bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–10–05
47 papers selected by
Christian Frezza, Universität zu Köln



  1. Cancer Res. 2025 Oct 01. OF1-OF3
      Metabolic changes are a major hallmark of cancer with the mitochondrial tricarboxylic acid (TCA) cycle playing a central role in this process. Remodeling of the TCA cycle occurs in cancer cells to sustain the increased anabolic and energetic demands required to grow, proliferate, and metastasize. Alternative splicing (AS) is increasingly recognized as a key regulator of cancer metabolism, yet its specific impact on TCA cycle enzymes remains unclear. In this issue of Cancer Research, Cheung and colleagues describe a novel splicing isoform of citrate synthase (CS), termed CS-ΔEx4, which is highly expressed in colorectal cancer. This CS-ΔEx4 isoform forms heterocomplexes with full-length CS, enhancing CS activity and promoting the metabolic reprogramming characteristic of malignancy. Overexpression of CS-ΔEx4 increases mitochondrial respiration and drives glycolytic carbon flux toward TCA intermediates, resulting in elevated levels of the metabolite 2-hydroxyglutarate. Mechanistically, this increase in 2-hydroxyglutarate, facilitated by increased activity of phosphoglycerate dehydrogenase, leads to epigenetic alterations that support oncogenic gene expression and tumor progression. Suppression of CS-ΔEx4 or pharmacologic inhibition of its activity reverts these metabolic and epigenetic changes, reducing cancer cell survival and metastatic potential. These findings establish a direct link between AS of a core metabolic enzyme and the emergence of cancer hallmarks, suggesting that targeting AS-derived variants like CS-ΔEx4 may represent a promising therapeutic strategy for colorectal cancer and potentially other malignancies in which such isoforms are expressed. See related article by Cheung et al., p. XX.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3356
  2. Nature. 2025 Oct 01.
      A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues1-8. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear. Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
    DOI:  https://doi.org/10.1038/s41586-025-09589-5
  3. Res Sq. 2025 Sep 23. pii: rs.3.rs-7483419. [Epub ahead of print]
      Iron is an essential cofactor for mitochondrial metabolism, yet the regulatory networks linking cellular iron homeostasis to colorectal cancer (CRC) progression remain incompletely understood. Here, we identify nuclear receptor coactivator 4 (NCOA4), a ferritinophagy receptor, as a context-dependent tumor suppressor that coordinates cytosolic and mitochondrial iron handling in CRC. Analysis of human tumors and colon-specific Ncoa4 knockout mice revealed that NCOA4 loss drives tumorigenesis by inducing transferrin receptor-mediated iron uptake and mitochondrial calcium uniporter (MCU)-dependent mitochondrial iron import. This dual iron overload elevates mitochondrial reactive oxygen species, activates STAT3 signaling, and enhances tumor cell proliferation. NCOA4 overexpression reverses these effects, reducing MCU expression and tumor growth. Pharmacological inhibition of MCU, STAT3, or mitochondrial iron transport mitigated tumorigenesis in NCOA4-deficient models. Our findings define an NCOA4-MCU-STAT3 metabolic signaling axis that couples iron metabolism to oncogenic progression and reveal mitochondrial iron handling as a therapeutic vulnerability in CRC.
    DOI:  https://doi.org/10.21203/rs.3.rs-7483419/v1
  4. bioRxiv. 2025 Sep 26. pii: 2025.09.25.678303. [Epub ahead of print]
      Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
    One-Sentence Summary: Aging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.
    DOI:  https://doi.org/10.1101/2025.09.25.678303
  5. Cell Rep Methods. 2025 Sep 26. pii: S2667-2375(25)00221-8. [Epub ahead of print] 101185
      Cytotoxic CD8+ T cells are essential mediators of immune responses against viral infections and tumors. Upon antigen encounter, antigen-specific CD8+ T cells undergo clonal expansion and produce effector cytokines, processes that require dynamic metabolic adaptation. However, profiling antigen-specific T cells at single-cell resolution remains technically challenging. We present a spectral flow cytometry-based workflow enabling metabolic profiling of antigen-specific CD8+ T cells identified via major histocompatibility complex (MHC) class I tetramers or CD137 upregulation. The approach integrates the analysis of metabolic protein expression to infer pathway activity, uptake of fluorescent probes to measure functional metabolism and metabolite utilization, and assays evaluating cellular energy metabolism. Applied to human and mouse samples, this method defined the metabolic profiles of cytomegalovirus-, SARS-CoV-2-, and tumor-specific CD8+ T cells across distinct activation states and tissues. By detailing each component of the workflow, we provide practical guidance for applying metabolic spectral flow cytometry to dissect disease mechanisms and therapeutic responses.
    Keywords:  CP: immunology; CP: metabolism; T cell; antigen-specific; metabolism; spectral flow cytometry
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101185
  6. Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01125-8. [Epub ahead of print]44(10): 116354
      Satellite cells (SCs), the skeletal muscle resident stem cells, maintain a state of quiescence yet exhibit robust circadian oscillations at the transcriptional level. How SC circadian rhythms are controlled is not well understood. Here, we use SC-specific reconstitution of the essential clock gene Bmal1 in mice to elucidate the role of the local SC clock and its interplay with the central clock in the brain. We find that 24-h rhythmicity of metabolic genes in SCs depends on central clock inputs, independent of the SC clock, and identify rhythmic feeding-fasting cycles as the key brain clock-dependent output controlling their oscillation. Functionally, central signals regulate SC metabolic state and SC-mediated muscle repair, and we identify intact autophagic function as a prerequisite for correct oscillation of metabolic transcripts. Overall, we show that the central clock acts dominantly via feeding-fasting cycles to control rhythmic gene expression and metabolic state in quiescent SCs.
    Keywords:  CP: Metabolism; CP: Stem cell research; autophagy; circadian clocks; circadian rhythms; inter-organ crosstalk; metabolism; muscle; quiescence; satellite cells; stem cells; time-restricted feeding
    DOI:  https://doi.org/10.1016/j.celrep.2025.116354
  7. bioRxiv. 2025 Sep 23. pii: 2025.09.18.676961. [Epub ahead of print]
      The proliferation of many cancer cells is methionine dependent and dietary methionine restriction (MR) has shown anti-tumor effects in a wide variety of immunodeficiency preclinical models. Yet, whether MR exerts an anti-tumor effect in the presence of an immune-competent background remains inconclusive. Accumulating evidence has shown an essential role of methionine in immune cell differentiation and function. Thus, competition for methionine between tumor cells and immune cells in the tumor microenvironment may drive tumor growth and tumor response to therapy. Here, we aim to define the impact of MR on tumor growth and associated immunity. We first assessed the effect of MR in a series of immunocompetent mouse models of melanoma, colorectal cancer, breast cancer, and lung. MR led to a broad tumor inhibition effect across these models and such tumor inhibition was not sex-or genetic background-dependent but appears to be fully or partially immune-dependent. Through flow cytometry analysis, we found a consistent increase in intratumoral activated CD8 + T cells across different tumor models and depletion of CD8 + T cells partially or completely reversed MR-induced tumor inhibition in a model dependent manner. Interestingly in young healthy non-tumor-bearing mice, MR increased spleen CD3 + and CD8 + T cell populations. Metabolomics and RNAseq analysis of spleen-derived CD8 + T cells revealed significant increase in purine metabolism and amino acid metabolism and that are in line with the metabolic feature of activated T cells. Furthermore, MR improved the efficacy of anti-PD1 immune checkpoint blockade. Together, MR primes T cell metabolism for its anti-tumor effect and improves the efficacy of anti-PD1 checkpoint blockade.
    DOI:  https://doi.org/10.1101/2025.09.18.676961
  8. bioRxiv. 2025 Sep 28. pii: 2025.09.25.678523. [Epub ahead of print]
      Lactate has emerged as a key metabolite involved in multiple physiological processes, including memory formation, immune response regulation, and muscle biogenesis. However, its role in aging and cellular protection remains unclear. Here, we show that lactate promotes longevity in C. elegans through a mechanism that requires early-life intervention, indicating a hormetic priming effect. This pro-longevity action depends on its metabolic conversion via LDH-1 and NADH, which drives redox-dependent metabolic reprogramming. Multi-omics approaches revealed that lactate induces early-stage metabolic adaptations, with a strong modulation of lipid metabolism, followed by late-life transcriptional remodeling. These shifts are characterized by enhanced stress response pathways and suppression of energy- associated metabolic processes. Our genetic screening identified sir-2.1 /SIRT1 and rict- 1/ RICTOR as essential for lactate-mediated lifespan extension. Our findings establish lactate as a pro-longevity metabolite that couples redox signaling with lipid remodeling and nutrient- sensing pathways. This work advances our understanding of lactate's dual role as a metabolic intermediary and geroprotector signaling molecule, offering insights into therapeutic strategies for age-related metabolic disorders.
    DOI:  https://doi.org/10.1101/2025.09.25.678523
  9. J Biomed Sci. 2025 Oct 03. 32(1): 91
      Dietary restriction (DR) refers to a broad set of interventions that limit the intake of specific nutrients or overall food consumption, either in quantity or timing, without causing malnutrition. DR has long been considered the most robust intervention for increasing healthspan and lifespan. This includes, not exhaustively, caloric restriction (CR), protein restriction (PR), amino acid restriction (AAR), intermittent fasting (IF), and time-restricted fasting (TRF), each with overlapping but distinct metabolic and physiological effects. This brief review examines the current scientific understanding of how some of the most commonly employed DR regimens may impact metabolism, lifespan, and healthspan. Particular attention is given to the underlying biological mechanisms and supporting evidence derived from both human clinical studies and fundamental biological research conducted with model organisms ranging from yeast to non-human primates.
    Keywords:  Anti-aging interventions; Caloric restriction; Dietary restriction; Intermittent fasting; Longevity and aging; Metabolic reprogramming; Multiple model organisms; Nutrient-sensing; Protein restriction; Time-restricted fasting
    DOI:  https://doi.org/10.1186/s12929-025-01188-w
  10. Mol Biol Rep. 2025 Sep 30. 52(1): 971
      Mitochondrial DNA (mtDNA), inherited exclusively from the mother, encodes genes essential for mitochondrial function, including oxidative phosphorylation (OXPHOS), which generates ATP, the cell's primary energy currency. Circadian rhythm is a crucial biological system that refers to the innate biological clock, whose core is in the suprachiasmatic nucleus (SCN) of the brain. This nucleus regulates various physiological processes, such as sleep-wake cycles, hormone secretion, cellular repair, energy homeostasis, and metabolism, on a roughly 24-hour cycle. Peripheral clocks exist in various tissues, including cells sensitive to external stimuli, and are linked to the circadian rhythm due to mitochondria's role in cellular energy metabolism. Core clock genes like Bmal1 and Clock influence mitochondrial biogenesis, oxidative phosphorylation, and mitophagy, while mitochondrial dysfunction disrupts circadian rhythms, leading to metabolic imbalance and disease progression. Emerging research suggests a bidirectional connection between circadian regulation and mitochondrial dynamics. This review focuses on the complex interplay between the circadian rhythm and mitochondrial processes, as regulated by various cellular proteins, transcription factors, ions, receptors, channels, and the mitochondrial genetic machinery, to understand the harmonious coordination between energy metabolism and timing mechanisms needed to optimize cellular processes and maintain physiological balance. The study of this relationship provides new insights into aging, neurodegenerative disorders, and metabolic diseases, potentially guiding future interventions focusing on chronotherapy and mitochondrial targeting.
    Keywords:  BMAL1; Circadian rhythm; Mitochondrial DNA (mtDNA); Mitochondrial biogenesis; PGC1-α; SIRT
    DOI:  https://doi.org/10.1007/s11033-025-11010-3
  11. Nat Commun. 2025 Sep 30. 16(1): 8733
      Intra-tumor heterogeneity is a primary cause of therapeutic failure, driving tumor progression. Within tumors, diverse cell states coexist, maintained by a specific chromatin landscape that influences various cell functions, including cancer stemness. Among factors that induce chromatin changes affecting cell state fitness, DNA damage and its repair have emerged as significant contributors. This perspective examines recent advances that elucidate the interplay between DNA repair, epigenome, and cell plasticity. We discuss how epigenome affects DNA repair and, conversely, how DNA repair-induced chromatin changes influence cell plasticity. Finally, we discuss emerging concepts and highlight the therapeutic implications of these interconnected mechanisms.
    DOI:  https://doi.org/10.1038/s41467-025-64445-4
  12. Trends Biochem Sci. 2025 Oct 02. pii: S0968-0004(25)00222-1. [Epub ahead of print]
      Mitochondrial protein homeostasis (proteostasis) keeps the mitochondrial proteome functional. Thus, proteostasis is essential for mitochondrial activity and overall cellular functions, and a reduction in its function corresponds with diseases and aging in humans. Recent studies in various model organisms highlight components and mechanisms of mitochondrial proteostasis from biogenesis, through assembly, to turnover. Key findings include the identification of new components and mechanistic insights into protein import and mitochondrial translation processes, the interconnectivity of protein biogenesis and quality control, and proteolytic degradation machineries. In this review we discuss these advances that improve our current understanding of the inner workings and significance of the mitochondrial proteostasis network in maintaining functional mitochondria.
    Keywords:  mitochondria; proteases; protein import; proteolysis; proteostasis; translation
    DOI:  https://doi.org/10.1016/j.tibs.2025.09.004
  13. Biochem Soc Trans. 2025 Sep 30. pii: BST20253101. [Epub ahead of print]
      The importance of the peroxisome as a site of oxidative metabolism in plants is well recognised, but the consequences of peroxisomal biochemistry for the broader metabolic network of plant cells are somewhat overlooked. In this review, we place a spotlight on the peroxisome as a redox-active organelle which mediates substantial flows of electrons. These electron flows not only have consequences within the peroxisome, but they also flow to and from the cytosol and at least two other major redox-active organelles, chloroplasts and mitochondria, with broad implications for metabolism and redox balance of electron carriers such as NADPH and NADH. We will outline the nature of these peroxisome-mediated electron flows and discuss the new appreciation of their quantitative significance derived from metabolic network flux analysis. We emphasise that the flows of reducing equivalents into and out of the peroxisome can be substantial - in some tissues equivalent to that to and from mitochondria. We also highlight key areas of uncertainty around specific redox reactions in the peroxisome and open questions about how redox state is balanced. Finally, we also consider the implications of peroxisomal electron flows in the context of re-engineering key metabolic processes such as photorespiration and lipid accumulation.
    Keywords:  fatty acid oxidation; lipids; oxidation reduction; peroxisomes; photorespiration; redox signalling
    DOI:  https://doi.org/10.1042/BST20253101
  14. Mol Cell. 2025 Oct 02. pii: S1097-2765(25)00714-2. [Epub ahead of print]85(19): 3554-3561
      Histone post-translational modifications (PTMs) are crucial to eukaryotic genome regulation, with a range of reported functions and mechanisms of action. Though often studied individually, it has long been recognized that the modifications function by combinatorial synergy or antagonism. Interplay may involve PTMs on the same histone, within the same nucleosome (containing a histone octamer), or between nucleosomes in higher-order chromatin. Given this, the field must distinguish ever greater complexity, and the context in which it is studied, with brevity and precision. The proteoform was introduced to define individual forms of a protein by sequence and PTMs, followed by the nucleoform to describe the particular gathering of histones within an individual nucleosome. There is now a need to define specific forms of these entities in prose while providing space for experimental nuance. To this end, we introduce a nomenclature that can express discrete PTMs, proteoforms, nucleoforms, or situations where defined PTMs exist in an uncertain context. Though specifically designed for the chromatin field, adaptions of the framework could be used to describe-and thus dissect-how proteoforms are configured in functionally distinct complexes across biology.
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.029
  15. Nat Commun. 2025 Sep 29. 16(1): 8572
      Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a significant unmet need for enhancing immunotherapy response given current modest efficacy. Here, we perform an in vivo CRISPR screen in an HNSCC mouse model to identify immune evasion genes. We identify several regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increases CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency attenuates extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional programs, which contribute to stromal desmoplasia, a histologic finding we describe as associated with reduced anti-PD1 response in human HNSCCs. COL17A1, a collagen highly and specifically expressed in HNSCC, mediates in part Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.
    DOI:  https://doi.org/10.1038/s41467-025-63592-y
  16. Adv Sci (Weinh). 2025 Oct 03. e07718
      Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome-wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC-intrinsic factor that promotes immune resistance. Immunologically "cold" OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2, whose function is to suppress ferroptosis activity. Consequently, METTL5 KO enhances tumor sensitivity to T cell-mediated antitumor immunity. Notably, the immune-sensitive phenotypes seen in METTL5-KO tumors can be reversed by either ATF4 overexpression or ferroptosis inhibition. These findings underscore the central role of the METTL5/ATF4/ferroptosis axis in controlling OC responses to immunotherapy.
    Keywords:  ATF4; CRISPR screen; METTL5; ferroptosis; immunotherapy; ovarian cancer
    DOI:  https://doi.org/10.1002/advs.202507718
  17. Nature. 2025 Oct 01.
      Microbial and viral co-evolution has created immunity mechanisms involving oligonucleotide signalling that share mechanistic features with human antiviral systems1. In these pathways, including cyclic oligonucleotide-based antiphage signalling systems (CBASSs) and type III CRISPR systems in bacteria and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in humans, oligonucleotide synthesis occurs upon detection of virus or foreign genetic material in the cell, triggering the antiviral response2-4. Here, in an unexpected inversion of this process, we show that the CRISPR-related enzyme mCpol synthesizes cyclic oligonucleotides constitutively as part of an active mechanism that represses a toxic effector. Cell-based experiments demonstrated that the absence or loss of mCpol-produced cyclic oligonucleotides triggers cell death, preventing the spread of viruses that attempt immune evasion by depleting host cyclic nucleotides. Structural and mechanistic investigation revealed mCpol to be a di-adenylate cyclase whose product, c-di-AMP, prevents toxic oligomerization of the effector protein 2TMβ. Analysis of cells by fluorescence microscopy showed that lack of mCpol allows 2TMβ-mediated cell death due to inner membrane collapse. These findings unveil a powerful defence strategy against virus-mediated immune suppression, expanding our understanding of the role of oligonucleotides in immunity.
    DOI:  https://doi.org/10.1038/s41586-025-09569-9
  18. Nat Cell Biol. 2025 Oct 01.
      Cellular mechanotransduction is a key informational system, yet its mechanisms remain elusive. Here we unveil the role of microtubules in mechanosignalling, operating downstream of subnuclear F-actin and nuclear envelope mechanics. Upon mechanical activation, microtubules reorganize from a perinuclear cage into a radial array nucleated by centrosomes. This structural rearrangement triggers degradation of AMOT proteins, which we identify as key mechanical rheostats that sequester YAP/TAZ in the cytoplasm. AMOT is stable in mechano-OFF but degraded in mechano-ON cell states, where microtubules allow AMOT rapid transport to the pericentrosomal proteasome in complex with dynein/dynactin. This process ensures swift control of YAP/TAZ function in response to changes in cell mechanics, with experimental loss of AMOT proteins rendering cells insensitive to mechanical modulations. Ras/RTK oncogenes promote YAP/TAZ-dependent tumorigenesis by corrupting this AMOT-centred mechanical checkpoint. Notably, the Hippo pathway fine-tunes mechanotransduction: LATS kinases phosphorylate AMOT, shielding it from degradation, thereby indirectly restraining YAP/TAZ. Thus, AMOT protein stability serves as a hub linking cytoskeletal reorganization and Hippo signalling to YAP/TAZ mechanosignalling.
    DOI:  https://doi.org/10.1038/s41556-025-01773-z
  19. Cancer Discov. 2025 Sep 30. OF1-OF30
      Given the propensity of aggressive epithelial tumors to form hepatic metastases, we performed an in vivo cDNA screen using the mouse liver and KRASG12D/TP53R273H pancreatic cells that identified the RNA-binding protein GCN1 as an integral component of hepatic outgrowth. RNAi experiments reveal that GCN1 triggers the integrated stress response (ISR) to activate serine, folate, and methionine biosynthetic pathways together with amino acid transporters, which act in concert to facilitate acquisition of metabolites and to restore redox homeostasis. Alongside the activation of the ISR, we found that GCN1 also functions in the nucleus where it interacts with HNRNPK to suppress the expression of MHC-I molecules and NK ligands. Intriguingly, we identified IMPACT as an endogenous competitive inhibitor of GCN1 that blocks both ISR-dependent metabolic control and disrupts HNRNPK interaction. In doing so, IMPACT enhances tumor immunogenicity to unleash NK cell killing, in addition to sensitizing metastatic tumor cells to immune checkpoint blockade.
    SIGNIFICANCE: Metastatic tumor cells display profound immunometabolic plasticity to colonize distant organs. We identify IMPACT, an inhibitor of GCN1-stress signaling, expression of which curtailed metabolic plasticity and augmented tumor immunogenicity, sensitizing metastatic tumor cells to NK cell-mediated destruction.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1055
  20. Nat Commun. 2025 Oct 03. 16(1): 8831
      Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-63880-7
  21. Nature. 2025 Oct 01.
      Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09539-1
  22. Nat Commun. 2025 Sep 30. 16(1): 8685
      Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-63813-4
  23. Adv Sci (Weinh). 2025 Oct 03. e08576
      Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor essential for host defense against microbial infections, but its role beyond innate immunity remains unclear. Here, a non-canonical function of cGAS in regulating aldehyde metabolism and lipid homeostasis is identified. This is demonstrated that cGAS directly binds to and suppresses ALDH2 (aldehyde dehydrogenase 2), a key enzyme in ethanol metabolism and lipid peroxidation. Loss of cGAS activates ALDH2, thereby enhancing ethanol tolerance in mice. Elevated ALDH2 activity upon cGAS loss increases aldehyde conversion into acetyl-CoA, promoting histone acetylation and transcription of lipid synthesis genes, which drives lipid droplet accumulation in cells and in cGas-/- mouse livers. These lipid droplets confer resistance to ferroptosis but simultaneously induce ER stress, impairing STING (stimulator of interferon genes) activation. Functionally, cGas-/- mice fed with a modified high-fat diet develop exacerbated metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive lipid droplet accumulation in livers compared to wild-type controls. In human MASLD patient cohorts, increased cGAS but reduced ALDH2 mRNA expression is observed relative to healthy individuals. Together, this findings uncover a previously unrecognized role of cGAS in metabolic regulation, independent of its innate immune function. By suppressing ALDH2, cGAS controls lipid droplet biogenesis and stress responses, with direct implications for MASLD pathogenesis.
    Keywords:  ALDH2; HFD; MASLD; cGAS; lipid droplets
    DOI:  https://doi.org/10.1002/advs.202508576
  24. Cancer Sci. 2025 Oct 03.
      Guanosine triphosphate (GTP) is increasingly recognized as a critical actor in cancer cell proliferation, yet its regulatory mechanism remains incompletely defined. A key contributor to elevated GTP levels in tumors is inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in the de novo guanine nucleotide biosynthetic pathway. Although IMPDH inhibitors, mycophenolic acid (MPA) and mycophenolate mofetil (MMF), have shown potential in cancer therapies, their success has been limited due to their immunosuppressive side effects and several unresolved regulatory mechanisms, including paradoxical control of IMPDH activity by GTP. This review provides a systematic summary of the current understanding of IMPDH biology, emphasizing its complex regulation and therapeutic relevance in cancer. We will outline key unresolved questions, including isozyme-specific roles and mechanisms for escaping regulation, and propose mechanistic and translational strategies to design IMPDH-targeted cancer therapies.
    Keywords:  GTP; IMPDH; drug repositioning; energy metabolism; metabolism
    DOI:  https://doi.org/10.1111/cas.70200
  25. bioRxiv. 2025 Apr 10. pii: 2025.04.10.647998. [Epub ahead of print]
      Staphylococcus aureus is a leading cause of healthcare-associated pneumonia, contributing significantly to morbidity and mortality worldwide. As a ubiquitous colonizer of the upper respiratory tract, S. aureus must undergo substantial metabolic adaptation to achieve persistent infection in the distinctive microenvironment of the lung. We observed that fumC , which encodes the enzyme that converts fumarate to malate, is highly conserved with low mutation rates in S. aureus isolates from chronic lung infections. Fumarate, a pro-inflammatory metabolite produced by macrophages during infection, is regulated by the host fumarate hydratase (FH) to limit inflammation. Here, we demonstrate that fumarate, which accumulates in the chronically infected lung, is detrimental to S. aureus , blocking primary metabolic pathways such as glycolysis and oxidative phosphorylation (OXPHOS). This creates a metabolic bottleneck that drives staphylococcal FH (FumC) activity for airway adaptation. FumC not only degrades fumarate but also directs its utilization into critical pathways including the tricarboxylic acid (TCA) cycle, gluconeogenesis and hexosamine synthesis to maintain metabolic fitness and form a protective biofilm. Itaconate, another abundant immunometabolite in the infected airway enhances FumC activity, in synergy with fumarate. In a mouse model of pneumonia, a Δ fumC mutant displays significant attenuation compared to its parent and complemented strains, particularly in fumarate- and itaconate-replete conditions. Our findings underscore the pivotal role of immunometabolites in promoting S. aureus pulmonary adaptation.
    DOI:  https://doi.org/10.1101/2025.04.10.647998
  26. Nat Metab. 2025 Sep 30.
      Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.
    DOI:  https://doi.org/10.1038/s42255-025-01367-x
  27. Aging Cell. 2025 Oct 03. e70254
      Caloric restriction (CR) is a dietary intervention that delays the onset of age-related diseases and enhances survival in diverse organisms, and although changes in adipose tissues have been implicated in the beneficial effects of CR, the molecular details are unknown. Here we show shared and depot-specific adaptations to life-long CR in subcutaneous and visceral adipose depots taken from advanced age male rhesus monkeys. Differential gene expression and pathway analysis identified key differences between the depots in metabolic, immune, and inflammatory pathways. In response to CR, RNA processing and proteostasis-related pathways were enriched in both depots, but changes in metabolic, growth, and inflammatory pathways were depot-specific. Commonalities and differences that distinguish adipose depots are shared among monkeys and humans, and the response to CR is highly conserved. These data reveal depot-specificity in adipose tissue adaptation that likely reflects differences in function and contribution to age-related disease vulnerability.
    Keywords:  adipose; caloric restriction; rhesus monkeys; subcutaneous; visceral
    DOI:  https://doi.org/10.1111/acel.70254
  28. Nat Commun. 2025 Sep 30. 16(1): 8732
      Aging is a complex biological process leading to functional decline and disease susceptibility. This article proposes that chronic activation of tissue damage response mechanisms drives aging, with aged organs exhibiting features similar to those seen after acute injury, such as histolysis, inflammation, immune cell infiltration, accumulation of lipid droplets, and induction of cellular senescence. The overlap between injury and aging phenotypes is supported by evidence that interventions slowing aging often impair healing, and vice versa. This perspective offers a unifying framework to understand aging and suggests new directions for treating age-related diseases, cancer, and the aging process.
    DOI:  https://doi.org/10.1038/s41467-025-64462-3
  29. Dev Cell. 2025 Sep 29. pii: S1534-5807(25)00539-8. [Epub ahead of print]
      DICER1-related tumors are characterized by germline loss-of-function mutations in one DICER1 allele (DICER1+/-) and a somatic "second hit" mutation in the remaining DICER1 allele. Whether the germline DICER1+/- mutation participates in tumorigenesis is unknown. We show that germline heterozygous loss of Dicer1 promotes tumor formation via aberrant neutrophil function in spontaneous and allograft mouse models of rhabdomyosarcoma. Germline heterozygous deletion of Dicer1 decreased tumor latency and increased tumor penetrance, while conditional heterozygous deletion in tumor cells did not, illustrating that non-cell-autonomous contributions were required for tumor promotion. We show that Dicer1+/- murine and human tumors were enriched for neutrophils and that tumor-bearing mice had abundant circulating neutrophil extracellular traps (NETs). Genetically and pharmacologically preventing NET release reduced tumor promotion in Dicer1+/- mice, suggesting NETs promote tumor growth. These findings demonstrate that germline DICER1+/- mutations promote tumor growth and suggest that targeting neutrophils/NET release may reduce cancer risk in DICER1+/- individuals.
    Keywords:  DICER; DICER1; NETosis; PADI4; cancer predisposition; microRNA; neutrophil; pediatric cancer; rhabdomyosarcoma; sarcoma
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.001
  30. bioRxiv. 2025 Sep 23. pii: 2025.09.22.677807. [Epub ahead of print]
      Metastatic cancer cells invade tissue, overcome nutrient stress, and survive transit to distant sites. Many of the mechanisms that support these processes are incompatible with proliferation. This study defines cellular transition states in breast epithelial cells undergoing epithelial-mesenchymal transition (EMT) driven by ERK2 and TGF-β signaling. EMT triggers robust endolysosomal system upregulation and metabolic adaptations that balance proliferative and invasive states. Surprisingly, invasive cells rely on scavenging via lysosomes and macropinocytosis to acquire amino acids, rather than plasma membrane transport, even in nutrient-rich conditions. Macropinocytosis increases intracellular amino acid storage, promoting survival during amino acid deprivation. This metabolic shift depends on c-MYC downregulation, an early EMT event. Reintroducing c-MYC suppresses the metabolic switch, endolysosomal induction, macropinocytosis, and the proliferation-to-migration transition. These findings reveal how cells dynamically balance proliferation and invasion, offering insights into transition states difficult to capture in models of breast cancer metastasis.
    DOI:  https://doi.org/10.1101/2025.09.22.677807
  31. Bioessays. 2025 Sep 28. e70073
      Cancer cells exhibit reprogrammed metabolic pathways to sustain aggressive phenotypes, including continuous cell division, stemness, invasion, and metastasis. Emerging evidence suggests that these metabolic adaptations profoundly impact DNA repair pathways, which contribute to the responses to therapy and influence overall outcomes. Metabolic processes such as the Warburg effect, nicotinamide adenine dinucleotide (NAD) metabolism, glutamine metabolism, and one-carbon metabolism support DNA repair by expanding the metabolite pool and facilitating post-translational modifications. Conversely, oncometabolites impair DNA repair pathways through epigenetic reprogramming, thereby promoting genomic instability. This review highlights recent discoveries that elucidate the intricate connections between metabolic hallmarks in cancer cells and DNA repair mechanisms, offering insights into potential therapeutic targets for future cancer treatments.
    Keywords:  DNA repair; Warburg effect; cancer metabolism; molecular targeting; oncometabolite
    DOI:  https://doi.org/10.1002/bies.70073
  32. Cell Rep. 2025 Sep 29. pii: S2211-1247(25)01132-5. [Epub ahead of print]44(10): 116361
      A central question in immune regulation is how cells coordinate transcriptional responses to environmental cues. It remains unclear whether transcriptional regulation is controlled by isolated mechanism or integrated regulatory programs. Here, we develop a high-sensitivity, genome-wide CRISPR-Cas9 screening platform with 47 transcriptional reporters in human B cell lymphoma, identifying 4,440 regulators and 17,638 regulatory interactions. To enable the exploration of these networks, we establish B-LEARN, an interactive portal for data visualization and discovery. Our results reveal a large number of shared regulators across our 47 screens that act as context-dependent activators or repressors. Globally, we uncover a biphasic regulatory architecture in which mTORC1 and GSK3 exert opposing control over the B cell transcriptome. Notably, mTOR inhibition broadly activates key B cell genes, an effect antagonized by GSK3. Thus, B cell transcription is governed by an integrated, pathway-driven circuit, offering new targets to modulate gene expression in lymphoma and autoimmune disease.
    Keywords:  CP: Immunology; GSK3; functional CRISPR screens; gene regulatory network; human B cell lymphoma; immune response gene expression; mTOR; reporter cell lines; small-molecule screening; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116361
  33. Cell Rep. 2025 Sep 26. pii: S2211-1247(25)01101-5. [Epub ahead of print] 116330
      Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), an oncofetal RNA-binding protein and a non-canonical reader of N6-methyladenosine (m6A) mRNA modifications, is known to be critical for leukemogenesis. To understand how the oncogenic function of IGF2BP3 impacts metabolism, we performed metabolic profiling and observed changes in glycolytic flux and one-carbon metabolism, including the biosynthesis of S-adenosyl methionine (SAM), a key substrate for methylation reactions within the cell. Using enhanced crosslinking immunoprecipitation (eCLIP) and polyribosome profiling, we found that IGF2BP3 promotes translation of the regulatory subunit of the methionine adenosyltransferase complex (MAT2B), which is involved in SAM production. Remarkably, IGF2BP3 promotes and alters the level and pattern of m6A modifications on mRNA. Taken together, these data suggest the intriguing hypothesis that IGF2BP3 rewrites the epitranscriptome in leukemia cells. Furthermore, this work highlights an interconnection between oncogenic metabolism and RNA modifications, suggesting that pervasive gene expression changes necessary for oncogenesis may be perpetuated by post-transcriptional gene regulation.
    Keywords:  B-acute lymphoblastic leukemia; CP: Metabolism; MLL-rearranged leukemia; RNA-binding protein; epitranscriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116330
  34. Nat Commun. 2025 Sep 29. 16(1): 8543
      Metabolic versatility enables unicellular organisms to grow in vastly different environments. Since growth occurs far from thermodynamic equilibrium, the second law of thermodynamics has long been believed to pose key constraints to life. Yet, such constraints remain largely unknown. Here, we integrate published data spanning decades of experiments on unicellular chemotrophic growth and compute the corresponding thermodynamic dissipation. Due to its span in chemical substrates and microbial species, this dataset samples the versatility of metabolism. We find two empirical thermodynamic rules: first, the amount of energy dissipation per unit of biomass grown is largely conserved across metabolic types and domains of life; second, aerobic respiration exhibits a trade-off between dissipation and growth, reflecting in its high thermodynamic efficiency. By relating these rules to the fundamental thermodynamic forces that drive and oppose growth, our results show that dissipation imposes tight constraints on metabolic versatility.
    DOI:  https://doi.org/10.1038/s41467-025-62975-5
  35. Development. 2025 Sep 15. pii: dev204841. [Epub ahead of print]152(18):
      The plant circadian clock aligns developmental processes with environmental cycles, a function traditionally attributed to a unified, systemic oscillator. However, this view is challenged by observations that mutations in specific clock genes can cause major developmental phenotypes without a proportional disruption to systemic rhythms. This Hypothesis proposes that clock genes perform dual roles: they act not only as components of the systemic oscillator that generates rhythmicity, but also as specific, context-dependent regulators that control the timing of key developmental events. We argue that this gene-centric perspective extends and refines the classical oscillator model, positing that the pleiotropic nature of clock genes reflects their evolutionary history, whereby transcription factors with pre-existing developmental roles were co-opted for timekeeping. Understanding this functional duality - how individual clock components are deployed in specific tissues and conditions - offers a new perspective for dissecting the complex interplay between timekeeping and development.
    Keywords:  Circadian clock; Developmental timing; Flowering time; Plant development; Pleiotropy
    DOI:  https://doi.org/10.1242/dev.204841
  36. Sci Adv. 2025 Oct 03. 11(40): eadz0693
      Complex I (CI; NADH ubiquinone oxidoreductase) is central to energy generation and metabolic homeostasis in mammalian cells but contributes to adverse outcome pathways under challenging conditions. During ischemia, mammalian CI transitions from a turnover-ready, structurally "closed" state toward a dormant "open" state that prevents it from functioning in reverse during reperfusion to produce reactive oxygen species. Unfortunately, simpler, genetically tractable CI models do not recapitulate the same regulatory behavior, compromising mechanistic studies. Here, we report the structure of isolated CI from the yeast Pichia pastoris (Pp-CI) and identify distinct closed and open states that resemble those of mammalian CI. Notably, a hitherto-unknown protein (NUQM) completes an interdomain bridge in only the closed state, implying that NUQM stabilizes it by restricting the conformational changes of opening. The direct correlation of NUQM binding with closed/open status in Pp-CI provides opportunities for investigating regulatory mechanisms relevant to reversible catalysis and ischemia-reperfusion injury.
    DOI:  https://doi.org/10.1126/sciadv.adz0693
  37. Philos Trans R Soc Lond B Biol Sci. 2025 Oct 02. 380(1936): 20240296
      The central dogma of molecular biology, as originally proposed by Crick, asserts that information passed into protein cannot flow back out. This principle has been interpreted as underpinning modern understandings of heredity and evolution, implying the unidirectionality of information flow from nucleic acids to proteins. Here, we propose a generalization of the central dogma as a division of labour between the transmission and expression of information: the transmitter (nucleic acids) perpetuates information across generations, whereas the expressor (protein) enacts this information to facilitate the transmitter's function without itself perpetuating information. We argue that this generalization offers two benefits. First, it provides a unifying perspective for comparing the central dogma to analogous divisions of labour observed at vastly different biological scales, including multicellular organisms, eukaryotic cells, organelles and bacteria. Second, it offers a theoretical framework to explain the central dogma as an outcome of evolution. Specifically, we review a mathematical model suggesting that the central dogma originates through spontaneous symmetry breaking driven by evolutionary conflicts between different levels of selection. By reframing the central dogma as an informational relationship between components of a system, this generalization underscores its broader relevance across the biological hierarchy and sheds light on its evolutionary origin.This article is part of the theme issue 'Origins of life: the possible and the actual'.
    Keywords:  Price equation; multilevel selection; origins of life; prebiotic evolution; reproductive division of labour; spontaneous symmetry breaking
    DOI:  https://doi.org/10.1098/rstb.2024.0296
  38. Nat Commun. 2025 Sep 29. 16(1): 8532
      Understanding the effect of heterogeneity is fundamental to numerous fields. In community ecology, classical theory postulates that habitat heterogeneity determines niche dimensionality and drives biodiversity. However, disparate heterogeneity-diversity relationships have been empirically observed, generating increasingly complex theoretical developments. Here we show that spurious heterogeneity-diversity relationships and subsequent theories arise as artifacts of heterogeneity measures that are mean-biased for bounded continuous variables. To solve this, we derive an alternative mean-independent measure of heterogeneity for beta and gamma distributed variables that disentangles statistical dispersion from mean. Using the mean-independent measure of heterogeneity, true monotonic positive heterogeneity-diversity relationships, consistent with classical theory, are revealed in data previously presented as evidence for both hump-shaped heterogeneity-diversity relationships and theories of an area-heterogeneity trade-off for biodiversity. This work sheds light on the source of conflicting results that have hindered understanding of heterogeneity relationships in broader ecology and numerous other fields. The mean-independent measure of heterogeneity is provided as a solution, essential for understanding true mean-independent heterogeneity relationships in wider research.
    DOI:  https://doi.org/10.1038/s41467-025-64287-0
  39. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2508237122
      Iron-bound tetrapyrroles (hemes) are essential for the regulation of cellular functions and bioenergetics. The processes of heme biosynthesis, transport, and degradation are responsible for the supply of heme in mitochondria and its insertion into other downstream proteins. What remains unresolved is how these processes interconnect and the wider implications for the cell in the restoration of homeostasis when heme concentrations change. We demonstrate a wide-ranging and coordinated response to changes in intracellular heme in HEK293 cells through a network of complementary mechanisms that extend well beyond the direct regulation of heme biosynthesis and degradation. These responses connect changes in heme homeostasis to mitochondrial function, including core metabolic processes such as the tricarboxylic acid cycle and oxidative phosphorylation, as well as to enzymes involved in the control and storage of iron. Our findings demonstrate far-reaching consequences to perturbations of heme homeostasis and provide insights into the complexity of the cellular hemome.
    Keywords:  biosensing; heme; heme biosynthesis; proteomics; tetrapyrroles
    DOI:  https://doi.org/10.1073/pnas.2508237122
  40. Science. 2025 Oct 02. 390(6768): eads8728
      During nutrient deprivation, activation of the protein kinase GCN2 regulates cell survival and metabolic homeostasis. In addition to amino acid stress, GCN2 is activated by a variety of cellular stresses. GCN2 activation has been linked to its association with uncharged tRNAs, specific ribosomal proteins, and conditions of translational arrest, but their relative contribution to activation is unclear. Here, we used in vitro translation to reconstitute GCN2 activation by amino acid stress and compared collided ribosome populations induced by diverse translational stressors. Initiation of GCN2 signaling required the di-ribosome sensor GCN1, which recruits GCN2 to ribosomes in a collision-dependent manner, where GCN2 becomes activated by key ribosomal interactions and stably associated with collided ribosomes. Our findings define the molecular requirements and dynamics of GCN2 activation.
    DOI:  https://doi.org/10.1126/science.ads8728
  41. Nat Cell Biol. 2025 Sep 29.
      Acquisition of specific cell shapes and morphologies is a central component of cell fate transitions. Although signalling circuits and gene regulatory networks that regulate pluripotent stem cell differentiation have been intensely studied, how these networks are integrated in space and time with morphological changes and mechanical deformations to control state transitions remains a fundamental open question. Here we focus on two distinct models of pluripotency, preimplantation inner cell mass cells of human embryos and primed pluripotent stem cells, to discover that cell fate transitions associate with rapid, compaction-triggered changes in nuclear shape and volume. These phenotypical changes and the associated active deformation of the nuclear envelope arise from growth factor signalling-controlled changes in cytoskeletal confinement and chromatin mechanics. The resulting osmotic stress state triggers global transcriptional repression, macromolecular crowding and remodelling of nuclear condensates that prime chromatin for a cell fate transition by attenuating repression of differentiation genes. However, while this mechano-osmotic chromatin priming has the potential to accelerate fate transitions and differentiation, sustained biochemical signals are required for robust induction of specific lineages. Our findings uncover a critical mechanochemical feedback mechanism that integrates nuclear mechanics, shape and volume with biochemical signalling and chromatin state to control cell fate transition dynamics.
    DOI:  https://doi.org/10.1038/s41556-025-01767-x
  42. J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]
      Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.
    Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells
    DOI:  https://doi.org/10.1172/JCI182480
  43. bioRxiv. 2025 Sep 26. pii: 2025.09.24.676871. [Epub ahead of print]
      Transcriptional regulatory elements (TREs) orchestrate gene expression programs fundamental to cellular identity and transitions between physiological and pathological states. Decoding the regulatory logic of human biology requires resolving where, when, and how these elements are transcriptionally engaged. Here, we profiled the active transcriptional regulatory landscape across all major organ systems and a broad spectrum of developmental and disease states using PRO-cap, a high-resolution method that captures nascent transcription start sites with unprecedented sensitivity and specificity. This atlas of active TREs highlights elements shaped by their cellular contexts and evolutionary constraints, sheds light on the genetic architecture of human traits and diseases, and reveals how patterns of transcription initiation and pausing encode regulatory logic. In cancer, nascent transcription enables the delineation of lineage-specific regulatory states, metastatic adaptations, and the co-option of pre-existing programs. Together, these findings establish nascent transcription as a core dimension of gene regulation, illuminating principles that govern development, physiology, and disease.
    DOI:  https://doi.org/10.1101/2025.09.24.676871
  44. Biogerontology. 2025 Sep 27. 26(5): 184
      Circadian time keeping system (CTS) consisting of network of central and peripheral clocks regulates physiological, metabolic, and behavioural processes in alignment with the 24 hour. Desynchrony between central and peripheral clocks contributes to the pathogenesis of age-related conditions such as metabolic syndrome, cognitive decline, immune dysfunction, and neurodegenerative diseases etc. Sex-specific susceptibilities further modulate circadian resilience, with hormonal changes and redox imbalances playing key roles in the aging trajectory. Immune senescence and hormonal dampening, particularly in cortisol and melatonin rhythms, exacerbate circadian misalignment, accelerating systemic decline with aging. Interestingly, aging and clock dysfunction is a bidirectional process, i.e. aging progressively influences circadian rhythms across multiple levels and vice versa, from the molecular architecture of core clock gene feedback loops to the functionality of the central pacemaker-the suprachiasmatic nucleus (SCN)-and its coordination with peripheral oscillators. This review critically highlights the complex alterations in circadian mechanisms associated with aging, including diminished transcriptional rhythmicity, epigenetic drift, mitochondrial desynchronization, and disruptions in neurotransmitter systems. Such changes in turn leads to weakened SCN output, impaired photic entrainment, and loss of temporal coherence across organ systems. Further, this review demonstrates CTS and aging at multiple levels such as behavioural, physiological, biochemical and molecular levels are linked in push-pull mechanism i.e., the breakdown in the harmony of circadian rhythms at systemic level pushes the organism towards early aging and aging in turn is linked to CTS disorders.
    Keywords:  Aging; Central and peripheral clocks; Circadian dysfunction; Circadian rhythms; Life span
    DOI:  https://doi.org/10.1007/s10522-025-10324-w