bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2025–12–21
48 papers selected by
Christian Frezza, Universität zu Köln
  1. Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
  2. TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
  3. The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
  4. Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression.
  5. Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
  6. Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities.
  7. The fate of pyruvate dictates cell growth by modulating cellular redox potential.
  8. Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
  9. MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
  10. Compression-induced NF-κB activation sustains tumor cell survival in confinement by detoxifying aldehydes and promotes metastasis.
  11. The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
  12. Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
  13. Inhibiting translation elongation by reducing eIF5A activity induces feedback inhibition of initiation, limiting tumour cell proliferation.
  14. Depletion of individual dietary amino acids induce distinct metabolic and chromatin states.
  15. Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer.
  16. BCL-X L Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers.
  17. A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes.
  18. The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
  19. Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
  20. AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.
  21. Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
  22. Mechanistically informed machine learning links non-canonical TCA cycle activity to Warburg metabolism and hallmarks of malignancy.
  23. VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
  24. FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
  25. Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
  26. Reductive death is averted by an ancient metabolic switch.
  27. Time and space: How the circadian clock controls DNA break repair location and pathway choice.
  28. Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression.
  29. Methylation-based lineage tracing in cancer.
  30. On biological and artificial consciousness: A case for biological computationalism.
  31. Systematic maps reveal how human chromosomes are organized.
  32. Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
  33. Multi-omics analysis reveals metabolic diversity underlying endothelial cell functions.
  34. Inferring cancer type-specific patterns of metastatic spread using Metient.
  35. RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
  36. Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.
  37. STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis.
  38. Deep Red Blood Cell Proteome Defines the Band 3 N-Terminus Interactome as a Regulator of Hypoxic Adaptation via BLVRB-Dependent S -Nitroso Transfer.
  39. Cuproptosis in cancer: from molecular mechanisms to therapeutic intervention.
  40. Transient hepatic reconstitution of trophic factors enhances aged immunity.
  41. Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis.
  42. Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
  43. Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
  44. SLC7A5 regulates B cell metabolism and plasma cell differentiation independent of leucine transport.
  45. The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells.
  46. There and back again: a cell biologist's journey from organelles to molecules.
  47. Lost but not least: Y chromosome loss as a driver of cancer.
  48. Circulating Tumor Cell Infiltration of Major Vessels Influences Cancer Prognosis.
  1. Nat Cell Biol. 2025 Dec 19.
    Autophagy-regulated mitochondrial inheritance controls early CD8+ T cell fate commitment.
    Mariana Borsa, Ana Victoria Lechuga-Vieco, Amir H Kayvanjoo, Edward Jenkins, Yavuz Yazicioglu, Ewoud B Compeer, Felix C Richter, Simon Rapp, Robert Mitchell, Tom Youdale, Hien Bui, Emilia Kuuluvainen, Michael L Dustin, Linda V Sinclair, Pekka Katajisto, Anna Katharina Simon.
      T cell immunity deteriorates with age, accompanied by a decline in autophagy and asymmetric cell division. Here we show that autophagy regulates mitochondrial inheritance in CD8+ T cells. Using a mouse model that enables sequential tagging of mitochondria in mother and daughter cells, we demonstrate that autophagy-deficient T cells fail to clear premitotic old mitochondria and inherit them symmetrically. By contrast, autophagy-competent cells that partition mitochondria asymmetrically produce daughter cells with distinct fates: those retaining old mitochondria exhibit reduced memory potential, whereas those that have not inherited old mitochondria and exhibit higher mitochondrial turnover are long-lived and expand upon cognate-antigen challenge. Multiomics analyses suggest that early fate divergence is driven by distinct metabolic programmes, with one-carbon metabolism activated in cells retaining premitotic mitochondria. These findings advance our understanding of how T cell diversity is imprinted early during division and support the development of strategies to modulate T cell function.
    DOI:  https://doi.org/10.1038/s41556-025-01835-2
  2. Nat Commun. 2025 Dec 17.
    TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
    Massimo Vetralla, Lena Wischhof, Asrat Kahsay, Vanessa Cadenelli, Enzo Scifo, Beijia Xie, Miriana Sbrissa, Maëlle Sandhira Habert, Dan Ehninger, Rosario Rizzuto, Daniele Bano, Diego De Stefani.
      The bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.
    DOI:  https://doi.org/10.1038/s41467-025-67647-y
  3. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00939-6. [Epub ahead of print]85(24): 4587-4601.e7
    The TIM22 carrier translocase supports cell proliferation by facilitating mitochondrial iron uptake for Fe-S biogenesis.
    Shuai Liu, Qingyu Li, Mengye Cao, Zefang Bimo Zhao, Cong Liu, Zhuoran Zhen, Jiankun Ren, Chengyang Liu, Danyang Ruan, Luna Zhang, Wenjuan Zhang, Hao Gong, Xiaolong Liu, Xuejie Zhang, Deng Pan, Weijun Pan, Jiajun Zhu.
      Mitochondria host a number of reductive biosynthetic pathways and rely on extensive metabolite exchanges with the cytosol to support cellular anabolic metabolism. Mitochondrial iron-sulfur cluster (Fe-S) biogenesis is essential for multiple cellular functions, and its disruption causes various inborn genetic diseases. How mammalian cells regulate Fe-S biogenesis remains incompletely understood. Here, mitochondria-focused CRISPR screening and DepMap-based gene co-essentiality analysis consistently reveal that components of the carrier translocase of the inner mitochondrial membrane (TIM22) complex, including TIMM29, are selectively required for Fe-S biogenesis. Mechanistically, loss of TIM22 complex function reduced iron transporter presence on mitochondria, thereby impairing iron uptake from the cytosol. Reconstituting mitochondrial iron level was sufficient to restore Fe-S biogenesis and proliferation of TIMM29-deficient cells or rescue the embryonic development of timm29-deficient zebrafish. Thus, a primary function of the TIM22 carrier translocase is to facilitate transporter-mediated iron uptake required for Fe-S biogenesis, underscoring a biosynthetic role of mitochondria in cellular anabolism.
    Keywords:  TIM22 carrier translocase; cellular metabolism; iron-sulfur cluster; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.022
  4. Nat Commun. 2025 Dec 18. 16(1): 11280
    Lack of caspase 8 directs neuronal progenitor-like reprogramming and small cell lung cancer progression.
    Ariadne Androulidaki, Fanyu Liu, Christina M Bebber, Ilmars Kisis, Vignesh Sakthivelu, Pascal Hunold, Lioba Koerner, Alina Dahlhaus, Fatma Isil Yapici, Christina Grimm, Alicja Pacholewska, Sofya Tishina, Franka Doskotz, Lucia A Torres Fernández, Jenny Stroh, Ali T Abdallah, Julia Beck, Lejla Mulalic, Anna Schmitt, Holger Grüll, Thorsten Persigehl, Alexander Quaas, Martin Peifer, Johannes Brägelmann, H Christian Reinhardt, Pascal Nieper, Robert Hänsel-Hertsch, Roman K Thomas, Julie George, Michal R Schweiger, Manolis Pasparakis, Filippo Beleggia, Silvia von Karstedt.
      Most neuroendocrine cancers lack caspase 8 protein expression. While this feature was thought to facilitate escape from extrinsic apoptosis, its cancer-regulatory function has remained unexplored. Here, we devise a mouse model of small cell lung cancer (SCLC) recapitulating the lack of expression of caspase 8 seen in humans and uncover an unexpected role for necroptosis-fueled pre-tumoral inflammation resulting in reprogramming towards a neuronal progenitor cell-like state and increased metastatic disease. Notably, transcriptional signatures of this cellular state are enriched in relapsed and metastatic human SCLC. Mechanistically, caspase 8 loss within the pre-tumoral niche promotes inflammation marked by increased recruitment of regulatory T cells (Tregs) which are responsible for the promotion of metastatic disease. Importantly, inactivation of the necroptosis executioner MLKL reverses pre-tumoral inflammation, decreases metastasis as well as neuronal-like reprogramming. Taken together, our findings suggest that pre-tumoral inflammatory cell death contributes to neuronal progenitor mimicry, immunosuppression and increased metastasis in SCLC.
    DOI:  https://doi.org/10.1038/s41467-025-67142-4
  5. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00943-8. [Epub ahead of print]85(24): 4483-4484
    Transporting the transporter: TIM22 translocates mitoferrins to enable mitochondrial iron-sulfur cluster synthesis.
    Erdem M Terzi, Richard Possemato.
      Iron is a critical nutrient, especially to power mitochondrial iron-sulfur cofactor synthesis. In this issue of Molecular Cell, Liu et al.1 engineer a fluorescent iron sensor, enabling them to define a critical function of the mitochondrial translocase, TIM22, in powering mitochondrial iron use by proper targeting of the mitochondrial iron importers, the mitoferrins.
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.026
  6. EMBO Mol Med. 2025 Dec 19.
    Mechanisms of resistance to VHL loss-induced genetic and pharmacological vulnerabilities.
    Jianfeng Ge, Shoko Hirosue, Leticia Castillon, Saroor A Patel, Ludovic Wesolowski, Anna Dyas, Cissy Yong, Sanne de Haan, Jarno Drost, Grant D Stewart, Anna C Obenauf, Daniel Muñoz-Espín, Sakari Vanharanta.
      The von Hippel-Lindau tumor suppressor (VHL) is a component of a ubiquitin ligase complex that controls cellular responses to hypoxia. Endogenous VHL is also utilized by proteolysis-targeting chimera (PROTAC) protein degraders, a promising class of anti-cancer agents. VHL is broadly essential for cell proliferation, yet it is a key tumor suppressor in renal cell carcinoma. To understand the functional consequences of VHL loss, and to identify targeted approaches for the elimination of VHL null cells, we have used genome-wide CRISPR-Cas9 screening in human renal epithelial cells. We find that, upon VHL loss, the HIF1A/ARNT complex is the central inhibitor of cellular fitness, suppressing mitochondrial respiration, and that VHL null cells show HIF1A-dependent molecular vulnerabilities that can be targeted pharmacologically. Combined VHL/HIF1A inactivation in breast and esophageal cancer cells can also provide resistance to ARV-771, a VHL-based bromodomain degrader that has anti-cancer activity. HIF1A stabilization can thus provide opportunities for early intervention in neoplastic VHL clones, and the VHL-HIF1A axis may be relevant for the development of resistance to the emerging class of PROTAC-based cancer therapies.
    Keywords:  CRISPR/Cas9 Screening; HIF1A; PROTAC; Renal Cancer; von Hippel-Lindau Tumor Suppressor (VHL)
    DOI:  https://doi.org/10.1038/s44321-025-00361-w
  7. Elife. 2025 Dec 16. pii: RP103705. [Epub ahead of print]13
    The fate of pyruvate dictates cell growth by modulating cellular redox potential.
    Ashish G Toshniwal, Geanette Lam, Alex J Bott, Ahmad A Cluntun, Rachel Skabelund, Hyuck-Jin Nam, Dona R Wisidagama, Carl S Thummel, Jared Rutter.
      Pyruvate occupies a central node in carbohydrate metabolism such that how it is produced and consumed can optimize a cell for energy production or biosynthetic capacity. This has been primarily studied in proliferating cells, but observations from the post-mitotic Drosophila fat body led us to hypothesize that pyruvate fate might dictate the rapid cell growth observed in this organ during development. Indeed, we demonstrate that augmented mitochondrial pyruvate import prevented cell growth in fat body cells in vivo as well as in cultured mammalian hepatocytes and human hepatocyte-derived cells in vitro. We hypothesize that this effect on cell size was caused by an increase in the NADH/NAD+ ratio, which rewired metabolism toward gluconeogenesis and suppressed the biomass-supporting glycolytic pathway. Amino acid synthesis was decreased, and the resulting loss of protein synthesis prevented cell growth. Surprisingly, this all occurred in the face of activated pro-growth signaling pathways, including mTORC1, Myc, and PI3K/Akt. These observations highlight the evolutionarily conserved role of pyruvate metabolism in setting the balance between energy extraction and biomass production in specialized post-mitotic cells.
    Keywords:  D. melanogaster; cell biology; cell growth; genetics; hepatocytes; human; pyruvate metabolism; redox state; translation
    DOI:  https://doi.org/10.7554/eLife.103705
  8. Nat Genet. 2025 Dec 18.
    Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
    Georgios Kanellos, Chiara Giacomelli, Alexander Raven, Nikola Vlahov, Hu Jin, Pauline Herviou, Sudhir B Malla, Nadia Nasreddin, Patricia P Centeno, Constantinos Alexandrou, Kathryn Gilroy, Rachel L Baird, Kathryn Pennel, June Munro, Joseph A Waldron, Holly Hall, Leah Officer-Jones, Sheila Bryson, Douglas Strathdee, Sergio Lilla, Sara Zanivan, Vivienne Morrison, Colin Nixon, Rachel A Ridgway, Crispin Miller, John R P Knight, Andrew D Campbell, Philip D Dunne, John Le Quesne, Joanne Edwards, Peter J Park, Martin Bushell, Owen J Sansom.
      Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02408-7
  9. Nat Cell Biol. 2025 Dec 15.
    MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
    Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.
      Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
    DOI:  https://doi.org/10.1038/s41556-025-01829-0
  10. Nat Commun. 2025 Dec 14.
    Compression-induced NF-κB activation sustains tumor cell survival in confinement by detoxifying aldehydes and promotes metastasis.
    Bing Liu, Min Liu, Yajuan Zhang, Yifei Zhu, Dingpei Zhou, Hong Gao, Fan Yang, Dong Gao, Yun Zhao, BangBao Tao, Feng Yao, Weiwei Yang.
      Metastasis remains the primary cause of cancer-related mortality. During dissemination, cancer cells must navigate spatially confined microenvironments, yet the underlying metabolic adaptations that facilitate this process remain unclear. Here, through an in vivo CRISPR screen targeting metabolic enzymes, we identify aldehyde dehydrogenase 1 family member B1 (ALDH1B1) as essential for tumor cell survival in confining capillaries. Mechanistically, compressive force induces casein kinase 2 alpha 3 (CSK23) to phosphorylate kappa-B kinase subunit beta (IKKβ) at Ser177/181, which activates the nuclear factor kappa B (NF-κB) pathway and upregulates ALDH1B1. The upregulation of ALDH1B1 enhances aldehyde detoxification, which suppresses ferroptosis and promotes tumor cell survival during migration through the capillaries, thereby facilitating metastasis. Importantly, genetic or pharmacological inhibition of CSK23 or ALDH1B1 effectively impairs metastasis. In lung cancer patients, confined tumor cells exhibit higher levels of ALDH1B1 and NF-κB activation, which correlates with metastatic recurrence. Our findings reveal a mechano-metabolic pathway that promotes metastasis and suggest CSK23 and ALDH1B1 as potential therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-025-67452-7
  11. Nat Commun. 2025 Dec 14.
    The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
    Ina Kirmes, Grace Ching Ching Hung, Anne Hahn, Chuan-Yang Dai, Daniel Campbell, Arnaud Ahier, Rachel Shin Yie Lee, Alexander Palmer, Steven Zuryn.
      Mitochondria play a central role in metabolism and biosynthesis, but function also as platforms that perceive and communicate environmental and physiological stressors to the nucleus and distal tissues. Systemic mitochondrial signaling is thought to synchronize and amplify stress responses throughout the whole body, but during severe or chronic damage, overactivation of mitochondrial stress pathways may be maladaptive and exacerbate aging and metabolic disorders. Here we uncover a protective micro(mi)RNA response to mtDNA damage in Caenorhabditis elegans that prolongs tissue health and function by interfering with mitochondrial stress signaling. Acting within muscle cells, we show that the miRNA miR-71 is induced during severe mitochondrial damage by the combined activities of DAF-16, HIF-1, and ATFS-1, where it restores sarcomere structure and animal locomotion by directly suppressing the inordinate activation of DVE-1, a key regulator of the mitochondrial unfolded protein response (UPRmt). Indirectly, miR-71 also reduces the levels of multiple neuro- and insulin-like peptides and their secretion machinery, resulting in decreased cell-non-autonomous signaling of mitochondrial stress from muscle to glia cells. miR-71 therefore beneficially coordinates the suppression of both local and systemic mitochondrial stress pathways during severe organelle dysfunction. These findings open the possibility that metabolic disorders could be ameliorated by limiting the overactivation of mitochondrial stress responses through targeted small RNAs.
    DOI:  https://doi.org/10.1038/s41467-025-67198-2
  12. Cell Rep. 2025 Dec 17. pii: S2211-1247(25)01507-4. [Epub ahead of print]45(1): 116735
    Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis.
    Meng Zhang, Xiashiyao Zhang, Yandan Chen, Mengmeng Li, Qingwei Ding, Liang Zheng, Junke Zheng, Jun Wan, Bin Guo.
      Mitochondrial proteostasis is essential for hematopoietic stem cell (HSC) maintenance, yet how proteolytic regulation coordinates with metabolic pathways remains unclear. Here, we identify Afg3l2 as a key regulator of cobalamin metabolism and amino acid homeostasis in HSCs through its mediation of Mmadhc degradation. Loss of Afg3l2 leads to Mmadhc accumulation, driving excessive mitochondrial cobalamin import and its conversion to adenosylcobalamin. Elevated adenosylcobalamin levels hyperactivate methylmalonyl-CoA mutase, diverting branched-chain amino acid catabolism toward excessive succinyl-CoA production. This overstimulates the tricarboxylic acid cycle and creates a compensatory dependency on anaplerotic amino acid replenishment. Consequently, Afg3l2-deficient HSCs exhibit increased oxidative stress due to mitochondrial hyperactivation and reactive oxygen species accumulation, ultimately impairing their maintenance and engraftment capacity. Remarkably, Mmadhc overexpression phenocopies these defects, whereas Mmadhc knockdown partially restores HSC function in Afg3l2-deficient models. Our work defines a proteostatic-metabolic circuit in which Afg3l2-mediated Mmadhc degradation regulates cobalamin flux to maintain amino acid and energy balance in HSCs.
    Keywords:  CP: Metabolism; CP: Stem cell research; TCA cycle; amino acid metabolism; cobalamin metabolism; hematopoietic stem cell; mitochondrial protease
    DOI:  https://doi.org/10.1016/j.celrep.2025.116735
  13. Nat Commun. 2025 Dec 13.
    Inhibiting translation elongation by reducing eIF5A activity induces feedback inhibition of initiation, limiting tumour cell proliferation.
    Aristeidis P Sfakianos, Rebecca M Raven, Tom Smith, Xiao-Ming Sun, Thomas E Mulroney, Mariavittoria Pizzinga, Veronica Dezi, Angela Rubio Tenor, Mark Stoneley, Cameron H Cole, Karam Al-Doori, Hashim Ahmed Nur, Rachel L Pennie, Ian Powley, Leah Officer-Jones, Ritwick Sawarkar, Martin Turner, Marion MacFarlane, Owen J Sansom, Martin Bushell, John Le Quesne, Robert F Harvey, Anne E Willis.
      Cancer development is associated with dysregulation of the translatome, and targeting canonical eukaryotic initiation and elongation factors can offer treatment avenues for various neoplasms. Emerging evidence indicates that dysregulated mRNA elongation, involving alterations in eEF2 activity and eIF5A expression, also contributes to tumour cell growth. In this study, we investigate whether targeting eIF5A with the inhibitor GC7 is a viable strategy to curtail aberrant cell growth. Our findings demonstrate that inhibiting elongation by reducing eIF5A activity induces feedback inhibition of initiation through eIF2α phosphorylation, decreasing ternary complex formation and shutting down bulk protein synthesis. Employing dynamic SILAC, we identify proteins impacted by reduced eIF5A activity, and show their decreased translation results from feedback inhibition to initiation or other processes downstream of eIF5A. Decreased eIF5A activity impairs mitochondrial function, which activates signalling through HRI to eIF2α phosphorylation, reducing cancer cell proliferation. These effects are reversed by treatment with the integrated stress response inhibitor, implying that the impact of GC7 on cancer cell proliferation is mediated via translation initiation rather than elongation inhibition. These data suggest that eIF5A inhibition could be used to target cancer cells that depend on mitochondrial function for their proliferation and survival.
    DOI:  https://doi.org/10.1038/s41467-025-66531-z
  14. J Biol Chem. 2025 Dec 17. pii: S0021-9258(25)02926-6. [Epub ahead of print] 111074
    Depletion of individual dietary amino acids induce distinct metabolic and chromatin states.
    Spencer A Haws, Yang Liu, Cara L Green, Krittisak Chaiyakul, Pragyan Mishra, Reji Babygirija, Eric A Armstrong, Anusha T Mehendale, Irene M Ong, Dudley W Lamming, John M Denu.
      Reducing dietary levels of protein or specific essential amino acids (EAAs) promotes favorable metabolic reprogramming, including improved glucose tolerance, increased insulin sensitivity and reduced fat mass. However, the extent to which shared or EAA-specific mechanisms facilitate diet-associated phenotypes remains unclear. Here, we compared the physiological and molecular responses to dietary levels of methionine, leucine, and isoleucine by feeding C57BL/6J mice diets in which each of these specific AAs is depleted. Dietary depletion of Met, Leu, or Ile (Met-D, Leu-D, or Ile-D) elicited distinct, AA-specific physiological and hepatic molecular (transcriptome, metabolome, histone proteome) responses that were not phenocopied by mTORC1 inhibition via rapamycin treatment. Ile-D yielded the most distinct and dramatic responses, highlighted by expression of select chromatin modifying and metabolic enzymes that led to a prominent epigenetic state of histone H2A/H4 hypoacetylation and maintained hepatic acetyl-CoA levels despite downregulated β-oxidation. Multi-Omics Factor Analysis of 14,139 data points objectively affirmed Ile-D phenotypes are distinct from Met-D or Leu-D and identified metabolic and chromatin features as primary discriminators. We further demonstrated the metabolic and epigenetic responses to Ile-D can be recapitulated in vitro, suggesting that these responses are cell intrinsic. Together, these results demonstrate that dietary depletion of EAAs induce unique phenotypes and highlight distinct molecular mechanisms by which individual EAAs may control metabolic health.
    Keywords:  epigenetics; isoleucine; leucine; methionine; post-translational modification; protein depletion
    DOI:  https://doi.org/10.1016/j.jbc.2025.111074
  15. Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00551-8. [Epub ahead of print]6(12): 102478
    Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer.
    Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann.
      Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death in vitro and attenuates tumor growth and prolongs overall survival at clinically achievable doses in orthotopic syngeneic mouse models of TNBC as well as in human cell line-derived xenograft models. Our study defines an unexplored mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.
    Keywords:  autophagy; eliglustat; extracellular vesicles; glucosylceramide synthase; mitochondria; sphingolipids; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102478
  16. bioRxiv. 2025 Dec 13. pii: 2025.12.10.693422. [Epub ahead of print]
    BCL-X L Dependence is a Subtype Agnostic Actionable Feature of Difficult-to-Treat Kidney Cancers.
    Tupa Basuroy, Treg Grubb, Ananthan Sadagopan, Xingping Qin, Kylee Madison, Autumn Hall, Belinda Willard, Sakari Vanharanta, Kristopher A Sarosiek, Srinivas R Viswanathan, Abhishek A Chakraborty.
      The BCL-X L anti-apoptotic protein is a clear cell Renal Cell Carcinoma (ccRCC) dependency; however, the mechanism of this dependence and its relevance in other aggressive kidney cancer contexts, including metastatic and/or rare RCC subtypes [e.g., Fumarate Hydratase (FH)-deficient and sarcomatoid RCCs], is unknown. Computational predictions, using a machine learning model trained on the human RCC TCGA dataset, and cell-based validations, confirmed BCL-X L dependence in all RCC subtypes. Remarkably, cell state changes, 'anoikis' programs, inflammatory state, and metabolic perturbations (e.g., fumarate production in FH-deficient RCCs) independently conferred increased BCL-X L dependence. Correlation studies revealed that increased AMPK isoform 2 ( PRKAA2 ) expression is a kidney-specific biomarker of BCL-X L dependence. Indeed, pharmacological AMPK activation sensitized RCCs to BCL-X L blockade. Finally, using functional studies, we developed a multivariate model that accurately predicted BCL-X L dependence in RCC. Our studies offer biomarkers for patient stratification and credential BCL-X L as a subtype agnostic vulnerability in difficult-to-treat RCCs.
    DOI:  https://doi.org/10.64898/2025.12.10.693422
  17. Elife. 2025 Dec 16. pii: RP98889. [Epub ahead of print]13
    A systematic bi-genomic split-GFP assay illuminates the mitochondrial matrix proteome and protein targeting routes.
    Yury S Bykov, Solene Zuttion, Dunya Edilbi, Marina Polozova, Johanna Arnold, Sergey Malitsky, Maxim Itkin, Bruno Senger, Ofir Klein, Yeynit Asraf, Hadar Meyer, Hubert D Becker, Roza Kucharczyk, Maya Schuldiner.
      The majority of mitochondrial proteins are encoded in the nuclear genome. Many of them lack clear targeting signals. Therefore, what constitutes the entire mitochondrial proteome is still unclear. We here build on our previously developed bi-genomic (BiG) split-GFP assay (Bader et al., 2020) to solidify the list of matrix and inner membrane mitochondrial proteins. The assay relies on one fragment (GFP1-10) encoded in the mitochondrial DNA enabling specific visualization of only the proteins tagged with a smaller fragment, GFP11, and localized to the mitochondrial matrix or the inner membrane. We used the SWAp-Tag (SWAT) strategy to tag every protein with GFP11 and mated them with the BiG GFP strain. Imaging the collection in six different conditions allowed us to visualize almost 400 mitochondrial proteins, 50 of which were never visualized in mitochondria before, and many are poorly studied dually localized proteins. We use structure-function analysis to characterize the dually localized protein Gpp1, revealing an upstream start codon that generates a mitochondrial targeting signal and explore its unique function. We also show how this data can be applied to study mitochondrial inner membrane protein topology and sorting. This work brings us closer to finalizing the mitochondrial proteome and the freely distributed library of GFP11-tagged strains will be a useful resource to study protein localization, biogenesis, and interactions.
    Keywords:  S. cerevisiae; automated microscopy; biochemistry; cell biology; chemical biology; dual localization; mitochondria; mitochondrial proteome; protein targeting; yeast genetics
    DOI:  https://doi.org/10.7554/eLife.98889
  18. Nat Cell Biol. 2025 Dec 19.
    The G3BP stress-granule proteins reinforce the integrated stress response translation programme.
    Jarrett Smith, David P Bartel.
      When mammalian cells are exposed to stress, they co-ordinate the condensation of stress granules (SGs) through the action of proteins G3BP1 and G3BP2 (G3BPs) and, simultaneously, undergo a massive reduction in translation. Although SGs and G3BPs have been linked to this translation response, their overall impact has been unclear. Here we investigate the question of how, and indeed whether, G3BPs and SGs shape the stress translation response. We find that SGs are enriched for mRNAs that are resistant to the stress-induced translation shutdown. Although the accurate recruitment of these stress-resistant mRNAs does require the context of stress, a combination of optogenetic tools and spike-normalized ribosome profiling demonstrates that G3BPs and SGs are necessary and sufficient to both help prioritize the translation of their enriched mRNAs and help suppress cytosolic translation. Together, these results support a model in which G3BPs and SGs reinforce the stress translation programme by prioritizing the translation of their resident mRNAs.
    DOI:  https://doi.org/10.1038/s41556-025-01834-3
  19. Nat Commun. 2025 Dec 15.
    Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
    Tonci Ivanisevic, Yan Ma, Emiel Van Boxel, Wout Magits, Benoit Lechat, Zeynep Koçberber, Phillipp Willnow, Sarah-Maria Fendt, Greetje Vande Velde, Raj Sewduth, Anna A Sablina.
      Activating mutations in KRAS occur in approximately 30% of lung adenocarcinomas. Despite advances in RAS-targeted therapies, intrinsic resistance limits their long-term efficacy. Here, we identify elevated levels of wild-type KRAS (WT-KRAS) protein as a key driver of intrinsic resistance in KRAS-mutant lung tumors. KRAS accumulation results from impaired LZTR1-mediated degradation, triggered either by LZTR1 loss or pharmacological RAS inhibition. Stabilized WT-KRAS activates the mTOR/HIF1α pathway by promoting lysosomal recruitment of the SLC3A2/SLC7A5 amino acid transporter complex, reprogramming lysosomal amino acid sensing. Shallow deletions of LZTR1, present in up to 40% of KRAS-mutant lung adenocarcinomas, are associated with increased mTOR activity and may contribute to therapeutic resistance to RAS inhibitors. Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.
    DOI:  https://doi.org/10.1038/s41467-025-67109-5
  20. Nat Commun. 2025 Dec 17. 16(1): 11252
    AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.
    Sahar Motamedi, Nina Ravoet, Jonas Dehairs, Frank Vanderhoydonc, Abril Escamilla-Ayala, Malgorzata A Sliwinska, Shuncong Wang, Jakub Idkowiak, Stefaan Soenen, Patrizia Agostinis, Jean-Christophe Marine, Johannes V Swinnen.
      Ferroptosis, a regulated form of cell death driven by lipid peroxidation, holds promise for targeting treatment-resistant cancer cells. Using a panel of melanoma cell lines, we uncover variability in the timing of ferroptosis onset upon exposure to iron and polyunsaturated fatty acids (PUFAs). This heterogeneity is linked to differences in PUFA sequestration into lipid droplets (LDs) and their subcellular distribution, particularly near lipid-metabolizing organelles such as mitochondria. In late-onset models, ferroptosis is delayed by peripheral LD retention and triggered by nutrient deprivation and AMP-activated protein kinase (AMPK) activation, which promotes LD trafficking toward mitochondria. Early responders bypass this mechanism. Our findings identify nutrient status and LD dynamics as key modulators of PUFA- and iron-induced ferroptosis, offering insights for therapeutic exploitation in cancer.
    DOI:  https://doi.org/10.1038/s41467-025-66113-z
  21. Cell Chem Biol. 2025 Dec 18. pii: S2451-9456(25)00390-3. [Epub ahead of print]32(12): 1439-1441
    Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
    Chih-Yao Chung, Kritarth Singh, Brigida R Pinho, Jorge M A Oliveira, Michael R Duchen.
      Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.010
  22. PLoS Comput Biol. 2025 Dec 18. 21(12): e1013384
    Mechanistically informed machine learning links non-canonical TCA cycle activity to Warburg metabolism and hallmarks of malignancy.
    Lihao Lin, Francesco Lapi, Bruno Giovanni Galuzzi, Marco Vanoni, Lilia Alberghina, Chiara Damiani.
      Cancer cells undergo extensive metabolic rewiring to support growth, survival, and phenotypic plasticity. A non-canonical variant of the tricarboxylic acid (TCA) cycle, characterized by mitochondrial-to-cytosolic citrate export, has emerged as critical for embryonic stem cell differentiation. However, its role in cancer remains poorly understood. Here, we present a two-step computational framework to systematically analyze the activity of this non-canonical TCA cycle across over 500 cancer cell lines and investigate its role in shaping hallmarks of malignancy. First, we applied constraint-based modeling to infer cycle activity, defining two complementary metrics: Cycle Propensity, measuring the likelihood of its engagement in each cell line, and Cycle Flux Intensity, quantifying average flux through the reaction identified as rate-limiting. We identified distinct tumor-specific patterns of pathway utilization. Notably, cells with high Cycle Propensity preferentially reroute cytosolic citrate via aconitase 1 (ACO1) and isocitrate dehydrogenase 1 (IDH1), promoting [Formula: see text]-ketoglutarate ([Formula: see text]KG) and NADPH production. Elevated engagement of this cycle strongly correlated with Warburg-like metabolic shifts, including decreased oxygen consumption and increased lactate secretion. In the second step, to uncover non-metabolic transcriptional signatures associated with non-canonical TCA cycle activity, we performed machine learning-based feature selection using ElasticNet and XGBoost, identifying robust gene signatures predictive of cycle activity. Over-representation analysis revealed enrichment in genes involved in metastatic behavior, angiogenesis, stemness, and key oncogenic signaling. SHapley Additive exPlanations (SHAP) further prioritized genes with the strongest predictive contributions, highlighting candidates for experimental validation. Correlation analysis of DepMap gene-dependency profiles revealed distinct vulnerability patterns associated with non-canonical TCA cycle activity, outlining a characteristic landscape of genetic dependencies. Together, our integrative framework uniting constraint-based metabolic modeling and machine learning systematically reveals how non-canonical TCA cycle dynamics underpin metabolic plasticity and promote malignant traits.
    DOI:  https://doi.org/10.1371/journal.pcbi.1013384
  23. Nat Commun. 2025 Dec 16.
    VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
    Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.
      Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.
    DOI:  https://doi.org/10.1038/s41467-025-67445-6
  24. J Exp Med. 2026 Mar 02. pii: e20250535. [Epub ahead of print]223(3):
    FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
    Liling Xu, Maria Bottermann, Paula M Villavicencio, John Warner, Stephanie R Weldon, Zhenfei Xie, Andrew Filby, Xiaotie Liu, Ian G Ganley, Alison E Ringel, Usha Nair, Facundo D Batista.
      Little is known about the role of autophagy in the human humoral immune system. Here, we found that in B cells, genetic ablation of FIP200, a mammalian metabolic sensor that regulates autophagy in response to a range of stimuli, led to diminished humoral immune responses in mice. FIP200-deficient B cells displayed decreased differentiation into plasma cells, as well as mitochondrial dysfunction, alterations in heme biosynthesis, and significant cell death. Notably, the addition of heme was sufficient to rescue plasma cell differentiation of FIP200-deficient B cells. Thus, FIP200 determines B cell fates by controlling mitophagy and metabolic reprogramming.
    DOI:  https://doi.org/10.1084/jem.20250535
  25. J Clin Invest. 2025 Dec 15. pii: e194134. [Epub ahead of print]135(24):
    Mitochondrial complex II orchestrates divergent effects in CD4+ and CD8+ T cells.
    Keisuke Seike, Shih-Chun A Chu, Yuichi Sumii, Takashi Ikeda, Meng-Chih Wu, Laure Maneix, Dongchang Zhao, Yaping Sun, Marcin Cieslik, Pavan Reddy.
      Mitochondrial metabolism orchestrates T cell functions, yet the role of specific mitochondrial components in distinct T cell subsets remains poorly understood. Here, we explored the role of mitochondrial complex II (MC II), the only complex from the electron transport chain (ETC) that plays a role in both ETC and metabolism, in regulating T cell functions. Surprisingly, MC II exerts divergent effects on CD4+ and CD8+ T cell activation and function. Using T cell-specific MC II subunit, succinate dehydrogenase A-deficient (SDHA-deficient) mice, we integrated single-cell RNA-seq and metabolic profiling, with in vitro and in vivo T cell functional assays to illuminate these differences. SDHA deficiency induced metabolic changes and remodeled gene expression exclusively in activated T cells. In CD4+ T cells, SDHA loss dampened both oxidative phosphorylation (OXPHOS) and glycolysis, impaired cytokine production, proliferation, and reduced CD4+ T cell-mediated graft-versus-host disease after allogeneic stem cell transplantation (SCT). In contrast, SDHA deficiency in CD8+ T cells reduced OXPHOS but paradoxically upregulated glycolysis and demonstrated enhanced cytotoxic functions in vitro and in vivo. This metabolic reprogramming endowed SDHA-KO CD8+ T cells with superior in vivo antitumor efficacy after immune checkpoint inhibitor therapy and allogeneic SCT. These findings reveal MC II as a bifurcation point for metabolic and functional specialization in CD4+ and CD8+ T cells.
    Keywords:  Bone marrow transplantation; Hematology; Immunology; Metabolism; Mitochondria; T cells
    DOI:  https://doi.org/10.1172/JCI194134
  26. bioRxiv. 2025 Nov 25. pii: 2025.11.24.690166. [Epub ahead of print]
    Reductive death is averted by an ancient metabolic switch.
    Fasih M Ahsan, Jen F Rotti, Armen I Yerevanian, Sinclair W Emans, Nicole L Stuhr, Jose A Aceves-Salvador, Wei Wang, Daniel J Baker, Dimitra Pouli, Owen S Skinner, Michael D Blower, Alexander A Soukas.
      Biguanides, including metformin, the world's most prescribed oral hypoglycemic, extend health-span and lifespan in vertebrates and invertebrates. Given the widespread use and apparent safety of metformin, it is assumed that its effects are not associated with toxicity, except when in marked excess. Here we determine that accumulation of damaging reducing equivalents is an unanticipated toxicity associated with biguanides, the defense against which requires post-transcriptional protection of de novo fatty acid biosynthesis. We demonstrate that biguanide treatment during impaired fatty acid biosynthesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require fatty acid biosynthesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat which can minimize biguanide-induced reductive stress whilst maximizing its pro-longevity outcomes and serve as an exploitable vulnerability in reductive stress sensitive cancers.
    HIGHLIGHTS: Biguanides inhibit cytosolic mRNA translation to extend lifespan in C. elegans . Fatty acid synthesis is translationally protected by eIF3 complex subunits. pod-2 / fasn-1 inactivation amplifies biguanide-induced reductive stress and death. NADPH-generating insults require fatty acid synthesis to buffer reductive stress.
    DOI:  https://doi.org/10.1101/2025.11.24.690166
  27. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00942-6. [Epub ahead of print]85(24): 4481-4482
    Time and space: How the circadian clock controls DNA break repair location and pathway choice.
    Catherine H Freudenreich.
      In this issue of Molecular Cell, Le Bozec et al.1 find that repair of DSBs within transcriptionally active regions of the human genome is dictated by spatial location within the nucleus, which is controlled by the circadian clock protein complex PERIOD.
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.025
  28. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00940-2. [Epub ahead of print]85(24): 4602-4620.e9
    Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression.
    Yameng Hu, Ziwen Li, Man Li, Xingui Wu, Shuxia Zhang, Miaoling Tang, Ruyuan Yu, Meisongzhu Yang, Xin Chen, Libing Song, Guido Kroemer, Valerian E Kagan, Hülya Bayir, Rui Kang, Jinbao Liu, Daolin Tang, Jun Li.
      Inducing lipid peroxidation-dependent ferroptosis is a promising anticancer strategy; however, the development of resistance poses a considerable challenge. This study identifies peroxiredoxin 6 (PRDX6) as a crucial modulator of glutathione peroxidase 4 (GPX4), affecting its localization and functional roles, thus contributing to ferroptosis resistance. PRDX6, endowed with phospholipase A2 activity, catalyzes the conversion of peroxy-phospholipids to lysophospholipids and oxidized fatty acids. Through targeted structural mutations and biochemical analyses, we demonstrate that PRDX6 binds to GPX4 via a C47 disulfide bond, facilitating GPX4's membrane translocation and enhanced production of hydroxy fatty acids. Combining the inhibition of PRDX6 with ferroptosis inducers increases lipid peroxidation, effectively suppressing tumor growth in liver and ovarian cancer mouse models, including patient-derived models. Furthermore, high PRDX6 expression correlates with shorter progression-free survival across multiple human cancer types. Collectively, our findings delineate a PRDX6-dependent mechanism in ferroptosis defense, offering new perspectives for targeted cancer therapy.
    Keywords:  PRDX6; cancer therapy; lysophospholipids; membrane translocation of GPX4
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.023
  29. Blood. 2025 Dec 15. pii: blood.2025028196. [Epub ahead of print]
    Methylation-based lineage tracing in cancer.
    Jiaoyi Chen, Benson Z Wu, Federico Gaiti.
      The evolutionary history of cancers is encoded in molecular patterns that provide critical insights into the mechanisms of tumor progression. However, reconstructing cancer lineages in patient tumors remains challenging, as conventional sequencing captures only static snapshots of an ongoing evolutionary process. DNA methylation at CpG sites is a heritable epigenetic mark that accumulates stochastic errors - termed epimutations - at rates far exceeding those of somatic DNA mutations. These epimutations serve as a 'molecular clock' and can be harnessed for retrospective lineage tracing. When applied at single-cell resolution, methylation-based lineage tracing enables the reconstruction of cancer phylogenies and provides a powerful framework for studying the dynamics of treatment resistance, cell-state heritability, and metastasis directly in human tumors. In this review, we outline the strengths and challenges of single-cell DNA methylation-based lineage tracing, highlight key insights gained from its application with an emphasis on hematological cancers where relevant, and discuss its future potential in advancing our understanding of cancer evolution.
    DOI:  https://doi.org/10.1182/blood.2024028196
  30. Neurosci Biobehav Rev. 2025 Dec 17. pii: S0149-7634(25)00525-1. [Epub ahead of print] 106524
    On biological and artificial consciousness: A case for biological computationalism.
    Borjan Milinkovic, Jaan Aru.
      The rapid advances in the capabilities of Large Language Models (LLMs) have galvanised public and scientific debates over whether artificial systems might one day be conscious. Prevailing optimism is often grounded in computational functionalism: the assumption that consciousness is determined solely by the right pattern of information processing, independent of the physical substrate. Opposing this, biological naturalism insists that conscious experience is fundamentally dependent on the concrete physical processes of living systems. Despite the centrality of these positions to the artificial consciousness debate, there is currently no coherent framework that explains how biological computation differs from digital computation, and why this difference might matter for consciousness. Here, we argue that the absence of consciousness in artificial systems is not merely due to missing functional organisation but reflects a deeper divide between digital and biological modes of computation and the dynamico-structural dependencies of living organisms. Specifically, we propose that biological systems support conscious processing because they (i) instantiate scale-inseparable, substrate-dependent multiscale processing as a metabolic optimisation strategy, and (ii) alongside discrete computations, they perform continuous-valued computations due to the very nature of the fluidic substrate from which they are composed. These features - scale inseparability and hybrid computations - are not peripheral, but essential to the brain's mode of computation. In light of these differences, we outline the foundational principles of a biological theory of computation and explain why current artificial intelligence systems are unlikely to replicate conscious processing as it arises in biology.
    Keywords:  Artificial consciousness; Artificial intelligence; Artificial neural networks; Biological computation; Biological naturalism; Computation; Computational functionalism; Consciousness; Digital computation; Emergence; Hybrid systems; Large language models; Multiscale dynamics; Scale inseparability
    DOI:  https://doi.org/10.1016/j.neubiorev.2025.106524
  31. Nature. 2025 Dec 17.
    Systematic maps reveal how human chromosomes are organized.
    Elzo de Wit.
      
    Keywords:  Cell biology; Computational biology and bioinformatics; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-03808-9
  32. Nat Commun. 2025 Dec 18.
    Lactate mitochondrial oxidation drives stemness potential in metastatic breast cancer.
    Jia-Jia Zhang, Ruo-Fei Tian, Chang-Geng Song, Rui Liu, Duo He, Gai-Qin Zhang, Xin-Yu Fan, Zi-Chuan Duan, Kun Zhang, Tian-Jiao Zhang, Ya-Tong Chen, Jian Zhang, Ke Wang, Ju-Mei Zhao, Xiang-Min Yang, Zhi-Nan Chen, Ling Li.
      Metastatic cancer cells, originating from cancer stem cells with metastatic capacity, utilize nutrient flexibility to navigate the challenges of the metastatic cascade. However, the nutrient required to maintain the stemness potentials of metastatic cancer cells remains unclear. Here, we reveal that metastatic breast cancer cells sustain stemness and initiate metastasis upon detachment by taking up and oxidizing lactate. In detached metastasizing breast cancer cells, lactate is incorporated into the tricarboxylic acid cycle, boosting oxidative phosphorylation, and promoting the stemness potentials via α-KG-DNMT3B-mediated SOX2 hypomethylation. Moreover, lactate is taken up and oxidized in mitochondria by the CD147/MCT1/LDHB complex, which correlates with stemness potentials and tumor metastasis in patients with breast cancer. An intracellularly expressed single-chain variable fragment targeting mitochondrial CD147 (mito-CD147 scFv) effectively disrupts the mitochondrial CD147/MCT1/LDHB complex, inhibits lactate-induced stemness potential, depletes circulating breast cancer cells, and reduces metastatic burden, suggesting promising clinical applications in reducing lactate-fueled metastasis.
    DOI:  https://doi.org/10.1038/s41467-025-67091-y
  33. Life Sci Alliance. 2026 Mar;pii: e202503526. [Epub ahead of print]9(3):
    Multi-omics analysis reveals metabolic diversity underlying endothelial cell functions.
    Stephan Durot, Peter F Doubleday, Lydia Schulla, Amélie Sabine, Tatiana V Petrova, Nicola Zamboni.
      Endothelial cells (ECs) line the vascular system and are key players in vascular homeostasis, yet their metabolic diversity across tissues, vascular beds, and growth states remains poorly understood. This study examines metabolic differences between proliferating and quiescent ECs and compares blood and lymphatic endothelium using proteomics and metabolomics. Our findings indicate that metabolism in quiescent ECs is not dormant but reorganized in a cell-specific manner, with decreased heme intermediates in human umbilical vein ECs and increased branched-chain amino acid catabolism across all quiescent ECs. Consistent with the differences identified in the omics data, perturbation studies revealed that inhibiting enzymes involved in heme, glutamate, fatty acid, and nucleotide biosynthesis led to distinct phenotypic responses in blood and lymphatic ECs. These findings highlight the importance of metabolic pathways in sustaining both proliferating and quiescent ECs and reveal how ECs from different vascular beds rely on distinct metabolic processes to maintain their functional states.
    DOI:  https://doi.org/10.26508/lsa.202503526
  34. Nat Methods. 2025 Dec 17.
    Inferring cancer type-specific patterns of metastatic spread using Metient.
    Divya Koyyalagunta, Karuna Ganesh, Quaid Morris.
      Cancers differ in how they spread. These routes of metastatic dissemination can be reconstructed from tumor sequencing data, but current reconstruction methods scale poorly or rely on assumptions that do not reflect known biology. Metient overcomes these limitations using gradient-based, multiobjective optimization to generate multiple hypotheses of metastatic spread that are rescored using independent genetic distance and organotropism data. Unlike current methods, Metient can be used with both clinical sequencing data and barcode-based lineage tracing in preclinical models. Here, applied to data from 167 patients and 479 tumors, Metient identifies distinct trends of metastatic dissemination in melanoma, high-risk neuroblastoma and non-small cell lung cancer. Its reconstructions usually match expert analyses but Metient often finds other plausible migration histories, ultimately positing more polyclonal and metastasis-to-metastasis seeding than previously reported. Metient's reconstructions thus challenge existing assumptions about metastatic dissemination and offer insights into cancer type-specific patterns of metastatic spread.
    DOI:  https://doi.org/10.1038/s41592-025-02924-8
  35. Nat Commun. 2025 Dec 14. 16(1): 11260
    RHOA regulates mitochondria-ER contact sites through modulation of the VAPB/PTPIP51 tether.
    Zheng Yang, Shintaro Nakajima, Hsiuchen Chen, Yogaditya Chakrabarty, Huibao Feng, David C Chan.
      The mitochondria-endoplasmic reticulum contact site (MERCS) is critical for calcium exchange, phospholipid transfer, and bioenergetics. Impairment of MERCS is implicated in numerous pathological conditions, including cancer and neurodegenerative diseases. Remodeling of MERCS can affect calcium signaling or metabolism, but the mechanisms involved in dynamic MERCS remodeling are unknown. Employing a genome-wide CRISPRi screen, we uncover the ability of the small GTPase RHOA to tune the cellular MERCS level. RHOA knockdown, or increasing its degradation by CUL3 overexpression, reduces the MERCS level; conversely, upregulation of RHOA increases the MERCS level. RHOA binds to the ER protein VAPB and regulates complex formation between VAPB and mitochondrial PTPIP51, which form a tethering complex at the interface between ER and mitochondria. Furthermore, this regulatory mechanism is perturbed by disease alleles of RHOA, CUL3, and VAPB involved in cancer, hyperkalemia, and neurodegeneration, suggesting that MERCS may be affected in a range of pathological conditions. This study identifies RHOA as a regulator of mitochondria-ER communication, providing mechanistic insights into the dynamic remodeling of MERCS and potential therapeutic strategies for diseases linked to MERCS dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-66138-4
  36. Cell Rep. 2025 Dec 12. pii: S2211-1247(25)01460-3. [Epub ahead of print]44(12): 116688
    Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism.
    Bryan Harris, Dinesh K Singh, Billy Truong, Michele Rhodes, Rachael Price, Susan Shinton, Monika Verma, Bridget Aylward, Shawn P Fahl, Shanna R Sprinkle, Sarah Aminov, Minshi Wang, Yong Zhang, Jaqueline Perrigoue, Rachel Kessel, Suraj Peri, Joshua West, Orsi Giricz, Jacqueline Boultwood, Andrea Pellagatti, K H Ramesh, Cristina Montagna, Kith Pradhan, Jeffrey W Tyner, Brian K Kennedy, Michael Holinstat, Ulrich Steidl, Stephen Sykes, Amit Verma, David L Wiest.
      We report here that expression of the ribosomal protein RPL22 is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), and reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism, including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid content, upon which the survival of Rpl22-deficient leukemias depends. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSCs through regulation of FAO and promotes leukemogenesis through Lin28b promotion of lipid synthesis.
    Keywords:  AML; CP: cancer; CP: molecular biology; Lin28b; MDS; Rpl22; fatty acid metabolism; hematopoietic stem cell; ribosomal protein; triglyceride
    DOI:  https://doi.org/10.1016/j.celrep.2025.116688
  37. Cell Signal. 2025 Dec 12. pii: S0898-6568(25)00737-5. [Epub ahead of print]139 112322
    STING-driven activation of TFEB/TFE3 establishes a negative feedback loop to control immune homeostasis.
    Yuyuan Wang, Yu Luo, Fei Zhou, Dan Li.
      Recently several studies have identified that transcription factor EB (TFEB) and transcription factor E3 (TFE3) are the crucial regulators bridging the crosstalk between lysosomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Moreover, this TFEB/TFE3-mediated pathway establishes an essential negative feedback loop, revealing a novel self-regulatory mechanism in innate immunity, which suppresses IRF3 phosphorylation and IFN secretion, reduces caspase-3 activation, and enhances cell survival. Collectively, these findings unveil a critical role for TFEB/TFE3 in the maintenance of immune homeostasis, highlighting their functions in preventing excessive immune responses and protecting cell survival. In this review, we will summarize these findings and discuss the new insights they bring to our understanding of the interplay among the cGAS-STING pathway, lysosomal function, and innate immunity.
    Keywords:  Autophagy; Lysosomes; TFE3; TFEB; cGAS-STING
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112322
  38. bioRxiv. 2025 Nov 30. pii: 2025.11.29.691178. [Epub ahead of print]
    Deep Red Blood Cell Proteome Defines the Band 3 N-Terminus Interactome as a Regulator of Hypoxic Adaptation via BLVRB-Dependent S -Nitroso Transfer.
    Aaron V Issaian, Monika Dzieciatkowska, Shaun Bevers, Safari Zohreh, Ariel Hay, Anthony Saviola, Jasmina S Redzic, Julie A Reisz, Gregory R Keele, Francesca I Cendali, Zachary B Haiman, Travis Nemkov, Daniel Stephenson, Christina Lisk, Francesca Vallese, Bernhard O Palsson, S Bruce King, Grier P Page, Allan Doctor, Krystalyn Hudson, Kirk C Hansen, David C Irwin, Narla Mohandas, James C Zimring, Elan Z Eisenmesser, Angelo D'Alessandro.
      Red blood cells (RBCs) have long been regarded as passive oxygen carriers, yet growing evidence reveals a complex, dynamic proteome independent of de novo gene expression. Here, we define the erythrocyte as an oxygen-responsive system organized around a Band 3 (SLC4A1)-centered metabolon. Using deep proteomics of ultra-pure RBCs and cross-linking interactomics, we identify biliverdin reductase B (BLVRB) as a previously unrecognized Band 3 interactor that binds the N-terminal cytosolic domain under normoxia and dissociates under hypoxia, when band 3-deoxyhemoglobin interactions increase threefold. This reversible interaction forms an oxygen-sensitive switch coupling structural, redox, and metabolic remodeling. In humanized mice, truncation of the Band 3 N-terminus disrupted glycolytic activation, reduced 2,3-bisphosphoglycerate synthesis, and impaired exercise tolerance despite preserved cardiopulmonary function, establishing the physiological relevance of this module. Population-scale proteome quantitative trait locus (pQTL) analyses revealed coordinated variation of SLC4A1 and BLVRB abundance but minimal association of biliverdin levels with BLVRB genotype, suggesting alternative functions beyond heme catabolism. Mechanistically, BLVRB Cys109 acts as a nitric oxide (NO) relay, trans-nitrosating glycolytic enzymes such as GAPDH at active site Cys152, transiently inhibiting glycolysis. This S-nitrosation-mediated feedback mirrors conserved mechanisms in plants, where GAPDH-SNO redirects carbon flow toward the Calvin-Benson cycle under nitrosative stress, revealing an evolutionary convergence in gas-responsive metabolic control. Collectively, our findings define a Band 3-BLVRB-hemoglobin axis that links oxygen sensing, NO signaling, and redox homeostasis, providing a unifying model for how an anucleate cell achieves environmental adaptability through reversible protein-protein interactions and post-translational chemistry.
    Graphic abstract: Issaian et al. define the most comprehensive proteome of ultra-pure human red blood cells (3,775 proteins) and map the O₂-dependent interactome, revealing a Band 3-BLVRB-hemoglobin module that links oxygen sensing to metabolic remodeling via reversible inhibitory S-nitrosation of GAPDH C152. In plants this redirects carbon toward photosynthesis, illustrating a conserved NO-dependent metabolic reprogramming mechanism across oxygen-regulated systems.
    Highlights: Deep proteomics defines a complete, contamination-free RBC proteome (3,775 proteins)Cross-linking proteomics maps an oxygen-sensitive Band 3-centered interactomeO2-dependent BLVRB-Band 3 binding regulates metabolism via S-nitrosation of GAPDHBand 3 N-terminus is required for hypoxic remodeling and exercise tolerance in vivo.
    DOI:  https://doi.org/10.1101/2025.11.29.691178
  39. Trends Cancer. 2025 Dec 18. pii: S2405-8033(25)00309-7. [Epub ahead of print]
    Cuproptosis in cancer: from molecular mechanisms to therapeutic intervention.
    Dadi Jiang, Li Zhuang, Albert C Koong, Boyi Gan.
      Cuproptosis, a recently discovered form of regulated cell death triggered by copper overload, is distinguished by the aggregation of lipoylated mitochondrial proteins and destabilization of iron-sulfur cluster proteins. Given the altered copper metabolism and metabolic dependencies of cancer cells, cuproptosis might represent a unique vulnerability with therapeutic potential. In this review we summarize current knowledge of copper homeostasis, the molecular mechanisms of cuproptosis and its roles in cancer biology. We highlight therapeutic strategies that harness cuproptosis, including copper ionophores, nanomedicine, and rational combination therapies, and discuss challenges such as systemic toxicity, resistance mechanisms, and biomarker development. Finally, we outline key questions and future directions for translating cuproptosis into the clinic.
    Keywords:  cancer therapy; copper; cuproptosis; protein lipoylation; regulated cell death
    DOI:  https://doi.org/10.1016/j.trecan.2025.12.002
  40. Nature. 2025 Dec 17.
    Transient hepatic reconstitution of trophic factors enhances aged immunity.
    Mirco J Friedrich, Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, Rhiannon K Macrae, Feng Zhang.
      Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy and vaccine failure1-3. Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility1,3-5. Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic mapping across central and peripheral niches in young and aged animals, leading to the identification of Notch and Fms-like tyrosine kinase 3 ligand (FLT3L) pathways, together with interleukin-7 (IL-7) signalling, as declining with age. Delivery of mRNAs encoding Delta-like ligand 1 (DLL1), FLT3L and IL-7 to hepatocytes expanded common lymphoid progenitors, boosted de novo thymopoiesis without affecting haematopoietic stem cell (HSC) composition, and replenished T cells while enhancing dendritic cell abundance and function. Treatment with these mRNAs improved peptide vaccine responses and restored antitumour immunity in aged mice by increasing tumour-specific CD8+ infiltration and clonal diversity and synergizing with immune checkpoint blockade. These effects were reversible after dosing ceased and did not breach self-tolerance, in contrast to the inflammatory and autoimmune liabilities of recombinant cytokine treatments6,7. These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.
    DOI:  https://doi.org/10.1038/s41586-025-09873-4
  41. bioRxiv. 2025 Nov 30. pii: 2025.11.26.690792. [Epub ahead of print]
    Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis.
    Jun-Wei B Hughes, Akshay Pujari, Anja Sandholm, Duncan Croll, Lea B Monk, Isaac Joshua, Rachel Butterfield, Cory Horton, Kevin Schneider, Fiona Senchyna, Ian Brown, Ana L Coelho, Tsung-Che Ho, Hideto Deguchi, Claude Jordan Le Saux, Stefanie Deinhardt-Emmer, Lisa M Ellerby, Alberto Vitari, David Furman, Cory M Hogoboam, Alex Laslavic, Pierre-Yves Desprez, Marco Quarta, Judith Campisi.
      Cellular senescence is a largely heterogeneous state of cell stress that deleteriously accumulates with age. Many types of heterogeneity in senescence have been described; however, cellular senescence within the same cell type has only started to be documented. Here, we show primary, human lung fibroblasts from donors who are healthy or diagnosed with idiopathic pulmonary fibrosis (IPF) exhibit a subtle form of heterogeneity over time after DNA damage. Moreover, senescent IPF lung fibroblasts display a dysregulated transcriptional-protein DNA damage response (DDR). Weighted gene correlation network analysis (WGCNA) reveals unique and known targets linking senescent IPF lung fibroblast heterogeneity to genes associated with DNA damage and repair, cytokine and chemokine responses, and extracellular matrix (ECM) signaling. We combine our healthy and IPF senescent gene expression signatures to develop a novel gene set of senescence-associated genes that identify disease-relevant cells in human single-cell RNA-seq (scRNA-seq) data. Collectively, our results uncover human-relevant senescence signatures, highlight IPF-specific DDR, cytokine and chemokine, and ECM targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.
    DOI:  https://doi.org/10.1101/2025.11.26.690792
  42. EMBO Mol Med. 2025 Dec 19.
    Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
    Márcio Augusto Campos-Ribeiro, Erminia Donnarumma, Hendrik Nolte, Paul Cobine, Elodie Vimont, Dusanka Milenkovic, Juan Diego Hernandez-Camacho, Francina Langa-Vives, Etienne Kornobis, Esthel Pénard, Sonny Yde, Thomas Langer, Véronique Paquis-Flucklinger, Timothy Wai.
      Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.
    Keywords:  CHCHD10; Cardiomyopathy; Cytochrome c; Mitochondrial Disease; OMA1
    DOI:  https://doi.org/10.1038/s44321-025-00358-5
  43. Nat Commun. 2025 Dec 15.
    Partial restoration of mitochondrial dysfunction by AAV-Ant1 protects from dilated cardiomyopathy in Ant1-/- plus mtDNA mutant mice.
    Alessia Angelin, Kierstin Keller, Peiran Lu, Joseph W Guarnieri, Gabrielle A Widjaja, Rasheed Sule, Kevin Janssen, Arnold Olali, Zimu Cen, Valeria Carosi, Maina Beauplan, Deborah G Murdock, Prasanth Potluri, Liming Pei, Douglas C Wallace.
      Primary mitochondrial disease (PMD) patients manifesting cardiomyopathy are twice as likely to die as other PMD patients. One PMD with cardiomyopathy is caused by null mutations in the heart-muscle isoform of the adenine nucleotide translocator (SLC25A4, ANT1) gene, with the severity of cardiomyopathy mediated by mitochondrial DNA. To optimize strategies for addressing mitochondrial cardiomyopathy, we generated an Ant1 null mouse and combined it with the ND6P25L mitochondrial DNA mutation to mimic the hypertrophic versus dilated cardiomyopathies observed in patients. Here, we transduce the neonatal Ant1-/- and Ant1-/-+ND6P25L mouse hearts with an AAV2/9-pDes-Gfp-mAnt1 cDNA vector. We show that restoration of just 10% of Ant1 gene expression was sufficient to ameliorate the cardiomyopathies in these mice. Proteomics and single-nucleus RNA sequencing reveal the reversal of dysregulated mitochondrial metabolic genes, including PGC1α, as well as cardiac contractile and extracellular matrix proteins. Hence, a modest increase in cardiac mitochondrial energetics can have profound benefits on cardiac function and is effective in treating mitochondrial cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41467-025-67134-4
  44. J Immunol. 2025 Dec 13. pii: vkaf328. [Epub ahead of print]
    SLC7A5 regulates B cell metabolism and plasma cell differentiation independent of leucine transport.
    Anthony Y Tao, Ke Hu, Lucile Noyer, Li Zhong, Wenyi Li, Liwei Wang, Stefan Feske.
      B cells play critical roles in humoral immunity to infection, vaccination, and autoimmunity. The differentiation of B cells into antibody-producing plasma cells (PCs) has been extensively studied, but the role of metabolic transporters that mediate nutrient uptake during PC differentiation is not well-understood. Here, we characterized the dependence of B cells and PC differentiation on the neutral amino acid transporter SLC7A5. We demonstrate that SLC7A5 promotes B cell functions including proliferation and PC differentiation in vitro and in vivo after immunization with T dependent and independent antigens. Deletion of SLC7A5 in B cells suppressed the function of mTORC1 and enforced mTORC1 activity rescued PC differentiation. The role of SLC7A5 in B cells appears to be unrelated to leucine uptake because B cells were insensitive to extracellular leucine depletion. Defects in SLC7A5-deficient B cells could, however, be rescued by extracellular methionine supplementation, suggesting a role for methionine in SLC7A5-dependent B cell function and PC differentiation. Our study provides evidence for a leucine-independent role of SLC7A5 in B cell function and PC differentiation.
    Keywords:  SLC7A5; leucine; mTORC1; metabolism; plasma cells
    DOI:  https://doi.org/10.1093/jimmun/vkaf328
  45. EMBO J. 2025 Dec 17.
    The transaminase-ω-amidase pathway senses oxidative stress to control glutamine metabolism and α-ketoglutarate levels in endothelial cells.
    Niklas Herrle, Pedro F Malacarne, Timothy Warwick, Alfredo Cabrera-Orefice, Yiheng Chen, Maedeh Gheisari, Souradeep Chatterjee, Matthias S Leisegang, Tamim Sarakpi, Sarah Wionski, Melina Lopez, Carine Kader, Tom Teichmann, Maria-Kyriaki Drekolia, Ina Koch, Marcus Keßler, Sabine Klein, Frank Erhard Uschner, Jonel Trebicka, Steffen Brunst, Ewgenij Proschak, Stefan Günther, Mónica Rosas-Lemus, Nina Baumgarten, Stephan Klatt, Thimoteus Speer, Sofia-Iris Bibli, Marta Segarra, Amparo Acker-Palmer, Julian U G Wagner, Ilka Wittig, Stefanie Dimmeler, Marcel H Schulz, J B Richards, Ralf Gilsbach, Travis T Denton, Ingrid Fleming, Luciana Hannibal, Ralf P Brandes, Flávia Rezende.
      Oxidative stress is a major driver of cardiovascular disease; however, the fast changes in cellular metabolism caused by short-lived reactive oxygen species (ROS) remain ill-defined. Here, we characterized changes in the endothelial cell metabolome in response to acute oxidative challenges and identified novel redox-sensitive metabolic enzymes. H2O2 selectively increased the amount of α-ketoglutaramate (αKGM), a largely uncharacterized metabolite produced by glutamine transamination and an unrecognized intermediate of endothelial glutamine catabolism. In addition, H2O2 impaired the catalytic activity of nitrilase-like 2 ω-amidase (NIT2), the enzyme that converts αKGM to α-ketoglutarate (αKG), by the reversible oxidation of specific cysteine residues. Moreover, a NIT2 gene variant exhibited decreased expression in humans and was associated with increased plasma αKGM concentration. Endothelial-specific knockout of NIT2 in mice increased cellular αKGM levels and impaired angiogenesis. Further, NIT2 depletion impaired endothelial cell proliferation, sprouting, and induced senescence. In conclusion, we uncover NIT2 as a redox-sensitive enzyme of the glutamine transaminase-ω-amidase pathway that acts as a metabolic switch modulating endothelial glutamine metabolism in mice and humans.
    Keywords:  Endothelial Cells; Glutamine Metabolism; Oxidative Stress; α-Ketoglutaramate; α-Ketoglutarate
    DOI:  https://doi.org/10.1038/s44318-025-00642-7
  46. Biol Chem. 2025 Dec 18.
    There and back again: a cell biologist's journey from organelles to molecules.
    Emma J Fenech, Yury S Bykov.
      Eukaryotic life is defined by the presence of organelles. Organelles, in turn, were classically defined as specialized membrane-bound compartments composed of a unique set of macromolecules which support specific functions. Over the last few decades, a concerted effort into uncovering which components are present in each organelle has shaped our view of cell biology. However, despite some organelles already being visualized over 100 years ago, we are still discovering new organelle residents. Furthermore, our concept of both 'organelles' and 'compartmentalization' has evolved together with our deepening understanding in a number of fields. These include: organelle substructure and organization; the network of contact sites which interconnects all organelles; and membraneless organelles and phase-separated condensates. This review explores how image- and mass spectrometry-based methods can be used to understand the spectrum of where components are localized: from complexes, to subdomains, and whole organelles. The components we mainly focus on are proteins of the mitochondria and secretory pathway organelles.
    Keywords:  contact sites; mass spectrometry; microscopy; organelle subdomains; organelles; protein complexes
    DOI:  https://doi.org/10.1515/hsz-2025-0185
  47. Trends Cancer. 2025 Dec 12. pii: S2405-8033(25)00283-3. [Epub ahead of print]
    Lost but not least: Y chromosome loss as a driver of cancer.
    Luis Antonio Corchete Sanchez, Esther Rheinbay.
      Traditionally neglected and frequently excluded from large-scale genomic studies, the Y chromosome is now emerging as a potential Achilles' heel of cancers in men. Recent evidence has suggested that loss of this chromosome - a phenomenon known as loss of Y chromosome (LOY) - is not a silent event, but rather an active driver that promotes tumor progression through loss of tumor suppressor genes, increasing tumor growth and enabling immune evasion. Importantly, LOY creates loss of heterozygosity of paralogous genes on the X chromosome, a vulnerability that can potentially be therapeutically exploited. The exact mechanisms of LOY in cancer, and the utility of LOY as a biomarker and therapeutic target, are open questions for the emerging field of Y chromosome-focused cancer research.
    Keywords:  LOY; Y chromosome; cancer sex bias; somatic alterations
    DOI:  https://doi.org/10.1016/j.trecan.2025.11.009
  48. Cancer Discov. 2025 Nov 28. OF1
    Circulating Tumor Cell Infiltration of Major Vessels Influences Cancer Prognosis.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2025-103
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