bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–06–15
fifty-six papers selected by
Christian Frezza, Universität zu Köln
  1. Endosymbiont control through non-canonical immune signaling and gut metabolic remodeling.
  2. Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
  3. Metabolic adaptations direct cell fate during tissue regeneration.
  4. GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
  5. An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.
  6. Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
  7. Cell death and cancer: Metabolic interconnections.
  8. Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.
  9. Mitochondrial molecule has unexpected role in tissue healing.
  10. The intersection between metabolism and translation through a subcellular lens.
  11. Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
  12. The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
  13. Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
  14. An adaptive organelle triad houses lipid droplets for dynamic regulation.
  15. Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments.
  16. Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
  17. Cell death: Dynamics and compartmentalization of NADH and FSP1 in ferroptosis.
  18. Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
  19. ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.
  20. Gut microbe-derived lactic acid optimizes host energy metabolism during starvation.
  21. Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
  22. Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis.
  23. Mitochondrial presequences harbor variable strengths to maintain organellar function.
  24. Lifting the veil on tumor metabolism: A GDH1-focused perspective.
  25. Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.
  26. Sexual selection, energetics and ecological innovation: How sexual selection diversifies the landscape of behavior, morphology and physiology.
  27. Fatty Acid Oxidation Fuels Mitochondrial Respiration to Drive Epidermal Stem Cell Fate and Barrier Regeneration.
  28. Potential of Metabolic MRI to Address Unmet Clinical Needs in Localised Kidney Cancer.
  29. Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A.
  30. Nutrient sensing and signalling of specific amino acids: Insights from Drosophila study.
  31. AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
  32. Early life high fructose impairs microglial phagocytosis and neurodevelopment.
  33. Hormetic elevation of taurine restrains inflammaging by deactivating the NLRP3 inflammasome.
  34. Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.
  35. Impact of PARL-mediated mitochondrial protease activity on calcium regulation.
  36. Origins and functions of microbiome rhythms.
  37. PFKFB2 is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
  38. Various cell types in tissues cooperate in networks that are disrupted in disease.
  39. Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment.
  40. A food-sensitive olfactory circuit drives anticipatory satiety.
  41. Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.
  42. How you breathe is like a fingerprint that can identify you.
  43. Aging and diet alter the protein ubiquitylation landscape in the mouse brain.
  44. Uncovering the principles coordinating systems-level organelle biogenesis with cellular growth.
  45. The microbiome diversifies long- to short-chain fatty acid-derived N-acyl lipids.
  46. Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy.
  47. Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.
  48. Targeting DNA damage in ageing: towards supercharging DNA repair.
  49. How machine learning can help us understand what we have grown in the dish.
  50. A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity via engineered Gro3P-Glycerol shunt.
  51. IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma.
  52. Clonal hematopoiesis driven by microbial metabolite.
  53. Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.
  54. No (innate immune) training without lactate.
  55. Uridine.
  56. Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.
  1. Cell Rep. 2025 Jun 06. pii: S2211-1247(25)00582-0. [Epub ahead of print]44(6): 115811
    Endosymbiont control through non-canonical immune signaling and gut metabolic remodeling.
    Sofie Burgmer, Fenja L Meyer Zu Altenschildesche, Akos Gyenis, Hyun Ju Lee, David Vilchez, Patrick Giavalisco, Arnaud Fichant, Mirka Uhlirova, Gilles Storelli.
      Animals coexist with bacteria and need to keep these microorganisms under tight control. To achieve such control, pattern recognition receptors (PRRs) sense bacterial cues and induce the production of antimicrobials. Here, we uncover a metabolic arm in the control of symbionts by PRRs. We show that, in Drosophila, the PRRs PGRP-LC and PGRP-LE act independently of canonical NF-κB signaling to repress essential metabolic functions in the gut, such as digestion and central carbon metabolism. This metabolic switch affects commensal populations and drastically reduces intestinal and systemic populations of the intracellular parasite Wolbachia. We propose that intestinal metabolic remodeling complements immune responses by imposing nutrient restriction on intracellular bacteria, whose lifestyle protects them from antimicrobials. Our findings reveal a role for PRRs in bacterial control beyond canonical immune pathways and provide insights into how microbial signals modulate symbiotic populations but also nutrition and metabolism in animals.
    Keywords:  CP: Immunology; CP: Metabolism; Drosophila; IMD; PGRP-LC; PGRP-LE; Wolbachia; endosymbiont; gut microbiome; innate immunity; metabolism; symbiosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115811
  2. Nature. 2025 Jun 11.
    Glycosaminoglycan-driven lipoprotein uptake protects tumours from ferroptosis.
    Dylan Calhoon, Lingjie Sang, Fubo Ji, Divya Bezwada, Sheng-Chieh Hsu, Feng Cai, Nathaniel Kim, Amrita Basu, Renfei Wu, Anastasia Pimentel, Bailey Brooks, Konnor La, Ana Paulina Serrano, Daniel L Cassidy, Ling Cai, Vanina Toffessi-Tcheuyap, Maryam E Moussa, Winnie Uritboonthai, Linh Truc Hoang, Meghana Kolli, Brooklyn Jackson, Vitaly Margulis, Gary Siuzdak, James Brugarolas, Ian Corbin, Derek A Pratt, Ryan J Weiss, Ralph J DeBerardinis, Kıvanç Birsoy, Javier Garcia-Bermudez.
      Lipids are essential components of cancer cells due to their structural and signalling roles1. To meet metabolic demands, many cancers take up extracellular lipids2-5; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify uptake of lipoproteins-the primary mechanism for lipid transport in circulation-as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas-a lipid-rich malignancy-exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared with normal kidney tissue. Together, our study establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.
    DOI:  https://doi.org/10.1038/s41586-025-09162-0
  3. Nature. 2025 Jun 11.
    Metabolic adaptations direct cell fate during tissue regeneration.
    Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.
      Although cell-fate specification is generally attributed to transcriptional regulation, emerging data also indicate a role for molecules linked with intermediary metabolism. For example, α-ketoglutarate (αKG), which fuels energy production and biosynthetic pathways in the tricarboxylic acid (TCA) cycle, is also a co-factor for chromatin-modifying enzymes1-3. Nevertheless, whether TCA-cycle metabolites regulate cell fate during tissue homeostasis and regeneration remains unclear. Here we show that TCA-cycle enzymes are expressed in the intestine in a heterogeneous manner, with components of the αKG dehydrogenase complex4-6 upregulated in the absorptive lineage and downregulated in the secretory lineage. Using genetically modified mouse models and organoids, we reveal that 2-oxoglutarate dehydrogenase (OGDH), the enzymatic subunit of the αKG dehydrogenase complex, has a dual, lineage-specific role. In the absorptive lineage, OGDH is upregulated by HNF4 transcription factors to maintain the bioenergetic and biosynthetic needs of enterocytes. In the secretory lineage, OGDH is downregulated through a process that, when modelled, increases the levels of αKG and stimulates the differentiation of secretory cells. Consistent with this, in mouse models of colitis with impaired differentiation and maturation of secretory cells, inhibition of OGDH or supplementation with αKG reversed these impairments and promoted tissue healing. Hence, OGDH dependency is lineage-specific, and its regulation helps to direct cell fate, offering insights for targeted therapies in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41586-025-09097-6
  4. Cell Rep. 2025 Jun 09. pii: S2211-1247(25)00545-5. [Epub ahead of print]44(6): 115774
    GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.
    Yubin Chen, Qian Yan, Shiye Ruan, Jinwei Cui, Zhenchong Li, Zhongyan Zhang, Jiayu Yang, Jike Fang, SiYang Liu, Shanzhou Huang, Baohua Hou, Chuanzhao Zhang.
      KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRASG12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.
    Keywords:  CP: Cancer; CP: Metabolism; GCLM; KRAS mutation; ferroptosis; glutamate-cysteine ligase modifier; pancreatic cancer; protein lactylation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115774
  5. EMBO Rep. 2025 Jun 09.
    An alternative mechanism by which If1 prevents ATP hydrolysis by the ATP synthase subcomplex in S. cerevisiae.
    Orane Lerouley, Isabelle Larrieu, Tom Louis Ducrocq, Benoît Pinson, Marie-France Giraud, Arnaud Mourier.
      The mitochondrial F1F0-ATP synthase is crucial for maintaining the ATP/ADP balance which is critical for cell metabolism, ion homeostasis and cell proliferation. This enzyme, conserved across evolution, is found in the mitochondria or chloroplasts of eukaryotic cells and the plasma membrane of bacteria. In vitro studies have shown that the mitochondrial F1F0-ATP synthase is reversible, capable of hydrolyzing instead of synthesizing ATP. In vivo, its reversibility is inhibited by the endogenous peptide If1 (Inhibitory Factor 1), which specifically prevents ATP hydrolysis in a pH-dependent manner. Despite its presumed importance, the loss of If1 in various model organisms does not cause severe phenotypes, suggesting its role may be confined to specific stress or metabolic conditions yet to be discovered. Our analyses indicate that inhibitory peptides are crucial in mitigating mitochondrial depolarizing stress under glyco-oxidative metabolic conditions. Additionally, we found that the absence of If1 destabilizes the nuclear-encoded free F1 subcomplex. This mechanism highlights the role of If1 in preventing harmful ATP wastage, offering new insights into its function under physiological and pathological conditions.
    Keywords:  ATP Synthase; Bioenergetics; F1 Subcomplex; IF1; Mitochondria
    DOI:  https://doi.org/10.1038/s44319-025-00430-8
  6. Life Metab. 2025 Jun;4(3): loaf012
    Brain-body mitochondrial distribution patterns lack coherence and point to tissue-specific regulatory mechanisms.
    Jack Devine, Anna S Monzel, David Shire, Ayelet M Rosenberg, Alex Junker, Alan A Cohen, Martin Picard.
      Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors. This predicts that some individuals should have consistently high, while others show consistently low mitochondrial oxidative phosphorylation (OxPhos) capacity across organ systems. Here, we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans. Across up to 22 mouse tissues, neither mitochondrial OxPhos capacity nor mitochondrial DNA (mtDNA) density was correlated between tissues (median r = -0.01 to 0.16), indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues. Similarly, RNA sequencing (RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men (genotype-tissue expression [GTEx]) showed only small to moderate coherence between some tissues, such as between brain regions (r = 0.26), but not between brain-body tissue pairs (r = 0.01). The mtDNA copy number (mtDNAcn) also lacked coherence across human tissues. Mechanistically, tissue-specific differences in mitochondrial gene expression were partially attributable to (i) tissue-specific activation of energy sensing pathways, including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the integrated stress response (ISR), and other molecular regulators of mitochondrial biology, and (ii) proliferative activity across tissues. Finally, we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes. These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.
    Keywords:  disease risk; energy sensing; gene regulation; inter-organ crosstalk; mitochondrial biogenesis; mitochondrion
    DOI:  https://doi.org/10.1093/lifemeta/loaf012
  7. Cell Rep. 2025 Jun 07. pii: S2211-1247(25)00575-3. [Epub ahead of print]44(6): 115804
    Cell death and cancer: Metabolic interconnections.
    Destiny Dalseno, Nikolai Gajic, Lyndsey Flanagan, Stephen W G Tait.
      Recent findings in the cell death field have transformed our understanding of the interplay between metabolism and cell death in the context of cancer. In this review, we discuss the relationships between metabolism and the cell death pathways of apoptosis, necroptosis, pyroptosis, and ferroptosis, with a particular focus on recent advancements. We will also explore the regulation of metabolism by the BCL-2 family and the participation of oncometabolites in the regulation of cell death. Finally, we examine the emerging links between cell death signaling and cellular persistence. As we highlight in this review, the intersection of metabolic and cell death pathways has implications for cancer cell survival, treatment resistance, and the tumor microenvironment.
    Keywords:  BCL-2; CP: Cancer; CP: Metabolism; apoptosis; cancer; cell death; ferroptosis; metabolism; necroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115804
  8. Methods Mol Biol. 2025 ;2925 203-222
    Metabolic Pathway Tracing for NAD+ Synthesis and Consumption.
    Tumpa Dutta, Stephen J Gardell.
      NAD+ is an abundant cellular metabolite which plays vital roles in central metabolism while serving as a cofactor for oxidoreductases and cosubstrate for sirtuins and poly(ADP-ribose)polymerases (PARPs). Decreased tissue NAD+ levels have been linked to aging-associated metabolic decline and a host of chronic diseases. Cellular steady-state NAD+ levels are governed by contemporaneous synthetic and consumptive processes. Hence, lower NAD+ levels in aged tissues can arise from decreased synthesis or increased consumption. A static snapshot of the tissue levels of NAD+ is inadequate for assessing the highly dynamic pathway network which mediates NAD+ synthesis and consumption. Metabolic pathway tracing with stable isotope-labeled NAD+ precursors (e.g., nicotinamide (NAM), nicotinic acid (NA), tryptophan) and high-resolution mass spectrometry (HRMS) can unveil the individual contributions of synthesis and consumption to the steady-state NAD+ concentration. The metabolic fate of the NAD+ precursor can also be traced to metabolic products of NAD+ including NADH, NADP, and NADPH as well as intermediates in the various NAD+ biosynthetic pathways. Metabolic tracing of NAD+ synthesis and degradation as well as conversion of NAD+ to its downstream products is a highly versatile technique. It can be used to interrogate isolated cells, tissues slices, or specimens collected from preclinical or clinical in vivo studies (e.g., blood, urine, tissues). Bold claims about the pivotal role of NAD+ in human health and disease are typically fraught with uncertainty due to an incomplete understanding of NAD+ metabolism. Insight gleaned from metabolic pathway tracing can shed important new light on NAD+ metabolism and help to critically evaluate the intriguing link between cellular NAD+ levels and healthy aging.
    Keywords:  Mass isotopomer distribution profiling; Mass spectrometry; NAD+ consumption; NAD+ flux; NAD+ metabolism; NAD+ synthesis; Stable isotope tracing
    DOI:  https://doi.org/10.1007/978-1-0716-4534-5_14
  9. Nature. 2025 Jun 11.
    Mitochondrial molecule has unexpected role in tissue healing.
    Ram P Chakrabarty, Navdeep S Chandel.
      
    Keywords:  Biochemistry; Cell biology; Metabolism; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01583-1
  10. Trends Cell Biol. 2025 Jun 09. pii: S0962-8924(25)00113-8. [Epub ahead of print]
    The intersection between metabolism and translation through a subcellular lens.
    Massimo M Santoro.
      The crosstalk between metabolism and mRNA translation (protein synthesis) is crucial for modulating cellular physiology. Signals from metabolic pathways or various metabolic states can influence multiple aspects of RNA biology and translation machinery. In turn, cells can reprogram their metabolism by controlling mRNA translation. Current studies have revealed that localized mRNA translation is specifically regulated by distinct metabolic states, suggesting the existence of specialized subcellular machinery that coordinates this interplay. This review aims to explore recent discoveries and provide an overview of the specialized methodologies developed in recent years on novel modes of translation-metabolism cross-regulation by subcellular localized cues. Spatial compartmentalization, especially in the context of metabolism and mRNA translation, offers a unique advantage, providing a novel mechanism for cellular regulation and function.
    Keywords:  RNA condensate; glycolysis; mRNA translation; mTOR signaling; metabolism; organelles; stress granules
    DOI:  https://doi.org/10.1016/j.tcb.2025.05.003
  11. bioRxiv. 2025 Jun 07. pii: 2025.06.06.658169. [Epub ahead of print]
    Dietary lipids, not ketone body metabolites, influence intestinal tumorigenesis in a ketogenic diet.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Johanna Ten Hoeve, Kevin J Williams, Tolga Sever, Isabela Fuentes, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state, and cellular dynamics. In the gastrointestinal tract, obesogenic high-fat diets enhance intestinal stem cell activity and tumorigenesis. However, the impact of ketogenic diets (KD), which contain even higher lipid content but induce ketogenesis, remains poorly understood. This is particularly relevant for patients with familial adenomatous polyposis (FAP), who face a high risk of small intestinal tumours. Here, we combine dietary, genetic, and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone body production. Through genetic manipulation of the ketogenic pathway, we modulate local and systemic ketone body production; however, neither inhibition nor augmentation of the ketogenic enzyme HMGCS2 nor disruption of ketolysis altered tumour progression. In contrast, inhibition of fatty acid oxidation did limit adenomatous formation. These findings reveal that dietary lipid content, through FAO rather than ketone body metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1101/2025.06.06.658169
  12. Cell Rep. 2025 Jun 05. pii: S2211-1247(25)00570-4. [Epub ahead of print]44(6): 115799
    The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
    Chao Wang, Allon Wagner, Johannes Fessler, David DeTomaso, Sarah Zaghouani, Yulin Zhou, Kerry Pierce, Raymond A Sobel, Clary Clish, Nir Yosef, Vijay K Kuchroo.
      Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate how individual glycolytic reactions determine the pathogenicity of T helper 17 (Th17) cells using Compass, an algorithm we previously developed for inferring metabolic states from single-cell RNA sequencing. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in Th17 cells. Indeed, perturbation of phosphoglycerate mutase (PGAM), the enzyme catalyzing 3PG to 2PG conversion, induces a pathogenic gene expression program by suppressing a gene module associated with the least pathogenic state of Th17 cells. Finally, PGAM inhibition in Th17 cells exacerbates neuroinflammation in the adoptive transfer model of experimental autoimmune encephalomyelitis, consistently with PGAM promoting the non-pathogenic phenotype of Th17 cells. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of pathogenic Th17 cell differentiation.
    Keywords:  CP: Immunology; CP: Metabolism; EGCG; PGAM; PGM; T helper 17; central carbon metabolism; epigallocatechin-3-gallate; glycolysis; immune metabolism; immunometabolism; phosphoglycerate mutase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115799
  13. bioRxiv. 2025 May 28. pii: 2025.05.25.655566. [Epub ahead of print]
    Mechanism of age-related accumulation of mitochondrial DNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Md Mesbah Uddin, Wenhan Lu, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ∼750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of "cryptic" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT , TCL1A , and SMC4 ) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT , clonal hematopoiesis, and observed mtDNA mutation accrual.
    DOI:  https://doi.org/10.1101/2025.05.25.655566
  14. Cell Rep. 2025 Jun 11. pii: S2211-1247(25)00584-4. [Epub ahead of print]44(6): 115813
    An adaptive organelle triad houses lipid droplets for dynamic regulation.
    Hong Qiu, Can Miao, Cunqi Ye.
      Cell organelles compartmentalize metabolic reactions and require inter-organelle communications to coordinate metabolic activities in fluctuating nutrient environments. While membrane contacts enable this communication by facilitating metabolite exchange, the functional organization of organelles through these contacts remains underexplored. Here, we show that excess lactate induces severe metabolic stress under nutrient deprivation in the budding yeast Saccharomyces cerevisiae, necessitating a rapid life cycle of lipid droplets (LDs) for cellular adaptation. This process uncovers a previously uncharacterized subcellular architecture-an organelle triad-comprising the vacuole, LDs, and the nuclear endoplasmic reticulum (ER). The vacuole undergoes expansion and deformation, enveloping the entire nucleus that is encircled by an orbit of LDs. Formation of this organelle triad depends on the timely and abundant expression of membrane-tethering proteins that mediate vacuole-LD contact sites and nuclear ER-vacuole junctions. This dynamic and reversible subcellular organization ensures efficient LD metabolism to support cell survival under nutrient stress.
    Keywords:  CP: Cell biology; LDO proteins; lipid droplet; membrane contact; nutrient stress; nvj1; subcellular architecture; the nucleus–vacuole junction; vac8; vacuole deformation
    DOI:  https://doi.org/10.1016/j.celrep.2025.115813
  15. J Cell Biol. 2025 Aug 04. pii: e202405061. [Epub ahead of print]224(8):
    Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments.
    Michalis Gounis, America V Campos, Engy Shokry, Louise Mitchell, Ruhi Deshmukh, Emmanuel Dornier, Nicholas Rooney, Sandeep Dhayade, Luis Pardo, Madeleine Moore, David Novo, Jenna Mowat, Craig Jamieson, Emily Kay, Sara Zanivan, Nikki R Paul, Claire Mitchell, Colin Nixon, Iain Macpherson, Saverio Tardito, David Sumpton, Karen Blyth, Jim C Norman, Cassie J Clarke.
      Altered cellular metabolism has been associated with the acquisition of invasive phenotypes during metastasis. To study this, we combined a genetically engineered mouse model of mammary carcinoma with syngeneic transplantation and primary tumor resection to generate isogenic cells from primary tumors and their corresponding lung micrometastases. Metabolic analyses indicated that micrometastatic cells increase proline production at the expense of glutathione synthesis, leading to a reduction in total glutathione levels. Micrometastatic cells also have altered sphingomyelin metabolism, leading to increased intracellular levels of specific ceramides. The combination of these metabolic adaptations alters extracellular vesicle (EV) production to render the microenvironment more permissive for invasion. Indeed, micrometastatic cells shut down Rab27-dependent production of EVs and, instead, switch on neutral sphingomyelinase-2 (nSM2)-dependent EV release. EVs released in an nSM2-dependent manner from micrometastatic cells, in turn, influence the ability of fibroblasts to deposit extracellular matrix, which promotes cancer cell invasiveness. These data provide evidence that metabolic rewiring drives invasive processes in metastasis by influencing EV release.
    DOI:  https://doi.org/10.1083/jcb.202405061
  16. Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00460-5. [Epub ahead of print]
    Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
    Su Jin Ham, Sunhoe Bang, Daihn Woo, Jae-Yoon Jo, Takwon Yoo, Eunju Yoon, Yeonju Kyoung, Daehyun Baek, Jong-Seo Kim, Jongkyeong Chung.
      Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology.
    Keywords:  ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.021
  17. Curr Biol. 2025 Jun 09. pii: S0960-9822(25)00441-5. [Epub ahead of print]35(11): R406-R409
    Cell death: Dynamics and compartmentalization of NADH and FSP1 in ferroptosis.
    Amalia H Megarioti, Kirandeep K Deol, James A Olzmann.
      A new study identifies the aldehyde dehydrogenase ALDH7A1 as a key regulator of ferroptosis. ALDH7A1 generates a pool of membrane-associated NADH, which is used by ferroptosis suppressor protein 1 to recycle the lipid antioxidant coenzyme Q10 and suppress ferroptosis.
    DOI:  https://doi.org/10.1016/j.cub.2025.04.012
  18. bioRxiv. 2025 May 29. pii: 2025.05.28.656437. [Epub ahead of print]
    Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
    Yash Flora, Dhriti Shastri, K Adam Bohnert.
      Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans , and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: mitochondria. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF- 16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11- defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
    DOI:  https://doi.org/10.1101/2025.05.28.656437
  19. JACC Basic Transl Sci. 2025 Jun 10. pii: S2452-302X(25)00221-9. [Epub ahead of print]10(7): 101301
    ATP-Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance and Is Depressed in Human Failing Myocardium.
    Mariam Meddeb, Navid Koleini, Mohammad Keykhaei, Ting Liu, Marcus Rhodehamel, Lorena Mandarano, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Gizem Keceli, Ismayil Ahmet, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.
      ATP-citrate lyase (ACLY) regulates lipogenesis and cell proliferation, and forms a cytosolic TCA-bypass circuit impacting NADH. We show that acute and chronic ACLY inhibition in cardiomyocytes depresses the NAD+/NADH ratio by increasing mitochondrial NADH. Acute suppression causes dose-dependent cytotoxicity, but at low doses augments aerobic respiration without impeding myocyte function. ACLY is reduced in human failing myocardium, and mice with myocardial or myocyte ACLY knockdown display mildly depressed function, particularly after pressure-overload, and exertional limitations. NAD+ enhancement ameliorates dysfunction/toxicity from ACLY inhibition. These results reveal that ACLY intrinsically regulates cardiac NAD+/NADH balance and respiration, which can affect rest and reserve heart function.
    Keywords:  TCA cycle; heart disease; metabolism; myocardium; redox; reductive stress
    DOI:  https://doi.org/10.1016/j.jacbts.2025.04.015
  20. bioRxiv. 2025 May 28. pii: 2025.05.27.656452. [Epub ahead of print]
    Gut microbe-derived lactic acid optimizes host energy metabolism during starvation.
    Jason William Millington, Jamie Alcira Lopez, Amin M Sajjadian, Robert J Scheffler, Brian C DeFelice, William Basil Ludington, Benjamin H Good, Lucy Erin O'Brien, Kerwyn Casey Huang.
      Gut microbes convert dietary compounds into an array of metabolites that can directly provide energy to their host and indirectly impact host metabolism as systemic endocrine signals. Here, we show that gut microbe-derived metabolites can extend Drosophila melanogaster survival during starvation, despite minimal alteration of dietary energy intake. Combining survival assays with mathematical modeling and untargeted metabolomics, we identify a single, dominant mediator of starvation resilience: lactic acid produced by the commensal bacterium Lactiplantibacillus plantarum . We discover that the basis of starvation resilience is not catabolism of lactic acid using lactate dehydrogenase, but rather increased dietary energy yield through lactic acid-driven promotion of oxidative phosphorylation. Our findings emphasize the role of the microbiome as a source of endocrine cues coordinating host metabolism and underscore the potential of microbiome-derived metabolites as therapeutic molecules for manipulating metabolic health and preventing disease.
    DOI:  https://doi.org/10.1101/2025.05.27.656452
  21. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
    Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
    Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020
  22. bioRxiv. 2025 Jun 07. pii: 2025.06.03.657464. [Epub ahead of print]
    Pancreatic cancer cachexia is mediated by PTHrP-driven disruption of adipose de novo lipogenesis.
    Nikita Bhalerao, Yamini Ogoti, Jessica Peura, Calvin Johnson, Qingbo Chen, Ekaterina D Korobkina, Faith N Keller, Maximilian Wengyn, Robert J Norgard, Claire Shamber, Kelsey Klute, Dominick DiMaio, Karine Sellin, Paul M Grandgenett, Rui Li, Michael A Hollingsworth, Adilson Guilherme, Michael P Czech, Richard Kremer, Lihua Julie Zhu, Emma V Watson, Marcus Ruscetti, David A Guertin, Jason R Pitarresi.
      Pancreatic cancer patients have the highest rates and most severe forms of cancer cachexia, yet cachexia etiologies remain largely elusive, leading to a lack of effective intervening therapies. PTHrP has been clinically implicated as a putative regulator of cachexia, with serum PTHrP levels correlating with increased weight loss in PDAC patients. Here we show that cachectic PDAC patients have high expression of tumor PTHrP and use a genetically engineered mouse model to functionally demonstrate that deletion of Pthlh (encoding the PTHrP protein) blocks cachectic wasting, dramatically extending overall survival. The re-expression of PTHrP in lowly cachectic models is sufficient to induce wasting and reduce survival in mice, which is reversed by the conditional deletion of the PTHrP receptor, Pth1r , in adipocytes. Mechanistically, tumor-derived PTHrP suppresses de novo lipogenesis in adipocytes, leading to a molecular rewiring of adipose depots to promote wasting in the cachectic state. Finally, the pharmacological disruption of the PTHrP-PTH1R signaling axis abrogates wasting, highlighting that a targeted disruption of tumor-adipose crosstalk is an effective means to limit cachexia.
    STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is the prototypical cancer type associated with cancer cachexia, a debilitating wasting syndrome marked by adipose tissue loss and muscle atrophy. Herein, we establish that PTHrP is a tumor-derived factor that facilitates cachexia by downregulating de novo lipogenesis in adipocytes and that blocking PTHrP is an effective means to limit wasting in preclinical mouse models.
    DOI:  https://doi.org/10.1101/2025.06.03.657464
  23. bioRxiv. 2025 May 29. pii: 2025.05.26.655807. [Epub ahead of print]
    Mitochondrial presequences harbor variable strengths to maintain organellar function.
    Youmian Yan, Baigalmaa Erdenepurev, Ian Collinson, Natalie M Niemi.
      Hundreds of mitochondrial-destined proteins rely on N-terminal presequences for organellar targeting and import. While generally described as positively charged amphipathic helices, presequences lack a consensus motif and thus likely promote the import of proteins into mitochondria with variable efficiencies. Indeed, the concept of presequence "strength" critically underlies biological models such as stress sensing, yet a quantitative analysis of what dictates "strong" versus "weak" presequences is lacking. Furthermore, the extent to which presequence strength affects mitochondrial function and cellular fitness remains unclear. Here, we capitalize on the high-throughput and kinetic nature of the MitoLuc mitochondrial protein import assay to quantify multiple aspects of presequence strength. We find that select presequences, including those that regulate the mitochondrial unfolded protein response (UPR mt ), are sufficient to impart differential import efficiencies during mitochondrial uncoupling. Surprisingly, we find that presequences beyond those classically associated with stress signaling promote highly variable import efficiency in stressed and basal (i.e., non-stressed) conditions in vitro, suggesting that presequence strength may influence a broader array of processes than currently appreciated. We exploit this variability to demonstrate that only presequences that promote robust import in vitro can fully rescue defects in respiratory growth in Complex IV-deficient yeast, suggesting that presequence strength dictates metabolic potential. Collectively, our findings demonstrate that presequence strength can describe numerous metrics, such as total imported protein, maximal import velocity, or sensitivity to uncoupling, suggesting that the annotation of presequences as "weak" versus "strong" requires more nuanced characterization than is typically performed. Importantly, we find that such variability in presequence strength meaningfully affects cellular fitness in processes beyond stress signaling, suggesting that organisms may broadly exploit presequence strength to fine-tune mitochondrial import and thus organellar homeostasis.
    DOI:  https://doi.org/10.1101/2025.05.26.655807
  24. iScience. 2025 Jun 20. 28(6): 112551
    Lifting the veil on tumor metabolism: A GDH1-focused perspective.
    Sisi Zhou, Huaer Wu, Yun Chen, Jiawei Lv, Shufang Chen, Hua Yu, Tiezhu Shi, Xiongjun Wang, Lingyun Xiao.
      Tumors depend on glutamine for energy production, biosynthesis, and redox homeostasis. Glutamate dehydrogenase 1 (GDH1) primarily catalyzes the oxidative deamination of glutamate to α-ketoglutarate (α-KG) and ammonia, utilizing NAD+ or NADP+ as cofactors. α-KG is a tricarboxylic acid (TCA) cycle intermediate at the nexus of multiple metabolic pathways, fueling the TCA cycle for energy production or providing intermediates essential for lipid, amino acid, and nucleotide synthesis. Its derivatives, succinate and fumarate, function as oncometabolites that promote tumor progression through diverse mechanisms. Additionally, α-KG is an essential cofactor for α-KG-dependent dioxygenases (2-OGDDs), regulating epigenetic modifications that drive tumorigenesis. GDH1 may also catalyze the reductive amination of α-KG to glutamate under glutamine deprivation or hypoxic conditions. The roles of GDH1 in tumors are context-dependent, influencing progression through metabolic and epigenetic mechanisms. This review discusses GDH1's multifaceted functions and advances in targeting it for cancer therapy.
    Keywords:  Cancer
    DOI:  https://doi.org/10.1016/j.isci.2025.112551
  25. PNAS Nexus. 2025 Jun;4(6): pgaf178
    Mitochondrial PTRH2 controls the deubiquitinase TRABID to regulate mt-ND5 stability and metabolism.
    Carlotta Giorgi, Femke J Aan, Natalija Glibetic, Daniela Ramaccini, Lorenzo Modesti, Veronica A M Vitto, Vanessa Montoya-Uribe, Austin Corpuz, Sonia Missiroli, Inês Simões, Yaiza Potes, Mariusz R Wieckowski, Joe W Ramos, Paolo Pinton, Michelle L Matter.
      The integrin effector, PTRH2, associates with mitochondria in adherent cells where its function has not been elucidated (Jan Y, et al. 2004. A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors. Cell. 116:751-762; Griffiths GS, et al. 2011. Bit-1 mediates integrin-dependent cell survival through activation of the NF{kappa}B pathway. J Biol Chem. 286:14713-14723). PTRH2 loss-of-function mutations cause multisystem disease in children through an unknown mechanism. We sought to determine the role of mitochondrial PTRH2. We used immunoprecipitation/mass spectrometric proteomics to identify PTRH2 interacting partners: TRABID (a deubiquitinase [DUB]) and respiratory complex I NADH: ubiquinone oxidoreductase core subunit 5 (mt-ND5). We show for the first time that mitochondrial PTRH2 regulates TRABID's ability to deubiquitylate mt-ND5. In cells lacking PTRH2 expression, mt-ND5 stability is significantly increased due to aberrant TRABID-mediated deubiquitylation of mt-ND5. This increase in mt-ND5 stability promotes complex I activity and ATP production, which under stress conditions leads to mitochondrial Ca2+ overload. Reexpression of mitochondrial PTRH2 blocks TRABID-mediated mt-ND5 deubiquitylation, resulting in mt-ND5 polyubiquitylation and proteasomal degradation. Inhibiting complex I or TRABID activity rescued PTRH2 loss-of-function mutant patient cells from mitochondrial Ca2+ overload under stress. Immunostaining analysis of ptrh2+/+ and ptrh2-/- mouse skeletal muscle revealed a negative relationship between PTRH2 and mt-ND5, confirming a regulatory role for PTRH2 in controlling mt-ND5 stability. Taken together, mitochondrial PTRH2 is a regulator of metabolic homeostasis that, when lost, promotes mitochondrial Ca2+ overload when cells are exposed to stress signals. Targeting mt-ND5 stability through PTRH2-mediated regulation of TRABID's DUB function provides a novel mechanistic approach to inhibit mitochondrial Ca2+ overload in diseases that occur due to dysregulated mitochondria.
    Keywords:  PTRH2; TRABID; metabolism; mitochondrial Ca2+ overload; mt-ND5
    DOI:  https://doi.org/10.1093/pnasnexus/pgaf178
  26. Integr Comp Biol. 2025 Jun 13. pii: icaf092. [Epub ahead of print]
    Sexual selection, energetics and ecological innovation: How sexual selection diversifies the landscape of behavior, morphology and physiology.
    Ummat Somjee, Matthew J Fuxjager, Purnati Khuntia, Rebecca E Koch, Luke Larter, Noah T Leith, Venkatesh Nagarajan-Radha, Alexandre V Palaoro, Anusha Shankar, Yash Sondhi, Silu Wang, Michael J Ryan, Justin C Havird.
      Sexual selection drives the evolution of a broad diversity of traits such as the enlarged claws of fiddler crabs, the high-energy behavioral displays of hummingbirds, the bright red plumage of house finches, the elaborated antennae of moths, the wing "snapping" displays of manakins, and the calculated calls of túngara frogs. A majority of work in sexual selection has aimed to measure the magnitude of these traits. Yet, we know surprisingly little about the physiology shaping such a diversity of sexually selected behavior and supportive morphology. The energetic properties underlying sexual signals are ultimately fueled by metabolic machinery at multiple scales, from mitochondrial properties and enzymatic activity to hormonal regulation and the modification of muscular and neural tissues. However, different organisms have different physiological constraints and face various ecological selection pressures; thus, selection operates and interacts at multiple scales to shape sexually selected traits and behavior. In this perspective piece, we describe illustrative case studies in different organisms to emphasize that understanding the physiological and energetic mechanisms that shape sexual traits may be critical to understanding their evolution and ramifications with ecological selection. We discuss: 1) the way sexual selection shapes multiple integrated components of physiology, behavior and morphology, 2) the way that sexually selected carotenoid pigments may reflect some aspects of cellular processes, 3) the relationship between sexually selected modalities and energetics, 4) the hormone ecdysone and its role in shaping sex-specific phenotypes in insects, 5) the way varied interaction strategies and social contexts select for signalling strategies that are responsive to social scenes, 6) the role that sexual selection may have in the exploitation of novel thermal niches. Our major objective is to describe how sexually selected behavior, physiology, and ecology are shaped in diverse organisms so that we may develop a deeper and more integrated understanding of sexual trait evolution and its ecological consequences.
    DOI:  https://doi.org/10.1093/icb/icaf092
  27. Res Sq. 2025 Jun 04. pii: rs.3.rs-6636875. [Epub ahead of print]
    Fatty Acid Oxidation Fuels Mitochondrial Respiration to Drive Epidermal Stem Cell Fate and Barrier Regeneration.
    Anna Mandinova, Kristina Todorova, Stefano Sol, Fabiana Boncimino, Andrea Clocchiatti, Kazuki Takagaki, Enkhtuul Gantumur, Mihaela Ruseva, Meaghan Cadieux, Michelle Liu, Victor Neel, Amy Colwell, Christine Lian, George Murphy, Peter Carmeliet.
      The skin's barrier function relies on the epidermis, whose structural integrity is maintained by basal stem cells that continuously renew and differentiate to form the multilayered epidermal architecture. Disruptions in epidermal differentiation underlie numerous hyperproliferative and inflammatory skin disorders. While transcriptional and epigenetic mechanisms are known to regulate the late stages of this process, the molecular events driving the early commitment to differentiation remain elusive. Here, we reveal that early mitochondrial reprogramming, characterized by the activation of oxidative phosphorylation (OXPHOS), is a critical determinant of differentiation initiation. Our findings identify fatty acid oxidation (FAO) as the primary metabolic pathway fueling OXPHOS during this process. Pharmacological and genetic inhibition of FAO, both in vitro and in vivo, disrupts differentiation and compromises the regeneration of the epidermal barrier, causing defective responses to physical insults. Mechanistically, FAO enables ATP production in committed epidermal cells to support the high energy demand of the differentiation process, establishing a direct link between lipid metabolism and epidermal homeostasis. These results uncover a previously unrecognized role for metabolic reprogramming in epidermal stem cell fate and highlight FAO as a novel target for therapeutic interventions to restore barrier function in pathological conditions.
    DOI:  https://doi.org/10.21203/rs.3.rs-6636875/v1
  28. Cancers (Basel). 2025 May 26. pii: 1773. [Epub ahead of print]17(11):
    Potential of Metabolic MRI to Address Unmet Clinical Needs in Localised Kidney Cancer.
    Ines Horvat-Menih, Grant D Stewart, Ferdia A Gallagher.
      Renal cell carcinoma (RCC) is a major global health issue with an increasing incidence and mortality rate. Current diagnostic methods are either invasive or limited in their ability to accurately differentiate between benign and malignant tumours and to predict early treatment response. This can lead to incorrect diagnosis, delayed treatment, patient anxiety, and suboptimal outcomes. RCC subtypes are known to exhibit distinct metabolic alterations, for example in glucose metabolism. These metabolic phenotypes offer potential targets for non-invasive imaging techniques to improve diagnosis and treatment, but current clinically available metabolic imaging tools such as 18F-FDG-PET and 99mTc-sestamibi SPECT have limitations. Therefore, new approaches are required to assess this metabolism, and novel metabolic MRI techniques including hyperpolarised [1-13C]pyruvate MRI and deuterium metabolic imaging offer promising alternatives. These techniques are non-radioactive, demonstrate spatial metabolic heterogeneity, and can probe metabolic flux beyond tracer uptake. This review aims to explore the potential of metabolic MRI in the clinical management of RCC by (1) summarising current clinical guidelines; (2) reviewing metabolic heterogeneity across RCC subtypes; (3) discussing the potential of metabolic MRI to advance the understanding of in vivo metabolism; (4) and finally suggesting future directions for research in this field.
    Keywords:  deuterium metabolic imaging; hyperpolarised [1-13C]pyruvate MRI; metabolic heterogeneity; renal cell carcinoma; renal mass biopsy; renal oncocytoma; sodium MRI; treatment response
    DOI:  https://doi.org/10.3390/cancers17111773
  29. Nat Genet. 2025 Jun;57(6): 1478-1492
    Chromothripsis-associated chromosome 21 amplification orchestrates transformation to blast-phase MPN through targetable overexpression of DYRK1A.
    Charlotte K Brierley, Bon Ham Yip, Giulia Orlando, Jeremy Wen, Sean Wen, Harsh Goyal, Max Levine, G Maria Jakobsdottir, Avraam Tapinos, Alex J Cornish, Antonio Rodriguez-Romera, Alba Rodriguez-Meira, Matthew Bashton, Angela Hamblin, Sally Ann Clark, Joseph C Hamley, Olivia Fox, Madalina Giurgiu, Jennifer O'Sullivan, Lauren Murphy, Assunta Adamo, Aude Anais Olijnik, Anitria Cotton, Emily Hendrix, Shilpa Narina, Shondra M Pruett-Miller, Amir Enshaei, Claire Harrison, Mark Drummond, Steven Knapper, Ayalew Tefferi, Iléana Antony-Debré, James Davies, Anton G Henssen, Supat Thongjuea, David C Wedge, Stefan N Constantinescu, Elli Papaemmanuil, Bethan Psaila, John D Crispino, Adam J Mead.
      Chromothripsis, the chaotic shattering and repair of chromosomes, is common in cancer. Whether chromothripsis generates actionable therapeutic targets remains an open question. In a cohort of 64 patients in blast phase of a myeloproliferative neoplasm (BP-MPN), we describe recurrent amplification of a region of chromosome 21q ('chr. 21amp') in 25%, driven by chromothripsis in a third of these cases. We report that chr. 21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. DYRK1A, a serine threonine kinase, is the only gene in the 2.7-megabase minimally amplified region that showed both increased expression and chromatin accessibility compared with non-chr. 21amp BP-MPN controls. DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development and is essential for BP-MPN cell proliferation in vitro and in vivo, and represents a druggable axis. Collectively, these findings define chr. 21amp as a prognostic biomarker in BP-MPN, and link chromothripsis to a therapeutic target.
    DOI:  https://doi.org/10.1038/s41588-025-02190-6
  30. Curr Opin Cell Biol. 2025 Jun 07. pii: S0955-0674(25)00085-7. [Epub ahead of print]95 102547
    Nutrient sensing and signalling of specific amino acids: Insights from Drosophila study.
    Ayano Oi, Fumiaki Obata.
      Maintaining amino acid (AA) homeostasis is necessary for organisms. To achieve this, organisms have evolved various signalling pathways regulated by sensing general or specific AA levels. Recently, advances in genetic and dietary manipulation have shed light upon how these AA signalling pathways regulate organismal physiology, metabolism, behaviour, and lifespan. However, elucidating the detailed mechanisms by which each AA is sensed and influences an animal's life is challenging. In some model organisms such as Drosophila melanogaster, chemically defined diet has been developed to manipulate single nutrients, which enables us to study the organismal response to dietary restriction of particular AAs. In this review, we aim to discuss the latest findings on animals' responses to dietary AAs, with a focus on recent studies in Drosophila.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102547
  31. Dev Cell. 2025 May 30. pii: S1534-5807(25)00319-3. [Epub ahead of print]
    AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
    Yann Cormerais, Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Jong Shin, Benjamin Stefadu, Jean Personnaz, Sandra Schrötter, Jessica Freed, Angelica D'Amore, Emma R Martin, Catherine L Salussolia, Mustafa Sahin, Suchithra Menon, Vanessa Byles, Brendan D Manning.
      Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.
    Keywords:  PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase
    DOI:  https://doi.org/10.1016/j.devcel.2025.05.008
  32. Nature. 2025 Jun 11.
    Early life high fructose impairs microglial phagocytosis and neurodevelopment.
    Zhaoquan Wang, Allie Lipshutz, Celia Martínez de la Torre, Alissa J Trzeciak, Zong-Lin Liu, Isabella C Miranda, Tomi Lazarov, Ana C Codo, Jesús E Romero-Pichardo, Achuth Nair, Tanya Schild, Waleska Saitz Rojas, Pedro H V Saavedra, Ann K Baako, Kelvin Fadojutimi, Michael S Downey, Frederic Geissmann, Giuseppe Faraco, Li Gan, Jon Iker Etchegaray, Christopher D Lucas, Marina Tanasova, Christopher N Parkhurst, Melody Y Zeng, Kayvan R Keshari, Justin S A Perry.
      Despite the success of fructose as a low-cost food additive, epidemiological evidence suggests that high fructose consumption during pregnancy or adolescence is associated with disrupted neurodevelopment1-3. An essential step in appropriate mammalian neurodevelopment is the phagocytic elimination of newly formed neurons by microglia, the resident professional phagocyte of the central nervous system4. Whether high fructose consumption in early life affects microglial phagocytosis and whether this directly affects neurodevelopment remains unknown. Here we show that offspring born to female mice fed a high-fructose diet and neonates exposed to high fructose exhibit decreased phagocytic activity in vivo. Notably, deletion of the high-affinity fructose transporter GLUT5 (also known as SLC2A5) in neonatal microglia completely reversed microglia phagocytic dysfunction, suggesting that high fructose directly affects neonatal development by suppressing microglial phagocytosis. Mechanistically, we found that high-fructose treatment of mouse and human microglia suppresses phagocytosis capacity, which is rescued in GLUT5-deficient microglia. Additionally, we found that high fructose drives significant GLUT5-dependent fructose uptake and catabolism to fructose 6-phosphate, rewiring microglial metabolism towards a hypo-phagocytic state in part by enforcing mitochondrial localization of the enzyme hexokinase 2. Mice exposed to high fructose as neonates develop anxiety-like behaviour as adolescents-an effect that is rescued in GLUT5-deficient mice. Our findings provide a mechanistic explanation for the epidemiological observation that high-fructose exposure during early life is associated with increased prevalence of adolescent anxiety disorders.
    DOI:  https://doi.org/10.1038/s41586-025-09098-5
  33. bioRxiv. 2025 May 31. pii: 2025.05.27.656381. [Epub ahead of print]
    Hormetic elevation of taurine restrains inflammaging by deactivating the NLRP3 inflammasome.
    Chenyang Guan, Seungjin Ryu, Mingze Dong, Yun-Hee Youm, Subhasis Mohanty, Rae Maeda, Lucie Orliaguet, Hee-Hoon Kim, Tamara Dlugos, Steven R Smith, Eric Ravussin, Janset Onyuru, Andrew Wang, Albert C Shaw, Hal M Hoffman, Yuval Kluger, Yuki Sugiura, Vishwa Deep Dixit.
      Taurine, the most abundant sulfonic amino acid in humans is largely obtained from diets rich in animal proteins. However, taurine is dietary non-essential because it can be synthesized from cysteine by activation of transsulfuration pathway (TSP) when food consumption is low or if the diet is predominantly plant based. The decline of taurine was proposed as the driver of aging through an undefined mechanism. Here, we found that mild food restriction in humans for one year that resulted in 14% reduction of calorie intake elevated the hypotaurine and taurine concentration in adipose tissue. Therefore, we investigated whether elevated taurine mimics caloric-restriction's beneficial effects on inflammation, a key mechanism of aging. Interestingly, aging increased the circulating and tissue concentrations of taurine suggesting that elevated taurine may serve as a hormetic stress response metabolite that regulates mechanism of age-related inflammation. The elevated taurine protected mice against mortality from sepsis and inhibited inflammasome-driven inflammation and gasdermin-D (GSDMD) mediated pyroptosis. Mechanistically, 'danger signals' including hypotonicity that activate NLRP3-inflammasome, caused upstream taurine efflux from macrophages, which triggered potassium (K + ) release and downstream canonical NLRP3 inflammasome assembly, caspase-1 activation, GSDMD cleavage and IL-1β and IL-18 secretion that was reversed by taurine restoration. Notably, taurine does not efflux from GSDMD pore and inhibited IL-1β from macrophages independently of known transporters SLC6A6 and SLC36A1. Increased taurine in old mice promotes healthspan by inducing anti-inflammatory pathways previously linked to youthfulness. These findings demonstrate that taurine is an upstream metabolic sensor of cellular perturbations that control NLRP3 inflammasome and lowers age-related inflammation.
    DOI:  https://doi.org/10.1101/2025.05.27.656381
  34. Autophagy. 2025 Jun 12.
    Tumorous cholesterol biosynthesis curtails anti-tumor immunity by preventing MTOR-TFEB-mediated lysosomal degradation of CD274/PD-L1.
    Huina Wang, Xiuli Yi, Di Qu, Xiangxu Wang, Hao Wang, Hengxiang Zhang, Yuqi Yang, Tianwen Gao, Weinan Guo, Chunying Li.
      Enhanced cholesterol biosynthesis is a hallmark metabolic characteristic of cancer, exerting an oncogenic role by supplying intermediate metabolites that regulate intracellular signaling pathways. The pharmacological blockade of cholesterol biosynthesis has been well documented as a promising therapeutic approach in cancer. Particularly, cholesterol biosynthesis is linked to macroautophagy/autophagy and lysosome metabolism, with the engagement of the critical autophagy regulators like MTOR to be fully activated by lysosomal cholesterol trafficking and accumulation. Previous studies have primarily focused on the role of cholesterol biosynthesis in tumor cell-intrinsic biological processes, whereas its involvement in tumor immune evasion and the underlying mechanisms related to autophagy or lysosome metabolism remain elusive. Herein, through bioinformatics analysis we discovered a negative correlation between cholesterol biosynthesis and the score of tumor-infiltrating lymphocytes in cancers. Inhibition of tumor cell cholesterol biosynthesis leads to increased infiltration and activation of CD8+ T cells in the tumor microenvironment, which is largely responsible for the impairment of tumor growth. Mechanistically, cholesterol biosynthesis inhibition impairs the activation of MTOR at lysosomes, thereby promoting the nuclear translocation of TFEB and downstream lysosome biosynthesis, facilitating the degradation of CD274/PD-L1 within lysosomes in tumor cells. Ultimately, the HMGCR-MTOR-LAMP1 axis that connects cholesterol, lysosome and tumor immunology, predicts poor response to immunotherapy and worse prognosis of patients with melanoma. These findings unveil an immunomodulatory role of tumorous cholesterol biosynthesis via the regulation of CD274 lysosomal degradation. Targeting cholesterol biosynthesis holds promise as a potential therapeutic strategy in cancer, particularly when combined with immune checkpoint blockade.
    Keywords:  Cholesterol; PD-L1; TFEB; immune evasion; lysosome; protein degradation
    DOI:  https://doi.org/10.1080/15548627.2025.2519066
  35. Biochim Biophys Acta Mol Cell Res. 2025 Jun 06. pii: S0167-4889(25)00103-X. [Epub ahead of print] 119998
    Impact of PARL-mediated mitochondrial protease activity on calcium regulation.
    Donato D'Angelo, Aya Al Saidi, Giorgia Ghirardo, Denis Vecellio Reane, Nicola Gasparini, Rosario Rizzuto, Anna Raffaello.
      The presenilin-associated rhomboid-like protein (PARL) is a mitochondrial inner membrane serine protease that is a key regulator of several cellular processes, including apoptosis, metabolism, inflammation and stress responses. While recent studies suggest that PARL may play a role in mitochondrial calcium homeostasis, the underlying mechanisms remain poorly understood. In this study, we investigated the effects of PARL modulation on mitochondrial and cytosolic calcium dynamics, as well as mitochondrial membrane potential. Our results show that altering PARL protein levels, through both overexpression and silencing, significantly affects mitochondrial calcium uptake, without influencing cytosolic calcium transients or mitochondrial membrane potential. Despite the observed changes in mitochondrial calcium dynamics, PARL does not interact with the mitochondrial calcium uniporter complex (mtCU) regulators MICU1 and MICU2, which are critical for regulating mitochondrial calcium influx. However, we observed alterations in the protein levels of MICU1 and MICU2, either in their monomeric or dimeric forms, suggesting that PARL may influence these mtCU components indirectly. Interestingly, the pore-forming subunit MCU, and the structural subunit EMRE, essential for the assembly of the mtCU, were unaffected by PARL modulation. These findings suggest that the role of PARL in modulating mitochondrial calcium homeostasis may involve indirect mechanisms, potentially involving other regulatory pathways. Overall, our study provides novel insights into the functional role of PARL in mitochondrial calcium regulation, offering potential avenues for further investigation into its broader cellular functions.
    Keywords:  Calcium signaling; Mitochondria; Mitochondrial calcium uniporter; Mitochondrial intermembrane proteolysis; PARL; Rhomboid protease
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119998
  36. Cell Host Microbe. 2025 Jun 11. pii: S1931-3128(25)00200-8. [Epub ahead of print]33(6): 808-819
    Origins and functions of microbiome rhythms.
    Silke Kiessling, Shuaitong Liu, Dirk Haller, Christoph A Thaiss.
      Daily oscillations in microbiota composition and function are emerging as an important element in host-microbiota interactions. Here, we summarize features of the microbiota that undergo diurnal rhythms, their development, their impact on the biology of the host, and their relevance to human health and disease. In particular, we focus on the intrinsic and extrinsic factors that regulate microbiota oscillations and the multifaceted roles that microbiota rhythmicity plays in host physiology, immunity, and metabolism. Given the pervasive impact of intestinal microorganisms on host health, understanding the origins and functions of microbiota rhythms is a critical aspect of the circadian biology of the meta-organism.
    Keywords:  circadian; clock; diet; disease; immune system; metabolism; microbiome; oscillations; rhythms
    DOI:  https://doi.org/10.1016/j.chom.2025.05.017
  37. bioRxiv. 2025 May 27. pii: 2025.05.26.656235. [Epub ahead of print]
    PFKFB2 is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
    Kylene M Harold, Satoshi Matsuzaki, Atul Pranay, Jie Zhu, Anna Faakye, Kenneth M Humphries.
       Background: The heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here we examined how cardiac mitochondrial flexibility and the post-translational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
    Methods: cKO and litter-matched controls (CON) were sacrificed in the fed or fasted (12 hours) states, with or without a 20 minute stimulant stress of caffeine and epinephrine.Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
    Results: cKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and CPT1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
    Conclusions: PFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.
    Graphic Abstract:
    Research Perspective: This study raises and answers three key questions: how PFKFB2 contributes to cardiac mitochondrial metabolic flexibility, how post-prandial status regulates O-GlcNAcylation in a PFKFB2-dependent manner, and how altered cardiac glucose use impacts systemic glucose homeostasis under stress.These findings highlight a novel role for nutrient state in regulating cardiac metabolism, and especially O-GlcNAcylation, with PFKFB2 loss.Future studies should investigate whether reducing O-GlcNAcylation through fasting is sufficient to ameliorate pathological changes observed in the absence of PFKFB2.
    DOI:  https://doi.org/10.1101/2025.05.26.656235
  38. Nature. 2025 Jun 11.
    Various cell types in tissues cooperate in networks that are disrupted in disease.
    Mirjana Efremova.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01455-8
  39. Nat Immunol. 2025 Jun 10.
    Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment.
    Jing Jin, Peidong Yan, Dongyao Wang, Lin Bai, Hao Liang, Xiaoyu Zhu, Huaiping Zhu, Chen Ding, Haiming Wei, Yi Wang.
      Dysfunction of natural killer (NK) cells can be associated with tumor-derived lactate in the tumor microenvironment. Lactate-induced lysine lactylation (Kla) is a posttranslational modification, and strategies aimed at augmenting NK cell resistance to Kla might enhance cytotoxicity. Here we show that increased Kla levels in NK cells are accompanied by impaired nicotinamide adenine dinucleotide metabolism, fragmented mitochondria and reduced cytotoxicity. Supplementation with nicotinamide riboside (a nicotinamide adenine dinucleotide precursor) and honokiol (a SIRT3 activator) enhanced NK cell cytotoxicity by reducing cellular Kla levels. This combination restores antileukemic activity of NK cells in vivo and ex vivo by modulating Kla on ROCK1, thereby inhibiting ROCK1-DRP1 signaling to prevent mitochondrial fragmentation. Altogether, this study shows how lactylation can compromise NK cells and highlights this lactylation as a target for NK cell-based immunotherapy to enhance resilience to lactate in the tumor microenvironment.
    DOI:  https://doi.org/10.1038/s41590-025-02178-8
  40. Nat Metab. 2025 Jun 11.
    A food-sensitive olfactory circuit drives anticipatory satiety.
    Janice Bulk, Joscha N Schmehr, Tobias Ackels, Rui de Oliveira Beleza, André Carvalho, Ayden Gouveia, Lionel Rigoux, Vincent Hellier, Anna Lena Cremer, Heiko Backes, Andreas Schaefer, Sophie M Steculorum.
      Food sensory perception has emerged as a potent regulator of specialized feeding circuits; yet, the consequences on feeding behaviour and the underlying neuronal basis remain poorly understood. Here, we reveal a sensory pathway that co-ordinately integrates food odours to control forthcoming nutrient intake in male mice. Unbiased whole-brain mapping of food odour-induced brain activity revealed a potent activation of the medial septum (MS), where food odours selectively activate MS glutamatergic neurons (MSVGLUT2). Activity dynamics of MSVGLUT2 neurons uncovered a biphasic modulation of their neuronal activity with a transient activation after detection of food odours and a long-lasting inhibition following food ingestion, independent of the caloric value and identity of the food. MSVGLUT2 neurons receive direct projections from the olfactory bulb (OB) and acute optogenetic stimulation of OB→MS projections selectively before food ingestion decreased feeding in lean mice. However, acute OB→MS optogenetic stimulation in diet-induced obese mice failed to reduce feeding, suggesting the involvement of this pathway in calorie-rich diet-induced hyperphagia and obesity development. Altogether, our study uncovered a sensory circuit by which the organism integrates olfactory food cues to prime satiety at the outset of a meal.
    DOI:  https://doi.org/10.1038/s42255-025-01301-1
  41. Cell Rep. 2025 Jun 06. pii: S2211-1247(25)00563-7. [Epub ahead of print]44(6): 115792
    Cholesterol metabolism regulated by CAMKK2-CREB signaling promotes castration-resistant prostate cancer.
    Chenchu Lin, Thomas L Pulliam, Jenny J Han, Jiaqian Xu, Carlos Vera Recio, Sandi R Wilkenfeld, Yan Shi, Manoj Kushwaha, Sarah Bench, Eduardo Ruiz, Sanjanaa Senthilkumar, Jayasurya Dileep, Peter D A Shepherd, Nora M Navone, Albert R Klekers, Elizabeth M Whitley, Michael M Ittmann, Livia S Eberlin, Wenyi Wang, Daniel E Frigo.
      Castration-resistant prostate cancer (CRPC) remains an incurable disease in need of improved treatments. CAMKK2 is an emerging therapeutic target whose oncogenic effects in prostate cancer have, to date, been largely attributed to its activation of AMP-activated protein kinase (AMPK). Here, we demonstrate that CAMKK2 promotes prostate cancer growth through an alternative downstream pathway involving CAMKI and CREB. Unbiased transcriptomics identify CREB-mediated transcription as a CAMKK2-regulated process, findings that we validate using diverse molecular, genetic, and pharmacological approaches in vitro and in vivo. CAMKK2 promotes CREB phosphorylation/activation through CAMKIα independently of AMPK, CAMKIV, or other CAMKI isoforms. Functionally, the CREB family members CREB1 and ATF1 exhibit close redundancy, necessitating co-targeting for optimal anti-tumor efficacy. An inhibitor of CREB1/ATF1 blocks CRPC with minimal side effects. Mechanistically, CAMKK2 and CREB increase CRPC growth through augmenting cholesterol metabolism. Together, these findings identify an oncogenic pathway that could be exploited for the treatment of CRPC.
    Keywords:  AMPK; CAMKI; CAMKK2; CP: Cancer; CP: Metabolism; CREB; androgen receptor; cholesterol; metabolism; prostate cancer
    DOI:  https://doi.org/10.1016/j.celrep.2025.115792
  42. Nature. 2025 Jun 12.
    How you breathe is like a fingerprint that can identify you.
    Humberto Basilio.
      
    Keywords:  Computer science; Human behaviour; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-01835-0
  43. Nat Commun. 2025 Jun 06. 16(1): 5266
    Aging and diet alter the protein ubiquitylation landscape in the mouse brain.
    Antonio Marino, Domenico Di Fraia, Diana Panfilova, Amit Kumar Sahu, Alberto Minetti, Omid Omrani, Emilio Cirri, Alessandro Ori.
      Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging.
    DOI:  https://doi.org/10.1038/s41467-025-60542-6
  44. Cell Syst. 2025 Jun 03. pii: S2405-4712(25)00100-0. [Epub ahead of print] 101267
    Uncovering the principles coordinating systems-level organelle biogenesis with cellular growth.
    Shixing Wang, Deepthi Kailash, Shankar Mukherji.
      A complete framework of eukaryotic cellular growth control must include the growth of its defining hallmarks: organelles. Organelle coordination with cellular growth is opaque without measuring multiple organelles in the same cell with adequate statistics to test theoretical frameworks. Here, we map out the correlation structure of systems-level organelle biogenesis with cellular growth using "rainbow yeast," simultaneously visualizing 6 major metabolically active organelles. Hyperspectral imaging of thousands of rainbow yeast cells revealed that systems-level organelle biogenesis is organized into collective organelle modes activated by changes in nutrient availability. Chemical biological dissection suggests that sensed growth rate and cell size specifically activate these organelle modes. Mathematical modeling and synthetic control of cytoplasmic availability suggest that the organelle mode structure allows growth homeostasis in constant environments and responsiveness to environmental change. This regulatory architecture may underlie how compartmentalization allows cell size and growth rate flexibility to satisfy otherwise incompatible environmental and developmental constraints.
    Keywords:  cellular growth; hyperspectral imaging; mathematical modeling; organelle biogenesis; systems cell biology
    DOI:  https://doi.org/10.1016/j.cels.2025.101267
  45. Cell. 2025 Jun 09. pii: S0092-8674(25)00565-3. [Epub ahead of print]
    The microbiome diversifies long- to short-chain fatty acid-derived N-acyl lipids.
    Helena Mannochio-Russo, Vincent Charron-Lamoureux, Martijn van Faassen, Santosh Lamichhane, Wilhan D Gonçalves Nunes, Victoria Deleray, Adriana V Ayala, Yuichiro Tanaka, Abubaker Patan, Kyle Vittali, Prajit Rajkumar, Yasin El Abiead, Haoqi Nina Zhao, Paulo Wender Portal Gomes, Ipsita Mohanty, Carlynda Lee, Aidan Sund, Meera Sharma, Yuanhao Liu, David Pattynama, Gregory T Walker, Grant J Norton, Lora Khatib, Mohammadsobhan S Andalibi, Crystal X Wang, Ronald J Ellis, David J Moore, Jennifer E Iudicello, Donald Franklin, Scott Letendre, Loryn Chin, Corinn Walker, Simone Renwick, Jasmine Zemlin, Michael J Meehan, Xinyang Song, Dennis Kasper, Zachary Burcham, Jane J Kim, Sejal Kadakia, Manuela Raffatellu, Lars Bode, Hiutung Chu, Karsten Zengler, Mingxun Wang, Dionicio Siegel, Rob Knight, Pieter C Dorrestein.
      N-Acyl lipids are important mediators of several biological processes including immune function and stress response. To enhance the detection of N-acyl lipids with untargeted mass spectrometry-based metabolomics, we created a reference spectral library retrieving N-acyl lipid patterns from 2,700 public datasets, identifying 851 N-acyl lipids that were detected 356,542 times. 777 are not documented in lipid structural databases, with 18% of these derived from short-chain fatty acids and found in the digestive tract and other organs. Their levels varied with diet and microbial colonization and in people living with diabetes. We used the library to link microbial N-acyl lipids, including histamine and polyamine conjugates, to HIV status and cognitive impairment. This resource will enhance the annotation of these compounds in future studies to further the understanding of their roles in health and disease and to highlight the value of large-scale untargeted metabolomics data for metabolite discovery.
    Keywords:  HIV; MASST; MassQL; N-acyl lipids; SCFA; metabolomics data mining; microbial; neurocognitive impairment; repository-scale analysis; short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.cell.2025.05.015
  46. Cancer Cell. 2025 Jun 04. pii: S1535-6108(25)00215-6. [Epub ahead of print]
    Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy.
    Alexander Benton, Jiageng Liu, Mathilde A Poussin, Andrea Lang Goldgewicht, Madhara Udawela, Adham S Bear, Nils Wellhausen, Beatriz M Carreno, Pete M Smith, Matthew D Beasley, Ben R Kiefel, Daniel J Powell.
      Despite the success of chimeric antigen receptor (CAR)-T cell therapies in hematological malignancies, clinical success against solid tumors is limited due to low therapeutic efficacy or dose-limiting toxicity. Developing therapies that trigger potent, yet manageable, immune responses capable of eliminating highly heterogeneous and immunosuppressive tumor cell populations remains a key challenge. Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS G12V mutations presented by peptide-MHC complexes. Subsequently, we incorporate these neoantigen binders into CAR-T cells (mKRAS NeoCARs) and demonstrate their efficacy in xenograft models of metastatic lung, pancreatic, and renal cell cancer. Finally, we enhance the in vivo efficacy and safety profile of mKRAS NeoCARs via inducible secretion of IL-12 and T cell receptor deletion. Together, these screening and engineering processes provide a modular platform for expanding the therapeutic index of cellular immunotherapies that target cancer.
    Keywords:  CART; CRISPR; IL-12; KRAS; T cell; armored CAR; cellular immunotherapy; neo-antigen; peptide; solid tumors; therapeutic index
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.006
  47. Cell. 2025 Jun 03. pii: S0092-8674(25)00563-X. [Epub ahead of print]
    Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.
    Joseph Stevens, Erica Culberson, Jeremy Kinder, Alicia Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-Yu Shao, Faris Al Gharaibeh, Laura Peterson, Shelby Steinmeyer, Emily M Eshleman, Shikha Negi, William Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh.
      Early-life susceptibility to respiratory viral infections remains a major public health concern, yet the underlying mechanisms are poorly understood. We demonstrate that antibiotic-induced dysbiosis impairs influenza-specific CD8+ T cell immunity in infant mice and humans through the disruption of nuclear factor interleukin 3 (NFIL3)-dependent T cell programming. Mechanistically, we show that dysbiosis reduces intestinal and circulating inosine levels, disrupting NFIL3's epigenetic regulation of T cell factor 1 (TCF1) expression. This leads to intrinsic defects in CD8+ T cell proliferation and differentiation, diminished effector responses, and impaired formation of tissue-resident memory cells. Bifidobacterium colonization restores intestinal and pulmonary inosine levels, establishing a specific pathway of gut-lung metabolic communication. Notably, inosine supplementation rescues NFIL3-dependent regulation of TCF1, enhancing CD8+ T cell responses and protection against influenza infection in dysbiotic infants. Our findings reveal how early-life microbial communities shape antiviral immunity and identify inosine as a therapeutic target for enhancing respiratory defenses in infants.
    Keywords:  T cell responses; immunology; infants; influenza; inosine; microbiota
    DOI:  https://doi.org/10.1016/j.cell.2025.05.013
  48. Nat Rev Drug Discov. 2025 Jun 12.
    Targeting DNA damage in ageing: towards supercharging DNA repair.
    Arturo Bujarrabal-Dueso, George A Garinis, Paul D Robbins, Jan Vijg, Björn Schumacher.
      Ageing is the most important risk factor for many common human diseases, including cancer, diabetes, neurodegeneration and cardiovascular disease. Consequently, combating ageing itself has emerged as a rational strategy for addressing age-related multimorbidity. Over the past three decades, multiple genetic and pharmacologic interventions have led to substantial extension of lifespan and healthspan in model organisms. However, it is unclear whether these interventions target the causal mechanisms of ageing or downstream consequences. Ample evidence suggests that DNA damage to the somatic genome is a major causal mechanism of ageing, which compromises essential cellular functions such as transcription and replication, and leads to cellular senescence, apoptosis and mutations. Recently, new concepts have emerged to target the main consequences of DNA damage and enhance DNA repair capacities, thereby extending maintenance of the genome. Here, we review advances in this field and discuss approaches to pharmacologically mitigate the adverse effects of DNA damage to delay ageing, prevent mutation-driven cancer and mitigate age-related degenerative diseases.
    DOI:  https://doi.org/10.1038/s41573-025-01212-6
  49. Nat Rev Mol Cell Biol. 2025 Jun 10.
    How machine learning can help us understand what we have grown in the dish.
    Roser Vento-Tormo.
      
    DOI:  https://doi.org/10.1038/s41580-025-00868-7
  50. bioRxiv. 2025 Jun 05. pii: 2025.06.02.657195. [Epub ahead of print]
    A genetically encoded bifunctional enzyme mitigates redox imbalance and lipotoxicity via engineered Gro3P-Glycerol shunt.
    Xingxiu Pan, Subrata Munan, Austin L Zuckerman, Andrew Pon, Sara Violante, Justin R Cross, Hardik Shah, Valentin Cracan.
      Dihydroxyacetone phosphate (DHAP), glycerol-3-phosphate (Gro3P) and reduced/oxidized nicotinamide adenine dinucleotide (NADH/NAD + ) are key metabolites of the Gro3P shuttle system that forms a redox circuit, allowing transfer of reducing equivalents between cytosol and mitochondria. Targeted activation of Gro3P biosynthesis was recently identified as a promising strategy to alleviate reductive stress by promoting NAD + recycling, including in cells with an impaired mitochondrial complex I. However, because Gro3P constitutes the backbone of triglycerides under some circumstances, its accumulation can lead to excessive fat deposition. Here, we present the development of a novel genetically encoded tool based on a di-domain glycerol-3-phosphate dehydrogenase from algae Chlamydomonas reinhardtii ( Cr GPDH), which is a bifunctional enzyme that can recycle NAD + while converting DHAP to Gro3P. In addition, this enzyme possesses an N-terminal domain which cleaves Gro3P into glycerol and inorganic phosphate (Pi) (in humans and other organisms, this reaction is catalyzed by a separate glycerol-3-phosphate phosphatase, a reaction also known as "glycerol shunt"). When expressed in mammalian cells, Cr GPDH diminished Gro3P levels and boosted the TCA cycle and fatty acid β-oxidation in mitochondria. Cr GPDH expression alone supported proliferation of HeLa cells under conditions of either inhibited activity of the mitochondrial electron transport chain or hypoxia. Moreover, human kidney cancer cells, which exhibit abnormal lipid accumulation, had decreased triglycerides levels when expressing Cr GPDH. Our findings suggest that the coordinated boosting of both Gro3P biosynthesis and glycerol shunt may be a viable strategy to alleviate consequences of redox imbalance and associated impaired lipogenesis in a wide repertoire of conditions, ranging from primary mitochondrial diseases to obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD).
    DOI:  https://doi.org/10.1101/2025.06.02.657195
  51. iScience. 2025 Jun 20. 28(6): 112567
    IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma.
    Julia L Schnabel, Thomas C Frost, Adam C Wang, Varsha Ananthapadmanabhan, Satvik Gurram, Kara M Soroko, Prafulla C Gokhale, James A DeCaprio.
      The rate-limiting isozyme of de novo guanosine biosynthesis, IMPDH2, was identified as an essential gene in Merkel cell carcinoma (MCC) but the consequences of its functional disruption were unclear. Inhibition of IMPDH2 led to reduced MCC cell viability, independent of functional p53 or Merkel cell polyomavirus status, but dependent on depletion of guanylate nucleotides. In contrast to other cancer models, inhibition of IMPDH2 in MCC led to rapid ablation of nascent DNA synthesis and the onset of replication stress without a significant effect on total or ribosomal RNA biosynthesis. Combining IMPDH inhibitors with ataxia telangiectasia mutated and Rad3-related (ATR) inhibitors significantly increased levels of replication stress in vitro and reduced tumor growth in vivo. These findings support replication stress as the dominant consequence of IMPDH2 inhibition in MCC and, when combined with ATR inhibition, indicate a potential therapeutic strategy.
    Keywords:  Cancer systems biology; Cell biology; Health sciences
    DOI:  https://doi.org/10.1016/j.isci.2025.112567
  52. Nat Aging. 2025 Jun 12.
    Clonal hematopoiesis driven by microbial metabolite.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-025-00912-3
  53. Cell Metab. 2025 Jun 09. pii: S1550-4131(25)00265-7. [Epub ahead of print]
    Derepressing nuclear pyruvate dehydrogenase induces therapeutic cancer cell reprogramming.
    Ting Zhao, Lingli He, Lai Ping Wong, Shenglin Mei, Jun Xia, Yanxin Xu, Jonathan G Van Vranken, Michael Mazzola, Lei Chen, Catherine Rhee, Tiancheng Fang, Tsuyoshi Fukushima, Leanne C Sayles, Matthew Diaz, J Alex B Gibbons, Raul Mostoslavsky, Steven P Gygi, Zhixun Dou, David B Sykes, Ruslan I Sadreyev, E Alejandro Sweet-Cordero, David T Scadden.
      Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-coenzyme A (CoA) constitutes a small fraction of the whole-cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we report a nucleus-specific acetyl-CoA regulatory mechanism that can be modulated to achieve therapeutic cancer cell reprogramming. Combining phenotypic chemical screen, genome-wide CRISPR screen, and proteomics, we identified that the nucleus-localized pyruvate dehydrogenase complex (nPDC) is constitutively inhibited by the nuclear protein ELMSAN1 through direct interaction. Pharmacologic inhibition of the ELMSAN1-nPDC interaction derepressed nPDC activity, enhancing nuclear acetyl-CoA generation and reprogramming cancer cells to a postmitotic state with diminished cell-of-origin signatures. Reprogramming was synergistically enhanced by histone deacetylase 1/2 inhibition, resulting in inhibited tumor growth, durably suppressed tumor-initiating ability, and improved survival in multiple cancer types in vivo, including therapy-resistant sarcoma patient-derived xenografts and carcinoma cell line xenografts. Our findings highlight the potential of targeting ELMSAN1-nPDC as an epigenetic cancer therapy.
    Keywords:  ELMSAN1; HDAC; ISX9; acetyl-CoA metabolism; cancer therapy; compartmentalized metabolism; epigenetic reprogramming; nuclear metabolism; pyruvate dehydrogenase complex; therapeutic reprogramming
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.009
  54. Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00448-4. [Epub ahead of print]85(11): 2065-2067
    No (innate immune) training without lactate.
    Jan Van den Bossche.
      A recent study in Cell unveils lactate production and downstream histone lactylation as a new player in the induction of trained immunity.1 It provides insight into the intricate metabolic-epigenetic interplay that governs innate immune memory and offers a potential target to reverse maladaptive trained immunity in chronic inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.014
  55. Trends Endocrinol Metab. 2025 Jun 11. pii: S1043-2760(25)00123-7. [Epub ahead of print]
    Uridine.
    Julia Ugras, Costas A Lyssiotis.
      
    DOI:  https://doi.org/10.1016/j.tem.2025.05.006
  56. bioRxiv. 2025 Jun 01. pii: 2025.05.29.656153. [Epub ahead of print]
    Ketogenesis is dispensable for the metabolic adaptations to caloric restriction.
    Chung-Yang Yeh, Lexie Borgelt, Brynn J Vogt, Alyssa A Clark, Ted T Wong, Isaac Grunow, Michelle M Sonsalla, Reji Babygirija, Yang Liu, Michaela E Trautman, Mariah F Calubag, Bailey A Knopf, Fan Xiao, Dudley W Lamming.
      Caloric restriction (CR) robustly extends the health and lifespan of diverse species. When fed once daily, CR-treated mice rapidly consume their food and endure a prolonged fast between meals. As fasting is associated with a rise in circulating ketones, we decided to investigate the role of ketogenesis in CR using mice with whole-body ablation of Hmgcs2 , the rate-limiting enzyme producing the main ketone body β-hydroxybutyrate (βHB). Here, we report that Hmgcs2 is largely dispensable for many metabolic benefits of CR, including CR-driven changes in adiposity, glycemic control, liver autophagy, and energy balance. Although we observed sex-specific effects of Hmgcs2 on insulin sensitivity, fuel selection, and adipocyte gene expression, the overall physiological response to CR remains robust in mice lacking Hmgcs2 . To gain insight into why deletion of Hmgcs2 does not disrupt CR, we measured fasting βHB levels as mice began a CR diet. Surprisingly, as CR-fed mice adapt to CR, they no longer engage high levels of ketogenesis during the daily fast. Our work suggests that the benefits of long-term CR in mice are not mediated by ketogenesis.
    DOI:  https://doi.org/10.1101/2025.05.29.656153
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