bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–03–16
57 papers selected by
Christian Frezza, Universität zu Köln
  1. Succinate dehydrogenase activity supports de novo purine synthesis.
  2. Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
  3. Mitochondrial genetics, signalling and stress responses.
  4. A Mathematical Exploration of SDH-b Loss in Chromaffin Cells.
  5. Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling.
  6. A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
  7. Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.
  8. MIA40 suppresses cell death induced by apoptosis-inducing factor 1.
  9. GSK3 coordinately regulates mitochondrial activity and nucleotide metabolism in quiescent oocytes.
  10. VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.
  11. Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation.
  12. High-dimensional signalling analysis of organoids.
  13. Modeling for understanding and engineering metabolism.
  14. Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.
  15. Quality control of mitochondrial nucleoids.
  16. CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer.
  17. Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors.
  18. Class I histone deacetylases catalyze lysine lactylation.
  19. Glycogen drives tumour initiation and progression in lung adenocarcinoma.
  20. Structure of human PINK1 at a mitochondrial TOM-VDAC array.
  21. MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC.
  22. When tumour cells get excited.
  23. A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan.
  24. Disrupting cholesterol homeostasis in T cells boosts antitumour responses.
  25. Dynamic investigation of hypoxia-induced L-lactylation.
  26. Seeing the world through the eyes of cultured cells.
  27. Plant acetyl-CoA carboxylase: The homomeric form and the heteromeric form.
  28. The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.
  29. Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency.
  30. Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair.
  31. Islet hormones at the intersection of glucose and amino acid metabolism.
  32. Mechanisms and functions of lysosomal lipid homeostasis.
  33. Spotiphy enables single-cell spatial whole transcriptomics across an entire section.
  34. Compromised epigenetic robustness in cancer: fueling evolution, exposing weakness.
  35. Fatty Acid Trafficking Between Lipid Droplets and Mitochondria: An Emerging Perspective.
  36. Understanding immune escape in lung cancer.
  37. Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis.
  38. Where and why have so many metabolic enzymes gone from developing spores of Bacillus subtilis?
  39. A dual-purification system to isolate mitochondrial subpopulations.
  40. Lactate: A key regulator of the immune response.
  41. Hyperactive histone genes fuel cancer.
  42. Aneuploidy as a cancer vulnerability.
  43. Piezo1 regulates colon stem cells to maintain epithelial homeostasis through SCD1-Wnt-β-catenin and programming fatty acid metabolism.
  44. Long term latency of highly mutated cells in normal mouse skin is reversed by exposure to tumor promoters and chronic tissue damage.
  45. Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity.
  46. How fast your brain ages is affected by these 64 genes.
  47. Compartmentation of multiple metabolic enzymes and their preparation in vitro and in cellulo.
  48. Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples.
  49. New routes for spermine biosynthesis.
  50. Sphingolipid metabolism drives mitochondria remodeling during aging and oxidative stress.
  51. Red blood cell metabolism: a window on systems health towards clinical metabolomics.
  52. The role of protein lactylation: A kaleidoscopic post-translational modification in cancer.
  53. RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.
  54. Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model.
  55. Making sense of fat in cancer.
  56. Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies.
  57. Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria.
  1. bioRxiv. 2025 Mar 01. pii: 2025.02.26.640389. [Epub ahead of print]
    Succinate dehydrogenase activity supports de novo purine synthesis.
    Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.
      The de novo purine synthesis pathway is fundamental for nucleic acid production and cellular energetics, yet the role of mitochondrial metabolism in modulating this process remains underexplored. In many cancers, metabolic reprogramming supports rapid proliferation and survival, but the specific contributions of the tricarboxylic acid (TCA) cycle enzymes to nucleotide biosynthesis are not fully understood. Here, we demonstrate that the TCA cycle enzyme succinate dehydrogenase (SDH) is essential for maintaining optimal de novo purine synthesis in normal and cancer cells. Genetic or pharmacological inhibition of SDH markedly attenuates purine synthesis, leading to a significant reduction in cell proliferation. Mechanistically, SDH inhibition causes an accumulation of succinate, which directly impairs the purine biosynthetic pathway. In response, cancer cells compensate by upregulating the purine salvage pathway, a metabolic adaptation that represents a potential therapeutic vulnerability. Notably, co-inhibition of SDH and the purine salvage pathway induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings not only reveal a signaling role for mitochondrial succinate in regulating nucleotide metabolism but also provide a promising therapeutic strategy for targeting metabolic dependencies in cancer.
    DOI:  https://doi.org/10.1101/2025.02.26.640389
  2. Cell. 2025 Mar 05. pii: S0092-8674(25)00194-1. [Epub ahead of print]
    Engineering mtDNA deletions by reconstituting end joining in human mitochondria.
    Yi Fu, Max Land, Tamar Kavlashvili, Ruobing Cui, Minsoo Kim, Emily DeBitetto, Toby Lieber, Keun Woo Ryu, Elim Choi, Ignas Masilionis, Rahul Saha, Meril Takizawa, Daphne Baker, Marco Tigano, Caleb A Lareau, Ed Reznik, Roshan Sharma, Ronan Chaligne, Craig B Thompson, Dana Pe'er, Agnel Sfeir.
      Recent breakthroughs in the genetic manipulation of mitochondrial DNA (mtDNA) have enabled precise base substitutions and the efficient elimination of genomes carrying pathogenic mutations. However, reconstituting mtDNA deletions linked to mitochondrial myopathies remains challenging. Here, we engineered mtDNA deletions in human cells by co-expressing end-joining (EJ) machinery and targeted endonucleases. Using mitochondrial EJ (mito-EJ) and mito-ScaI, we generated a panel of clonal cell lines harboring a ∼3.5 kb mtDNA deletion across the full spectrum of heteroplasmy. Investigating these cells revealed a critical threshold of ∼75% deleted genomes, beyond which oxidative phosphorylation (OXPHOS) protein depletion, metabolic disruption, and impaired growth in galactose-containing media were observed. Single-cell multiomic profiling identified two distinct nuclear gene deregulation responses: one triggered at the deletion threshold and another progressively responding to heteroplasmy. Ultimately, we show that our method enables the modeling of disease-associated mtDNA deletions across cell types and could inform the development of targeted therapies.
    Keywords:  DOGMA-seq; end joining; mitochondrial pathologies; mtDNA; mtDNA deletion
    DOI:  https://doi.org/10.1016/j.cell.2025.02.009
  3. Nat Cell Biol. 2025 Mar;27(3): 393-407
    Mitochondrial genetics, signalling and stress responses.
    Yasmine J Liu, Jonathan Sulc, Johan Auwerx.
      Mitochondria are multifaceted organelles with crucial roles in energy generation, cellular signalling and a range of synthesis pathways. The study of mitochondrial biology is complicated by its own small genome, which is matrilineally inherited and not subject to recombination, and present in multiple, possibly different, copies. Recent methodological developments have enabled the analysis of mitochondrial DNA (mtDNA) in large-scale cohorts and highlight the far-reaching impact of mitochondrial genetic variation. Genome-editing techniques have been adapted to target mtDNA, further propelling the functional analysis of mitochondrial genes. Mitochondria are finely tuned signalling hubs, a concept that has been expanded by advances in methodologies for studying the function of mitochondrial proteins and protein complexes. Mitochondrial respiratory complexes are of dual genetic origin, requiring close coordination between mitochondrial and nuclear gene-expression systems (transcription and translation) for proper assembly and function, and recent findings highlight the importance of the mitochondria in this bidirectional signalling.
    DOI:  https://doi.org/10.1038/s41556-025-01625-w
  4. Bull Math Biol. 2025 Mar 13. 87(4): 53
    A Mathematical Exploration of SDH-b Loss in Chromaffin Cells.
    Elías Vera-Sigüenza, Himani Rana, Ramin Nashebi, Ielyaas Cloete, Katarína Kl'uvčková, Fabian Spill, Daniel A Tennant.
      The succinate dehydrogenase (SDH) is a four-subunit enzyme complex (SDH-a, SDH-b, SDH-c, and SDH-d) central to cell carbon metabolism. The SDH bridges the tricarboxylic acid cycle to the electron transport chain. A pathological loss of the SDH-b subunit leads to a cell-wide signalling cascade that shifts the cell's metabolism into a pseudo-hypoxic state akin to the so-called Warburg effect (or aerobic glycolysis). This trait is a hallmark of phaeochromocytomas, a rare tumour arising from chromaffin cells; a type of cell that lies in the medulla of the adrenal gland. In this study, we leverage the insights from a mathematical model constructed to underpin the metabolic implications of SDH-b dysfunction in phaeochromocytomas. We specifically investigate why chromaffin cells seemingly have the ability to maintain electron transport chain's Complex I function when confronted with the loss of the SDH-b subunit while other cells do not. Our simulations indicate that retention of Complex I is associated with cofactor oxidation, which enables cells to manage mitochondrial swelling and limit the reversal of the adenosine triphosphate synthase, supporting cell fitness, without undergoing lysis. These results support previous hypotheses that point to mitochondrial proton leaks as a critical factor of future research. Moreover, the model asserts that control of the proton gradient across the mitochondrial inner membrane is rate-limiting upon fitness management of SDH-b deficient cells.
    Keywords:  Adrenal glands; Chromaffin cell; Dynamical systems; Electron transport chain; Phaeochromocytoma; Succinate dehydrogenase; Systems metabolism; TCA cycle
    DOI:  https://doi.org/10.1007/s11538-025-01427-z
  5. Science. 2025 Mar 14. 387(6739): eadm9805
    Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling.
    Nikos Koundouros, Michal J Nagiec, Nayah Bullen, Evan K Noch, Guillermo Burgos-Barragan, Zhongchi Li, Long He, Sungyun Cho, Bobak Parang, Dominique Leone, Eleni Andreopoulou, John Blenis.
      Diet influences macronutrient availability to cells, and although mechanisms of sensing dietary glucose and amino acids are well characterized, less is known about sensing lipids. We defined a nutrient signaling mechanism involving fatty acid-binding protein 5 (FABP5) and mechanistic target of rapamycin complex 1 (mTORC1) that is activated by the essential polyunsaturated fatty acid (PUFA) ω-6 linoleic acid (LA). FABP5 directly bound to the regulatory-associated protein of mTOR (Raptor) to enhance formation of functional mTORC1 and substrate binding, ultimately converging on increased mTOR signaling and proliferation. The amounts of FABP5 protein were increased in tumors and serum from triple-negative compared with those from receptor-positive breast cancer patients, which highlights its potential role as a biomarker that mediates cellular responses to ω-6 LA intake in this disease subtype.
    DOI:  https://doi.org/10.1126/science.adm9805
  6. Nat Metab. 2025 Mar 10.
    A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.
    Samantha Pretto, Qian Yu, Pierre Bourdely, Sarah Trusso Cafarello, Heleen H Van Acker, Joren Verelst, Elena Richiardone, Lotte Vanheer, Amir Roshanzadeh, Franziska Schneppenheim, Charlotte Cresens, Maria Livia Sassano, Jonas Dehairs, Martin Carion, Shehab Ismail, Patrizia Agostinis, Susana Rocha, Tobias Bald, Johan Swinnen, Cyril Corbet, Sophia Y Lunt, Bernard Thienpont, Mario Di Matteo, Massimiliano Mazzone.
      Reprogramming T cell metabolism can improve intratumoural fitness. By performing a CRISPR/Cas9 metabolic survey in CD8+ T cells, we identified 83 targets and we applied single-cell RNA sequencing to disclose transcriptome changes associated with each metabolic perturbation in the context of pancreatic cancer. This revealed elongation of very long-chain fatty acids protein 1 (Elovl1) as a metabolic target to sustain effector functions and memory phenotypes in CD8+ T cells. Accordingly, Elovl1 inactivation in adoptively transferred T cells combined with anti-PD-1 showed therapeutic efficacy in resistant pancreatic and melanoma tumours. The accumulation of saturated long-chain fatty acids in Elovl1-deficient T cells destabilized INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol and stronger T cell receptor signalling. Elovl1-deficient T cells increased mitochondrial fitness and fatty acid oxidation, thus withstanding the metabolic stress imposed by the tumour microenvironment. Finally, ELOVL1 in CD8+ T cells correlated with anti-PD-1 response in patients with melanoma. Altogether, Elovl1 targeting synergizes with anti-PD-1 to promote effective T cell responses.
    DOI:  https://doi.org/10.1038/s42255-025-01233-w
  7. bioRxiv. 2025 Mar 02. pii: 2025.02.26.640463. [Epub ahead of print]
    Pathway Coessentiality Mapping Reveals Complex II is Required for de novo Purine Biosynthesis in Acute Myeloid Leukemia.
    Amy E Stewart, Derek K Zachman, Pol Castellano-Escuder, Lois M Kelly, Ben Zolyomi, Michael D I Aiduk, Christopher D Delaney, Ian C Lock, Claudie Bosc, John Bradley, Shane T Killarney, Olga R Ilkayeva, Christopher B Newgard, Navdeep S Chandel, Alexandre Puissant, Kris C Wood, Matthew D Hirschey.
      Understanding how cellular pathways interact is crucial for treating complex diseases like cancer, yet our ability to map these connections systematically remains limited. Individual gene-gene interaction studies have provided insights 1,2 , but they miss the emergent properties of pathways working together. To address this challenge, we developed a multi-gene approach to pathway mapping and applied it to CRISPR data from the Cancer Dependency Map 3 . Our analysis of the electron transport chain revealed certain blood cancers, including acute myeloid leukemia (AML), depend on an unexpected link between Complex II and purine metabolism. Through stable isotope metabolomic tracing, we found that Complex II directly supports de novo purine biosynthesis and exogenous purines rescue AML from Complex II inhibition. The mechanism involves a metabolic circuit where glutamine provides nitrogen to build the purine ring, producing glutamate that Complex II must oxidize to sustain purine synthesis. This connection translated to a metabolic vulnerability whereby increasing intracellular glutamate levels suppresses purine production and sensitizes AML to Complex II inhibition. In mouse models, targeting Complex II triggered rapid disease regression and extended survival in aggressive AML. The clinical relevance of this pathway emerged in human studies, where higher Complex II gene expression correlates with both resistance to mitochondria-targeted therapies and worse survival outcomes specifically in AML patients. These findings establish Complex II as a central regulator of de novo purine biosynthesis and identify it as a promising therapeutic target in AML.
    DOI:  https://doi.org/10.1101/2025.02.26.640463
  8. EMBO Rep. 2025 Mar 07.
    MIA40 suppresses cell death induced by apoptosis-inducing factor 1.
    Ben Hur Marins Mussulini, Klaudia K Maruszczak, Piotr Draczkowski, Mayra A Borrero-Landazabal, Selvaraj Ayyamperumal, Artur Wnorowski, Michal Wasilewski, Agnieszka Chacinska.
      Mitochondria harbor respiratory complexes that perform oxidative phosphorylation. Complex I is the first enzyme of the respiratory chain that oxidizes NADH. A dysfunction in complex I can result in higher cellular levels of NADH, which in turn strengthens the interaction between apoptosis-inducing factor 1 (AIFM1) and Mitochondrial intermembrane space import and assembly protein 40 (MIA40) in the mitochondrial intermembrane space. We investigated whether MIA40 modulates the activity of AIFM1 upon increased NADH/NAD+ balance. We found that in model cells characterized by an increase in NADH the AIFM1-MIA40 interaction is strengthened and these cells demonstrate resistance to AIFM1-induced cell death. Either silencing of MIA40, rescue of complex I, or depletion of NADH through the expression of yeast NADH-ubiquinone oxidoreductase-2 sensitized NDUFA13-KO cells to AIFM1-induced cell death. These findings indicate that the complex of MIA40 and AIFM1 suppresses AIFM1-induced cell death in a NADH-dependent manner. This study identifies an effector complex involved in regulating the programmed cell death that accommodates the metabolic changes in the cell and provides a molecular explanation for AIFM1-mediated chemoresistance of cancer cells.
    Keywords:  Cancer; Metabolism; Mitochondria; Programmed Cell Death; Protein Import
    DOI:  https://doi.org/10.1038/s44319-025-00406-8
  9. Biol Open. 2025 Mar 06. pii: bio.061815. [Epub ahead of print]
    GSK3 coordinately regulates mitochondrial activity and nucleotide metabolism in quiescent oocytes.
    Leah Eller, Lei Wang, Mehmet Oguz Gok, Helin Hocaoglu, Shenlu Qin, Parul Gupta, Matthew H Sieber.
      As cells transition between periods of growth and quiescence, their metabolic demands change. During this transition, cells must coordinate changes in mitochondrial function with the induction of biosynthetic processes. Mitochondrial metabolism and nucleotide biosynthesis are key rate-limiting factors in regulating early growth. However, it remains unclear what coordinates these mechanisms in developmental systems. Here, we show that during quiescence, as mitochondrial activity drops, nucleotide breakdown increases. However, at fertilization, mitochondrial oxidative metabolism and nucleotide biosynthesis are coordinately activated to support early embryogenesis. We have found that the serine/threonine kinase GSK3 is a key factor in coordinating mitochondrial metabolism with nucleotide biosynthesis during transitions between quiescence and growth. Silencing GSK3 in quiescent oocytes causes increased levels of mitochondrial activity and a shift in the levels of several redox metabolites. Interestingly, silencing GSK3 in quiescent oocytes also leads to a precocious induction of nucleotide biosynthesis in quiescent oocytes. Taken together, these data indicate that GSK3 functions to suppress mitochondrial oxidative metabolism and prevent the premature onset of nucleotide biosynthesis in quiescent eggs. These data reveal a key mechanism that coordinates mitochondrial function and nucleotide synthesis with fertilization.
    Keywords:  Drosophila; Embryo; Metabolism; Mitochondria; Oocyte
    DOI:  https://doi.org/10.1242/bio.061815
  10. Nat Commun. 2025 Mar 11. 16(1): 2416
    VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes.
    Shamim Naghdi, Piyush Mishra, Soumya Sinha Roy, David Weaver, Ludivine Walter, Erika Davies, Anil Noronha Antony, Xuena Lin, Gisela Moehren, Mark A Feitelson, Christopher A Reed, Tullia Lindsten, Craig B Thompson, Hien T Dang, Jan B Hoek, Erik S Knudsen, György Hajnóczky.
      Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.
    DOI:  https://doi.org/10.1038/s41467-025-56898-4
  11. EMBO J. 2025 Mar 10.
    Mitochondrial fatty acid oxidation regulates adult muscle stem cell function through modulating metabolic flux and protein acetylation.
    Feng Yue, Lijie Gu, Jiamin Qiu, Stephanie N Oprescu, Linda M Beckett, Jessica M Ellis, Shawn S Donkin, Shihuan Kuang.
      During homeostasis and regeneration, satellite cells, the resident stem cells of skeletal muscle, have distinct metabolic requirements for fate transitions between quiescence, proliferation and differentiation. However, the contribution of distinct energy sources to satellite cell metabolism and function remains largely unexplored. Here, we uncover a role of mitochondrial fatty acid oxidation (FAO) in satellite cell integrity and function. Single-cell RNA sequencing revealed progressive enrichment of mitochondrial FAO and downstream pathways during activation, proliferation and myogenic commitment of satellite cells. Deletion of Carnitine palmitoyltransferase 2 (Cpt2), the rate-limiting enzyme in FAO, hampered muscle stem cell expansion and differentiation upon acute muscle injury, markedly delaying regeneration. Cpt2 deficiency reduces acetyl-CoA levels in satellite cells, impeding the metabolic flux and acetylation of selective proteins including Pax7, the central transcriptional regulator of satellite cells. Notably, acetate supplementation restored cellular metabolic flux and partially rescued the regenerative defects of Cpt2-null satellite cells. These findings highlight an essential role of fatty acid oxidation in controlling satellite cell function and suggest an integration of lipid metabolism and protein acetylation in adult stem cells.
    Keywords:  CPT2; Fatty Acid Oxidation; Muscle Regeneration; Muscle Satellite Cell; Protein Acetylation
    DOI:  https://doi.org/10.1038/s44318-025-00397-1
  12. Curr Opin Cell Biol. 2025 Mar 09. pii: S0955-0674(25)00026-2. [Epub ahead of print]94 102488
    High-dimensional signalling analysis of organoids.
    Aurélie Dobric, Christopher J Tape.
      Cellular phenotypes are regulated by dynamic signalling processes that involve proteins, post-translational modifications, epigenetic events, and transcriptional responses. Functional perturbation studies are required to understand cell signalling mechanisms and organoids have recently emerged as scalable biomimetic models amenable to large-scale perturbation. Here, we review the recent advances in high-dimensional analysis of cell signalling in organoids. Single-cell technologies provide cell-type specific analysis of multiple biochemical modalities, enabling a deeper understanding of the signalling mechanisms driving cell-fate dynamics. Emerging multimodal techniques are further revealing coordination between signalling layers and are poised to increase our mechanistic understanding of cell signalling.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102488
  13. QRB Discov. 2025 ;6 e11
    Modeling for understanding and engineering metabolism.
    Jens Nielsen, Dina Petranovic.
      Metabolism is at the core of all functions of living cells as it provides Gibbs free energy and building blocks for synthesis of macromolecules, which are necessary for structures, growth, and proliferation. Metabolism is a complex network composed of thousands of reactions catalyzed by enzymes involving many co-factors and metabolites. Traditionally it has been difficult to study metabolism as a whole network and most traditional efforts were therefore focused on specific metabolic pathways, enzymes, and metabolites. By using engineering principles of mathematical modeling to analyze and study metabolism, as well as engineer it, that is, design and build, new metabolic features, it is possible to gain many new fundamental insights as well as applications in biotechnology. Here, we present the history and basic principles of engineering metabolism, as well as the newest developments in the field. We are using examples of applications in: (1) production of protein pharmaceuticals and chemicals; (2) basic studies of metabolism; and (3) impacting health care. We will end by discussing how engineering metabolism can benefit from advances in artificial intelligence (AI)-based models.
    Keywords:  metabolic engineering; synthetic biology; systems biology
    DOI:  https://doi.org/10.1017/qrd.2025.1
  14. Nat Commun. 2025 Mar 08. 16(1): 2338
    Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle.
    Simon T Bond, Emily J King, Shannen M Walker, Christine Yang, Yingying Liu, Kevin H Liu, Aowen Zhuang, Aaron W Jurrjens, Haoyun A Fang, Luke E Formosa, Artika P Nath, Sergio Ruiz Carmona, Michael Inouye, Thy Duong, Kevin Huynh, Peter J Meikle, Simon Crawford, Georg Ramm, Sheik Nadeem Elahee Doomun, David P de Souza, Danielle L Rudler, Anna C Calkin, Aleksandra Filipovska, David W Greening, Darren C Henstridge, Brian G Drew.
      During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is known to be activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for activation of the mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe an inducible, tissue specific model of PolG mutation, which in muscle specific animals leads to rapid development of mitochondrial dysfunction and muscular degeneration in male animals from ~5 months of age. Detailed molecular profiling demonstrated robust activation of the mtISR in muscles from these animals. This was accompanied by striking alterations to enzymes in the mitochondrial folate cycle that was likely driven by a specific depletion in the folate cycle metabolite 5,10 methenyl-THF, strongly implying imbalanced folate intermediates as a previously unrecognised pathology linking the mtISR and mitochondrial disease.
    DOI:  https://doi.org/10.1038/s41467-025-57299-3
  15. Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]
    Quality control of mitochondrial nucleoids.
    Hao Liu, Haixia Zhuang, Du Feng.
      Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.
    Keywords:  mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.005
  16. Nat Commun. 2025 Mar 07. 16(1): 2278
    CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer.
    Fangquan Chen, Hu Tang, Changfeng Li, Rui Kang, Daolin Tang, Jiao Liu.
      Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, and lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent cell death. We reveal CYP51A1, a gene involved in cholesterol synthesis, as a key suppressor of alkalization-induced cell death in pancreatic cancer cells. Inducing intracellular alkalization by the small molecule JTC801 leads to a decrease in endoplasmic reticulum cholesterol levels, subsequently activating SREBF2, a transcription factor responsible for controlling the expression of genes involved in cholesterol biosynthesis. Specifically, SREBF2-driven upregulation of CYP51A1 prevents cholesterol accumulation within lysosomes, leading to TMEM175-dependent lysosomal proton efflux, ultimately resulting in the inhibition of cell death. In animal models, including xenografts, syngeneic orthotopic, and patient-derived models, the genetic or pharmacological inhibition of CYP51A1 enhances the effectiveness of JTC801 in suppressing pancreatic tumors. These findings demonstrate a role of the CYP51A1-dependent lysosomal pathway in inhibiting alkalization-induced cell death and highlight its potential as a targetable vulnerability in pancreatic cancer.
    DOI:  https://doi.org/10.1038/s41467-025-57583-2
  17. EMBO Mol Med. 2025 Mar 07.
    Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors.
    Xun Zhou, Eva Berenger, Yong Shi, Vera Shirokova, Elena Kochetkova, Tina Becirovic, Boxi Zhang, Vitaliy O Kaminskyy, Yashar Esmaeilian, Kayoko Hosaka, Cecilia Lindskog, Per Hydbring, Simon Ekman, Yihai Cao, Maria Genander, Marcin Iwanicki, Erik Norberg, Helin Vakifahmetoglu-Norberg.
      Tumors often recapitulate programs to acquire invasive and dissemination abilities, during which pro-metastatic proteins are distinctively stabilized in cancer cells to drive further progression. Whether failed protein degradation affects the metastatic programs of cancer remains unknown. Here, we show that the human cancer cell-specific knockout (KO) of LAMP-2A, a limiting protein for chaperone-mediated autophagy (CMA), promotes the aggressiveness of mesenchymal tumors. Deficient CMA resulted in widespread tumor cell dissemination, invasion into the vasculature and cancer metastasis. In clinical samples, metastatic lesions showed suppressed LAMP-2A expression compared to primary tumors from the same cancer patients. Mechanistically, while stimulating TGFβ signaling dampens LAMP-2A levels, genetic suppression of CMA aggravated TGFβ signaling in cancer cells and tumors. Conversely, pharmacological inhibition of TGFβ signaling repressed the growth of LAMP-2A KO-driven tumors. Furthermore, we found that multiple EMT-driving proteins, such as TGFβR2, are degraded by CMA. Our study demonstrates that the tumor suppressive function of CMA involves negative regulation of TGFβ-driven EMT and uncovers a mechanistic link between CMA and a major feature of metastatic invasiveness.
    Keywords:  Cancer; Chaperone-mediated Autophagy; EMT; Metastasis; TGFβ
    DOI:  https://doi.org/10.1038/s44321-025-00210-w
  18. bioRxiv. 2025 Feb 28. pii: 2025.02.25.640220. [Epub ahead of print]
    Class I histone deacetylases catalyze lysine lactylation.
    Takeshi Tsusaka, Mohd Altaf Najar, Isha Sharma, Mariola M Marcinkiewicz, Claudia Veronica Da Silva Crispim, Nathaniel W Snyder, George M Burslem, Emily L Goldberg.
      Metabolism and post-translational modifications (PTMs) are intrinsically linked and the number of identified metabolites that can covalently modify proteins continues to increase. This metabolism/PTM crosstalk is especially true for lactate, the product of anaerobic metabolism following glycolysis. Lactate forms an amide bond with the ε-amino group of lysine, a modification known as lysine lactylation, or Kla. Multiple independent mechanisms have been proposed in the formation of Kla, including p300/CBP-dependent transfer from lactyl-CoA, via a high-energy intermediate lactoylglutathione species that non-enzymatically lactylates proteins, and several enzymes are reported to have lactyl transferase capability. We recently discovered that class I histone deacetylases (HDACs) 1, 2, and 3 can all reverse their canonical chemical reaction to catalyze lysine β-hydroxybutyrylation. Here we tested the hypothesis that HDACs can also catalyze Kla formation. Using biochemical, pharmacological, and genetic approaches, we found that HDAC-catalyzed lysine lactylation accounts for the majority of Kla formation in cells. Dialysis experiments confirm this is a reversible reaction that depends on lactate concentration. We also directly quantified intracellular lactyl-CoA and found that Kla abundance can be uncoupled from lactyl-CoA levels. Therefore, we propose a model in which the majority of Kla is formed through enzymatic addition of lactate by HDACs 1, 2, and 3.
    DOI:  https://doi.org/10.1101/2025.02.25.640220
  19. Nat Metab. 2025 Mar 11.
    Glycogen drives tumour initiation and progression in lung adenocarcinoma.
    Harrison A Clarke, Tara R Hawkinson, Cameron J Shedlock, Terrymar Medina, Roberto A Ribas, Lei Wu, Zizhen Liu, Xin Ma, Yi Xia, Yu Huang, Xing He, Josephine E Chang, Lyndsay E A Young, Jelena A Juras, Michael D Buoncristiani, Alexis N James, Anna Rushin, Matthew E Merritt, Annette Mestas, Jessica F Lamb, Elena C Manauis, Grant L Austin, Li Chen, Pankaj K Singh, Jiang Bian, Craig W Vander Kooi, B Mark Evers, Christine F Brainson, Derek B Allison, Matthew S Gentry, Ramon C Sun.
      Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.
    DOI:  https://doi.org/10.1038/s42255-025-01243-8
  20. Science. 2025 Mar 13. eadu6445
    Structure of human PINK1 at a mitochondrial TOM-VDAC array.
    Sylvie Callegari, Nicholas S Kirk, Zhong Yan Gan, Toby Dite, Simon A Cobbold, Andrew Leis, Laura F Dagley, Alisa Glukhova, David Komander.
      Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.
    DOI:  https://doi.org/10.1126/science.adu6445
  21. Nature. 2025 Mar 12.
    MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC.
    Elena Fiorini, Antonia Malinova, Daniel Schreyer, Davide Pasini, Michele Bevere, Giorgia Alessio, Diego Rosa, Sabrina D'Agosto, Luca Azzolin, Salvatore Milite, Silvia Andreani, Francesca Lupo, Lisa Veghini, Sonia Grimaldi, Serena Pedron, Monica Castellucci, Craig Nourse, Roberto Salvia, Giuseppe Malleo, Andrea Ruzzenente, Alfredo Guglielmi, Michele Milella, Rita T Lawlor, Claudio Luchini, Antonio Agostini, Carmine Carbone, Christian Pilarsky, Andrea Sottoriva, Aldo Scarpa, David A Tuveson, Peter Bailey, Vincenzo Corbo.
      Intratumour heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance1,2. Oncogene dosage variation contributes to cell-state transitions and phenotypic heterogeneity3, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNAs drive varying levels of MYC dosage, depending on their regulatory landscape, enabling cancer cells to rapidly and reversibly adapt to microenvironmental changes. In the absence of selective pressure, a high ecDNA copy number imposes a substantial fitness cost on PDAC cells. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors. Our work provides a detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.
    DOI:  https://doi.org/10.1038/s41586-025-08721-9
  22. Nat Rev Cancer. 2025 Mar 07.
    When tumour cells get excited.
    Daniela Senft.
      
    DOI:  https://doi.org/10.1038/s41568-025-00808-9
  23. Nat Aging. 2025 Mar 07.
    A torpor-like state in mice slows blood epigenetic aging and prolongs healthspan.
    Lorna Jayne, Aurora Lavin-Peter, Julian Roessler, Alexander Tyshkovskiy, Mateusz Antoszewski, Erika Ren, Aleksandar Markovski, Senmiao Sun, Hanqi Yao, Vijay G Sankaran, Vadim N Gladyshev, Robert T Brooke, Steve Horvath, Eric C Griffith, Sinisa Hrvatin.
      Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase healthspan, remain unknown. Here we demonstrate that the activity of a spatially defined neuronal population in the preoptic area, which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor-like state (TLS) in mice. Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves healthspan. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the decelerating effect of TLSs on aging is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the decelerating effects of torpor and hibernation on aging and support the growing body of evidence that Tb is an important mediator of the aging processes.
    DOI:  https://doi.org/10.1038/s43587-025-00830-4
  24. Nat Metab. 2025 Mar 10.
    Disrupting cholesterol homeostasis in T cells boosts antitumour responses.
    Kelly T Kennewick, Steven J Bensinger.
      
    DOI:  https://doi.org/10.1038/s42255-025-01240-x
  25. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2404899122
    Dynamic investigation of hypoxia-induced L-lactylation.
    Jinjun Gao, Ruilong Liu, Kevin Huang, Ziyuan Li, Xinlei Sheng, Kasturi Chakraborty, Chang Han, Di Zhang, Lev Becker, Yingming Zhao.
      The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (KL-la), two isomeric modifications, lysine D-lactylation (KD-la) and N-ε-(carboxyethyl) lysine (Kce), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular KL-la, but not KD-la or Kce, is up-regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on KD-la, Kce, or hypoxia-induced KL-la. Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of KL-la but increased KD-la and Kce. We further observed a correlation between the level of KL-la and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and KL-la in lung cancer tissues and that patient samples with higher grade tend to have higher KL-la levels. Using a proteomics approach, we quantified 66 KL-la sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced KL-la. Collectively, our study demonstrates that KL-la, rather than KD-la or Kce, is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between KL-la and the hypoxia-induced adaptation of tumor cells.
    Keywords:  LC–MS/MS; hypoxia; lactylation; posttranslational modification (PTM)
    DOI:  https://doi.org/10.1073/pnas.2404899122
  26. Cell Metab. 2025 Mar 07. pii: S1550-4131(25)00051-8. [Epub ahead of print]
    Seeing the world through the eyes of cultured cells.
    Joycelyn Tan, Guy B Kunzmann, Sam Virtue, Jason R Cantor, Daniel J Fazakerley.
      The metabolic environment experienced by cultured cells often differs from physiological conditions. Here, we highlight the effects that the microenvironment can have on cultured cell behavior and advocate for researchers to re-evaluate culture practices to enhance the relevance and translational potential of in vitro studies.
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.027
  27. BBA Adv. 2025 ;7 100148
    Plant acetyl-CoA carboxylase: The homomeric form and the heteromeric form.
    Dilawar Niazi, Greg B G Moorhead.
      Across the domains of life, the enzyme acetyl-CoA carboxylase (ACC) converts HCO3 -, ATP, and acetyl-CoA to malonyl-CoA, ADP, and Pi. Malonyl-CoA is the building block for all de novo fatty acid biosynthesis. ACC is found in two forms, (1) as a heteromeric enzyme, and (2) as a homomeric enzyme. Whether a single polypeptide, or various subunit combinations, they all catalyze the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Here, we explore five burning questions pertaining to this fascinatingly intricate and complicated molecular machine, and the prospect of increasing oil production in plant vegetative tissues through its manipulation. We ask: 1. Can we manipulate the interplay of starch-lipid biosynthesis to increase the total TAG content in the vegetative tissues of plants? 2. Why is ACC such a complex enzyme? 3. How is ACC regulated? 4. Why is the plant plastid ACC recruited to the chloroplast membrane? 5. Will structural biology provide insights into the regulation of plant ACC?
    Keywords:  Acetyl-CoA carboxylase; Carboxyltransferase interactors; Heteromeric; Homomeric; Phosphorylation; Plastid
    DOI:  https://doi.org/10.1016/j.bbadva.2025.100148
  28. Cell Rep. 2025 Mar 06. pii: S2211-1247(25)00174-3. [Epub ahead of print]44(3): 115403
    The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis.
    Jianing Xu, Matthew Wakai, Kun Xiong, Yanfeng Yang, Adithya Prabakaran, Sophia Wu, Diana Ahrens, Maria Del Pilar Molina-Portela, Min Ni, Yu Bai, Tea Shavlakadze, David J Glass.
      Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.
    Keywords:  ATP; CP: Immunology; ERRα; ESRRA; HIF1A; HIF1α; IL6; PGC1α; PGC1β; PPARGC1A; PPARGC1B; aging; gp130; inflammation; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2025.115403
  29. Nat Genet. 2025 Mar 10.
    Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency.
    Natalia Brzozowska, Lily Y D Wu, Vera Khodzhaeva, William J Griffiths, Adam Duckworth, Hyunchul Jung, Tim H H Coorens, Yvette Hooks, Joseph E Chambers, Peter J Campbell, Stefan J Marciniak, Matthew Hoare.
      Somatic variants accumulate in non-malignant tissues with age. Functional variants, leading to clonal advantage of hepatocytes, accumulate in the liver of patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing etiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or hemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered at the carboxyl terminus of A1AT, leading to truncation. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting that functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.
    DOI:  https://doi.org/10.1038/s41588-025-02125-1
  30. Sci Adv. 2025 Mar 14. 11(11): eadt1241
    Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair.
    Jui-Chung Chiang, Zengfu Shang, Tracy Rosales, Ling Cai, Wei-Min Chen, Feng Cai, Hieu Vu, John D Minna, Min Ni, Anthony J Davis, Robert D Timmerman, Ralph J DeBerardinis, Yuanyuan Zhang.
      Lung cancer exhibits altered metabolism, influencing its response to radiation. To investigate the metabolic regulation of radiation response, we conducted a comprehensive, metabolic-wide CRISPR-Cas9 loss-of-function screen using radiation as selection pressure in human non-small cell lung cancer. Lipoylation emerged as a key metabolic target for radiosensitization, with lipoyltransferase 1 (LIPT1) identified as a top hit. LIPT1 covalently conjugates mitochondrial 2-ketoacid dehydrogenases with lipoic acid, facilitating enzymatic functions involved in the tricarboxylic acid cycle. Inhibiting lipoylation, either through genetic LIPT1 knockout or a lipoylation inhibitor (CPI-613), enhanced tumor control by radiation. Mechanistically, lipoylation inhibition increased 2-hydroxyglutarate, leading to H3K9 trimethylation, disrupting TIP60 recruitment and ataxia telangiectasia mutated (ATM)-mediated DNA damage repair signaling, impairing homologous recombination repair. In summary, our findings reveal a critical role of LIPT1 in regulating DNA damage and chromosome stability and may suggest a means to enhance therapeutic outcomes with DNA-damaging agents.
    DOI:  https://doi.org/10.1126/sciadv.adt1241
  31. Nat Rev Endocrinol. 2025 Mar 07.
    Islet hormones at the intersection of glucose and amino acid metabolism.
    Phillip J White, Nicolai J Wewer Albrechtsen, Jonathan E Campbell.
      The pancreatic islets of Langerhans are central to fine-tuning metabolism to ensure metabolic homeostasis during the transition between fasting and feeding. Insulin and glucagon, the principal hormones generated and secreted by islets, exert powerful control in various metabolic tissues to drive nutrient uptake, storage and metabolism. Their canonical actions on glycaemia have positioned these hormones in opposition, however, their metabolic actions extend beyond controlling blood levels of glucose. Indeed, these islet hormones are just as influential in regulating lipid and amino acid metabolism and it is becoming clear that many of these actions involve an interplay between insulin and glucagon, which is contrary to the dogmatic view that these hormones are antagonistic in nature. Finally, we postulate that examining the effects of islet hormones on the metabolism of individual metabolites is overly simplistic. Here, we discuss the actions of each islet hormone alone and in combination with the others in regulating glucose and amino acid metabolism and explore how these signalling networks are closely linked and strongly influence one another.
    DOI:  https://doi.org/10.1038/s41574-025-01100-4
  32. Cell Chem Biol. 2025 Feb 28. pii: S2451-9456(25)00035-2. [Epub ahead of print]
    Mechanisms and functions of lysosomal lipid homeostasis.
    Michael Ebner, Florian Fröhlich, Volker Haucke.
      Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.
    Keywords:  contact sites; lipids; lysosomes; membrane homeostasis; phosphoinositides; signalling
    DOI:  https://doi.org/10.1016/j.chembiol.2025.02.003
  33. Nat Methods. 2025 Mar 12.
    Spotiphy enables single-cell spatial whole transcriptomics across an entire section.
    Jiyuan Yang, Ziqian Zheng, Yun Jiao, Kaiwen Yu, Sheetal Bhatara, Xu Yang, Sivaraman Natarajan, Jiahui Zhang, Qingfei Pan, John Easton, Koon-Kiu Yan, Junmin Peng, Kaibo Liu, Jiyang Yu.
      Spatial transcriptomics (ST) has advanced our understanding of tissue regionalization by enabling the visualization of gene expression within whole-tissue sections, but current approaches remain plagued by the challenge of achieving single-cell resolution without sacrificing whole-genome coverage. Here we present Spotiphy (spot imager with pseudo-single-cell-resolution histology), a computational toolkit that transforms sequencing-based ST data into single-cell-resolved whole-transcriptome images. Spotiphy delivers the most precise cellular proportions in extensive benchmarking evaluations. Spotiphy-derived inferred single-cell profiles reveal astrocyte and disease-associated microglia regional specifications in Alzheimer's disease and healthy mouse brains. Spotiphy identifies multiple spatial domains and alterations in tumor-tumor microenvironment interactions in human breast ST data. Spotiphy bridges the information gap and enables visualization of cell localization and transcriptomic profiles throughout entire sections, offering highly informative outputs and an innovative spatial analysis pipeline for exploring complex biological systems.
    DOI:  https://doi.org/10.1038/s41592-025-02622-5
  34. Trends Cancer. 2025 Mar 06. pii: S2405-8033(25)00044-5. [Epub ahead of print]
    Compromised epigenetic robustness in cancer: fueling evolution, exposing weakness.
    Thomas Stuart Wilson, Paola Scaffidi.
      The complex network of proteins that regulate chromatin and DNA methylation landscapes is often disrupted in cancer. Clonal and subclonal mutations targeting a wide range of molecular functions are frequently observed across cancer types, and emerging evidence suggests that loss of robust epigenetic control promotes both cancer initiation and evolution, independently of context-specific effects. Here, we review how diverse genetic alterations that destabilize the epigenetic regulatory network (ERN) may converge into common phenotypes. We also discuss the implications of altered network topology and systemic epigenetic disorder for the evolution, vulnerability, and therapeutic resistance of cancers.
    Keywords:  cancer; epigenetics; evolution; systems level; vulnerability
    DOI:  https://doi.org/10.1016/j.trecan.2025.02.001
  35. Int J Biol Sci. 2025 ;21(5): 1863-1873
    Fatty Acid Trafficking Between Lipid Droplets and Mitochondria: An Emerging Perspective.
    Katarína Smolková, Klára Gotvaldová.
      The current understanding of lipid droplets (LDs) in cell biology has evolved from being viewed merely as storage compartments. LDs are now recognized as metabolic hubs that act as cytosolic buffers against the detrimental effects of free fatty acids (FAs). Upon activation, FAs traverse various cellular pathways, including oxidation in mitochondria, integration into complex lipids, or storage in triacylglycerols (TGs). Maintaining a balance among these processes is crucial in cellular FA trafficking, and under metabolically challenging circumstances the routes of FA metabolism adapt to meet the current cellular needs. This typically involves an increased demand for anabolic intermediates or energy and the prevention of redox stress. Surprisingly, LDs accumulate under certain conditions such as amino acid starvation. This review explores the biochemical aspects of FA utilization in both physiological contexts and within cancer cells, focusing on the metabolism of TGs, cholesteryl esters (CEs), and mitochondrial FA oxidation. Emphasis is placed on the potential toxicity associated with non-esterified FAs in cytosolic and mitochondrial compartments. Additionally, we discuss mechanisms that lead to increased LD biogenesis due to an inhibited mitochondrial import of FAs.
    Keywords:  CPT1; ferroptosis; lipid droplets; lipotoxicity; mitochondria; triglycerides
    DOI:  https://doi.org/10.7150/ijbs.105361
  36. Nat Genet. 2025 Mar;57(3): 486
    Understanding immune escape in lung cancer.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02144-y
  37. Nat Rev Genet. 2025 Mar 10.
    Integrating model systems and genomic insights to decipher mechanisms of cancer metastasis.
    Michelle M Leung, Charles Swanton, Nicholas McGranahan.
      Deciphering metastatic processes is crucial for understanding cancer progression and potential treatment options. Genetic studies of model systems engineered to mimic metastatic disease, including organoids, genetically engineered mice and human cell lines, have had an important role in shaping our understanding of the metastatic cascade and how it can be manipulated. More recently, advances in high-throughput sequencing have enabled human metastases to be studied at single-cell and single-nucleotide resolution, providing insights into metastatic evolution and phenotypes of both cancer cells and immune cells. However, human tissue studies are often correlative and descriptive, whereas experimental models are reductionistic by nature, meaning that individual results should be interpreted with caution. Crucially, these seemingly disparate branches of metastasis research can and should complement each other to strengthen and validate findings. Here we explore the synergies between model systems and sequencing studies and outline key areas that must be explored to improve our understanding of the metastatic process.
    DOI:  https://doi.org/10.1038/s41576-025-00825-2
  38. Genes Dev. 2025 Mar 14.
    Where and why have so many metabolic enzymes gone from developing spores of Bacillus subtilis?
    Peter Setlow.
      Developing spores (forespores) of Bacillus subtilis lack TCA cycle and amino acid and ribonucleotide biosynthetic enzymes but still carry out much macromolecular synthesis to make a spore-but how and why? Work by many showed that the mother cell supplies ATP and metabolites to the forespore via a feeding tube. Two recent studies in this issue of Genes & Development, by Massoni and colleagues (doi:10.1101/gad.352498.124) and Riley and colleagues (doi:10.1101/gad.352535.124), now show that specific metabolic enzymes disappear early in forespore development via proteolysis by ClpCP and a forespore-specific activator termed MdfA. Future work may clarify how this proteolysis recognizes specific metabolic enzymes and determine the advantages of this overall process for spores.
    Keywords:  AAA+ proteases; Bacillus subtilis; ClpC; ClpCP; MdfA; X-ray crystallography; YjbA; adaptor; metabolic reprogramming; metabolism; oxidative stress; protein degradation; proteolysis; sporulation
    DOI:  https://doi.org/10.1101/gad.352755.125
  39. J Cell Sci. 2025 Mar 13. pii: jcs.263693. [Epub ahead of print]
    A dual-purification system to isolate mitochondrial subpopulations.
    Corey N Cunningham, Jonathan G Van Vranken, Jakeline Larios, Katarina Heyden, Steven P Gygi, Jared Rutter.
      Mitochondria perform diverse functions, such as producing ATP through oxidative phosphorylation, synthesizing macromolecule precursors, maintaining redox balance, and many others. Given this diversity of functions, we and others have hypothesized that cells maintain specialized subpopulations of mitochondria. To begin addressing this hypothesis, we developed a new dual-purification system to isolate subpopulations of mitochondria for chemical and biochemical analyses. We used APEX2 proximity labeling such that mitochondria were biotinylated based on proximity to another organelle. All mitochondria were isolated by an elutable MitoTag-based affinity precipitation system. Biotinylated mitochondria were then purified using immobilized avidin. We used this system to compare the proteomes of endosome- and lipid droplet-associated mitochondria in U-2 OS cells, which demonstrated that these subpopulations were indistinguishable from one another but were distinct from the global mitochondria proteome. Our results suggest that this purification system could aid in describing subpopulations that contribute to intracellular mitochondrial heterogeneity, and that this heterogeneity might be more substantial than previously imagined.
    Keywords:  Biochemistry; Mitochondria; Proximity Labeling; Purification
    DOI:  https://doi.org/10.1242/jcs.263693
  40. Immunity. 2025 Mar 11. pii: S1074-7613(25)00075-5. [Epub ahead of print]58(3): 535-554
    Lactate: A key regulator of the immune response.
    Alba Llibre, Salih Kucuk, Atrayee Gope, Michelangelo Certo, Claudio Mauro.
      Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.
    Keywords:  immune regulation; lactate; lactate sensing; lactate signaling; lactylation
    DOI:  https://doi.org/10.1016/j.immuni.2025.02.008
  41. Nat Genet. 2025 Mar;57(3): 486
    Hyperactive histone genes fuel cancer.
    Tiago Faial.
      
    DOI:  https://doi.org/10.1038/s41588-025-02145-x
  42. Curr Opin Cell Biol. 2025 Mar 06. pii: S0955-0674(25)00028-6. [Epub ahead of print]94 102490
    Aneuploidy as a cancer vulnerability.
    Jinghui Cao, Cai Liang, Hongtao Yu.
      Aneuploidy is prevalent in cancer and has complicated roles in tumorigenesis. Paradoxically, artificially engineered aneuploidy in normal cells reduces cellular fitness by inducing proteotoxic and genotoxic stresses. A better molecular understanding of the multifaceted roles of aneuploidy in cancer evolution offers promising avenues for future cancer therapies. Here, we discuss the patterns and consequences of aneuploidy in human cancer. We highlight recent efforts to explore aneuploidy as a cancer vulnerability and new interventions that exploit this vulnerability for cancer treatment.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102490
  43. Cell Rep. 2025 Mar 12. pii: S2211-1247(25)00171-8. [Epub ahead of print]44(3): 115400
    Piezo1 regulates colon stem cells to maintain epithelial homeostasis through SCD1-Wnt-β-catenin and programming fatty acid metabolism.
    Feifei Fang, Gangping Li, Xueyan Li, Jiandi Wu, Ying Liu, Haoren Xin, Zhe Wang, Jianhua Fang, Yudong Jiang, Wei Qian, Xiaohua Hou, Jun Song.
      Piezo1, which maintains the integrity and function of the intestinal epithelial barrier, is essential for colonic epithelial homeostasis. However, whether and how Piezo1 regulates colon stem cell fate remains unclear. Here, we show that Piezo1 inhibition promotes colon stem cell proliferation. Mechanistically, stearoyl-CoA 9-desaturase 1 (SCD1) is downstream of Piezo1 to affect colon stem cell stemness by acting on the Wnt-β-catenin pathway. For mice, the altered colon stem cell stemness after Piezo1 knockdown and activation was accompanied by a reprogrammed fatty acid (FA) metabolism in colon crypts. Notably, we found that GsMTX4 protects injured colon stem cell stemness in mouse and human colitis organoids. Our results elucidated the role of Piezo1 in regulating normal and postinjury colon stem cell fates through SCD1-Wnt-β-catenin and the SCD1-mediated FA desaturation process. These results provide fresh perspectives on the mechanical factors regulating colon stem cell fate and therapeutic strategies for related intestinal diseases.
    Keywords:  CP: Metabolism; CP: Stem cell research; Piezo1; SCD1; colitis; colon stem cell; fatty acid metabolism; intestinal epithelial homeostasis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115400
  44. Cancer Discov. 2025 Mar 13.
    Long term latency of highly mutated cells in normal mouse skin is reversed by exposure to tumor promoters and chronic tissue damage.
    Yun Rose Li, Eve Kandyba, Kyle Halliwill, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, Olga K Mirzoeva, Melissa Quino Reeves, S M Ashiqul Islam, Laura Riva, Erik N Bergstrom, Kavya Achanta, John DiGiovanni, Ludmil B Alexandrov, Allan Balmain.
      Historical studies performed nearly a century ago using mouse skin models identified two key steps in cancer evolution: initiation, a likely mutational event, and promotion, driven by inflammation and cell proliferation. Initiation was proposed to be permanent, with promotion as the critical rate-limiting step for cancer development. Here, we carried out whole genome sequencing to demonstrate that initiated cells with thousands of mutagen-induced mutations can persist for long periods and are not removed by cell competition or by immune intervention, thus mimicking the persistence of cells with cancer driver mutations in normal human tissues. In the mouse, these cells do not give rise to tumors unless exposed to the tumor promoter TPA. Tissue damage and regenerative proliferation, but not normal cell turnover, consistently trigger tumor formation. Wounding, promoter treatment, and obesity enhance promotion without increasing mutational burden, supporting the possibility of future cancer prevention efforts directed at promotional risk factors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1379
  45. Cell Death Dis. 2025 Mar 12. 16(1): 172
    Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity.
    Claudio Laquatra, Alessia Magro, Federica Guarra, Matteo Lambrughi, Lavinia Ferrone, Giulio Fracasso, Melissa Bacchin, Martina La Spina, Elisabetta Moroni, Elena Papaleo, Giorgio Colombo, Andrea Rasola.
      The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity.
    DOI:  https://doi.org/10.1038/s41419-025-07467-6
  46. Nature. 2025 Mar 12.
    How fast your brain ages is affected by these 64 genes.
    Miryam Naddaf.
      
    Keywords:  Ageing; Brain; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-00766-0
  47. Biochim Biophys Acta Gen Subj. 2025 Mar 07. pii: S0304-4165(25)00032-7. [Epub ahead of print]1869(6): 130787
    Compartmentation of multiple metabolic enzymes and their preparation in vitro and in cellulo.
    Sayoko Ito-Harashima, Natsuko Miura.
      Compartmentalization of multiple enzymes in cellulo and in vitro is a means of controlling the cascade reaction of metabolic enzymes. The compartmentation of enzymes through liquid-liquid phase separation may facilitate the reversible control of biocatalytic cascade reactions, thereby reducing the transcriptional and translational burden. This has attracted attention as a potential application in bioproduction. Recent research has demonstrated the existence and regulatory mechanisms of various enzyme compartments within cells. Mounting evidence suggests that enzyme compartmentation allows in vitro and in vivo regulation of cellular metabolism. However, the comprehensive regulatory mechanisms of enzyme condensates in cells and ideal organization of cellular systems remain unknown. This review provides an overview of the recent progress in multiple enzyme compartmentation in cells and summarizes strategies to reconstruct multiple enzyme assemblies in vitro and in cellulo. By examining parallel examples, we have evaluated the consensus and future perspectives of enzyme condensation.
    Keywords:  Artificial organelle; Coacervate droplet; Electrostatic interaction; Enzyme compartmentation; Liquid–liquid phase separation; Membraneless organelle; Polyelectrolyte
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130787
  48. Sci Adv. 2025 Mar 14. 11(11): eadn2830
    Spatial 3D genome organization reveals intratumor heterogeneity in primary glioblastoma samples.
    Qixuan Wang, Juan Wang, Radhika Mathur, Mark W Youngblood, Qiushi Jin, Ye Hou, Lena Ann Stasiak, Yu Luan, Hengqiang Zhao, Stephanie Hilz, Chibo Hong, Susan M Chang, Janine M Lupo, Joanna J Phillips, Joseph F Costello, Feng Yue.
      Glioblastoma (GBM) is the most prevalent malignant brain tumor with poor prognosis. Although chromatin intratumoral heterogeneity is a characteristic feature of GBM, most current studies are conducted at a single tumor site. To investigate the GBM-specific 3D genome organization and its heterogeneity, we conducted Hi-C experiments in 21 GBM samples from nine patients, along with three normal brain samples. We identified genome subcompartmentalization and chromatin interactions specific to GBM, as well as extensive intertumoral and intratumoral heterogeneity at these levels. We identified copy number variants (CNVs) and structural variations (SVs) and demonstrated how they disrupted 3D genome structures. SVs could not only induce enhancer hijacking but also cause the loss of enhancers to the same gene, both of which contributed to gene dysregulation. Our findings provide insights into the GBM-specific 3D genome organization and the intratumoral heterogeneity of this organization and open avenues for understanding this devastating disease.
    DOI:  https://doi.org/10.1126/sciadv.adn2830
  49. J Biol Chem. 2025 Mar 10. pii: S0021-9258(25)00239-X. [Epub ahead of print] 108390
    New routes for spermine biosynthesis.
    Bin Li, Hamid R Baniasadi, Jue Liang, Margaret A Phillips, Anthony J Michael.
      The polyamine spermine is a flexible linear teraamine found in bacteria and eukaryotes, and in all known cases is synthesized from triamine spermidine by addition of an aminopropyl group acquired from decarboxylated S-adenosylmethionine (dcAdoMet). We have now identified in bacteria a second biosynthetic route for spermine based on the formation of carboxyspermine from spermidine, dependent on aspartate β-semialdehyde (ASA). This route also produces thermospermine from spermidine via carboxythermospermine. Two enzymes, carboxyspermidine dehydrogenase and carboxyspermidine decarboxylase, are responsible for ASA-dependent production of spermidine, spermine and thermospermine from diamine putrescine. Production of spermine/thermospermine from spermidine is controlled primarily by carboxyspermidine dehydrogenase, not carboxyspermidine decarboxylase. This new ASA-dependent spermine biosynthetic pathway is an example of convergent evolution, employing nonanalogous, nonhomologous enzymes to produce the same biosynthetic products as the dcAdoMet-dependent spermine pathway. We have also identified bacteria that encode hybrid spermine biosynthetic pathways dependent on both dcAdoMet and ASA. In the hybrid pathways, spermidine is produced from agmatine primarily by the ASA-dependent route, and spermine is synthesized from agmatine or spermidine by dcAdoMet-dependent modules. Both parts of the hybrid pathway initiate from agmatine and each produces N1-aminopropylagmatine, so that agmatine, N1-aminopropylagmatine and spermidine are common, potentially shared metabolites. Bacteria such as Clostridium leptum that encode the hybrid pathway may explain the origin of spermine produced by the gut microbiota. This is the first example of convergent evolution of hybrid dcAdoMet- and ASA-dependent N1-aminopropylagmatine, spermidine and spermine biosynthesis encoded in the same genomes, and suggests additional polyamine biosynthetic diversification remains to be discovered.
    Keywords:  N(1)-aminopropylagmatine; aspartate β-semialdehyde; bacteria; biosynthesis; carboxyspermidine; carboxyspermine; convergent evolution; polyamine; spermidine; spermine; thermospermine
    DOI:  https://doi.org/10.1016/j.jbc.2025.108390
  50. bioRxiv. 2025 Feb 27. pii: 2025.02.26.640157. [Epub ahead of print]
    Sphingolipid metabolism drives mitochondria remodeling during aging and oxidative stress.
    Adam C Ebert, Nathaniel L Hepowit, Thyandra A Martinez, Henrik Vollmer, Hayley L Singkhek, Kyrie D Frazier, Sophia A Kantejeva, Maulik R Patel, Jason A MacGurn.
      One of the hallmarks of aging is a decline in the function of mitochondria, which is often accompanied by altered morphology and dynamics. In some cases, these changes may reflect macromolecular damage to mitochondria that occurs with aging and stress, while in other cases they may be part of a programmed, adaptive response. In this study, we report that mitochondria undergo dramatic morphological changes in chronologically aged yeast cells. These changes are characterized by a large, rounded morphology, decreased co-localization of outer membrane and matrix markers, and decreased mitochondrial membrane potential. Notably, these transitions are prevented by pharmacological or genetic interventions that perturb sphingolipid biosynthesis, indicating that sphingolipids are required for these mitochondrial transitions in aging cells. Consistent with these findings, we observe that overexpression of inositol phospholipid phospholipase (Isc1) prevents these alterations to mitochondria morphology in aging cells. We also report that mitochondria exhibit similar sphingolipid-dependent morphological transitions following acute exposure to oxidative stress. These findings suggest that sphingolipid metabolism contributes to mitochondrial remodeling in aging cells and during oxidative stress, perhaps as a result of damaged sphingolipids that localize to mitochondrial membranes. These findings underscore the complex relationship between mitochondria function and sphingolipid metabolism, particularly in the context of aging and stress.
    DOI:  https://doi.org/10.1101/2025.02.26.640157
  51. Curr Opin Hematol. 2025 Mar 12.
    Red blood cell metabolism: a window on systems health towards clinical metabolomics.
    Angelo D'Alessandro.
       PURPOSE OF REVIEW: This review focuses on recent advances in the understanding of red blood cell (RBC) metabolism as a function of hypoxia and oxidant stress. In particular, we will focus on RBC metabolic alterations during storage in the blood bank, a medically relevant model of erythrocyte responses to energy and redox stress.
    RECENT FINDINGS: Recent studies on over 13 000 healthy blood donors, as part of the Recipient Epidemiology and Donor Evaluation Study (REDS) III and IV-P RBC omics, and 525 diversity outbred mice have highlighted the impact on RBC metabolism of biological factors (age, BMI), genetics (sex, polymorphisms) and exposure (dietary, professional or recreational habits, drugs that are not grounds for blood donor deferral).
    SUMMARY: We review RBC metabolism from basic biochemistry to storage biology, briefly discussing the impact of inborn errors of metabolism and genetic factors on RBC metabolism, as a window on systems metabolic health. Expanding on the concept of clinical chemistry towards clinical metabolomics, monitoring metabolism at scale in large populations (e.g., millions of blood donors) may thus provide insights into population health as a complementary tool to genetic screening and standard clinical measurements.
    DOI:  https://doi.org/10.1097/MOH.0000000000000863
  52. Mol Cell. 2025 Mar 05. pii: S1097-2765(25)00142-X. [Epub ahead of print]
    The role of protein lactylation: A kaleidoscopic post-translational modification in cancer.
    Marta Iozzo, Elisa Pardella, Elisa Giannoni, Paola Chiarugi.
      The recently discovered lysine lactylation represents a critical post-translational modification with widespread implications in epigenetics and cancer biology. Initially identified on histones, lysine lactylation has been also described on non-histone proteins, playing a pivotal role in transcriptional activation, protein function, and cellular processes. Two major sources of the lactyl moiety have been currently distinguished: L-lactyl-CoA (precursor of the L-lactyl moiety) and S-D-lactylglutathione (precursor of the D-lactyl moiety), which enable enzymatic and non-enzymatic mechanisms of lysine lactylation, respectively. Although the specific writers, erasers, and readers of this modification are still unclear, acetyltransferases and deacetylases have been proposed as crucial mediators of lysine lactylation. Remarkably, lactylation exerts significant influence on critical cancer-related pathways, thereby shaping cellular behavior during malignant transformation and the metastatic cascade. Hence, as recent insights into lysine lactylation underscore its growing potential in tumor biology, targeting this modification is emerging as a significant opportunity for cancer treatment.
    Keywords:  cancer aggressiveness; histone lactylation; lactyl-CoA; lactylglutathione; non-histone protein lactylation
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.011
  53. Cancer Discov. 2025 Mar 12.
    RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression.
    Augusto Bleve, Martina Incerti, Francesca Maria Consonni, Valentina Garlatti, Giulia Ballerini, Chiara Pandolfo, Marta Noemi Monari, Simone Serio, Daniela Pistillo, Marina Sironi, Chiara Alì, Marcello Manfredi, Elettra Barberis, Giovanna Finocchiaro, Marco Antonio Cassatella, Cristina Panico, Gianluigi Condorelli, Antonio Sica.
      Despite well-documented metabolic and hematopoietic alterations during tumor development, the mechanisms underlying this crucial immunometabolic intersection remain elusive. Of particular interest is the connection between lipid metabolism and the retinoic-acid-related orphan receptor (RORC1/RORγ), whose transcriptional activity modulates cancer-related emergency myelopoiesis and is boosted by cholesterol metabolites, while hypercholesterolemia itself is associated with dysregulated myelopoiesis. Here, we show that cancer and hypercholesterolemic diet independently or cooperatively activate RORγ-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2-polarized tumor-associated macrophages (TAMs), supporting cancer spread. Moreover, we report that tumor-induced expression of IL-1b and IL-6 promotes hepatic expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) in preclinical models and patients. Importantly, lowering cholesterol levels, by genetic or pharmacological inhibition of PCSK9, prevents MDSC expansion, M2 TAM accumulation and tumor progression in a RORγ-dependent manner, unleashing specific anti-tumor immunity. Overall, we identify RORγ as a key sensor of lipid disorders, bridging hypercholesterolemia and pro-tumor myelopoiesis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0199
  54. Elife. 2025 Mar 11. pii: RP96925. [Epub ahead of print]13
    Propionyl-CoA carboxylase subunit B regulates anti-tumor T cells in a pancreatic cancer mouse model.
    Han V Han, Richard Efem, Barbara Rosati, Kevin Lu, Sara Maimouni, Ya-Ping Jiang, Valeria Montoya, Ando Van Der Velden, Wei-Xing Zong, Richard Z Lin.
      Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca-/- KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
    Keywords:  CD8 T cells; KPC cells; PD1; cancer biology; mouse; pancreatic cancer
    DOI:  https://doi.org/10.7554/eLife.96925
  55. Science. 2025 Mar 14. 387(6739): 1147-1148
    Making sense of fat in cancer.
    Estela Jacinto.
      A lipid chaperone enables sensing of an essential fatty acid to drive tumor growth.
    DOI:  https://doi.org/10.1126/science.adw1956
  56. Cancer Cell. 2025 Mar 12. pii: S1535-6108(25)00078-9. [Epub ahead of print]
    Distinct CD8+ T cell dynamics associate with response to neoadjuvant cancer immunotherapies.
    Housaiyin Li, Dan P Zandberg, Aditi Kulkarni, Simion I Chiosea, Patricia M Santos, Brian R Isett, Marion Joy, Gabriel L Sica, Kevin J Contrera, Curtis M Tatsuoka, Matthias Brand, Umamaheswar Duvvuri, Seungwon Kim, Mark Kubik, Shaum Sridharan, Fei Tu, Jie Chen, Tullia C Bruno, Dario A A Vignali, Anthony R Cillo, Riyue Bao, Jing Hong Wang, Lazar Vujanovic, Robert L Ferris.
      We leverage a clinical trial (NCT04080804) that compared neoadjuvant anti-PD-1, anti-PD-1+CTLA-4, and anti-PD-1+LAG-3 therapies in head and neck squamous cell carcinoma patients. Combination therapies promote higher pathologic response rates versus monotherapy, and major pathologic response is associated with better survival. To address whether successful immune checkpoint inhibitor (ICI) regimens act through similar or distinct pathways, we robustly and longitudinally characterize transcriptional and proteomic dynamics of CD8+ tumor-infiltrating lymphocytes (TILs) in a clonal manner. Anti-PD-1+LAG-3 reprograms CD8+ TIL with type-I interferon response and exhaustion gene programs into effector memory and resident memory (TEM/TRM). In contrast, anti-PD-1+CTLA-4 activates and expands pre-existing TEM/TRM CD8+ TIL, but does not rejuvenate exhausted phenotypes into T effector cells. Anti-PD-1+LAG-3, but not anti-PD-1+CTLA-4, induces widespread TCR sharing among the different transcriptional states, as well as increased TCR diversity in responding patients. Our data suggest doublet regimen-specific transcriptional and clonal dynamics of tumor-reactive CD8+ T cells.
    Keywords:  CTLA-4; Head and neck cancer; LAG-3; PD-1; T cell dynamics; clinical trial; combination immunotherapy; multispectral imaging; single-cell genomics; tumor immunology
    DOI:  https://doi.org/10.1016/j.ccell.2025.02.026
  57. Commun Biol. 2025 Mar 11. 8(1): 410
    Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria.
    Matthew C S Denley, Monique S Straub, Giulio Marcionelli, Miriam A Güra, David Penton, Igor Delvendahl, Martin Poms, Beata Vekeriotaite, Sarah Cherkaoui, Federica Conte, Ferdinand von Meyenn, D Sean Froese, Matthias R Baumgartner.
      Methylmalonic aciduria (MMA) is an inborn error of metabolism resulting in loss of function of the enzyme methylmalonyl-CoA mutase (MMUT). Despite acute and persistent neurological symptoms, the pathogenesis of MMA in the central nervous system is poorly understood, which has contributed to a dearth of effective brain specific treatments. Here we utilised patient-derived induced pluripotent stem cells and in vitro differentiation to generate a human neuronal model of MMA. We reveal strong evidence of mitochondrial dysfunction caused by deficiency of MMUT in patient neurons. By employing patch-clamp electrophysiology, targeted metabolomics, and bulk transcriptomics, we expose an altered state of excitability, which is exacerbated by application of dimethyl-2-oxoglutarate, and we suggest may be connected to metabolic rewiring. Our work provides first evidence of mitochondrial driven neuronal dysfunction in MMA, which through our comprehensive characterisation of this paradigmatic model, enables first steps to identifying effective therapies.
    DOI:  https://doi.org/10.1038/s42003-025-07828-z
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