bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–03–30
forty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Oxidation of retromer complex controls mitochondrial translation.
  2. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  3. Function of intramitochondrial melatonin and its association with Warburg metabolism.
  4. A human brain map of mitochondrial respiratory capacity and diversity.
  5. Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
  6. A map of mitochondrial biology reveals the energy landscape of the human brain.
  7. SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.
  8. Ferroptosis spreads to neighboring cells via plasma membrane contacts.
  9. A BCAA-haem axis regulates brown fat function.
  10. Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
  11. In situ architecture of the human prohibitin complex.
  12. Drugs that target 'zombie' cells soothe an aching back.
  13. The metabolic significance of peripheral tissue clocks.
  14. The fate of mitochondrial respiratory complexes in aging.
  15. Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
  16. H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
  17. Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells.
  18. Reversible histone deacetylase activity catalyzes lysine acylation.
  19. Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases.
  20. First map of human brain mitochondria is 'groundbreaking' achievement.
  21. Tackling the next decade of cancer research.
  22. Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.
  23. Antagonistic roles for MITF and TFE3 in melanoma plasticity.
  24. The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
  25. Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.
  26. ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes.
  27. Fasting for weight loss is all the rage: what are the health benefits?
  28. Harnessing lysohormesis for healthy ageing.
  29. TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma.
  30. The role of microbial succinate in the pathophysiology of inflammatory bowel disease: mechanisms and therapeutic potential.
  31. Current Understanding of Pathogenic Mechanisms and Disease Models of Citrin Deficiency.
  32. Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.
  33. Identification of a SNAI1 enhancer RNA that drives cancer cell plasticity.
  34. The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.
  35. KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.
  36. Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force.
  37. Unclogging of the TOM complex under import stress.
  38. Phospholipid Biosynthesis: An Unforeseen Modulator of Nuclear Metabolism.
  39. Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
  40. Plasticity of the mammalian integrated stress response.
  41. Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.
  42. The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
  43. Metabolic constraint of human telomere length by nucleotide salvage efficiency.
  44. In vivo targeted and deterministic single-cell malignant transformation.
  45. Assessing cancer therapeutic efficacy in vivo using [2H7]glucose deuterium metabolic imaging.
  46. Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis.
  1. Nature. 2025 Mar 26.
    Oxidation of retromer complex controls mitochondrial translation.
    Junbing Zhang, Md Yousuf Ali, Harrison Byron Chong, Pei-Chieh Tien, James Woods, Carolina Noble, Tristan Vornbäumen, Zehra Ordulu, Anthony P Possemato, Stefan Harry, Jay Miguel Fonticella, Lina Fellah, Drew Harrison, Maolin Ge, Neha Khandelwal, Yingfei Huang, Maëva Chauvin, Anica Tamara Bischof, Grace Marie Hambelton, Magdy Farag Gohar, Siwen Zhang, MinGyu Choi, Sara Bouberhan, Esther Oliva, Mari Mino-Kenudson, Natalya N Pavlova, Michael Lawrence, Justin F Gainor, Sean A Beausoleil, Nabeel Bardeesy, Raul Mostoslavsky, David Pépin, Christopher J Ott, Brian Liau, Liron Bar-Peled.
      Reactive oxygen species (ROS) underlie human pathologies including cancer and neurodegeneration1,2. However, the proteins that sense ROS levels and regulate their production through their cysteine residues remain ill defined. Here, using systematic base-editing and computational screens, we identify cysteines in VPS35, a member of the retromer trafficking complex3, that phenocopy inhibition of mitochondrial translation when mutated. We find that VPS35 underlies a reactive metabolite-sensing pathway that lowers mitochondrial translation to decrease ROS levels. Intracellular hydrogen peroxide oxidizes cysteine residues in VPS35, resulting in retromer dissociation from endosomal membranes and subsequent plasma membrane remodelling. We demonstrate that plasma membrane localization of the retromer substrate SLC7A1 is required to sustain mitochondrial translation. Furthermore, decreasing VPS35 levels or oxidation of its ROS-sensing cysteines confers resistance to ROS-generating chemotherapies, including cisplatin, in ovarian cancer models. Thus, we identify that intracellular ROS levels are communicated to the plasma membrane through VPS35 to regulate mitochondrial translation, connecting cytosolic ROS sensing to mitochondrial ROS production.
    DOI:  https://doi.org/10.1038/s41586-025-08756-y
  2. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  3. Cell Signal. 2025 Mar 21. pii: S0898-6568(25)00167-6. [Epub ahead of print]131 111754
    Function of intramitochondrial melatonin and its association with Warburg metabolism.
    Russel J Reiter, Ramaswamy Sharma, Yidong Bai, Luiz Gustavo de Almeida Chuffa, Doris Loh, Lihong Fan, Daniel P Cardinali.
      Warburg metabolism (aerobic glycolysis) is accompanied by high mitochondrial reactive oxygen species (ROS) generation from the electron transport chain; this is a "Hallmark of Cancer". The elevated ROS sustain the growth and proliferation of the cancer cells. Melatonin is a potent and functionally diverse free radical scavenger and antioxidant that is synthesized in the mitochondria of non-pathological cells and normally aids in keeping mitochondrial ROS levels low and in maintaining redox homeostasis. Because the glucose metabolite, pyruvate, does not enter mitochondria of Warburg metabolizing cells due to the inhibition of pyruvate dehydrogenase complex (PDH), acetyl coenzyme A production is diminished. Acetyl coenzyme A is a necessary co-substrate with serotonin for melatonin synthesis; thus, intramitochondrial melatonin levels become reduced in cancer cells. The hypothesis is that the depressed melatonin levels initiate aerobic glycolysis and allow the exaggerated ROS concentrations to go uncontested; the authors speculate that the elevated mtROS upregulates hypoxia inducible factor 1α (HIF-1α)/pyruvate dehydrogenase kinase (PDK) axis which inhibits PDH, thereby supporting cancer cell proliferation and stimulating cancer biomass. Exposing Warburg metabolizing cancer cells to melatonin elevates intramitochondrial melatonin, thereby reducing mtROS and concurrently interrupting aerobic glycolysis and inhibiting tumor cell proliferation. Mechanistically, higher mitochondrial melatonin levels by supplementation directly upregulates the sirtuin 3 (SIRT3)/FOXO/PDH axis, allowing pyruvate entry into mitochondria and enhancing intrinsic mitochondrial melatonin production as in non-pathological cells. Additionally, melatonin inhibits HIF1α, thereby decreasing PDK activity and disinhibiting PDH, so pyruvate enters mitochondria and is metabolized to acetyl coenzyme A, resulting in reversal of Warburg metabolism.
    Keywords:  Acetyl coenzyme A; Antioxidant; Hypoxia inducible factor; Pyruvate dehydrogenase; Pyruvate metabolism; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111754
  4. Nature. 2025 Mar 26.
    A human brain map of mitochondrial respiratory capacity and diversity.
    Eugene V Mosharov, Ayelet M Rosenberg, Anna S Monzel, Corey A Osto, Linsey Stiles, Gorazd B Rosoklija, Andrew J Dwork, Snehal Bindra, Alex Junker, Ya Zhang, Masashi Fujita, Madeline B Mariani, Mihran Bakalian, David Sulzer, Philip L De Jager, Vilas Menon, Orian S Shirihai, J John Mann, Mark D Underwood, Maura Boldrini, Michel Thiebaut de Schotten, Martin Picard.
      Mitochondrial oxidative phosphorylation (OXPHOS) powers brain activity1,2, and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders3,4. To understand the basis of brain activity and behaviour, there is a need to define the molecular energetic landscape of the brain5-10. Here, to bridge the scale gap between cognitive neuroscience and cell biology, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3 × 3 × 3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes, including OXPHOS enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains diverse mitochondrial phenotypes driven by both topology and cell types. Compared with white matter, grey matter contains >50% more mitochondria. Moreover, the mitochondria in grey matter are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backwards linear regression model that integrates several neuroimaging modalities11 to generate a brain-wide map of mitochondrial distribution and specialization. This model predicted mitochondrial characteristics in an independent brain region of the same donor brain. This approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain function. This resource also relates to neuroimaging data and defines the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders. All data are available at http://humanmitobrainmap.bcblab.com .
    DOI:  https://doi.org/10.1038/s41586-025-08740-6
  5. Nat Metab. 2025 Mar 25.
    Haem biosynthesis regulates BCAA catabolism and thermogenesis in brown adipose tissue.
    Dylan J Duerre, Julia K Hansen, Steven V John, Annie Jen, Noah D Carrillo, Hoang Bui, Yutong Bao, Matias Fabregat, J Leon Catrow, Li-Yu Chen, Katherine A Overmyer, Evgenia Shishkova, Quentinn Pearce, Mark P Keller, Richard A Anderson, Vincent L Cryns, Alan D Attie, James E Cox, Joshua J Coon, Jing Fan, Andrea Galmozzi.
      The distinctive colour of brown adipose tissue (BAT) is attributed to its high content of haem-rich mitochondria. However, the mechanisms by which BAT regulates intracellular haem levels remain largely unexplored. Here we demonstrate that haem biosynthesis is the primary source of haem in brown adipocytes. Inhibiting haem biosynthesis results in an accumulation of the branched-chain amino acids (BCAAs) valine and isoleucine, owing to a haem-associated metabolon that channels BCAA-derived carbons into haem biosynthesis. Haem synthesis-deficient brown adipocytes display reduced mitochondrial respiration and lower UCP1 levels than wild-type cells. Although exogenous haem supplementation can restore intracellular haem levels and mitochondrial function, UCP1 downregulation persists. This sustained UCP1 suppression is linked to epigenetic regulation induced by the accumulation of propionyl-CoA, a byproduct of disrupted haem synthesis. Finally, disruption of haem biosynthesis in BAT impairs thermogenic response and, in female but not male mice, hinders the cold-induced clearance of circulating BCAAs in a sex-hormone-dependent manner. These findings establish adipose haem biosynthesis as a key regulator of thermogenesis and sex-dependent BCAA homeostasis.
    DOI:  https://doi.org/10.1038/s42255-025-01253-6
  6. Nature. 2025 Mar 26.
    A map of mitochondrial biology reveals the energy landscape of the human brain.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00872-z
  7. Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00205-0. [Epub ahead of print]44(4): 115434
    SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.
    Nurul Khalida Ibrahim, Sabine Schreek, Buesra Cinar, Anna Sophie Stasche, Su Hyun Lee, Andre Zeug, Tim Dolgner, Julia Niessen, Evgeni Ponimaskin, Halyna Shcherbata, Beate Fehlhaber, Jean-Pierre Bourquin, Beat Bornhauser, Martin Stanulla, Andreas Pich, Alejandro Gutierrez, Laura Hinze.
      Adaptation to changes in amino acid availability is crucial for cellular homeostasis, which requires an intricate orchestration of involved pathways. Some cancer cells can maintain cellular fitness upon amino acid shortage, which has a poorly understood mechanistic basis. Leveraging a genome-wide CRISPR-Cas9 screen, we find that superoxide dismutase 2 (SOD2) has a previously unrecognized dismutase-independent function. We demonstrate that SOD2 regulates global proteasomal protein degradation and promotes cell survival under conditions of metabolic stress in malignant cells through the E3 ubiquitin ligases UBR1 and UBR2. Consequently, inhibition of SOD2-mediated protein degradation highly sensitizes different cancer entities, including patient-derived xenografts, to amino acid depletion, highlighting the pathophysiological relevance of our findings. Our study reveals that SOD2 is a regulator of proteasomal protein breakdown upon starvation, which serves as an independent catabolic source of amino acids, a mechanism co-opted by cancer cells to maintain cellular fitness.
    Keywords:  CP: Cancer; CP: Molecular biology; SOD2; UBR1; UBR2; amino acid starvation; cancer; drug resistance; leukemia; protein degradation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115434
  8. Nat Commun. 2025 Mar 26. 16(1): 2951
    Ferroptosis spreads to neighboring cells via plasma membrane contacts.
    Bernhard F Roeck, Sara Lotfipour Nasudivar, Michael R H Vorndran, Lena Schueller, F Isil Yapici, Matthias Rübsam, Silvia von Karstedt, Carien M Niessen, Ana J Garcia-Saez.
      Ferroptosis is a lytic, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and associated with necrosis spread in diseased tissues through unknown mechanisms. Using a novel optogenetic system for light-driven ferroptosis induction via degradation of the anti-ferroptotic protein GPX4, we show that lipid peroxidation and ferroptotic death can spread to neighboring cells through their closely adjacent plasma membranes. Ferroptosis propagation is dependent on cell distance and completely abolished by disruption of α-catenin-dependent intercellular contacts or by chelation of extracellular iron. Remarkably, bridging cells with a lipid bilayer or increasing contacts between neighboring cells enhances ferroptosis spread. Reconstitution of iron-dependent spread of lipid peroxidation between pure lipid, contacting liposomes provides evidence for the physicochemical mechanism involved. Our findings support a model in which iron-dependent lipid peroxidation propagates across proximal plasma membranes of neighboring cells, thereby promoting the transmission of ferroptotic cell death with consequences for pathological tissue necrosis spread.
    DOI:  https://doi.org/10.1038/s41467-025-58175-w
  9. Nat Metab. 2025 Mar 25.
    A BCAA-haem axis regulates brown fat function.
      
    DOI:  https://doi.org/10.1038/s42255-025-01266-1
  10. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2424046122
    Control of circadian muscle glucose metabolism through the BMAL1-HIF axis in obesity.
    Claire A Chaikin, Abhishek V Thakkar, Adam W T Steffeck, Eric M Pfrender, Kaitlyn Hung, Pei Zhu, Nathan J Waldeck, Rino Nozawa, Weimin Song, Christopher R Futtner, Mattia Quattrocelli, Joseph Bass, Issam Ben-Sahra, Clara B Peek.
      Disruptions of circadian rhythms are widespread in modern society and lead to accelerated and worsened symptoms of metabolic syndrome. In healthy mice, the circadian clock factor BMAL1 is required for skeletal muscle function and metabolism. However, the importance of muscle BMAL1 in the development of metabolic diseases, such as diet-induced obesity (DIO), remains unclear. Here, we demonstrate that skeletal muscle-specific BMAL1-deficient mice exhibit worsened glucose tolerance upon high-fat diet feeding, despite no evidence of increased weight gain. Metabolite profiling from Bmal1-deficient muscles revealed impaired glucose utilization specifically at early steps in glycolysis that dictate the switch between anabolic and catabolic glucose fate. We provide evidence that this is due to abnormal control of the nutrient stress-responsive hypoxia-inducible factor (HIF) pathway. Genetic HIF1α stabilization in muscle Bmal1-deficient mice restores glucose tolerance and expression of 217/736 dysregulated genes during DIO, including glycolytic enzymes. Together, these data indicate that during DIO, skeletal muscle BMAL1 is an important regulator of HIF-driven glycolysis and metabolic flexibility, which influences the development of high-fat-diet-induced glucose intolerance.
    Keywords:  circadian rhythm; diet-induced obesity; hypoxia; skeletal muscle
    DOI:  https://doi.org/10.1073/pnas.2424046122
  11. Nat Cell Biol. 2025 Mar 21.
    In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      Prohibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others. The human prohibitins prohibitin 1 and prohibitin 2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organization has remained elusive. Here we determined the molecular organization of the human prohibitin complex within the mitochondrial inner membrane using an integrative structural biology approach combining quantitative western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling. The proposed bell-shaped structure consists of 11 alternating prohibitin 1 and prohibitin 2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3% of the crista membrane area. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organization of the mitochondrial inner membrane.
    DOI:  https://doi.org/10.1038/s41556-025-01620-1
  12. Nature. 2025 Mar;639(8056): 841
    Drugs that target 'zombie' cells soothe an aching back.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00770-4
  13. Commun Biol. 2025 Mar 26. 8(1): 497
    The metabolic significance of peripheral tissue clocks.
    A Louise Hunter, David A Bechtold.
      The circadian clock is a transcriptional-translational feedback loop which oscillates in virtually all nucleated cells of the body. In the decades since its discovery, it has become evident that the molecular clockwork is inextricably linked to energy metabolism. Given the frequency with which metabolic dysfunction and clock disruption co-occur, understanding why and how clock and metabolic processes are reciprocally coupled will have important implications for supporting human health and wellbeing. Here, we discuss the relevance of molecular clock function in metabolic tissues and explore its role not only as a driver of day-night variation in gene expression, but as a key mechanism for maintaining metabolic homeostasis in the face of fluctuating energy supply and demand.
    DOI:  https://doi.org/10.1038/s42003-025-07932-0
  14. Trends Cell Biol. 2025 Mar 26. pii: S0962-8924(25)00042-X. [Epub ahead of print]
    The fate of mitochondrial respiratory complexes in aging.
    Hanna Salmonowicz, Karolina Szczepanowska.
      While mitochondrial dysfunction is one of the canonical hallmarks of aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, the mitochondrial respiratory complexes (MRCs). The causes and consequences of these defects hold research attention. In this review, we assess the lifecycle of respiratory complexes, from biogenesis to degradation, and look closely at the mechanisms that could underpin their dysfunction in aged cells. We discuss how these processes could be altered by aging and expand on the fate of MRCs in age-associated pathologies. Given the complexity behind MRC maintenance and functionality, several traits could contribute to the phenomenon known as age-associated mitochondrial dysfunction. New advances will help us better understand the fate of this machinery in aging and age-related diseases.
    Keywords:  OXPHOS; age-associated diseases; dysfunction; mitochondria; protein complexes, aging hallmarks
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.008
  15. Science. 2025 Mar 28. 387(6741): eadr8589
    Running a genetic stop sign accelerates oxygen metabolism and energy production in horses.
    Gianni M Castiglione, Xin Chen, Zhenhua Xu, Nadir H Dbouk, Anamika A Bose, David Carmona-Berrio, Emiliana E Chi, Lingli Zhou, Tatiana N Boronina, Robert N Cole, Shirley Wu, Abby D Liu, Thalia D Liu, Haining Lu, Ted Kalbfleisch, David Rinker, Antonis Rokas, Kyla Ortved, Elia J Duh.
      Horses are among nature's greatest athletes, yet the ancestral molecular adaptations fueling their energy demands are poorly understood. Within a clinically important pathway regulating redox and metabolic homeostasis (NRF2/KEAP1), we discovered an ancient mutation-conserved in all extant equids-that increases mitochondrial respiration while decreasing tissue-damaging oxidative stress. This mutation is a de novo premature opal stop codon in KEAP1 that is translationally recoded into a cysteine through previously unknown mechanisms, producing an R15C mutation in KEAP1 that is more sensitive to electrophiles and reactive oxygen species. This recoding enables increased NRF2 activity, which enhances mitochondrial adenosine 5'-triphosphate production and cellular resistance to oxidative damage. Our study illustrates how recoding of a de novo stop codon, a strategy thought restricted to viruses, can facilitate adaptation in vertebrates.
    DOI:  https://doi.org/10.1126/science.adr8589
  16. J Biol Chem. 2025 Mar 20. pii: S0021-9258(25)00282-0. [Epub ahead of print] 108433
    H2S remodels mitochondrial ultrastructure and destabilizes respiratory supercomplexes.
    David A Hanna, Brandon Chen, Yatrik M Shah, Oleh Khalimonchuk, Brian Cunniff, Ruma Banerjee.
      Mitochondrial form and function are intimately interconnected, responding to cellular stresses and changes in energy demand. Hydrogen sulfide, a product of amino acid metabolism, has dual roles as an electron transport chain substrate and complex IV (CIV) inhibitor, leading to a reductive shift, which has pleiotropic metabolic consequences. Luminal sulfide concentration in colon is high due to microbial activity, and in this study, we demonstrate that chronic sulfide exposure of colonocyte-derived cells leads to lower Mic60 and Mic19 expression that is correlated with a profound loss of cristae and lower mitochondrial networking. Sulfide-induced depolarization of the inner mitochondrial membrane activates Oma1-dependent cleavage of Opa1 and is associated with a profound loss of CI and CIV activities associated with respirasomes. Our study reveals a potential role for sulfide as an endogenous modulator of mitochondrial dynamics and suggests that this regulation is corrupted in hereditary or acquired diseases associated with elevated sulfide.
    Keywords:  Cristae; cristae; electron transport chain; hydrogen sulfide; mitochondrial dynamics; respirasome
    DOI:  https://doi.org/10.1016/j.jbc.2025.108433
  17. Genome Biol. 2025 Mar 26. 26(1): 70
    Clonal expansion dictates the efficacy of mitochondrial lineage tracing in single cells.
    Xin Wang, Kun Wang, Weixing Zhang, Zhongjie Tang, Hao Zhang, Yuying Cheng, Da Zhou, Chao Zhang, Wen-Zhao Zhong, Qing Ma, Jin Xu, Zheng Hu.
       BACKGROUND: Mitochondrial DNA (mtDNA) variants hold promise as endogenous barcodes for tracking human cell lineages, but their efficacy as reliable lineage markers are hindered by the complex dynamics of mtDNA in somatic tissues.
    RESULTS: Here, we use computational modeling and single-cell genomics to thoroughly interrogate the origin and clonal dynamics of mtDNA variants across various biological settings. Our findings reveal that the majority of mtDNA variants which are specifically present in a cell subpopulation, termed subpopulation-specific variants, are pre-existing heteroplasmies in the first cell instead of de novo somatic mutations during divisions. Moreover, subpopulation-specific variants demonstrate limited discriminatory power among different genuine lineages under weak clonal expansion; however, certain subpopulation-specific variants with consistently high frequencies among a subpopulation are capable of faithfully labeling cell lineages in scenarios of stringent clonal expansion, such as strongly expanded T cell populations in diseased conditions and clonal hematopoiesis in aged individuals. Inspired by our simulations, we introduce a lineage informative score, facilitating the identification of reliable mitochondrial lineage tracing markers across different modalities of single-cell genomic data.
    CONCLUSIONS: Combining computational modeling and single-cell sequencing, our study reveals that the performance of mitochondrial lineage tracing is highly dependent on the extent of clonal expansion, which thus should be considered when applying mitochondrial lineage tracing.
    Keywords:  Clonal dynamics; Lineage tracing; Single-cell genomics; mtDNA variants
    DOI:  https://doi.org/10.1186/s13059-025-03540-7
  18. Nat Chem Biol. 2025 Mar 26.
    Reversible histone deacetylase activity catalyzes lysine acylation.
    Takeshi Tsusaka, Mohd Altaf Najar, Benjamin Schwarz, Eric Bohrnsen, Juan A Oses-Prieto, Helena Neudorf, Christina Lee, Jonathan P Little, Alma L Burlingame, Catharine M Bosio, George M Burslem, Emily L Goldberg.
      The dynamic modification of proteins by many metabolites suggests an intimate link between energy metabolism and post-translational modifications (PTMs). For instance, starvation and low-carbohydrate diets lead to the accumulation of β-hydroxybutyrate (BHB), whose blood concentrations can reach millimolar levels, concomitant with the accumulation of lysine β-hydroxybutyrylation (Kbhb) of proteins. Here we report that class I histone deacetylases (HDACs) unexpectedly catalyze the formation of Kbhb. Through mutational analysis, we show a shared reliance on key active site amino acids for classical deacetylation and noncanonical HDAC-catalyzed β-hydroxybutyrylation. On the basis of these data, we propose that HDACs catalyze a condensation reaction between the free amine group on lysine and the BHB carboxylic acid, thereby generating an amide bond. This reversible HDAC activity is not limited to BHB and extends to multiple short-chain fatty acids, representing a novel mechanism of PTM deposition relevant to metabolically sensitive proteome modifications.
    DOI:  https://doi.org/10.1038/s41589-025-01869-5
  19. Sci Adv. 2025 Mar 28. 11(13): eadu1710
    Xenotopic synthetic biology: Prospective tools for delaying aging and age-related diseases.
    Andrey A Parkhitko, Valentin Cracan.
      Metabolic dysregulation represents one of the major driving forces in aging. Although multiple genetic and pharmacological manipulations are known to extend longevity in model organisms, aging is a complex trait, and targeting one's own genes may be insufficient to prevent age-dependent deterioration. An alternative strategy could be to use enzymes from other species to reverse age-associated metabolic changes. In this review, we discuss a set of enzymes from lower organisms that have been shown to affect various metabolic parameters linked to age-related processes. These enzymes include modulators of steady-state levels of amino acids (METase, ASNase, and ADI), NADPH/NADP+ and/or reduced form of coenzyme Q (CoQH2)/CoQ redox potentials (NDI1, AOX, LbNOX, TPNOX, EcSTH, RquA, LOXCAT, Grubraw, and ScURA), GSH (StGshF), mitochondrial membrane potential (mtON and mito-dR), or reactive oxygen species (DAAO and KillerRed-SOD1). We propose that leveraging non-mammalian enzymes represents an untapped resource that can be used to delay aging and age-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adu1710
  20. Nature. 2025 Mar 26.
    First map of human brain mitochondria is 'groundbreaking' achievement.
    Nora Bradford.
      
    Keywords:  Brain; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-00848-z
  21. Trends Cancer. 2025 Mar 24. pii: S2405-8033(25)00072-X. [Epub ahead of print]
    Tackling the next decade of cancer research.
    Raza Ali, Brittany Jenkins, Wouter Karthaus, Jana Lipkova, Sandra Misale, Jens Puschhof, Melody Smith, Santosha Vardhana, Xin Zhou.
      
    DOI:  https://doi.org/10.1016/j.trecan.2025.03.004
  22. JCI Insight. 2025 Mar 25. pii: e183706. [Epub ahead of print]
    Vitamin A-Retinoic Acid Contributes to Muscle Stem Cell andMitochondrial Function Loss in Old Age.
    Paula M Fraczek, Pamela Duran, Benjamin A Yang, Valeria Ferre, Leanne Alawieh, Jesus A Castor-Macias, Vivian T Wong, Steve D Guzman, Celeste Piotto, Klimentini Itsani, Jacqueline A Larouche, Carlos A Aguilar.
      Adult stem cells decline in number and function in old age and identifying factors that can delay or revert age-associated adult stem cell dysfunction are vital for maintaining healthy lifespan. Here we show that Vitamin A, a micronutrient that is derived from diet and metabolized into retinoic acid, acts as an antioxidant and transcriptional regulator in muscle stem cells. We first show that obstruction of dietary Vitamin A in young animals drives mitochondrial and cell cycle dysfunction in muscle stem cells that mimics old age. Next, we pharmacologically targeted retinoic acid signaling in myoblasts and aged muscle stem cells ex vivo and in vivo and observed reductions in oxidative damage, enhanced mitochondrial function, and improved maintenance of quiescence through fatty acid oxidation. We next detected the receptor for vitamin A derived retinol, stimulated by retinoic acid 6 or Stra6, was diminished with muscle stem cell activation and in old age. To understand the relevance of Stra6 loss, we knocked down Stra6 and observed an accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial morphology and respiration. These results demonstrate that Vitamin A regulates mitochondria and metabolism in muscle stem cells and highlight a unique mechanism connecting stem cell function with vitamin intake.
    Keywords:  Adult stem cells; Aging; Muscle; Muscle biology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.183706
  23. Cell Rep. 2025 Mar 25. pii: S2211-1247(25)00245-1. [Epub ahead of print]44(4): 115474
    Antagonistic roles for MITF and TFE3 in melanoma plasticity.
    Jeremy Chang, Katelyn R Campbell-Hanson, Marion Vanneste, Nicholas I Bartschat, Ryan Nagel, Asdis K Arnadottir, Hong Nhung Vu, Collin Montgomery, Julius Yevdash, Jiarui Jiang, Ardith Bhinu, Annika Helverson, Michael D Henry, Eiríkur Steingrímsson, Ronald J Weigel, Robert A Cornell, Colin Kenny.
      Melanoma cells can switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intratumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated transcription factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog, TFE3, and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.
    Keywords:  CP: Cancer; CP: Genomics; MITF; TFE3; cell plasticity; mTORC1; melanoma; metastasis; phenotype switching; protein stability
    DOI:  https://doi.org/10.1016/j.celrep.2025.115474
  24. Cell Rep. 2025 Mar 21. pii: S2211-1247(25)00227-X. [Epub ahead of print]44(4): 115456
    The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
    Diogo Fonseca-Pereira, Sena Bae, Slater L Clay, Monia Michaud, Meghan H MacDonald, Jonathan N Glickman, Wendy S Garrett.
      Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased reactive oxygen species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.
    Keywords:  CP: Immunology; CP: Metabolism; ILC3; LKB1; group 3 innate lymphoid cells; liver kinase B1; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.115456
  25. Mol Cell. 2025 Mar 21. pii: S1097-2765(25)00200-X. [Epub ahead of print]
    Three-dimensional regulatory hubs support oncogenic programs in glioblastoma.
    Sarah L Breves, Dafne Campigli Di Giammartino, James Nicholson, Stefano Cirigliano, Syed Raza Mahmood, Uk Jin Lee, Alexander Martinez-Fundichely, Johannes Jungverdorben, Richa Singhania, Sandy Rajkumar, Raphael Kirou, Lorenz Studer, Ekta Khurana, Alexander Polyzos, Howard A Fine, Effie Apostolou.
      Dysregulation of enhancer-promoter communication in the three-dimensional (3D) nucleus is increasingly recognized as a potential driver of oncogenic programs. Here, we profiled the 3D enhancer-promoter networks of patient-derived glioblastoma stem cells to identify central regulatory nodes. We focused on hyperconnected 3D hubs and demonstrated that hub-interacting genes exhibit high and coordinated expression at the single-cell level and are associated with oncogenic programs that distinguish glioblastoma from low-grade glioma. Epigenetic silencing of a recurrent hub-with an uncharacterized role in glioblastoma-was sufficient to cause downregulation of hub-connected genes, shifts in transcriptional states, and reduced clonogenicity. Integration of datasets across 16 cancers identified "universal" and cancer-type-specific 3D hubs that enrich for oncogenic programs and factors associated with worse prognosis. Genetic alterations could explain only a small fraction of hub hyperconnectivity and increased activity. Overall, our study provides strong support for the potential central role of 3D regulatory hubs in controlling oncogenic programs and properties.
    Keywords:  3D chromatin organization; CRISPRi; HiChIP; clonogenicity; enhancer hubs; enhancer-promoter interactions; glioblastoma; oncogenic program; regulatory hubs; single-cell RNA-seq; structural variants
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.007
  26. Nat Commun. 2025 Mar 21. 16(1): 2814
    ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes.
    Jonathon Nixon-Abell, Francesco S Ruggeri, Seema Qamar, Therese W Herling, Magdalena A Czekalska, Yi Shen, Guozhen Wang, Christopher King, Michael S Fernandopulle, Tomas Sneideris, Joseph L Watson, Visakh V S Pillai, William Meadows, James W Henderson, Joseph E Chambers, Jane L Wagstaff, Sioned H Williams, Helena Coyle, Greta Šneiderienė, Yuqian Lu, Shuyuan Zhang, Stefan J Marciniak, Stefan M V Freund, Emmanuel Derivery, Michael E Ward, Michele Vendruscolo, Tuomas P J Knowles, Peter St George-Hyslop.
      Phase transitions of cellular proteins and lipids play a key role in governing the organisation and coordination of intracellular biology. Recent work has raised the intriguing prospect that phase transitions in proteins and lipids can be co-regulated. Here we investigate this possibility in the ribonucleoprotein (RNP) granule-ANXA11-lysosome ensemble, where ANXA11 tethers RNP granules to lysosomal membranes to enable their co-trafficking. We show that changes to the protein phase state within this system, driven by the low complexity ANXA11 N-terminus, induces a coupled phase state change in the lipids of the underlying membrane. We identify the ANXA11 interacting proteins ALG2 and CALC as potent regulators of ANXA11-based phase coupling and demonstrate their influence on the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules. The phenomenon of protein-lipid phase coupling we observe within this system serves as a potential regulatory mechanism in RNA trafficking and offers an important template to understand other examples across the cell whereby biomolecular condensates closely juxtapose organellar membranes.
    DOI:  https://doi.org/10.1038/s41467-025-58142-5
  27. Nature. 2025 Mar;639(8056): 855-857
    Fasting for weight loss is all the rage: what are the health benefits?
    Nic Fleming.
      
    Keywords:  Ageing; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-00895-6
  28. Nat Cell Biol. 2025 Mar 24.
    Harnessing lysohormesis for healthy ageing.
    Jay Xiaojun Tan.
      
    DOI:  https://doi.org/10.1038/s41556-025-01634-9
  29. EMBO Mol Med. 2025 Mar 27.
    TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma.
    Alexandra Helleux, Guillaume Davidson, Antonin Lallement, Fatima Al Hourani, Alexandre Haller, Isabelle Michel, Anas Fadloun, Christelle Thibault-Carpentier, Xiaoping Su, Véronique Lindner, Thibault Tricard, Hervé Lang, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf.
      The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos). Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumor aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance.
    Keywords:  Cancer Associated Fibroblasts; Ferroptosis; Metabolism; RNA Synthesis; TFE3
    DOI:  https://doi.org/10.1038/s44321-025-00221-7
  30. Curr Opin Microbiol. 2025 Mar 24. pii: S1369-5274(25)00021-9. [Epub ahead of print]85 102599
    The role of microbial succinate in the pathophysiology of inflammatory bowel disease: mechanisms and therapeutic potential.
    Sonia Fernández-Veledo, Carme Grau-Bové, Sara Notararigo, Isabel Huber-Ruano.
      Inflammatory bowel disease (IBD) is a chronic immune-mediated condition linked to gut microbiota dysbiosis and altered production of bacterial metabolites, including succinate, which is also a key intermediate in human mitochondrial energy metabolism in human cells. Succinate levels in the gut are influenced by microbial community dynamics and cross-feeding interactions, highlighting its dual metabolic and ecological importance. Extracellular succinate acts as a key signaling metabolite linking microbial metabolism to host physiology, with transient rises supporting metabolic regulation but chronic elevations contributing to metabolic disorders and disease progression. Succinate signals through its cognate receptor SUCNR1, which mediates adaptive metabolic responses under normal conditions but drives inflammation and fibrosis when dysregulated. IBD patients display a dysbiotic gut microbiota characterized by an increased prevalence of succinate-producing bacteria, contributing to elevated succinate levels in the gut and circulation. This imbalance drives inflammation, worsens IBD severity, and contributes to complications like Clostridioides difficile infection and fibrosis. Emerging evidence highlights the potential of intestinal and systemic succinate levels as indicators of microbial dysbiosis, with a bidirectional relationship between microbial composition and succinate metabolism. Understanding the factors influencing succinate levels and their interaction with dysbiosis shows promise in the development of therapeutic strategies to restore microbial balance. Approaches such as dietary fiber enrichment, prebiotics, and probiotics to enhance succinate-consuming bacteria, combined with targeted modulation of succinate pathways (e.g. SDH inhibitors, SUCNR1 antagonists), hold promise for mitigating inflammation and improving gut health in IBD.
    DOI:  https://doi.org/10.1016/j.mib.2025.102599
  31. J Inherit Metab Dis. 2025 Mar;48(2): e70021
    Current Understanding of Pathogenic Mechanisms and Disease Models of Citrin Deficiency.
    Denis Lacabanne, Alice P Sowton, Bosco Jose, Edmund R S Kunji, Sotiria Tavoulari.
      Citrin deficiency (CD) is a complex mitochondrial disease with three different age-related stages: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and type II citrullinemia (CTLN2), recently renamed adolescent and adult CD (AACD). While highly prevalent in the Asian population, CD is pan-ethnic and remains severely underdiagnosed. The disease is caused by the dysfunction or absence of the mitochondrial aspartate/glutamate carrier 2 (AGC2/SLC25A13), also known as citrin. Citrin deficiency results in a direct impairment of the malate-aspartate shuttle and the urea cycle, with expected knock-on effects on a multitude of other metabolic pathways, leading to a complicated pathophysiology. Here, we discuss our current knowledge of the molecular mechanism of substrate transport by citrin, including recent advances  suggesting against its calcium regulation. We also discuss the different types of pathogenic variants found in CD patients and new insights into their pathogenic mechanisms. Additionally, we provide a summary and assessment of the efforts to develop preclinical models as well as treatments for the disease.
    Keywords:  citrin deficiency; disease models; mitochondrial transport; urea cycle disorders
    DOI:  https://doi.org/10.1002/jimd.70021
  32. Mol Cell. 2025 Mar 20. pii: S1097-2765(25)00197-2. [Epub ahead of print]
    Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.
    Luke Lambourne, Kaia Mattioli, Clarissa Santoso, Gloria Sheynkman, Sachi Inukai, Babita Kaundal, Anna Berenson, Kerstin Spirohn-Fitzgerald, Anukana Bhattacharjee, Elisabeth Rothman, Shaleen Shrestha, Florent Laval, Brent S Carroll, Stephen P Plassmeyer, Ryan J Emenecker, Zhipeng Yang, Deepa Bisht, Jared A Sewell, Guangyuan Li, Anisa Prasad, Sabrina Phanor, Ryan Lane, Devlin C Moyer, Toby Hunt, Dawit Balcha, Marinella Gebbia, Jean-Claude Twizere, Tong Hao, Alex S Holehouse, Adam Frankish, Josh A Riback, Nathan Salomonis, Michael A Calderwood, David E Hill, Nidhi Sahni, Marc Vidal, Martha L Bulyk, Juan I Fuxman Bass.
      Most human transcription factor (TF) genes encode multiple protein isoforms differing in DNA-binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators," both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.
    Keywords:  alternative splicing; gene regulation; isoforms; transcription factors; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.004
  33. Nat Commun. 2025 Mar 25. 16(1): 2890
    Identification of a SNAI1 enhancer RNA that drives cancer cell plasticity.
    Chuannan Fan, Qian Wang, Peter H L Krijger, Davy Cats, Miriam Selle, Olga Khorosjutina, Soniya Dhanjal, Bernhard Schmierer, Hailiang Mei, Wouter de Laat, Peter Ten Dijke.
      Enhancer RNAs (eRNAs) are a pivotal class of enhancer-derived non-coding RNAs that drive gene expression. Here we identify the SNAI1 enhancer RNA (SNAI1e; SCREEM2) as a key activator of SNAI1 expression and a potent enforcer of transforming growth factor-β (TGF-β)/SMAD signaling in cancer cells. SNAI1e depletion impairs TGF-β-induced epithelial-mesenchymal transition (EMT), migration, in vivo extravasation, stemness, and chemotherapy resistance in breast cancer cells. SNAI1e functions as an eRNA to cis-regulate SNAI1 enhancer activity by binding to and strengthening the enrichment of the transcriptional co-activator bromodomain containing protein 4 (BRD4) at the local enhancer. SNAI1e selectively promotes the expression of SNAI1, which encodes the EMT transcription factor SNAI1. Furthermore, we reveal that SNAI1 interacts with and anchors the inhibitory SMAD7 in the nucleus, and thereby prevents TGF-β type I receptor (TβRI) polyubiquitination and proteasomal degradation. Our findings establish SNAI1e as a critical driver of SNAI1 expression and TGF-β-induced cell plasticity.
    DOI:  https://doi.org/10.1038/s41467-025-58032-w
  34. Semin Cancer Biol. 2025 Mar 25. pii: S1044-579X(25)00053-7. [Epub ahead of print]
    The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.
    Haowen Jiang, Jiangbin Ye.
      Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.
    Keywords:  Warburg effect; cell dedifferentiation; epigenetic remodeling; metabolic reprogramming; metabolic therapy; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.semcancer.2025.03.006
  35. Cell Rep. 2025 Mar 24. pii: S2211-1247(25)00215-3. [Epub ahead of print]44(4): 115444
    KRAS G12V mutation-selective requirement for ACSS2 in colorectal adenoma formation.
    Konstantin Budagyan, Alexa C Cannon, Adam Chatoff, Dorothy Benton, Alison M Kurimchak, Daniela Araiza-Olivera, Anastasiia Gerasimova, Nathaniel W Snyder, James S Duncan, Cristina Uribe-Alvarez, Jonathan Chernoff.
      Oncogenic KRAS mutations are prevalent in colorectal cancer (CRC) and linked to poor prognosis and therapeutic resistance. Emerging evidence suggests that specific KRAS mutations differentially influence treatment responses. In this study, we generate isogenic Apc-null mouse colon epithelial cells with four common KRAS mutations. Transcriptomic and proteomic analyses reveal significant enrichment of cholesterol and lipid metabolism pathways in KRAS G12V cells, driven by increased SREBP1 expression and mTORC1 activation. Furthermore, KRAS G12V cells exhibit elevated ACSS2 expression and greater dependence on ACSS2 for proliferative advantage compared to other mutants. Inhibition of ACSS2 uniquely sensitizes KRAS G12V cells to MEK inhibition, highlighting a distinct therapeutic vulnerability. Finally, ACSS2 plays a critical role in early KRAS G12V adenoma development, unlike in KRAS G12D adenomas. These findings highlight mutation-specific metabolic reprogramming in KRAS-driven CRC and identify ACSS2 as a potential therapeutic target.
    Keywords:  ACSS2; CP: Cancer; KRAS; acetate; acetyl-CoA; acetylation; adenoma; colorectal cancer; drug resistance; metabolism; signal transduction
    DOI:  https://doi.org/10.1016/j.celrep.2025.115444
  36. Cell. 2025 Mar 20. pii: S0092-8674(25)00258-2. [Epub ahead of print]
    Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force.
    Zili Xie, Lillian Rose, Jing Feng, Yonghui Zhao, Yisi Lu, Harry Kane, Timothy J Hibberd, Xueming Hu, Zhen Wang, Kaikai Zang, Xingliang Yang, Quentin Richardson, Rahmeh Othman, Olivia Venezia, Ademi Zhakyp, Fang Gao, Nobuya Abe, Keren Vigeland, Hongshen Wang, Camren Branch, Coco Duizer, Liwen Deng, Xia Meng, Lydia Zamidar, Max Hauptschein, Ronan Bergin, Xinzhong Dong, Issac M Chiu, Brian S Kim, Nick J Spencer, Hongzhen Hu, Ruaidhrí Jackson.
      The gastrointestinal (GI) tract experiences a myriad of mechanical forces while orchestrating digestion and barrier immunity. A central conductor of these processes, the enteric nervous system (ENS), detects luminal pressure to regulate peristalsis independently of extrinsic input from the central and peripheral nervous systems. However, how the ∼500 million enteric neurons that reside in the GI tract sense and respond to force remains unknown. Herein, we establish that the mechanosensor Piezo1 is functionally expressed in cholinergic enteric neurons. Optogenetic stimulation of Piezo1+ cholinergic enteric neurons drives colonic motility, while Piezo1 deficiency reduces cholinergic neuronal activity and slows peristalsis. Additionally, Piezo1 deficiency in cholinergic enteric neurons abolishes exercise-induced acceleration of GI motility. Finally, we uncover that enteric neuronal Piezo1 function is required for motility alterations in colitis and acts to prevent aberrant inflammation and tissue damage. This work uncovers how the ENS senses and responds to mechanical force.
    Keywords:  Piezo1; cholinergic neurons; enteric nervous system; inflammation; inflammatory bowel disease; mechanosensation; motility; neuro-immune; peristalsis
    DOI:  https://doi.org/10.1016/j.cell.2025.02.031
  37. Biol Chem. 2025 Mar 28.
    Unclogging of the TOM complex under import stress.
    Joshua Jackson, Thomas Becker.
      Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor proteins on cytosolic ribosomes. Mitochondrial protein translocases sort the precursor proteins into the mitochondrial sub-compartments: outer and inner membrane, the intermembrane space and the matrix. The translocase of the outer mitochondrial membrane (TOM complex) constitutes the major import site for most of these precursor proteins. Defective protein translocases, premature folding of the precursor, or depletion of the membrane potential can cause clogging of the TOM channel by a precursor protein. This clogging impairs further protein import and leads to accumulation of precursor proteins in the cell that perturbates protein homeostasis, leading to proteotoxic stress in the cell. Therefore, unclogging of the translocon is critical for maintaining mitochondrial and cellular function. Ubiquitylation and AAA-ATPases play a central role in the extraction of the precursor proteins to deliver them to the proteasome for degradation. Here we summarize our understanding of the molecular mechanisms that remove such translocation-stalled precursor proteins from the translocation channel to regenerate the TOM complex for protein import.
    Keywords:  AAA ATPases; TOM complex; mitochondria; protein import; quality control; ubiquitylation
    DOI:  https://doi.org/10.1515/hsz-2025-0110
  38. Biol Cell. 2025 Mar;117(3): e70002
    Phospholipid Biosynthesis: An Unforeseen Modulator of Nuclear Metabolism.
    Hong Qiu, Cunqi Ye.
      Glycerophospholipid biosynthesis is crucial not only for providing structural components required for membrane biogenesis during cell proliferation but also for facilitating membrane remodeling under stress conditions. The biosynthetic pathways for glycerophospholipid tails, glycerol backbones, and diverse head group classes intersect with various other metabolic processes, sharing intermediary metabolites. Recent studies have revealed intricate connections between glycerophospholipid synthesis and nuclear metabolism, including metabolite-mediated crosstalk with the epigenome, signaling pathways that govern genome integrity, and CTP-involved regulation of nucleotide and antioxidant biosynthesis. This review highlights recent advances in understanding the functional roles of glycerophospholipid biosynthesis beyond their structural functions in budding yeast and mammalian cells. We propose that glycerophospholipid biosynthesis plays an integrative role in metabolic regulation, providing a new perspective on lipid biology.
    DOI:  https://doi.org/10.1111/boc.70002
  39. J Cell Biol. 2025 May 05. pii: e202405060. [Epub ahead of print]224(5):
    Ceramide mediates cell-to-cell ER stress transmission by modulating membrane fluidity.
    Yazhen Huo, Xinlu Liu, Chen Lu, Tao Li, Zaili Yang, Fenfen Xu, Si Chen, Kailin Yin, Likun Wang.
      Under endoplasmic reticulum (ER) stress (ERS), cells initiate the unfolded protein response (UPR) to maintain ER homeostasis. Recent studies revealed ERS transmission between cells and tissues, by activating the cell-nonautonomous UPR in cells that do not experience ERS directly. Here, we report that ERS triggers a rapid release of ceramide independent of the UPR, but requiring the acid sphingomyelinase activity. Carried by lipoproteins, ceramide is delivered to receiving cells to induce the UPR and regulate cell functions at multiple aspects, including lipid accumulation, cell death, and cytokine production. Mechanistically, extracellular ceramide stimulates ceramide synthesis at the transcription level in receiving cells, leading to ceramide accumulation in the ER so as to reduce membrane fluidity to disrupt ER calcium homeostasis, thus activating the UPR. Sphingomyelin counterbalanced the effect of ceramide. UPR induction is the frontline response to protect cells from ceramide insult. Our study suggests ceramide-mediated ERS transmission as a universal cell-cell communication model regulating a wide range of physiological events.
    DOI:  https://doi.org/10.1083/jcb.202405060
  40. Nature. 2025 Mar 26.
    Plasticity of the mammalian integrated stress response.
    Chien-Wen Chen, David Papadopoli, Krzysztof J Szkop, Bo-Jhih Guan, Mohammed Alzahrani, Jing Wu, Raul Jobava, Mais M Asraf, Dawid Krokowski, Anastasios Vourekas, William C Merrick, Anton A Komar, Antonis E Koromilas, Myriam Gorospe, Matthew J Payea, Fangfang Wang, Benjamin L L Clayton, Paul J Tesar, Ashleigh Schaffer, Alexander Miron, Ilya Bederman, Eckhard Jankowsky, Christine Vogel, Leoš Shivaya Valášek, Jonathan D Dinman, Youwei Zhang, Boaz Tirosh, Ola Larsson, Ivan Topisirovic, Maria Hatzoglou.
      An increased level of phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity of eIF2B is a hallmark of the 'canonical' integrated stress response (c-ISR)1. It is unclear whether impaired eIF2B activity in human diseases including leukodystrophies2, which occurs in the absence of eIF2α-p induction, is synonymous with the c-ISR. Here we describe a mechanism triggered by decreased eIF2B activity, distinct from the c-ISR, which we term the split ISR (s-ISR). The s-ISR is characterized by translational and transcriptional programs that are different from those observed in the c-ISR. Opposite to the c-ISR, the s-ISR requires eIF4E-dependent translation of the upstream open reading frame 1 and subsequent stabilization of ATF4 mRNA. This is followed by altered expression of a subset of metabolic genes (for example, PCK2), resulting in metabolic rewiring required to maintain cellular bioenergetics when eIF2B activity is attenuated. Overall, these data demonstrate a plasticity of the mammalian ISR, whereby the loss of eIF2B activity in the absence of eIF2α-p induction activates the eIF4E-ATF4-PCK2 axis to maintain energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-08794-6
  41. Mol Syst Biol. 2025 Mar 25.
    Persistent epigenetic memory of SARS-CoV-2 mRNA vaccination in monocyte-derived macrophages.
    Alexander Simonis, Sebastian J Theobald, Anna E Koch, Ram Mummadavarapu, Julie M Mudler, Andromachi Pouikli, Ulrike Göbel, Richard Acton, Sandra Winter, Alexandra Albus, Dmitriy Holzmann, Marie-Christine Albert, Michael Hallek, Henning Walczak, Thomas Ulas, Manuel Koch, Peter Tessarz, Robert Hänsel-Hertsch, Jan Rybniker.
      Immune memory plays a critical role in the development of durable antimicrobial immune responses. How precisely mRNA vaccines train innate immune cells to shape protective host defense mechanisms remains unknown. Here we show that SARS-CoV-2 mRNA vaccination significantly establishes histone H3 lysine 27 acetylation (H3K27ac) at promoters of human monocyte-derived macrophages, suggesting epigenetic memory. However, we found that two consecutive vaccinations were required for the persistence of H3K27ac, which matched with pro-inflammatory innate immune-associated transcriptional changes and antigen-mediated cytokine secretion. H3K27ac at promoter regions were preserved for six months and a single mRNA booster vaccine potently restored their levels and release of macrophage-derived cytokines. Interestingly, we found that H3K27ac at promoters is enriched for G-quadruplex DNA secondary structure-forming sequences in macrophage-derived nucleosome-depleted regions, linking epigenetic memory to nucleic acid structure. Collectively, these findings reveal that mRNA vaccines induce a highly dynamic and persistent training of innate immune cells enabling a sustained pro-inflammatory immune response.
    Keywords:  Epigenetic Memory; G-quadruplex; H3K27ac; SARS-Cov-2 mRNA Vaccination; Trained Innate Immunity
    DOI:  https://doi.org/10.1038/s44320-025-00093-6
  42. Biomolecules. 2025 Mar 14. pii: 416. [Epub ahead of print]15(3):
    The Pathogenesis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency.
    Shashwat Sharma, Matthew McKenzie.
      Living systems require energy to maintain their existence and perform tasks such as cell division. This energy is stored in several molecular forms in nature, specifically lipids, carbohydrates, and amino acids. At a cellular level, energy is extracted from these complex molecules and transferred to adenosine triphosphate (ATP) in the cytoplasm and mitochondria. Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are crucial metabolic processes involved in generating ATP, with defects in these pathways causing mitochondrial disease. Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000. Similar to other mitochondrial disorders, there is no cure for VLCADD, with symptomatic treatment comprising dietary management and supplementation with medium-chain fatty acids to bypass the enzyme deficiency. While this addresses the primary defect in VLCADD, there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function. Here, we review our current understanding of VLCADD with a focus on the associated biochemical and molecular defects that can disrupt multiple aspects of mitochondrial function. We describe the interactions between FAO proteins and the OXPHOS complexes and how these interactions are critical for maintaining the activity of both metabolic pathways. In particular, we describe what is now known about the protein-protein interactions between VLCAD and the OXPHOS supercomplex and how their disruption contributes to overall VLCADD pathogenesis.
    Keywords:  FAO; FAOD; OXPHOS; VLCAD; VLCADD; fatty acid oxidation disorder; fatty acid β-oxidation; oxidative phosphorylation; very long-chain acyl-CoA dehydrogenase; very long-chain acyl-CoA dehydrogenase deficiency
    DOI:  https://doi.org/10.3390/biom15030416
  43. Nat Commun. 2025 Mar 27. 16(1): 3000
    Metabolic constraint of human telomere length by nucleotide salvage efficiency.
    William Mannherz, Andrew Crompton, Noah Lampl, Suneet Agarwal.
      Human telomere length is tightly regulated and associated with diseases at either extreme, but how these bounds are established remains incompletely understood. Here, we developed a rapid cell-based telomere synthesis assay and found that nucleoside salvage bidirectionally constrains human telomere length. Metabolism of deoxyguanosine (dG) or guanosine via purine nucleoside phosphorylase (PNP) and hypoxanthine-guanine phosphoribosyltransferase to form guanine ribonucleotides strongly inhibited telomerase and shortened telomeres. Conversely, salvage of dG to its nucleotide forms via deoxycytidine kinase drove potent telomerase activation, the extent of which was controlled by the dNTPase SAMHD1. Circumventing limits on salvage by expressing Drosophila melanogaster deoxynucleoside kinase or augmenting dG metabolism using the PNP inhibitor ulodesine robustly lengthened telomeres in human cells, including those from patients with lethal telomere diseases. Our results provide an updated paradigm for telomere length control, wherein telomerase reverse transcriptase activity is actively and bidirectionally constrained by the availability of its dNTP substrates, in a manner that may be therapeutically actionable.
    DOI:  https://doi.org/10.1038/s41467-025-58221-7
  44. Elife. 2025 Mar 25. pii: RP97650. [Epub ahead of print]13
    In vivo targeted and deterministic single-cell malignant transformation.
    Pierluigi Scerbo, Benjamin Tisserand, Marine Delagrange, Héloise Debare, David Bensimon, Bertrand Ducos.
      Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the 'ground state theory of cancer initiation' through 'short-range dispersal' of the first malignant cells preceding tumor growth.
    Keywords:  Danio rerio; cancer; cancer biology; optogenetics; zebrafish
    DOI:  https://doi.org/10.7554/eLife.97650
  45. Sci Adv. 2025 Mar 28. 11(13): eadr0568
    Assessing cancer therapeutic efficacy in vivo using [2H7]glucose deuterium metabolic imaging.
    Mario C Chang, Vinay R Malut, Rohit Mahar, Anna Rushin, Marc A McLeod, Geraldine L Pierre, Indu R Malut, Stephen J Staklinski, Max E Glanz, Mukundan Ragavan, Gaurav Sharma, Manoj Madheswaran, Arshee Badar, Aparna D Rao, Brian K Law, Michael S Kilberg, James H P Collins, Vikram D Kodibagkar, James A Bankson, Ralph J DeBerardinis, Matthew E Merritt.
      Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention. Deuterium magnetic resonance imaging (DMRI) with [6,6-2H2]glucose is nonradioactive, achieves tumor metabolic contrast, but can be improved by enriched contrast from deuterated water (HDO) based imaging. Here, we developed a DMRI protocol employing [2H7]glucose. Imaging 2H-signal and measuring HDO production in tumor-bearing mice detected differential glucose utilization across baseline tumors, tumors treated with vehicle control or anti-glycolytic BRAFi and MEKi therapy, and contralateral healthy tissue. Control tumors generated the most 2H-signal and HDO. To our knowledge this is the first application of DMRI with [2H7]glucose for tumoral treatment monitoring. This approach demonstrates HDO as a marker of tumor glucose utilization and suggests translational capability in humans due to its safety, noninvasiveness, and suitability for serial monitoring.
    DOI:  https://doi.org/10.1126/sciadv.adr0568
  46. Am J Physiol Lung Cell Mol Physiol. 2025 Mar 27.
    Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis.
    Rishi Rajesh, Agnes Anna Mooslechner, Hannah Schweighofer, Svetlana Pahernik, Ilse Lanz, Reham Atallah, Wolfgang Platzer, Clemens Aigner, Alberto Benazzo, Stefano Angiari, Leigh Marsh, Grazyna Kwapiszewska, Akos Heinemann, Thomas Bärnthaler.
       INTRODUCTION: Idiopathic pulmonary fibrosis(IPF) is a chronic progressive lung disease that leads to destruction of alveoli and replacement by fibrotic tissue. Metabolic profiling of lung tissue and serum from IPF patients has revealed that levels of tricarboxylic acid (TCA) cycle metabolites such as succinate are altered in patients with IPF. In our study, we aim to evaluate the role of succinate and its receptor- succinate receptor 1 (SUCNR1) in the pathogenesis of lung fibrosis, with a focus on fibroblasts, a central cell in IPF.
    METHODS: SUCNR1 expression was investigated using Western blots, qPCR, and FISH. In vitro assays with IPF and normal human lung fibroblasts(NHLF) were used to evaluate the effect of succinate treatment on the expression of fibrotic markers, fibroblast-myofibroblast transition, apoptosis and signaling mechanisms. Studies with the bleomycin mouse model of PF were used to evaluate the effect of succinate in vivo.
    RESULTS: Several cell types in the lung express SUCNR1 including ATII cells, fibroblasts, and macrophages. In IPF patient fibroblasts, succinate treatment increased expression of fibrosis associated markers such as alpha smooth muscle actin and collagen. Moreover, succinate exaggerated TGF-β-mediated fibroblast-to-myofibroblast transition in NHLF. In vivo, succinate treatment significantly increased collagen accumulation in the lung and enhanced weight loss in bleomycin-treated mice. Importantly, succinate-mediated elevation of fibrosis-associated markers was lost upon knockdown of SUCNR1 or inhibition of ERK activation in IPF patient-derived fibroblasts.
    CONCLUSION: Succinate exerted pro-fibrotic effects in vitro and in vivo. Thus, SUCNR1 antagonism may be a potential therapeutic target for the treatment of IPF.
    Keywords:  fibroblast biology; idiopathic pulmonary fibrosis; metabolism; pulmonary fibrosis
    DOI:  https://doi.org/10.1152/ajplung.00286.2024
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