for a mitochondrial enzyme.
    Xicong Tang, Hongyu Qiu.
      The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
    Keywords:  aging; arginase; fibrosis; heart; human; inflammation; macrophages; medicine; mouse; rat
    DOI:  https://doi.org/10.7554/eLife.107882
  32. Aging Cell. 2025 Jun 18. e70127
    Senescence Cell Induction Methods Display Diverse Metabolic Reprogramming and Reveal an Underpinning Serine/Taurine Reductive Metabolic Phenotype.
    Domenica Berardi, Gillian Farrell, Abdullah AlSultan, Ashley McCulloch, Nicole M Hall, Rui Pedro Pereira Sousa, Melanie Jimenez, Colin Selman, Ilaria Bellantuono, Caroline H Johnson, Zahra Rattray, Nicholas J W Rattray.
      The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop understanding of these subphenotypes, we developed and employed a novel bioanalytical pipeline integrating untargeted metabolomics, label-free proteomics, and stable isotope tracing alongside cellular deformability measurements and established senescence biomarkers. Initially, standard senescent markers indicated all induction methods were consistent by showing elevated SA-β-Gal expression, p21 levels, and γH2AX DNA damage markers alongside a decrease in Ki67 and an increase in shape, volume, and deformability. However, when probed at the metabolic and protein levels, all senescence models indicated both shared and unique biomolecular responses. A metabolic shift toward reductive pathways (driven by serine and taurine rewiring) and impaired proteostasis was an observed shared response. These findings suggest that targeting metabolic redox circuits, alongside serine and taurine metabolic processes, presents novel therapeutic strategies for addressing senescence and aging. But importantly, alongside this general shift, we found that significant metabolic and proteomic heterogeneity also exists across different senescence induction methods. This demonstrates that the method of senescence induction significantly influences cell metabolic and proteomic profiles. Critically, methods of senescence induction are not interchangeable, and careful consideration is needed when choosing between different induction methods and when comparing cellular phenotypes across different in vitro senescence experiments.
    Keywords:  aging; isotope labeling; metabolomics; proteomics; rheo‐morphology; senescence
    DOI:  https://doi.org/10.1111/acel.70127
  33. Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2503677122
    Gut sulfide metabolism modulates behavior and brain bioenergetics.
    Roshan Kumar, Delawrence J Sykes, Victor I Band, Megan L Schaller, Romel Patel, Victor Vitvitsky, Peter Sajjakulnukit, Rashi Singhal, Harrison K A Wong, Suchitra K Hourigan, Fumito Ichinose, Costas A Lyssiotis, Yatrik M Shah, Ruma Banerjee.
      The host-microbiome interface is rich in metabolite exchanges and exquisitely sensitive to diet. Hydrogen sulfide (H2S) is present at high concentrations at this interface and is a product of both microbial and host metabolism. The mitochondrial enzyme, sulfide quinone oxidoreductase (SQOR), couples H2S detoxification to oxidative phosphorylation; its inherited deficiency presents as Leigh disease. Since an estimated two-thirds of systemic H2S metabolism originates in the gut, it raises questions as to whether impaired sulfide clearance in this compartment contributes to disease and whether it can be modulated by dietary sulfur content. In this study, we report that SQOR deficiency confined to murine intestinal epithelial cells perturbs colon bioenergetics that is reversed by antibiotics, revealing a significant local contribution of microbial H2S to host physiology. We also find that a 2.5-fold higher methionine intake, mimicking the difference between animal and plant proteins, synergizes with intestinal SQOR deficiency to adversely impact colon architecture and alter microbiome composition. In serum, increased thiosulfate, a biomarker of H2S oxidation, reveals that intestinal SQOR deficiency combined with higher dietary methionine affects sulfide metabolism globally and perturbs energy metabolism as indicated by higher ketone bodies. The mice exhibit lower exploratory locomotor activity while brain MRI reveals an atypical reduction in ventricular volume, which is associated with lower aquaporin 1 that is important for cerebrospinal fluid secretion. Our study reveals the dynamic interaction between dietary sulfur intake and sulfide metabolism at the host-microbe interface, impacting gut health, and the potential for lower dietary methionine intake to modulate pathology.
    Keywords:  gut–brain axis; hydrogen sulfide; ketone body; methionine; sulfide quinone oxidoreductase
    DOI:  https://doi.org/10.1073/pnas.2503677122
  34. Immunity. 2025 Jun 13. pii: S1074-7613(25)00237-7. [Epub ahead of print]
    ILC3s sense gut microbiota through STING to initiate immune tolerance.
    JRI Live Cell Bank
      Immune tolerance to gut microbiota is necessary for health, yet the mechanisms initiating it remain elusive. We profiled MHC II+ cells at single-cell resolution from the large intestine. Following colonization with the pathobiont Helicobacter hepaticus, group 3 innate lymphoid cells (ILC3s) were a key RORγt+ antigen-presenting cell that expressed low levels of pattern-recognition receptors but upregulated signatures for antigen presentation and STING signaling. We revealed that STING signaling in ILC3s permitted direct sensing of microbes and enhanced CCR7-dependent migration to gut-draining lymph nodes. ILC3-intrinsic STING signaling supported the instruction of microbiota-specific regulatory T cells and restrained chronic inflammation. However, gut inflammation induced exuberant STING activation, which resulted in the cell death of ILC3s. Our results define STING as a key sensor of gut microbiota in ILC3s. At steady state, this endows ILC3s with the ability to instruct immune tolerance, but heightened STING activation becomes detrimental and eliminates this tissue-protective cell type.
    Keywords:  IBD; ILC3s; RORγt(+) antigen-presenting cells; STING; chronic inflammation; immune tolerance; microbiota
    DOI:  https://doi.org/10.1016/j.immuni.2025.05.016
  35. Nat Immunol. 2025 Jun 17.
    pDCs drive immunopathology by sensing oxidized mitochondrial DNA.
    Moshe Arditi, Timothy R Crother.
      
    DOI:  https://doi.org/10.1038/s41590-025-02193-9
  36. Cell Death Dis. 2025 Jun 19. 16(1): 460
    PUMA reduces FASN ubiquitination to promote lipid accumulation and tumor progression in human clear cell renal cell carcinoma.
    Qianqian Luo, Qi Wang, Jian Shi, Qingyang Lv, Zirui Dong, Wen Li, Yaru Xia, Jingchong Liu, Hongmei Yang.
      While the p53 upregulated modulator of apoptosis (PUMA) is traditionally recognized for promoting cell apoptosis and enhancing chemotherapy efficacy in various cancers, its role in clear cell renal cell carcinoma (ccRCC) remains unclear due to ccRCC's chemotherapy resistance. In this study, we discover a novel oncogenic role for PUMA in ccRCC, diverging from its known apoptotic function, through assessments of public datasets, clinical tissue samples, and cell line experiments. Abnormally high expression of PUMA positively correlates with clinical stages and poor prognosis. Notably, PUMA's role in ccRCC appears to be independent of apoptosis. Instead, it facilitates tumor progression and lipid accumulation through mechanisms involving the key metabolic regulator, fatty acid synthase (FASN). Specifically, the N44-102 amino acid sequence of PUMA, distinct from the previously studied BH3 domain, is crucial for its interaction with FASN. As a mechanism, PUMA stabilizes FASN by binding to ubiquitin-specific protease 15 (USP15), reducing FASN ubiquitination and degradation, thereby forming the PUMA-USP15-FASN axis. These findings challenge the established view of PUMA's role in cancer biology. Furthermore, PUMA knockdown significantly inhibits tumor growth and enhances the sensitivity of ccRCC tumors to metabolic inhibition. These results position PUMA as a novel metabolic regulator and a potential therapeutic target in ccRCC. The combined inhibition of PUMA and FASN further supports the therapeutic potential of targeting this metabolic axis.
    DOI:  https://doi.org/10.1038/s41419-025-07782-y
  37. J Comput Aided Mol Des. 2025 Jun 16. 39(1): 32
    Thermodynamic free energy map for the non-oxidative glycolysis pathways.
    Adittya Pal.
      Designing reaction pathways that maximize the production of a target compound in a given metabolic network is a fundamental problem in systems biology. In this study, we systematically explore the non-oxidative glycolysis metabolic network, guided by the principle that reactions with negative Gibbs free energy differences are thermodynamically favored. We enumerate alternative pathways that implement the net non-oxidative glycolysis reaction, categorized by their length. Our analysis reveals several alternative thermodynamically favorable pathways beyond the experimentally reported ones. Additionally, we identify molecules within the network, such as 3-hydroxypropionic acid, that may have significant potential for further investigation.
    Keywords:  3-hydroxypropionic acid; Metabolic networks; Mixed integer linear programming; Non-oxidative glycolysis; Systems biology; Thermodynamic analysis of molecular networks; Thermodynamics in biology
    DOI:  https://doi.org/10.1007/s10822-025-00604-5
  38. Cell. 2025 Jun 12. pii: S0092-8674(25)00561-6. [Epub ahead of print]
    Bivalent chromatin instructs lineage specification during hematopoiesis.
    Masaki Yagi, Gracia Bonilla, Michael S Hoetker, Nikolaos Tsopoulidis, Joy E Horng, Chuck Haggerty, Alexander Meissner, Ruslan I Sadreyev, Hanno Hock, Konrad Hochedlinger.
      Developmental gene expression is regulated by the dynamic interplay of histone H3 lysine 4 (H3K4) and histone H3 lysine 27 (H3K27) methylation, yet the physiological roles of these epigenetic modifications remain incompletely understood. Here, we show that mice depleted for all forms of H3K4 methylation, using a dominant histone H3-lysine-4-to-methionine (H3K4M) mutation, succumb to a severe loss of all major blood cell types. H3K4M-expressing hematopoietic stem cells (HSCs) and committed progenitors are present at normal numbers, indicating that H3K4 methylation is dispensable for HSC maintenance and commitment but essential for progenitor cell maturation. Mechanistically, we reveal that H3K4 methylation opposes the deposition of repressive H3K27 methylation at differentiation-associated genes enriched for a bivalent (i.e., H3K4/H3K27-methylated) chromatin state in HSCs and progenitors. Indeed, by concomitantly suppressing H3K27 methylation in H3K4-methylation-depleted mice, we rescue the acute lethality, hematopoietic failure, and gene dysregulation. Our results provide functional evidence for the interaction between two crucial chromatin marks in mammalian tissue homeostasis.
    Keywords:  H3K27 methylation; H3K27M; H3K4 methylation; H3K4M; bivalent genes; differentiation; hematopoiesis; hematopoietic stem and progenitor cells; histone methylation; lysine-to-methionine mutation
    DOI:  https://doi.org/10.1016/j.cell.2025.05.011
  39. Cancer Cell. 2025 Jun 04. pii: S1535-6108(25)00221-1. [Epub ahead of print]
    A unified pan-cancer proteome atlas.
    Yang Du, Jianmin Wu.
      In this issue of Cancer Cell, Knol et al. present the Pan-Cancer Proteome Atlas (TPCPA), a proteomic resource developed using single-shot data-independent acquisition mass spectrometry (DIA-MS). TPCPA provides proteome-scale quantifications of 999 tumors across 22 cancer types in a unified manner, for discovering tumor biology, biomarkers, and therapeutic targets.
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.012
  40. Cell Syst. 2025 Jun 18. pii: S2405-4712(25)00131-0. [Epub ahead of print]16(6): 101298
    Reframing the role of the objective function in its proper context for metabolic network modeling.
    Mohammad Mazharul Islam, William Shao, Mariska Batavia, Roseanne M Ford, Bernhard O Palsson, Jens Nielsen, Costas D Maranas, Sang Yup Lee, Jason A Papin.
      The "objective function" is a core concept in metabolic network modeling. Its use has enabled the analysis of large data to drive deeper understanding of cellular metabolism. This commentary reframes how the objective function is discussed to enhance its value and clarify misunderstandings in metabolic network modeling.
    DOI:  https://doi.org/10.1016/j.cels.2025.101298
  41. iScience. 2025 Jun 20. 28(6): 112681
    Integrated spatial omics of metabolic reprogramming and the tumor microenvironment in pancreatic cancer.
    Hao Wu, Qiyao Zhang, Zhen Cao, Hongtao Cao, Mengwei Wu, Mengdi Fu, Tingping Huang, Xianlin Han, Xiaoyan Chang, Ziwen Liu.
      Metabolic reprogramming is a defining feature of pancreatic cancer, influencing tumor progression and the tumor microenvironment. By integrating single-cell transcriptomics, spatial transcriptomics, and spatial metabolomics, this study visualized the spatial co-localization of metabolites and gene expression within tumor samples, uncovering metabolic heterogeneity and intercellular interactions. Spatial transcriptomics identified distinct pathological regions, which were further characterized using single-cell transcriptomic data and pathologist annotations. Pseudotime trajectory analysis revealed metabolic shifts along the malignant progression, while single-cell Metabolism (scMetabolism) delineated metabolic differences between pathological regions, classifying them as hypermetabolic or hypometabolic. Notably, aberrant cell communication between cancer cells, macrophages, and fibroblasts was observed, with key receptor-ligand pairs significantly co-expressed in malignant regions and correlated with poor prognosis. Spatial metabolomics imaging identified signature metabolites, highlighting metabolic alterations in amino acid metabolism, polyamine metabolism, fatty acid synthesis, and phospholipid metabolism. This integrated analysis provides critical insights into pancreatic cancer metabolism, offering potential avenues for targeted therapeutic interventions.
    Keywords:  Cancer; Metabolomics; Microenvironment; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.112681
  42. J Cell Biol. 2025 Jul 07. pii: e202407141. [Epub ahead of print]224(7):
    ALDH9A1 deficiency as a source of endogenous DNA damage that requires repair by the Fanconi anemia pathway.
    Moonjung Jung, Jungwoo Kim, Yeji Park, Isaac Ilyashov, Fan Yang, Haruna B Choijilsuren, Danielle Keahi, Jordan A Durmaz, Habin Bea, Audrey M Goldfarb, Mia D Stein, Claudia Wong, Ryan R White, Sunandini Sridhar, Raymond Noonan, Tom F Wiley, Thomas S Carroll, Francis P Lach, Sangmoo Jeong, Ileana C Miranda, Agata Smogorzewska.
      The Fanconi anemia (FA) DNA repair pathway is required for the repair of DNA interstrand cross-links (ICLs). ICLs are caused by genotoxins, such as chemotherapeutic agents or reactive aldehydes. Inappropriately repaired ICLs contribute to hematopoietic stem cell (HSC) failure and tumorigenesis. While endogenous acetaldehyde and formaldehyde are known to induce HSC failure and leukemia in FA patients, the effects of other toxic metabolites on FA pathogenesis have not been systematically investigated. Using a metabolism-focused CRISPR screen, we found a synthetically lethal interaction between ALDH9A1 and the deficiency of the FA pathway. Combined deficiency of ALDH9A1 and FANCD2 causes genomic instability, apoptosis, and decreased hematopoietic colony formation. Fanca-/-Aldh9a1-/- mice exhibited an increased incidence of ovarian tumors. A suppressor CRISPR screen revealed that the loss of ATP13A3, a polyamine transporter, resulted in improved survival of FANCD2-/-ALDH9A1-/- cells. These findings nominate high intracellular polyamines and the resulting 3-aminopropanal and acrolein as sources of endogenous DNA damage in patients with FA.
    DOI:  https://doi.org/10.1083/jcb.202407141
  43. Front Immunol. 2025 ;16 1587256
    LKB1 regulates ILC3 postnatal development and effector function through metabolic programming.
    Huasheng Zhang, Linfeng Zhao, Qingbing Zhang, Lin Hu, Xiaohui Su, Jiping Sun, Lei Shen.
       Introduction: Group 3 Innate Lymphoid Cells (ILC3s) are important for maintaining intestinal homeostasis and host defense. Emerging studies have shown that metabolic regulation plays a crucial role in regulating ILC3 activation and function. However, the role of Liver Kinase B1 (LKB1), a key metabolic regulator, in regulating ILC3 function and intestinal immunity remains poorly understood.
    Methods: To investigate the role of LKB1 in intestinal ILC3s, we generated LKB1 conditional knockout mice by crossing Rorc cre and Stk11 flox/flox mice. Cell number and cytokine production was examined using flow cytometry. Citrobacter rodentium infection model were used to determine the role of LKB1 in intestinal defense. RT-qPCR, flow cytometry and immunohistochemistry were used to assess the intestinal inflammatory responses.
    Results: In this study, we show that LKB1 is essential for ILC3 postnatal development, effector function, and intestinal immunity. LKB1-deficient mice exhibit a marked decrease in ILC3 number at 2 -3 weeks after birth. Ablation of LKB1 in ILC3s results in diminished IL-22 production and less protection against Citrobacter rodentium infection. Moreover, LKB1 deficiency leads to impaired cell metabolism, as indicated by reduced glycolysis and oxidative phosphorylation and less mitochondrial mass. Together, our data demonstrate that LKB1 promotes ILC3 postnatal development and effector function to maintain intestinal immune homeostasis.
    Discussion: Our findings reveal that LKB1 is a key regulator of intestinal ILC3 development, function, and metabolism, thereby linking metabolic control to intestinal immune homeostasis and offering potential therapeutic implications.
    Keywords:  Liver Kinase B1 (LKB1); group 3 innate lymphoid cells (ILC3s); inflammation; intestinal immune homeostasis; metabolic programming
    DOI:  https://doi.org/10.3389/fimmu.2025.1587256
  44. Nat Rev Cancer. 2025 Jun 16.
    Neuro-immune cross-talk in cancer.
    Moran Amit, Tuany Eichwald, Anais Roger, Jennifer Anderson, Aeson Chang, Paola D Vermeer, Karen O Dixon, Nicole N Scheff, Sebastien Talbot.
      The nervous and immune systems have co-evolved to detect and respond to internal and external threats, working together to restore homeostasis after tissue injury or infection. Sharing several receptors and ligands, they engage in direct cross-talk that substantially influences disease development. The emerging field of cancer neuro-immunity focuses on the intricate interactions between the nervous system, immune responses and tumour growth. Additional findings have revealed that nerve fibres infiltrating peripheral tumours can release neuromodulatory factors that shape both immune cell behaviour and tumour progression. Conversely, tumour-infiltrating immune cells can modify the activity of local neurons, including pain-transmitting nociceptive sensory neurons. Beyond sensory fibres, sympathetic signalling can foster immunosuppression by recruiting myeloid-derived suppressor cells and promoting T cell exhaustion. This Review summarizes current evidence on how neuronal signalling regulates peripheral antitumour immune responses within the tumour microenvironment. We describe the complex, reciprocal interactions among neurons, immune cells and malignant cells, highlighting the key parts played by the peripheral nervous system in modulating immunity against cancer. By understanding this neuro-immune axis, novel therapeutic approaches may be uncovered to strengthen antitumour immunity and enhance responses to existing cancer treatments.
    DOI:  https://doi.org/10.1038/s41568-025-00831-w
  45. Nat Cell Biol. 2025 Jun;27(6): 878
    Grow up, beta cells.
    Angela R Parrish.
      
    DOI:  https://doi.org/10.1038/s41556-025-01705-x
  46. Nat Commun. 2025 Jun 20. 16(1): 5282
    Quantitative measurement of phenotype dynamics during cancer drug resistance evolution using genetic barcoding.
    Frederick J H Whiting, Maximilian Mossner, Calum Gabbutt, Christopher Kimberley, Chris P Barnes, Ann-Marie Baker, Erika Yara-Romero, Andrea Sottoriva, Richard A Nichols, Trevor A Graham.
      Cancer treatment frequently fails due to the evolution of drug-resistant cell phenotypes driven by genetic or non-genetic changes. The origin, timing, and rate of spread of these adaptations are critical for understanding drug resistance mechanisms but remain challenging to observe directly. We present a mathematical framework to infer drug resistance dynamics from genetic lineage tracing and population size data without direct measurement of resistance phenotypes. Simulation experiments demonstrate that the framework accurately recovers ground-truth evolutionary dynamics. Experimental evolution to 5-Fu chemotherapy in colorectal cancer cell lines SW620 and HCT116 validates the framework. In SW620 cells, a stable pre-existing resistant subpopulation was inferred, whereas in HCT116 cells, resistance emerged through phenotypic switching into a slow-growing resistant state with stochastic progression to full resistance. Functional assays, including scRNA-seq and scDNA-seq, validate these distinct evolutionary routes. This framework facilitates rapid characterisation of resistance mechanisms across diverse experimental settings.
    DOI:  https://doi.org/10.1038/s41467-025-59479-7
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