bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–08–17
53 papers selected by
Christian Frezza, Universität zu Köln
  1. Mitochondria protect against an intracellular pathogen by restricting access to folate.
  2. Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.
  3. Respiration defects limit serine synthesis required for lung cancer growth and survival.
  4. Mitochondria and redox homeostasis - the backseat drivers in glioma.
  5. Species-specific serine metabolism differentially controls natural killer cell functions.
  6. Metabolic regulation of immunological aging.
  7. Ageing, immune fitness and cancer.
  8. Clone copy number diversity is linked to survival in lung cancer.
  9. D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.
  10. A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
  11. Energy deprivation in youth and old age.
  12. Mitochondria and the Metabolic Logic of Oncocytic Tumours.
  13. RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis.
  14. RNA triggers chronic stress during neuronal aging.
  15. MacroD1 sustains mitochondrial integrity and oxidative metabolism.
  16. Mitochondrial dysfunction and lipid dysregulation in yeast lacking phosphatidylserine.
  17. Resolving early embryonic metabolism in Drosophila through single-embryo metabolomics and transcriptomics.
  18. Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.
  19. Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.
  20. Metabolic regulation of RIPK1.
  21. Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
  22. Selective loss of ATP carriers in favour of SLC25A43 orthologues in metamonad mitochondria adapted to anaerobiosis.
  23. Uridine as a hub in cancer metabolism and RNA biology.
  24. Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
  25. Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.
  26. The liver metabolizes dietary galactose to fuel antitumour T cell immunity.
  27. A growing problem: the many unsolved mysteries of cell growth.
  28. CKDx: Simplicity matters, implementation is key.
  29. Principles of cotranslational mitochondrial protein import.
  30. Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
  31. Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.
  32. Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt.
  33. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  34. MetaSage: Machine Learning-Based Prioritization of Metabolic Regulators from Multi-Omics Data.
  35. The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
  36. Global profiling of N-terminal cysteine-dependent degradation mechanisms.
  37. Resilience and vulnerabilities of tumor cells under purine shortage stress.
  38. Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs.
  39. Study how screen time affects circadian rhythms.
  40. Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
  41. SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.
  42. The Malate-Aspartate Shuttle supports thermogenic lipid mobilization in brown adipocytes.
  43. Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.
  44. Chemogenetic detection and quantitation of H2O2 in living cells.
  45. Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells.
  46. Inhibition of tumor cell macropinocytosis driver DHODH reverses immunosuppression and overcomes anti-PD1 resistance.
  47. The insulin signalling network.
  48. Expanding the cytokine receptor alphabet reprograms T cells into diverse states.
  49. Mitochondrial clone tracing within spatially intact human tissues.
  50. ROS-dependent localization of glycolytic enzymes to mitochondria.
  51. Structural and enzymatic divergence between human MDH isoforms underlies their specialized regulatory roles in metabolism.
  52. A novel application of LC-MS/MS accurately quantifies the labile redox pools of cellular coenzymes Q9 and Q10.
  53. A Case of a Fumarate Hydratase Deficient Astrocytoma in Association With a Germline Fumarate Hydratase Mutation With Review of the Literature: Considerations for Patients With Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome.
  1. Science. 2025 Aug 14. 389(6761): eadr6326
    Mitochondria protect against an intracellular pathogen by restricting access to folate.
    Tânia Catarina Medeiros, Jana Ovciarikova, Xianhe Li, Patrick Krueger, Tim Bartsch, Silvia Reato, John C Crow, Michelle Tellez Sutterlin, Bruna Martins Garcia, Irina Rais, Kira Allmeroth, Matías D Hartman, Martin S Denzel, Martin Purrio, Andrea Mesaros, Kit-Yi Leung, Nicholas D E Greene, Lilach Sheiner, Patrick Giavalisco, Lena Pernas.
      As major consumers of cellular metabolites, mitochondria are poised to compete with invading microbes for the nutrients that they need to grow. Whether cells exploit mitochondrial metabolism to protect from infection is unclear. In this work, we found that the activating transcription factor 4 (ATF4) activates a mitochondrial defense based on the essential B vitamin folate. During infection of cultured mammalian cells with the intracellular pathogen Toxoplasma gondii, ATF4 increased mitochondrial DNA levels by driving the one-carbon metabolism processes that use folate in mitochondria. Triggered by host detection of mitochondrial stress induced by parasite effectors, ATF4 limited Toxoplasma access to folates required for deoxythymidine monophosphate synthesis, thereby restricting parasite growth. Thus, ATF4 rewires mitochondrial metabolism to mount a folate-based metabolic defense against Toxoplasma.
    DOI:  https://doi.org/10.1126/science.adr6326
  2. Elife. 2025 Aug 11. pii: RP89225. [Epub ahead of print]12
    Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics.
    Raymond Laboy, Marjana Ndoci, Shamsh Tabrez Syed, Maximilian Vonolfen, Eugen Ballhysa, Tim Droth, Klara Schilling, Anna Loehrke, Ilian Atanassov, Adam Antebi.
      The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in Caenorhabditis elegans. These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism. Here, we found that knockdown of various glucose metabolic enzymes decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as the most vigorous regulators of MML-1 function. Upon hexokinase knockdown, MML-1 redistributes to mitochondria and lipid droplets (LDs), and concomitantly, transcriptional targets are downregulated and germline longevity is abolished. Further, we found that hxk-1 regulates MML-1 through mitochondrial β-oxidation, while hxk-2 regulates MML-1 by modulating the pentose phosphate pathway (PPP) and its coordinated association with LDs. Similarly, inhibition of the PPP rescues mammalian MondoA nuclear translocation and transcriptional function upon starvation. These studies reveal how metabolic signals and organellar communication regulate a key convergent metabolic transcription factor to promote longevity.
    Keywords:  C. elegans; MML-1; MondoA; cell biology; hexokinase; human; longevity; metabolism
    DOI:  https://doi.org/10.7554/eLife.89225
  3. Nat Commun. 2025 Aug 15. 16(1): 7621
    Respiration defects limit serine synthesis required for lung cancer growth and survival.
    Eduardo Cararo Lopes, Fuqian Shi, Akshada Sawant, Maria Ibrahim, Maria Gomez-Jenkins, Zhixian Hu, Pranav Manchiraju, Vrushank Bhatt, Wenping Wang, Christian S Hinrichs, Douglas C Wallace, Xiaoyang Su, Joshua D Rabinowitz, Chang S Chan, Jessie Yanxiang Guo, Shridar Ganesan, Edmund C Lattime, Eileen White.
      Mitochondrial function supports energy and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations impair these processes, causing mitochondrial diseases. Their role in human cancers is less clear; while some cancers harbor high mtDNA mutation burden, others do not. Here we show that a proofreading mutant of DNA polymerase gamma (PolGD256A) increases the mtDNA mutation burden in non-small-cell lung cancer (NSCLC). This mutation promotes the accumulation of defective mitochondria, reduces tumor cell proliferation and viability, and improves cancer survival. In NSCLC, pathogenic mtDNA mutations enhance glycolysis and create a glucose dependency to support mitochondrial energy, but at the expense of a lower NAD+/NADH ratio that hinders de novo serine synthesis. Thus, mitochondrial function in NSCLC is essential for maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for tumor growth, explaining why these cancers preserve functional mtDNA.
    DOI:  https://doi.org/10.1038/s41467-025-62911-7
  4. Free Radic Res. 2025 Aug 14. 1-20
    Mitochondria and redox homeostasis - the backseat drivers in glioma.
    Shruti Patrick, Ellora Sen.
      Mitochondrial function and redox regulatory processes are crucial aspects of cellular metabolism and energy production. Cancers, including gliomas, largely exhibit altered mitochondrial function, which can lead to changes in cellular signaling pathways and redox homeostasis. Aberrant redox signaling can promote glioma progression by influencing cell proliferation, metastasis and therapeutic response. Several cancer-associated driver mutations - genetic alterations that confer survival and growth advantage to cancer cells, are associated with gliomas and affect mitochondrial function and redox states. Here is an overview of the crucial intersection between mitochondrial function and driver genes in glioma, highlighting some of the recent advances that augment our understanding of this intersection.
    Keywords:  Cancer drivers; Driver mutations; Glioma; Mitochondria; Redox homeostasis
    DOI:  https://doi.org/10.1080/10715762.2025.2548479
  5. Nat Metab. 2025 Aug 14.
    Species-specific serine metabolism differentially controls natural killer cell functions.
    Joey H Li, Qinyan Feng, Andréa B Ball, Cassidy D Lee, Michelle L Wallerius, Jan G Bormin, Edmund D Kapelczak, Wesley R Armstrong, Leen Hermans, Abigail Krall, Nedas Matulionis, Tara TeSlaa, Heather R Christofk, Ajit S Divakaruni, Timothy E O'Sullivan.
      Immune cells undergo rapid metabolic reprogramming to fuel effector responses. However, whether the metabolic pathways that supply these functions differ between human and mouse immune cells is poorly understood. Using a comparative metabolomics approach, here we show both conserved and species-distinct metabolite alterations in cytokine-activated primary human and mouse natural killer (NK) cells. Activated human NK cells fail to perform de novo serine synthesis, resulting in broadly impaired effector functions when serine starved ex vivo or during in vivo dietary serine restriction, limiting their antitumour function. In contrast, activated mouse NK cells perform de novo serine synthesis to fuel one-carbon metabolism and proliferation, resulting in increased metabolic flexibility during ex vivo and dietary serine restriction. While NK cells from both species require one-carbon metabolism to proliferate and produce interferon-γ, GCLC-dependent glutathione synthesis tunes cytotoxic versus inflammatory function in human NK cells. Thus, activated NK cell functions display species-specific requirements for serine metabolism, and environmental serine availability dictates activated human NK cell functions.
    DOI:  https://doi.org/10.1038/s42255-025-01348-0
  6. Nat Aging. 2025 Aug;5(8): 1425-1440
    Metabolic regulation of immunological aging.
    Hee-Hoon Kim, Vishwa Deep Dixit.
      All biological activities require energy through the intake and generation of metabolites. After reproductive age, altered metabolism, together with cellular and molecular perturbations in the immune system, are linked to organismal functional decline. Unresolved chronic inflammation originating from innate immune cells and loss of naive T cells with restriction of T cell receptor repertoire diversity emanating from age-related thymic involution are some of the mechanisms that limit healthspan and even lifespan. Here, we provide an overview of the hallmarks of immunological aging and synthesize how the immune system, coupled to cellular and organismal metabolism, controls disease susceptibility. Furthermore, we highlight the potential unifying immunometabolic mechanisms of various genetic, pharmacological and dietary interventions that may underlie lifespan-healthspan extension. Given that immune and metabolic systems are modifiable and targetable, understanding the role of myriads of organ-resident immune cells and the underlying metabolic mechanisms that cause dysfunction can have transformational potential for the health of older adults.
    DOI:  https://doi.org/10.1038/s43587-025-00921-2
  7. Nat Rev Cancer. 2025 Aug 14.
    Ageing, immune fitness and cancer.
    Melissa Dolan, Kendra A Libby, Alison E Ringel, Peter van Galen, Sandra S McAllister.
      The immune system undergoes substantial changes throughout life, with ageing broadly impacting immune cell composition, function and regenerative capacity. Emerging evidence suggests that age-associated changes in immune fitness - the ability to respond to and eliminate infection, pathogens and malignancy while maintaining self-tolerance - reshape antitumour immunity and influence the efficacy of immunotherapies. Technological advances in high-dimensional immunoprofiling have begun to reveal the complex interplay between ageing, immune fitness and cancer biology, uncovering new therapeutic vulnerabilities and challenges. In this Review, we discuss recent insights derived from age-resolved immunoprofiling of the human tumour microenvironment, how ageing haematopoiesis affects immune cells that contribute to the microenvironment and impact cancer progression, and what is known from preclinical modelling about the functional consequences of immune ageing on tumour control. We further highlight emerging age-stratified analyses of treatment responses, which are beginning to inform hypotheses about how ageing shapes immunotherapy outcomes. Together, these perspectives provide a framework for integrating age as a critical biological variable, underscore the need to consider age in both preclinical models and clinical trial design, and identify key challenges and priorities for the field moving forward.
    DOI:  https://doi.org/10.1038/s41568-025-00858-z
  8. Nature. 2025 Aug 13.
    Clone copy number diversity is linked to survival in lung cancer.
    Piotr Pawlik, Kristiana Grigoriadis, Abigail Bunkum, Helena Coggan, Alexander M Frankell, Carlos Martinez-Ruiz, Takahiro Karasaki, Ariana Huebner, Andrew Rowan, Jasmin Fisher, Allan Hackshaw, Charles Swanton, Simone Zaccaria, Nicholas McGranahan.
      Both single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) accumulate in cancer cells during tumour development, fuelling clonal evolution. However, accurate estimation of clone-specific copy numbers from bulk DNA-sequencing data is challenging. Here we present allele-specific phylogenetic analysis of copy number alterations (ALPACA), a method to infer SNV and SCNA coevolution by leveraging phylogenetic trees reconstructed from multi-sample bulk tumour sequencing data using SNV frequencies. ALPACA estimates the SCNA evolution of simulated tumours with a higher accuracy than current state-of-the-art methods1-4. ALPACA uncovers loss-of-heterozygosity and amplification events in minor clones that may be missed using standard approaches and reveals the temporal order of somatic alterations. Analysing clone-specific copy numbers in TRACERx421 lung tumours5,6, we find evidence of increased chromosomal instability in metastasis-seeding clones and enrichment for losses affecting tumour suppressor genes and amplification affecting CCND1. Furthermore, we identify increased SCNA rates in both tumours with polyclonal metastatic dissemination and tumours with extrathoracic metastases, and an association between higher clone copy number diversity and reduced disease-free survival in patients with lung cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09398-w
  9. Nat Metab. 2025 Aug 12.
    D-cysteine impairs tumour growth by inhibiting cysteine desulfurase NFS1.
    Joséphine Zangari, Oliver Stehling, Sven A Freibert, Kaushik Bhattacharya, Florian Rouaud, Veronique Serre-Beinier, Kinsey Maundrell, Sylvie Montessuit, Sabrina Myriam Ferre, Evangelia Vartholomaiou, Vinzent Schulz, Karim Zuhra, Víctor González-Ruiz, Sahra Hanschke, Takashi Tsukamoto, Michaël Cerezo, Csaba Szabo, Serge Rudaz, Michal T Boniecki, Miroslaw Cygler, Roland Lill, Jean-Claude Martinou.
      Selective targeting of cancer cells is a major challenge for cancer therapy. Many cancer cells overexpress the cystine/glutamate antiporter xCT/CD98, an L-cystine transport system that strengthens antioxidant defences, thereby promoting tumour survival and progression. Here, we show that the D-enantiomer of cysteine (D-Cys) is selectively imported into xCT/CD98-overexpressing cancer cell lines and impairs their proliferation, particularly under high oxygen concentrations. Intracellular D-Cys specifically inhibits the mitochondrial cysteine desulfurase NFS1, a key enzyme of cellular iron-sulfur protein biogenesis, by blocking sulfur mobilization due to steric constraints. NFS1 inhibition by D-Cys affects all cellular iron-sulfur cluster-dependent functions, including mitochondrial respiration, nucleotide metabolism and maintenance of genome integrity, leading to decreased oxygen consumption, DNA damage and cell cycle arrest. D-Cys administration diminishes tumour growth of human triple-negative breast cancer cells implanted orthotopically into the mouse mammary gland. Hence, D-Cys could represent a simple therapy to selectively target those forms of cancer characterized by overexpression of xCT/CD98.
    DOI:  https://doi.org/10.1038/s42255-025-01339-1
  10. Autophagy. 2025 Aug 11.
    A novel mitochondrial regulon for ferroptosis during fungal pathogenesis.
    Qing Shen, Madiha Natchi Samu Shihabdeen, Fan Yang, Naweed I Naqvi.
      Ferroptosis remains an underexamined iron- and lipid peroxides-driven cell death modality despite its importance to several human and plant diseases and to immunity thereof. Here, we utilized chemical cell biology, molecular genetics and biochemical analyses to gain insights into how the fungal pathogen Magnaporthe oryzae undergoes ferroptosis strictly in the spore cells to successfully transit to infectious development. We reveal a complex functional interdependency and crosstalk between intrinsic ferroptosis and autophagy-mediated mitochondrial degradation. Mechanistically, the requirement of mitophagy for ferroptotic cell death was attributed to its ability to maintain a pool of metabolically active mitochondria. Pharmacological disruption of the electron transport chain or membrane potential led to complete inhibition of ferroptosis, thus simulating the loss of mitophagy phenotypes. Conversely, increased mitochondrial membrane potential in a mitophagy-defective mutant alleviated the ferroptosis defects therein. Graded inhibition of mitochondrial coenzyme Q biosynthesis with or without ferroptosis inhibitor liproxstatin-1 distinguished its antioxidant function in such regulated cell death. Membrane potential-dependent regulation of ATP synthesis and iron homeostasis, as well as dynamics of tricarboxylic acid cycle enzyme AcoA (aconitase A) in the presence or absence of mitophagy, mitochondrial poisoning or iron chelation further linked mitochondrial metabolism to ferroptosis. Last, we present an important bioenergetics- and redox-based mitochondrial regulon essential for intrinsic ferroptosis and its precise role in fungal pathogenesis leading up to the establishment of the devastating rice blast disease.
    Keywords:  Cell death; coenzyme Q; iron; mitochondrial metabolism; mitophagy; rice blast
    DOI:  https://doi.org/10.1080/15548627.2025.2546944
  11. J Cell Sci. 2025 Aug 15. pii: jcs264018. [Epub ahead of print]138(16):
    Energy deprivation in youth and old age.
    Michael Stern.
      In youth, energy deprivation primarily results from fasting. Because inconsistent nutrient availability is common for most organisms, natural selection has provided mechanisms that detect nutrient-deprived states, followed by adaptive responses that increase the likelihood of survival until nutrients are restored. Organisms respond to fasting first by oxidizing the cellular cytoplasm, then by activating redox-sensitive kinases - namely the c-Jun N-terminal kinases (henceforth collectively termed JNK) and AMP-activated protein kinase (AMPK) - and Foxo transcription factors (henceforth referred to collectively as Foxo). Together, JNK, AMPK and Foxo induce autophagy. This fasting response is beneficial because autophagy supplies substrates for metabolism that replace missing nutrients and enhances removal of damaged organelles such as mitochondria, which increases lifespan and enhances survival through the fast. Although this response is adaptive in the context of acute nutrient deprivation, it can have harmful consequences when activated chronically. Here, I propose that cells from old organisms are constitutively energy deprived because of lifetime accumulation of dysfunctional mitochondria. As a result, these cells reactivate the fasting response seen in youth. Hence, old organisms constitutively oxidize the cellular cytoplasm and activate JNK, AMPK, Foxo and, finally, autophagy. However, because energy deprivation in old age is driven by mitochondrial insufficiency rather than nutrient deprivation, this response fails to restore ATP production and becomes chronic and deleterious. I suggest that many age-related pathologies, such as oxidative stress, neurodegeneration and sarcopenia, result from aberrant activation of the fasting response.
    Keywords:  Aging; Autophagy; Nutrient deprivation; Oxidative Stress; Signal transduction
    DOI:  https://doi.org/10.1242/jcs.264018
  12. Acta Cytol. 2025 Aug 14. 1-9
    Mitochondria and the Metabolic Logic of Oncocytic Tumours.
    Valdemar Máximo, Vania Nosé, Sule Canberk.
      Oncocytic tumors, long recognized for their distinctive granular cytoplasm, have historically posed challenges to classical cancer models due to their enigmatic molecular profiles and exceptional mitochondrial burden. This review revisits the path from the early histological discovery of mitochondria to their central role in modern metabolic theories of oncogenesis. Drawing parallels between mitochondrial history and oncocytic tumor pathology, we explore how mitochondrial dysfunction, rather than nuclear genomic instability, may underlie the oncocytic phenotype. Revisiting the Somatic Mutation Theory (SMT) alongside the emerging Mitochondrial Metabolic Theory (MMT), we highlight the explanatory potential of mitochondrial bioenergetic disruption in tumorigenesis. Despite being rich in structurally abnormal mitochondria, oncocytic tumors, particularly in the thyroid, remain underrepresented in mainstream metabolic cancer models. By integrating insights from historical cytology, modern pathology, and molecular oncology, this article proposes that oncocytic neoplasms serve as morphologically overt and biochemically aligned exemplars of MMT, underlining the need for deeper cross-disciplinary dialogue. This contribution lays the conceptual groundwork for the organ-specific studies featured in this special issue, positioning oncocytic tumors as both diagnostic challenges and metabolic sentinels in cancer biology.
    DOI:  https://doi.org/10.1159/000547939
  13. bioRxiv. 2025 Jul 14. pii: 2025.07.11.664440. [Epub ahead of print]
    RICTOR regulates an interspecies crosstalk that influences longevity through a novel methionine cycle-mitophagy axis.
    Simran Motwani, Somya Bhandari, Shivani Chitkara, Rajat Ujjainiya, Shantanu Sengupta, Arnab Mukhopadhyay.
      Adaptive modulation of physiological traits in response to environmental variability, particularly dietary fluctuations, is essential for organismal fitness. Such adaptability is governed by complex gene-diet interactions, yet the molecular circuits integrating microbe-derived metabolites with host metabolic and stress response pathways remain less explored. Here, we identify the conserved mechanistic target of rapamycin complex 2 (mTORC2) component, RICTOR, as a critical regulator of dietary plasticity in Caenorhabditis elegans , specifically in response to bacterially derived vitamin B12 (B12). Loss of rict-1 , the C. elegans ortholog of RICTOR, confers enhanced osmotic stress tolerance and longevity on B12-rich bacterial diets. These phenotypic adaptations require two B12-dependent enzymes: methionine synthase (METR-1), functioning in the folate-methionine cycle (Met-C), and methylmalonyl-CoA mutase (MMCM-1), a mitochondrial enzyme essential for propionate catabolism. The latter catalyzes the formation of succinyl-CoA, subsequently converted to succinate via the tricarboxylic acid (TCA) cycle. Elevated succinate levels were found to induce mitochondrial fragmentation, thereby activating mitophagy, an autophagic process indispensable for the increased stress resilience and longevity observed in the rict-1 mutants. Crucially, this Met-C-mitophagy axis is modulated by microbial inputs, with B12 and methionine acting as proximal dietary signals. Our findings delineate a mechanistic framework through which RICTOR restrains host sensitivity to microbial-derived metabolites, thus maintaining mitochondrial homeostasis and regulating lifespan. This work reveals a pivotal role for RICTOR in insulating host physiology from environmental nutrient-driven perturbations by modulating organellar quality control pathways.
    DOI:  https://doi.org/10.1101/2025.07.11.664440
  14. bioRxiv. 2025 Aug 05. pii: 2025.08.04.668575. [Epub ahead of print]
    RNA triggers chronic stress during neuronal aging.
    Kevin Rhine, Elle Epstein, Natasha M Carlson, Xuezhen Ge, Orel Mizrahi, Anika Kamat, Anita Hermann, William R Brothers, John Ravits, Eric J Bennett, Gülçin Pekkurnaz, Gene W Yeo.
      Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might contribute to aging and neurodegeneration. Here, we leverage directed transdifferentiation of human fibroblasts into aged neurons to determine the source of ISR activation. We demonstrate that increased accumulation of cytoplasmic double-stranded RNA (dsRNA) activates the eIF2α kinase PKR, which in turn triggers the ISR in aged neurons and leads to sequestration of dsRNA in stress granules. Aged neurons accumulate endogenous mitochondria-derived dsRNA that directly binds to PKR. This mitochondrial dsRNA leaks through damaged mitochondrial membranes and forms cytoplasmic foci in aged neurons. Finally, we demonstrate that PKR inhibition leads to the cessation of stress, resumption of cellular translation, and restoration of RNA-binding protein expression. Together, our results identify a source of RNA stress that destabilizes aged neurons and may contribute to neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.08.04.668575
  15. Nat Commun. 2025 Aug 15. 16(1): 7595
    MacroD1 sustains mitochondrial integrity and oxidative metabolism.
    Ann-Katrin Hopp, Lorenza P Ferretti, Lisa Schlicker, Amalia Ruiz-Serrano, Udo Hetzel, Francesco Prisco, Anja Kipar, Lukas Muskalla, Elena Ferrari, Carsten C Scholz, Karsten Hiller, Francisco Verdeguer, Deena M Leslie Pedrioli, Michael O Hottiger.
      The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-62410-9
  16. Mol Biol Cell. 2025 Aug 13. mbcE25030128
    Mitochondrial dysfunction and lipid dysregulation in yeast lacking phosphatidylserine.
    Alaumy Joshi, Zakery N Baker, Rachel A Stanfield, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Mitochondrial membrane phospholipids impact mitochondrial structure and function by influencing the assembly and activity of membrane proteins. While the specific roles of the three most abundant mitochondrial phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL), have been extensively studied, the precise function of less abundant phosphatidylserine (PS) is not yet determined. Here, we used genetic and nutritional manipulation to engineer a set of yeast mutants, including a mutant completely devoid of PS, to assess its role in mitochondrial bioenergetics and lipid homeostasis. To circumvent the confounding effect of downstream PS products, PE and PC, we exogenously supplied ethanolamine that allows their biosynthesis via an alternate pathway. Using this system, we demonstrate that PS does not impact the abundance or the assembly of mitochondrial respiratory chain complexes; however, mitochondrial respiration is impaired. PS-lacking mitochondria cannot maintain mitochondrial membrane potential and exhibit leaky membranes. A mass spectrometry-based analysis of the cellular and mitochondrial lipidomes revealed an unexpected increase in odd-chain fatty acid-containing lipids in PS-lacking cells that may impact mitochondrial bioenergetics. Our study uncovers novel roles of PS in mitochondrial membrane biogenesis and bioenergetics and provides a viable eukaryotic system to unravel the cellular functions of PS.
    DOI:  https://doi.org/10.1091/mbc.E25-03-0128
  17. Nat Metab. 2025 Aug 13.
    Resolving early embryonic metabolism in Drosophila through single-embryo metabolomics and transcriptomics.
    J Eduardo Pérez-Mojica, Zachary B Madaj, Christine Isaguirre, Joe Roy, Kin H Lau, Ryan D Sheldon, Adelheid Lempradl.
      Early embryonic development marks a shift from maternal factor reliance to zygotic control. Although transcriptional regulation during this period is well characterized, concurrent metabolic events remain largely unknown. Progress has been limited by technical challenges in analysing the small amounts of material and the rapid progression of development. Here, we present a high-resolution, single-embryo multi-omics dataset that captures transcriptional and metabolic dynamics during the first 3 h of Drosophila development. By profiling individual embryos, we uncover stage-specific transcriptional and metabolic programmes, including previously unrecognized transitions in nucleotides, amino acids and other metabolites. Integration of metabolites and transcript modules reveals a limited, selective functional coupling between metabolism and gene expression. This work reframes the maternal-to-zygotic transition as both a transcriptional and metabolic handoff and provides a valuable framework for studying metabolic regulation during development and beyond.
    DOI:  https://doi.org/10.1038/s42255-025-01351-5
  18. Sci Adv. 2025 Aug 15. 11(33): eadr6012
    Complex II assembly drives metabolic adaptation to OXPHOS dysfunction.
    Roopasingam Kugapreethan, Sheik Nadeem Elahee Doomun, Joanna Sacharz, Ann E Frazier, Tanavi Sharma, Yau Chung Low, Shuai Nie, Michael G Leeming, Linden Muellner-Wong, Karena Last, Tegan Stait, David P De Souza, David R Thorburn, Malcolm J McConville, David A Stroud.
      During acute oxidative phosphorylation (OXPHOS) dysfunction, reversal of succinate dehydrogenase (complex II) maintains the redox state of the Coenzyme Q (Q)-pool by using fumarate as terminal electron acceptor in certain tissues and cell lines. We identified the action of SDHAF2 protein, a complex II assembly factor, as critical for metabolic adaptation during complex III dysfunction in HEK293T cells. SDHAF2 loss during complex III inhibition led to a net reductive TCA cycle from loss of succinate oxidation, loss of SDHA active site-derived reactive oxygen species (ROS) signaling, insufficient glycolytic adaptation, and a severe growth impairment. Glycolysis adapted cells, however, did not accumulate SDHAF2 upon Q-pool stress, exhibited a net reductive TCA cycle and mild growth phenotypes regardless of SDHAF2 presence. Thus, our study reveals how complex II assembly controls a balance between dynamics of TCA cycle directionality, protection from Q-pool stress, and an ability to use ROS-meditated signaling to overcome acute OXPHOS dysfunction in cells reliant on mitochondrial respiration.
    DOI:  https://doi.org/10.1126/sciadv.adr6012
  19. Nat Immunol. 2025 Aug 13.
    Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.
    Steven B Wells, Daniel B Rainbow, Michal Mark, Peter A Szabo, Can Ergen, Daniel P Caron, Ana Raquel Maceiras, Elior Rahmani, Eli Benuck, Valeh Valiollah Pour Amiri, David Chen, Allon Wagner, Sarah K Howlett, Lorna B Jarvis, Karen L Ellis, Masaru Kubota, Rei Matsumoto, Krishnaa Mahbubani, Kouresh Saeb-Parsy, Cecilia Dominguez Conde, Laura Richardson, Chuan Xu, Shuang Li, Lira Mamanova, Liam Bolt, Alicja Wilk, Sarah A Teichmann, Donna L Farber, Peter A Sims, Joanne L Jones, Nir Yosef.
      The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.
    DOI:  https://doi.org/10.1038/s41590-025-02241-4
  20. Nat Cell Biol. 2025 Aug;27(8): 1201
    Metabolic regulation of RIPK1.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-025-01742-6
  21. Nature. 2025 Aug 13.
    Multiple oestradiol functions inhibit ferroptosis and acute kidney injury.
    Wulf Tonnus, Francesca Maremonti, Shubhangi Gavali, Marlena Nastassja Schlecht, Florian Gembardt, Alexia Belavgeni, Nadja Leinung, Karolin Flade, Natalie Bethe, Sofia Traikov, Anne Haag, Danny Schilling, Sider Penkov, Melodie Mallais, Christine Gaillet, Claudia Meyer, Melika Katebi, Anushka Ray, Louisa M S Gerhardt, Anne Brucker, Jorunn Naila Becker, Mirela Tmava, Lisa Schlicker, Almut Schulze, Nina Himmerkus, Andrej Shevchenko, Mirko Peitzsch, Uladzimir Barayeu, Sonia Nasi, Juliane Putz, Kenneth S Korach, Joel Neugarten, Ladan Golestaneh, Christian Hugo, Jan Ulrich Becker, Joel M Weinberg, Svenja Lorenz, Bettina Proneth, Marcus Conrad, Eckhard Wolf, Bernd Plietker, Raphaël Rodriguez, Derek A Pratt, Tobias P Dick, Maria Fedorova, Stefan R Bornstein, Andreas Linkermann.
      Acute tubular necrosis mediates acute kidney injury (AKI) and nephron loss1, the hallmark of end-stage renal disease2-4. For decades, it has been known that female kidneys are less sensitive to AKI5,6. Acute tubular necrosis involves dynamic cell death propagation by ferroptosis along the tubular compartment7,8. Here we demonstrate abrogated ferroptotic cell death propagation in female kidney tubules. 17β-oestradiol establishes an anti-ferroptotic state through non-genomic and genomic mechanisms. These include the potent direct inhibition of ferroptosis by hydroxyoestradiol derivatives, which function as radical trapping antioxidants, are present at high concentrations in kidney tubules and, when exogenously applied, protect male mice from AKI. In cells, the oxidized hydroxyoestradiols are recycled by FSP19,10, but FSP1-deficient female mice were not sensitive to AKI. At the genomic level, female ESR1-deficient kidney tubules partially lose their anti-ferroptotic capacity, similar to ovariectomized mice. While ESR1 promotes the anti-ferroptotic hydropersulfide system, male tubules express pro-ferroptotic proteins of the ether lipid pathway which are suppressed by ESR1 in female tissues until menopause. In summary, we identified non-genomic and genomic mechanisms that collectively explain ferroptosis resistance in female tubules and may function as therapeutic targets for male and postmenopausal female individuals.
    DOI:  https://doi.org/10.1038/s41586-025-09389-x
  22. Open Biol. 2025 Aug;15(8): 240202
    Selective loss of ATP carriers in favour of SLC25A43 orthologues in metamonad mitochondria adapted to anaerobiosis.
    Natalia Janowicz, Vít Dohnálek, Justyna Zítek, Priscila Peña-Diaz, Eva Pyrihová, Martin S King, Michaela Husová, Vojtěch Žárský, Edmund Kunji, Alena Zikova, Vladimír Hampl, Pavel Dolezal.
      Metamonada is a eukaryotic supergroup of free-living and parasitic anaerobic protists. Their characteristic feature is the presence of highly reduced mitochondria that have lost the ability to produce ATP by oxidative phosphorylation and in some cases even by substrate phosphorylation, with all ATP being imported from the cytosol. Given this striking difference in cellular ATP metabolism when compared to aerobic mitochondria, we studied the presence of mitochondrial carrier proteins (MCPs) mediating the transport of ATP across the inner mitochondrial membrane. Our bioinformatic analyses revealed remarkable reduction of MCP repertoire in Metamonada with striking loss of the major ADP/ATP carrier (AAC). Instead, nearly all species retained carriers orthologous to human SLC25A43 protein, a little-characterized MCP. Heterologous expression of metamonad SLC25A43 carriers confirmed their mitochondrial localization, and functional analysis revealed that SLC25A43 orthologues represent a distinct group of ATP transporters, which we designate as ATP-importing carriers (AIC). Together, our findings suggest that AIC facilitate the ATP import into highly reduced anaerobic mitochondria, compensating for their diminished or absent energy metabolism.
    Keywords:  ADP/ATP carrier; Metamonada; SLC25A43; mitochondrial carrier protein; mitochondrial evolution; mitochondrion-related organelle
    DOI:  https://doi.org/10.1098/rsob.240202
  23. Exp Mol Med. 2025 Aug 14.
    Uridine as a hub in cancer metabolism and RNA biology.
    Kyoung-Min Choi, Brennon A Berard, Je-Hyun Yoon, Dohoon Kim.
      Uridine is the ubiquitous nucleoside form of the RNA base uracil. It occupies a prominent 'hub' position in energy metabolism; for example, it is metabolically linked to de novo pyrimidine biosynthesis and glycolysis and biologically linked to diverse processes, such as RNA synthesis/degradation and glycosylation. It is a vital interorgan 'currency' nutrient readily imported by mammalian cells, and its supplementation can exert both cytoprotective and toxic effects, for which the underlying mechanisms are poorly understood. Importantly, it is a route by which the decay of RNA can be repurposed as an alternative fuel source under nutrient-limiting conditions to aid in tumor initiation, development and metastasis. Here we explain how the upstream inputs and downstream metabolic fates of uridine influence cancer traits and illustrate both established and hypothetical strategies targeting uridine metabolism for cancer therapy.
    DOI:  https://doi.org/10.1038/s12276-025-01402-7
  24. Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]
    Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
    Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.
      Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.
    Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
  25. Nat Commun. 2025 Aug 14. 16(1): 7566
    Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions.
    Yuan-Hung Lo, Hudson T Horn, Mo-Fan Huang, Wei-Chieh Yu, Chia-Mei Young, Qing Liu, Madeline Tomaske, Martina Towers, Antonia Dominguez, Michael C Bassik, Dung-Fang Lee, Lei S Qi, Jonathan S Weissman, Jin Chen, Calvin J Kuo.
      Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the level of individual cells and uncover an unexpected link between fucosylation and cisplatin sensitivity. We identify TAF6L as a regulator of cell recovery from cisplatin-induced cytotoxicity. These results highlight the utility of human organoid models for dissecting gene-drug interactions and offer insights into therapeutic vulnerabilities in gastric cancer.
    DOI:  https://doi.org/10.1038/s41467-025-62818-3
  26. Nat Cell Biol. 2025 Aug;27(8): 1208-1209
    The liver metabolizes dietary galactose to fuel antitumour T cell immunity.
      
    DOI:  https://doi.org/10.1038/s41556-025-01717-7
  27. Mol Biol Cell. 2025 Aug 13. mbcE21070359
    A growing problem: the many unsolved mysteries of cell growth.
    Douglas R Kellogg.
      Growth is the essential vital process that drives life forward and always occurs within cells. Cell growth fuels the cell divisions that drive proliferation of single-celled organisms and growth of multi-cellular organisms. Mechanisms that control the extent and location of growth within cells generate the extraordinary diversity of cell sizes and shapes seen across the tree of life and within the human body, and nearly all cancers show profound defects in control of cell growth that lead to severe aberrations in cell size and shape. Yet we know little about how cell growth occurs or how it is controlled. For decades we have known how basic building blocks such as amino acids and lipids are built, but an enormous gap has always remained in our understanding of how these building blocks are used to build out cells of highly diverse sizes and shapes under varying environmental conditions and in diverse developmental contexts. Given the fundamental importance of growth in biology and cancer, our minimal understanding of cell growth is a growing problem. Here, a few of the intriguing and important questions about cell growth are considered.
    DOI:  https://doi.org/10.1091/mbc.E21-07-0359
  28. Nephrol Dial Transplant. 2025 Aug 11. pii: gfaf137. [Epub ahead of print]
    CKDx: Simplicity matters, implementation is key.
    Emilie Cornec-Le Gall, Jan Halbritter, Roman Ulrich Müller.
      
    DOI:  https://doi.org/10.1093/ndt/gfaf137
  29. Cell. 2025 Aug 07. pii: S0092-8674(25)00811-6. [Epub ahead of print]
    Principles of cotranslational mitochondrial protein import.
    Zikun Zhu, Saurav Mallik, Taylor A Stevens, Riming Huang, Emmanuel D Levy, Shu-Ou Shan.
      Nearly all mitochondrial proteins are translated on cytosolic ribosomes. How these proteins are subsequently delivered to mitochondria remains poorly understood. Using selective ribosome profiling, we show that nearly 20% of mitochondrial proteins can be imported cotranslationally in human cells. Cotranslational import requires an N-terminal presequence on the nascent protein and contributes to localized translation at the mitochondrial surface. This pathway does not favor membrane proteins but instead prioritizes large, multi-domain, topologically complex proteins, whose import efficiency is enhanced when targeted cotranslationally. In contrast to the early onset of cotranslational protein targeting to the endoplasmic reticulum (ER), the presequence on mitochondrial proteins is inhibited from initiating targeting early during translation until a large globular domain emerges from the ribosome. Our findings reveal a multi-layered protein sorting strategy that controls the timing and specificity of mitochondrial protein targeting.
    Keywords:  NAC; TOM complex; cotranslational protein import; localized translation; mitochondria; mitochondrial targeting sequence; nascent polypeptide-associated complex; protein folding; protein targeting; ribosome profiling
    DOI:  https://doi.org/10.1016/j.cell.2025.07.021
  30. bioRxiv. 2025 Aug 06. pii: 2025.08.04.668533. [Epub ahead of print]
    Exoproteome of calorie-restricted humans identifies complement deactivation as an immunometabolic checkpoint reducing inflammaging.
    Manish Mishra, Hee-Hoon Kim, Yun-Hee Youm, Elsie Gonzalez-Hurtado, Konstantin Zaitsev, Tamara Dlugos, Irina Shchukina, Christy Gliniak, Eric Ravussin, Subhasis Mohanty, Albert C Shaw, Philipp E Scherer, Maxim N Artyomov, Vishwa Deep Dixit.
      Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.
    DOI:  https://doi.org/10.1101/2025.08.04.668533
  31. Cancer Lett. 2025 Aug 09. pii: S0304-3835(25)00547-6. [Epub ahead of print] 217977
    Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.
    Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen.
      Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. Furthermore, pyruvate dehydrogenase kinases 1 (PDK1) was upregulated in KO cells, leading to the inactivation of the tricarboxylic acid (TCA) cycle enzyme, pyruvate dehydrogenase (PDH). This metabolic shift towards glycolytic metabolism resulted in increased glycolytic metabolism, elevated lactic acid production, and higher glucose consumption, making TRAP1-depleted cancer cells more dependent on this altered metabolism for survival. Treatment with DCA, a PDK inhibitor, restored PDH activity, exacerbated oxidative stress, and increased cell death in KO cells. Our study here sheds light on how TRAP1 depletion affects metabolic plasticity, driving colon cancer cells to adapt to metabolic and oxidative stress. These findings highlight TRAP1 as a promising therapeutic target for manipulating metabolic plasticity and overcoming drug resistance in cancer therapy.
    Keywords:  HIF1A; Metabolism; PDH; ROS; TRAP1; mitochondria
    DOI:  https://doi.org/10.1016/j.canlet.2025.217977
  32. Nat Immunol. 2025 Aug 13.
    Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt.
    Bishan Bhattarai, Alina Ulezko Antonova, Jose L Fachi, Leone S Hopkins, Matthew V D McCullen, Ankita Saini, Sarah de Oliveira, Wandy L Beatty, Erik S Musiek, Vijay K Kuchroo, Mitchell A Lazar, Eugene M Oltz, Marco Colonna.
      The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a -2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.
    DOI:  https://doi.org/10.1038/s41590-025-02240-5
  33. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  34. bioRxiv. 2025 Jul 14. pii: 2025.07.09.663994. [Epub ahead of print]
    MetaSage: Machine Learning-Based Prioritization of Metabolic Regulators from Multi-Omics Data.
    Chenwei Wang, John M Elizarraras, Bing Zhang.
      Dysregulation of metabolites is a hallmark of cancer, yet the underlying regulatory mechanisms remain poorly understood. To systematically explore metabolic regulation across cancers, we developed an XGBoost-based machine learning pipeline, MetaSage, that integrates context-agnostic knowledge graph with multi-omics datasets. Using harmonized data from 15 cohorts spanning 11 cancer types, we identified 442 variable metabolites and found that both genes and upstream metabolites showed comparable regulatory influence. Predictable metabolites, defined by a significant correlation between predicted and measured levels, were identified using our pipeline and varied widely across cohorts-partially due to the batch effect. For each predictable metabolite, key regulatory features were determined using Shapley values. This yielded 1,146 gene features and 363 precursor metabolites as important regulators. Network analysis of 22 recurrent metabolites revealed a mix of conserved and cancer type-specific regulatory patterns. Our framework enables robust discovery of metabolite regulation and therapeutic insights in cancer.
    DOI:  https://doi.org/10.1101/2025.07.09.663994
  35. Int J Mol Sci. 2025 Aug 07. pii: 7654. [Epub ahead of print]26(15):
    The Loss of Complex I in Renal Oncocytoma Is Associated with Defective Mitophagy Due to Lysosomal Dysfunction.
    Lin Lin, Neal Patel, Lucia Fernandez-Del-Rio, Cristiane Benica, Blake Wilde, Eirini Christodoulou, Shinji Ohtake, Anhyo Jeong, Aboubacar Kaba, Nedas Matulionis, Randy Caliliw, Xiaowu Gai, Heather Christofk, David Shackelford, Brian Shuch.
      Renal oncocytoma (RO) is a benign renal neoplasm characterized by dense accumulation of dysfunctional mitochondria possibly resulting from increased mitochondrial biogenesis and decreased mitophagy; however, the mechanisms controlling these mitochondrial changes are unclear. ROs harbor recurrent inactivating mutations in mitochondrial genes encoding the Electron Transport Chain (ETC) Complex I, and we hypothesize that Complex I loss in ROs directly impairs mitophagy. Our analysis of ROs and normal kidney (NK) tissues shows that a significant portion (8 out of 17) of ROs have mtDNA Complex I loss-of-function mutations with high variant allele frequency (>50%). ROs indeed exhibit reduced Complex I expression and activity. Analysis of the various steps of mitophagy pathway demonstrates that AMPK activation in ROs leads to induction of mitochondrial biogenesis, autophagy, and formation of autophagosomes. However, the subsequent steps involving lysosome biogenesis and function are defective, resulting in an overall inhibition of mitophagy. Inhibiting Complex I in a normal kidney cell line recapitulated the observed lysosomal and mitophagy defects. Our data suggest Complex I loss in RO results in defective mitophagy due to lysosomal loss and dysfunction.
    Keywords:  autophagy/mitophagy; complex I; lysosome; metabolism; mitochondrial dysfunction; renal oncocytoma
    DOI:  https://doi.org/10.3390/ijms26157654
  36. Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2501681122
    Global profiling of N-terminal cysteine-dependent degradation mechanisms.
    Aizat Bekturova, Yaara Makaros, Shahar Ben-David, Itay Koren.
      Hypoxia, a condition characterized by insufficient oxygen supply, challenges cellular homeostasis and energy production, triggering adaptive responses to promote survival under these stressful conditions. One key strategy involves enzymatic oxidation of N-terminal cysteine residues coupled with proteolysis through the Cys-Arg/N-degron pathway. Despite hundreds of human proteins possessing N-terminal cysteine, very few have been identified as substrates of this pathway, and its substrate selectivity remains unclear. Moreover, the biological role of this pathway in the cellular response to hypoxia is not well defined. Here, by systematically screening protein stability using an N-terminome library, we reveal a broad set of cysteine-initiating proteins regulated by this pathway. Mutagenesis experiments further revealed the specificity of Cys-Arg/N-degron pathway, showing a preference for hydrophobic and positively charged residues following cysteine. Additionally, we uncovered full-length substrates that are regulated by this pathway during hypoxia, including IP6K1. Loss of IP6K1 impaired glucose uptake, glycolytic ATP production, and overall mitochondrial function. Consequently, IP6K1-deficient cells exhibited disrupted metabolic adaptation under hypoxic conditions and reduced survival under stress. These findings underscore the importance of the Cys-Arg/N-degron pathway in regulating metabolic responses and highlight its potential importance in hypoxia-related disorders.
    Keywords:  E3 ligases; N-degron; cysteine; hypoxia; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2501681122
  37. Clin Cancer Res. 2025 Aug 11.
    Resilience and vulnerabilities of tumor cells under purine shortage stress.
    Jianpeng Yu, Chen Jin, Cheng Su, David Moon, Michael Sun, Hong Zhang, Xue Jiang, Fan Zhang, Nomi Tserentsoodol, Michelle L Bowie, Christopher J Pirozzi, Daniel George, Robert Wild, Xia Gao, David M Ashley, Yiping He, Jiaoti Huang.
       PURPOSE: Purine metabolism is a promising therapeutic target in cancer; however, how cancer cells respond to purine shortage, particularly their adaptation and vulnerabilities, remains unclear.
    EXPERIMENTAL DESIGN: Using the recently developed purine shortage-inducing prodrug DRP-104 and genetic approaches, we investigated the responses in prostate, lung, and glioma cancer models.
    RESULTS: We demonstrate that when de novo purine biosynthesis is compromised, cancer cells employ microtubules to assemble purinosomes, multi-protein complexes of de novo purine biosynthesis enzymes that enhance purine biosynthesis efficiency. While this process enables tumor cells to adapt to purine shortage stress, it also renders them more susceptible to the microtubule-stabilizing chemotherapeutic drug Docetaxel. Furthermore, we show that although cancer cells primarily rely on de novo purine biosynthesis, they also exploit Methylthioadenosine Phosphorylase (MTAP)-mediated purine salvage as a crucial alternative source of purine supply, especially under purine shortage stress. In support of this finding, combining DRP-104 with an MTAP inhibitor significantly enhances tumor suppression in prostate cancer (PCa) models in vivo. Finally, despite the resilience of the purine supply machinery, purine shortage-stressed tumor cells exhibit increased DNA damage and activation of the cGAS-STING pathway, which may contribute to impaired immunoevasion and provide a molecular basis of the previously observed DRP-104-induced anti-tumor immunity.
    CONCLUSIONS: Together, these findings reveal purinosome assembly and purine salvage as key mechanisms of cancer cell adaptation and resilience to purine shortage while identifying microtubules, MTAP, and immunoevasion deficits as therapeutic vulnerabilities.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1667
  38. Sci Adv. 2025 Aug 15. 11(33): eadu2906
    Somatic CRISPR tumorigenesis and multiomic analysis reveal a pentose phosphate pathway disruption vulnerability in MPNSTs.
    Gavin R McGivney, Qierra R Brockman, Nicholas Borcherding, Amanda Scherer, Adam J Rauckhorst, Wade R Gutierrez, Shane R Solst, Collin D Heer, Akshaya Warrier, Warren Floyd, David G Kirsch, Vickie L Knepper-Adrian, Emily A Laverty, Grace A Roughton, Douglas R Spitz, Eric B Taylor, Rebecca D Dodd.
      Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive and chemo-resistant sarcomas with poor survival rates. Loss of CDKN2A or P53 following NF1 disruption is a key event in MPNST development. Here, we used CRISPR-Cas9 somatic tumorigenesis in mice to identify transcriptomic and metabolomic features distinguishing CDKN2A- versus P53-deleted MPNSTs. Convergent, multiomic analyses revealed that CDKN2A-deleted MPNSTs are especially dependent on the pentose phosphate pathway (PPP) and NADPH metabolism for growth and viability. Disruption of glucose-6-phosphate dehydrogenase (G6PD), the PPP rate-limiting enzyme, slowed CDKN2A-deleted MPNST growth and sensitized MPNSTs to standard-of-care chemotherapy. Knockdown of the redox-regulated transcription factor NRF2 slowed MPNST growth and decreased G6PD transcription. Analysis of patient MPNSTs identified a NRF2 gene signature correlating with tumor transformation. Furthermore, G6PD and NRF2 expression in PanCancer TCGA samples correlates with patient survival. This work identifies NRF2-PPP dependency as a targetable vulnerability in these difficult-to-treat MPNSTs, particularly in the NF1/CDKN2A-deleted majority.
    DOI:  https://doi.org/10.1126/sciadv.adu2906
  39. Nature. 2025 Aug;644(8076): 338
    Study how screen time affects circadian rhythms.
    Fouzia Kiran, Yaping Jin, Yalin Yuan, Huatao Chen.
      
    Keywords:  Media; Physiology; Psychology; Technology
    DOI:  https://doi.org/10.1038/d41586-025-02570-2
  40. bioRxiv. 2025 Aug 06. pii: 2025.08.05.668752. [Epub ahead of print]
    Vitamin B2 metabolism promotes FSP1 stability to prevent ferroptosis.
    Kirandeep K Deol, Cynthia A Harris, Sydney J Tomlinson, Cody E Doubravsky, Alyssa J Mathiowetz, James A Olzmann.
      Ferroptosis, a regulated form of cell death driven by excessive lipid peroxidation, has emerged as a promising therapeutic target in cancer. Ferroptosis suppressor protein 1 (FSP1) is a critical regulator of ferroptosis resistance, yet the mechanisms controlling its expression and stability remain mostly unexplored. To uncover regulators of FSP1 abundance, we conducted CRISPR-Cas9 screens utilizing a genome-edited, dual-fluorescent FSP1 reporter cell line, identifying both transcriptional and post-translational mechanisms that determine FSP1 levels. Notably, we identified riboflavin kinase (RFK) and FAD synthase (FLAD1), enzymes which are essential for synthesizing flavin adenine dinucleotide (FAD) from vitamin B2, as key contributors to FSP1 stability. Biochemical and cellular analyses revealed that FAD binding is critical for FSP1 activity. FAD deficiency, and mutations blocking FSP1-FAD binding, triggered FSP1 degradation via a ubiquitin-proteasome pathway that involves the E3 ligase RNF8. Unlike other vitamins that inhibit ferroptosis by scavenging radicals, vitamin B2 supports ferroptosis resistance through FAD cofactor binding, ensuring proper FSP1 stability and function. This study provides a rich resource detailing mechanisms that regulate FSP1 abundance and highlights a novel connection between vitamin B2 metabolism and ferroptosis resistance with implications for therapeutic strategies targeting FSP1 in cancer.
    DOI:  https://doi.org/10.1101/2025.08.05.668752
  41. Cell Rep. 2025 Aug 12. pii: S2211-1247(25)00918-0. [Epub ahead of print]44(8): 116147
    SUCLG1 deficiency-induced histone succinylation impairs oncogene expression in acute myeloid leukemia.
    Mengqing Gao, Minhui Shi, Hao Ding, Lei Xu, Na Zhao, Li Wang, Shujuan Huang, Hui Jiang, Ekaterina Bourova-Flin, Jianqing Mi, Saadi Khochbin, Domenico Iuso, Xiaoyu Zhu.
      Mitochondria-driven histone lysine succinylation is emerging as a critical signaling system that links cellular metabolism to the pathogenesis of diseases, including cancer. Here, we report that a global increase in protein/histone succinylation is associated with mitochondrial tricarboxylic acid cycle defects in acute myeloid leukemia (AML). Depletion of the succinyl-coenzyme A (CoA) synthetase alpha subunit SUCLG1 causes protein/histone hypersuccinylation in leukemia cells, which impairs cell proliferation and leukemia progression in xenograft models. Mechanistically, increased histone succinylation, which could compete with acetylation, attenuates the interaction of the bromodomain-containing protein 4 (BRD4) bromodomain with chromatin, hence disrupting BRD4-mediated leukemogenic gene transcription and restoring BRD4-dependent fine-tuned gene regulatory circuits. Our study uncovers the crucial role of metabolism-controlled histone succinylation in cancer development and highlights it as an innovative therapeutic approach.
    Keywords:  BRD4; CP: Cancer; CP: Metabolism; SUCLG1; acute myeloid leukemia; histone succinylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116147
  42. bioRxiv. 2025 Aug 06. pii: 2025.08.04.667739. [Epub ahead of print]
    The Malate-Aspartate Shuttle supports thermogenic lipid mobilization in brown adipocytes.
    Michaela Veliova, Caroline M Ferreira, Katrina Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Linsey Stiles, Marc Liesa, Orian S Shirihai, Marcus F Oliveira.
      Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD⁺ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle, and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh-namely the oxoglutarate carrier (OGC1) and aspartate-glutamate carrier (Aralar1) had no apparent effects on respiratory rates. However, silencing either OGC1 or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.
    DOI:  https://doi.org/10.1101/2025.08.04.667739
  43. Cell. 2025 Aug 11. pii: S0092-8674(25)00853-0. [Epub ahead of print]
    Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming.
    Jinlong Y Lu, William B Tu, Ronghui Li, Mingxi Weng, Bhargav D Sanketi, Baolei Yuan, Pradeep Reddy, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte.
      The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a "mesenchymal drift" (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.
    Keywords:  Yamanaka factors; aging; chronic kidney disease; epithelial-mesenchymal transition; fibrosis; heart failure; idiopathic pulmonary fibrosis; metabolic dysfunction-associated steatohepatitis; partial reprogramming; rejuvenation
    DOI:  https://doi.org/10.1016/j.cell.2025.07.031
  44. Nat Protoc. 2025 Aug 11.
    Chemogenetic detection and quantitation of H2O2 in living cells.
    Mohammad Eid, Uladzimir Barayeu, Tobias P Dick.
      Hydrogen peroxide (H2O2) is a natural product of aerobic metabolism. It acts as a signaling molecule and regulates fundamental cellular functions. However, it has remained difficult to measure intracellular H2O2 with high specificity and in a quantitative manner. Here, we present a detailed protocol for a chemogenetic method that enables the detection and quantitation of H2O2 in living cells by converting intracellular H2O2 into fluorescent or luminescent signals. This is achieved by expressing the engineered heme peroxidase APEX2 in cells and subcellular locations of interest and by providing an appropriate fluorogenic or luminogenic substrate from outside. This method differs fundamentally from previously developed genetically encoded H2O2 probes; those are reversible and measure the balance between probe thiol oxidation and reduction. By contrast, APEX2 turns over its substrate irreversibly and therefore directly measures endogenous H2O2 availability. Our detailed step-by-step protocol covers the generation of APEX2-expressing cell lines, the implementation of fluorescent and luminescent measurements and examples for application. Ectopic expression of APEX2 can be achieved in 3 days, while the actual measurements typically require 1-2 h. This protocol is intended for entry-level scientists.
    DOI:  https://doi.org/10.1038/s41596-025-01226-9
  45. Metab Eng. 2025 Aug 07. pii: S1096-7176(25)00121-1. [Epub ahead of print]
    Metabolic flux and flux balance analyses indicate the relevance of metabolic thermogenesis and aerobic glycolysis in cancer cells.
    Nobuyuki Okahashi, Tomoki Shima, Yuya Kondo, Chie Araki, Shuma Tsuji, Akane Sawai, Hikaru Uehara, Susumu Kohno, Hiroshi Shimizu, Chiaki Takahashi, Fumio Matsuda.
      Adenosine triphosphate (ATP) regeneration by substrate-level phosphorylation is a general feature of cancer metabolism, even under normoxic conditions (aerobic glycolysis). However, it is unclear why cancer cells prefer inefficient aerobic glycolysis over the highly efficient process of oxidative phosphorylation for ATP regeneration. To investigate the metabolic principles underlying aerobic glycolysis, we performed 13C-metabolic flux analysis of 12 cultured cancer cell lines and explored the metabolic constraints required to reproduce the results using in silico metabolic simulations. We found that the measured flux distribution can be reproduced by maximizing the ATP consumption in the flux balance analysis considering a limitation of metabolic heat dissipation (enthalpy change). Consistent with the simulation, OXPHOS inhibition induced metabolic redirection to aerobic glycolysis while maintaining the intracellular temperature. Furthermore, the dependency on aerobic glycolysis was partly alleviated upon culturing at low temperatures. Our data suggest that metabolic thermogenesis is an important factor in understanding aerobic glycolysis in cancer cells and that an advantage of aerobic glycolysis is the reduction in metabolic heat generation during ATP regeneration.
    Keywords:  Aerobic glycolysis; Caner metabolism; Flux balance analysis; Metabolic flux analysis; Metabolic heat
    DOI:  https://doi.org/10.1016/j.ymben.2025.08.002
  46. Immunity. 2025 Aug 12. pii: S1074-7613(25)00322-X. [Epub ahead of print]
    Inhibition of tumor cell macropinocytosis driver DHODH reverses immunosuppression and overcomes anti-PD1 resistance.
    Yujia Wang, Yangyang Chai, Yanfang Liu, Xinpeng Liu, Yunkai Zhang, Zhen Yang, Shenhui Yin, Jianhua Luo, Zhiqing Li, Yan Gu, Yizhi Yu, Xuetao Cao.
      Tumor cells' macropinocytosis sustains their growth under nutrient-limiting conditions. However, the metabolic regulation of cancer macropinocytosis in immune escape and its effect on immunotherapy remain unclear. Through the metabolism compound library and genome-wide CRISPR-Cas9 screenings, we identified dihydroorotate dehydrogenase (DHODH) as an essential driver of tumor cell macropinocytosis. DHODH sustained O-GlcNAcylation of the macropinocytic mediator neuropilin-1 (NRP1) and its membrane localization, mediating tumor cell macropinocytosis. Moreover, the DHODH-NRP1 axis-driven macropinocytosis increased intracellular amounts of lysine and tryptophan, which promoted glutarylation of the transcription factor class II transactivator (CIITA) to repress cancer cell major histocompatibility complex class II (MHC class II) expression. Pharmacological inhibition or genetic deletion of tumor cell-expressed DHODH potently recruited more immune cell infiltration and activated antitumor immunity in vivo, overcoming anti-programmed cell death protein 1 (PD1) resistance. High expression of DHODH and NRP1 in human breast and lung cancer tissues predicted patients' poor prognosis. Therefore, targeting DHODH to inhibit tumor cell macropinocytosis provides a potential approach to reverse immunosuppression for improving cancer immunotherapy.
    Keywords:  O-GlcNAcylation; cancer immunotherapy; dihydroorotate dehydrogenase; glutarylation; macropinocytosis; neuropilin-1, MHC class II; pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.013
  47. Nat Metab. 2025 Aug 11.
    The insulin signalling network.
    James G Burchfield, Alexis Diaz-Vegas, David E James.
      Insulin signalling is a central regulator of metabolism, orchestrating nutrient homeostasis and coordinating carbohydrate, protein and lipid metabolism. This network operates through dynamic, tightly regulated protein phosphorylation events involving key kinases such as AKT, shaping cellular responses with remarkable precision. Advances in phosphoproteomics have expanded our understanding of insulin signalling, revealing its intricate regulation and links to disease, particularly cardiometabolic disease. Major insights, such as the mechanisms of AKT activation and the influence of genetic and environmental factors, have emerged from studying this network. In this Review, we examine the architecture of insulin signalling, focusing on its precise temporal regulation. We highlight AKT's central role in insulin action and its vast substrate repertoire, which governs diverse cellular functions. Additionally, we explore feedback and crosstalk mechanisms, such as insulin receptor substrate protein signalling, which integrates inputs through phosphorylation at hundreds of distinct sites. Crucially, phosphoproteomics has uncovered complexities in insulin-resistant states, where network rewiring is characterized by disrupted phosphorylation and the emergence of novel sites that are absent in healthy cells. These insights redefine insulin signalling and its dysfunction, highlighting new therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s42255-025-01349-z
  48. Nature. 2025 Aug 13.
    Expanding the cytokine receptor alphabet reprograms T cells into diverse states.
    Yang Zhao, Masato Ogishi, Aastha Pal, Leon L Su, Pingdong Tao, Hua Jiang, Grayson E Rodriguez, Xiaojing Chen, Qinli Sun, Lea Wenting Rysavy, Sam Limsuwannarot, Deepa Waghray, Anusha Kalbasi, K Christopher Garcia.
      T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK-STAT signalling and gene expression programs1. However, the potential combinatorial diversity of JAK-STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γc) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK-STAT receptor pairings using an orthogonal cytokine receptor platform2-4 to expand the γc signalling code. We tested receptors from γc cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γc or are not naturally expressed on T cells. These receptors simulated their natural counterparts but also induced contextually unique transcriptional programs. This led to distinct T cell fates in tumours, including myeloid-like T cells with phagocytic capacity driven by orthogonal GSCFR (oGCSFR), and type 2 cytotoxic T (TC2) and helper T (TH2) cell differentiation driven by orthogonal IL-4R (o4R). T cells with orthogonal IL-22R (o22R) and oGCSFR, neither of which are natively expressed on T cells, exhibited stem-like and exhaustion-resistant transcriptional and chromatin landscapes, enhancing anti-tumour properties. Non-native receptor pairings and their resultant JAK-STAT signals open a path to diversifying T cell states beyond those induced by natural cytokines.
    DOI:  https://doi.org/10.1038/s41586-025-09393-1
  49. bioRxiv. 2025 Jul 17. pii: 2025.07.11.664452. [Epub ahead of print]
    Mitochondrial clone tracing within spatially intact human tissues.
    Sydney A Bracht, Jiazhen Rong, Rodrigo A Gier, Maureen DeMarshall, Hailey Golden, Diya Dhakal, Jayne C McDevitt, Feiyan Mo, Emma E Furth, Alexandra Strauss Starling, Amanda B Muir, Gary W Falk, Bryson W Katona, Ben Z Stanger, Nancy R Zhang, Sydney M Shaffer.
      Understanding tissue development and intra-tissue evolution requires the ability to trace clones in intact tissues coupled with high-plex molecular profiling preserving spatial context. However, current lineage tracing tools are incompatible with spatial omics. Here, we present SUMMIT (Spatially Unveiling Mitochondrial Mutations In Tissues), a spatially-resolved lineage tracing technology that integrates gene expression profiling with mitochondrial mutation-based clone identification. Unlike synthetic lineage recording methods, SUMMIT relies only on endogenous mutations and thus can be applied to human tissues. To address the compositional mixing of cell types within spatial spots, SUMMIT includes a rigorous statistical framework to confidently assign variants to specific cell subpopulations and achieves high power for spatially localized clones by pooling information across neighboring spots. We validated SUMMIT using a controlled model in which we mixed two cancer cell lines in a mouse tumor, then demonstrated it on multiple human tissues including Barrett's esophagus, gastric cardia, small bowel, and colorectal cancer. Across these samples, we distinguished between global mutations and mutations marking locally restricted clones. The coupled transcriptomic data allowed us to characterize the cell type composition within each clone and delineate their spatial configuration. This integrated approach provides a framework to understand spatially-defined clonal evolution in preserved human tissue.
    DOI:  https://doi.org/10.1101/2025.07.11.664452
  50. Redox Biol. 2025 Aug 12. pii: S2213-2317(25)00325-8. [Epub ahead of print]86 103812
    ROS-dependent localization of glycolytic enzymes to mitochondria.
    Pau B Esparza-Moltó, Arvind V Goswami, Süleyman Bozkurt, Christian Münch, Laura E Newman, Alexandra G Moyzis, Gladys R Rojas, Deann Guan, Jeffrey R Jones, Fred H Gage, Gerald S Shadel.
      Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.
    Keywords:  Alzheimer's disease; Glycolytic enzymes; Mitochondria; Proximity labeling; Reactive oxygen species; Stress signaling
    DOI:  https://doi.org/10.1016/j.redox.2025.103812
  51. bioRxiv. 2025 Jul 15. pii: 2025.07.15.665002. [Epub ahead of print]
    Structural and enzymatic divergence between human MDH isoforms underlies their specialized regulatory roles in metabolism.
    Chris Berndsen, Angela J Kayll, Ruhi Rahman, Jackson R Tester, Trip Beaver, Caroline Tuck, Sonja Neve-Hoversten, Lisa Gentile, Tamerat Mandanis, Joseph J Provost.
      Malate dehydrogenase (MDH: EC:1.1.1.37) catalyzes a key NAD + -dependent redox reaction integral to cellular metabolism. In humans, the cytosolic (hMDH1) and mitochondrial (hMDH2) isoforms operate in distinct compartments, suggesting potential differences in regulation. Here, we present a comparative analysis of hMDH1 and hMDH2 under physiologically relevant conditions, integrating enzymatic assays, ligand binding studies, small-angle X-ray scattering (SAXS), and molecular modeling. Our findings reveal that hMDH2 activity is inhibited by α-ketoglutarate, glutamate, NAD + , ATP, and citrate at concentrations consistent with mitochondrial metabolic states characterized by elevated amino acid catabolism or redox stress. Conversely, hMDH1 exhibits minimal impact by these metabolites, with only modest inhibition observed in the presence of ATP and ADP. SAXS analyses confirm that both isoforms maintain stable dimeric structures upon ligand binding, indicating that regulation is not mediated by global conformational changes. Structural modeling and normal mode analyses identify increased flexibility in hMDH1, particularly within the active site loop, thumb loop, and a partially disordered C-terminal helix. In contrast, hMDH2 displays a more rigid architecture and a more electropositive active site environment, correlating with its heightened sensitivity to anionic metabolites. Fluorescence quenching experiments further support these distinctions, demonstrating stronger binding affinities for nucleotide-based ligands in hMDH2 compared to hMDH1. Collectively, these results suggest that isoform-specific regulation of human MDH arises from differences in local structural dynamics and electrostatics, rather than large-scale structural rearrangements. hMDH2 appears adapted to integrate mitochondrial metabolic signals, modulating malate oxidation in response to cellular conditions, while hMDH1 maintains consistent cytosolic function across diverse metabolic states.
    DOI:  https://doi.org/10.1101/2025.07.15.665002
  52. Free Radic Biol Med. 2025 Aug 12. pii: S0891-5849(25)00891-3. [Epub ahead of print]
    A novel application of LC-MS/MS accurately quantifies the labile redox pools of cellular coenzymes Q9 and Q10.
    Akash Jain, Vince W Li, Julia Salem, Srinivasa T Reddy, Nicolaos J Palaskas, David Meriwether.
      The antioxidant coenzyme Q (CoQ) plays an essential role in the electron transport chain (ETC). CoQ cycles between oxidized and reduced forms. Redox balance changes in the CoQ pool are associated with altered mitochondrial function. Thus, determining the CoQ redox pool is important for investigating cellular redox regulation. Existing quantification methods inadequately account for artefactual sample oxidation. To overcome these limitations, we found that a reduced stable isotope-labeled internal standard (IS) can correct for oxidation of extracted CoQ9 and CoQ10. The reduced IS oxidizes at the same rate as both CoQ isoforms. Employing this correction factor rescues artefactual oxidation of the CoQ redox pool when measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). We validated our method within murine and human cellular systems. Statin treatment dose-dependently decreased total CoQ, while directional perturbation of the mitochondrial ETC altered the CoQ redox pool as expected. The pro-oxidant tert-butyl hydroperoxide partially oxidized the cellular CoQ redox pool. Finally, we found that primary murine macrophages deficient in PON2, a mitochondrial antioxidant enzyme, contain a partially oxidized CoQ9 redox pool. These results were revealed only after correcting for sample oxidation. Whereas prior LC-MS/MS methods for measuring the CoQ redox pool inadequately account for artefactual oxidation, the presented method rescues this error and potentiates accurate measurement of murine and human CoQ redox pools.
    Keywords:  Coenzyme Q; liquid chromatography-mass spectrometry; mitochondria; oxidative stress; redox measurement
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.08.022
  53. Am J Surg Pathol. 2025 Aug 11.
    A Case of a Fumarate Hydratase Deficient Astrocytoma in Association With a Germline Fumarate Hydratase Mutation With Review of the Literature: Considerations for Patients With Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome.
    Rasha Alfattal, Priyadharsini Nagarajan, Barbara O'Brien, Martha Quezado, Kenneth Aldape, Leomar Y Ballester, Maria A Gubbiotti.
      Diffuse adult-type gliomas are delineated based on their molecular composition including the presence or absence of mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2), a key enzyme in the citric acid cycle. IDH-mutant tumors are associated with better survival than IDH-wildtype counterparts and can be further subdivided into astrocytoma or oligodendroglioma. Rare gliomas with fumarate hydratase (FH) deficiency have been reported. Given that FH is also a critical enzyme in the citric acid cycle, such tumors seem to be epigenetically similar to IDH-mutant tumors and, despite meeting criteria as IDH-wildtype gliomas per the current recommendations set forth by the World Health Organization, may behave in a manner akin to IDH-mutant neoplasms. Hereditary leiomyoma and renal cell cancer syndrome is associated with cutaneous and uterine leiomyomas and renal cell carcinoma caused by a germline FH alteration. To date, only rare examples of patients with known germline FH mutation subsequently diagnosed with a glioma have been reported. We report a case of a young patient with a glioma harboring features of IDH-mutant astrocytoma without evidence of IDH1/2 alterations. After the identification of cutaneous FH-deficient leiomyomas, a retrospective analysis of his brain tumor revealed FH deficiency and a germline FH alteration was ultimately identified after further molecular studies. Although rare, we conclude that FH mutations seem to be part of the spectrum of alterations in diffuse gliomas.
    Keywords:  citric acid cycle; fumarate hydratase; glioma; hereditary leiomyoma and renal cell cancer; isocitrate dehydrogenase
    DOI:  https://doi.org/10.1097/PAS.0000000000002463
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