bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–06–21
forty-one papers selected by
Christian Frezza, Universität zu Köln
  1. Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
  2. Understanding the somatic evolution of metabolic traits.
  3. Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.
  4. Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.
  5. LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance.
  6. Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
  7. Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma.
  8. Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis.
  9. Metabolic flexibility secures skeletal progenitor function upon reduced glycolysis driven by PFKFB3 loss.
  10. An aminoacyl-tRNA synthetase governs dsRNA-mediated trade-off between longevity and innate immunity.
  11. Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
  12. Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases.
  13. Limiting neurodegeneration in ALS: A phosphatase paves the way.
  14. Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
  15. Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
  16. Aging disrupts spatiotemporal coordination in the cycling murine ovary.
  17. Metabolic regulatory nodes of the inflammasome and inflammatory cell death.
  18. SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
  19. Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer.
  20. Fibroblastic aspartoacylase suppresses TGFβ-mediated responses and cancer progression.
  21. The pyruvate transporter hermes regulates autophagy and health by modulating ROS production.
  22. Substrate selectivity as a paradigm shift in mTORC1 signaling.
  23. A multi-organ metabolomics atlas reveals molecular dysregulations in Alzheimer's disease mouse models.
  24. ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
  25. Arginine metabolism supports de novo pyrimidine biosynthesis to block DNA damage and maintain Epstein-Barr virus latency.
  26. Abiotic sources of fixed nitrogen sustained early ecosystems for several hundred million years after the origin of life.
  27. Blood signatures of cell type-specific aging forecast disease risk and resilience.
  28. Metabolic Reprogramming and Molecular Mechanisms in Renal Cell Carcinoma: Therapeutic Implications and Future Perspectives.
  29. Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.
  30. NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
  31. Cell-Resolved Mass Spectrometry Imaging Integrated with Isotope Tracing Elucidates Macrophage Polarization-Specific Metabolic Reprogramming.
  32. P5CS represses tumor progression via inhibiting assembly of 48S pre-translation initiation complex.
  33. Rethinking mitochondrial metabolism: Intraindividual variability meets population constraints.
  34. Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.
  35. Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.
  36. Moderate iron restriction improves metabolism via epigenetic regulation of GDF15.
  37. Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1.
  38. Regulation and function of specialized membrane protrusions in intercellular communication.
  39. Tumor suppressor genotype influences the extent and mode of immunosurveillance in lung cancer.
  40. Single-cell map of the healthy human immune system across the lifespan reveals unique infant immune signatures.
  41. Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
  1. Nat Cell Biol. 2026 Jun 15.
    Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
    Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.
      Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.
    DOI:  https://doi.org/10.1038/s41556-026-01991-z
  2. Nat Metab. 2026 Jun 16.
    Understanding the somatic evolution of metabolic traits.
    Radhika Khandelwal, Anand Kumar Sharma.
      
    DOI:  https://doi.org/10.1038/s42255-026-01551-7
  3. Nat Commun. 2026 06 15. pii: 5288. [Epub ahead of print]17(1):
    Oncogenic KRAS-driven type I interferon signalling primes pancreatic cancer for necroptosis.
    Sofya Tishina, Alina Dahlhaus, Marta Manik, Lejla Mulalic, Janine Murr, Michael Kotliar, Hassan Rakhsh-Khorshid, Myrto Kostopoulou, Florian Hocher, Jenny Stroh, Julia Beck, Riley M Williams, Gülce G Balta, Fanyu Liu, Ali T Abdallah, Christina M Bebber, Moritz Reese, Jonathan K M Lim, Alexander Quaas, Johannes Brägelmann, Manolis Pasparakis, Filippo Beleggia, Siddharth Balachandran, Anna Trauzold, Gianmaria Liccardi, Igor Astsaturov, Maximilian Reichert, Ariadne Androulidaki, Silvia von Karstedt.
      Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death within this decade. Here, we show that its major driver oncogene KRAS activates the cGAS-STING-TBK1 axis, inducing a type I interferon (IFN) response that primes PDAC cells for necroptosis. Using genetically engineered mouse models, we find that cancer cell-specific deletion of caspase-8 is sufficient to trigger necroptotic cell death, eliminating most pancreatic precursor lesions. Mechanistically, KRAS-driven IFN signalling induces ISGF3-dependent expression of necroptosis-related interferon-stimulated genes, including MLKL. This renders PDAC cells selectively vulnerable to necroptosis upon caspase-8 inhibition. Therapeutically, pharmacologic caspase inhibition reduces tumour burden in aggressive PDAC models and human patient-derived organoids. A pan-cancer transcriptomic analysis links necroptosis gene expression with Ras pathway activity and IFN signatures across multiple tumour types. These findings reveal a KRAS-induced IFN program that sensitises tumour cells to necroptosis, highlighting a therapeutic vulnerability in PDAC with broader relevance across IFN-activated cancers.
    DOI:  https://doi.org/10.1038/s41467-026-73189-8
  4. Nat Cell Biol. 2026 Jun 19.
    Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.
    Steven T Nguyen, Richard L Watson, Fangyuan Gao, Melissa Campos, Sunhee Jung, Laurence J Seabrook, Maxwell C Kim, Eric A Hanse, Ying Yang, Mei Kong, Jonathan E Zuckerman, Renata C Pereira, Isidro B Salusky, Sergio D Catz, Cholsoon Jang, Dorota Skowronska-Krawczyk, Lauren V Albrecht.
      Lysosomes are integral organelles that communicate cellular status to an entire tissue through mechanisms that are poorly defined. Here we developed an unbiased platform, integrating human plasma metabolomes and single-lysosome metabolomics, and show the byproducts of proteolysis are an unexpected class of signalling molecules. We show that dimethylarginine is a lysosomal-derived metabolite and a predictor of patient morbidity. Genetic depletion of a lysosomal exporter, cystinosin, accumulated dimethylarginine in lysosomes. Leveraging a lysosomal storage disease with cystinosin mutations, we show that the rapid plasticity of dimethylarginine compartmentalization ensures cell and tissue homeostasis. Strikingly, lysosomal entrapment of dimethylarginine in patients and disease models corresponds with lipid accumulation, lipid droplets and lipotoxicity. Exogenously restoring asymmetric dimethylarginine buffers oxidative stress, decreasing lipid peroxidation and cell death. These data show that dimethylarginine engages an interorganellar process-with peroxisomes, lysosomes and lipid droplets-that confers a crucial adaptive response mechanism.
    DOI:  https://doi.org/10.1038/s41556-026-01970-4
  5. Mol Cell. 2026 Jun 19. pii: S1097-2765(26)00385-0. [Epub ahead of print]
    LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance.
    Dylan E Ramage, Lianne H E Wieske, Charlotte Crowe, Jens B Christensen, Theo A von Wilmowski, Zoe Bannister, Drew W Grant, Mark A Nakasone, Kevin Haubrich, Mark Dorward, Iva A Tchasovnikarova, Michael P Weekes, Nicholas J Matheson, N Sumru Bayin, Alessio Ciulli, Richard T Timms.
      Adaptation to fluctuating nutrient supply is essential for organismal survival, but how human cells monitor the abundance of many critical nutrients remains undefined. Characterizing the conditional degradation of CDO1, the critical enzyme responsible for cysteine catabolism, here we identify a Cullin-RING E3 ligase complex defined by the substrate adaptor LRRC58 that is sensitive to cysteine abundance. When cysteine is replete, LRRC58 activity is restrained through ubiquitination and proteasomal degradation. Upon cysteine deprivation, LRRC58 is stabilized to permit CDO1 degradation. Through saturation mutagenesis stability profiling, we systematically validate a structural model of the CDO1-LRRC58 interaction and identify residues at the LRRC58 C terminus required for cysteine-dependent instability. CDO1 degradation prevents ferroptotic cell death upon cysteine scarcity, and CDO1 mutations causing neurodevelopmental defects in humans encode dominant-active proteins refractory to LRRC58 recognition. Altogether, these data reveal the CDO1-LRRC58 axis as a critical regulator of cysteine homeostasis that safeguards neural development.
    Keywords:  CDO1; Cullin-RING E3 ligase; LRRC58; amino acid sensing; conditional protein degradation; cysteine; cysteine catabolism; ferroptosis; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.014
  6. J Clin Invest. 2026 Jun 16. pii: e196687. [Epub ahead of print]
    Elevated mitochondrial protein import in acute myeloid leukemia increases reliance on mitochondrial protease LONP1.
    Matthew Tcheng, Veronique Voisin, Geethu Emily Thomas, Anastasija A Piric, Marcela Gronda, Rose Hurren, Dakai Ling, Yongran Yan, Lan Xin Zhang, Yue Feng, Ali Chegini, Nathan Duong, Ross S Mancini, Stefan Quinn W Currie, Zaynab Mamai, Brady Stock, Shahbaz Khan, Yulia Jitkova, Chaitra Sarathy, Edward Ayoub, Po Yee Mak, Andrea Arruda, Thomas Kislinger, Mark Reed, Bing Z Carter, Michael Andreeff, Steven M Kornblau, Mark D Minden, Siavash Vahidi, Aaron D Schimmer.
      Most mitochondrial proteins are nuclear encoded, translated in the cytosol, and imported into the mitochondria. Through gene expression analysis and functional assays, we demonstrated that mitochondrial protein import is increased in acute myeloid leukemia (AML) cells compared to normal hematopoietic cells. Increased mitochondrial protein import was positively correlated with increased mitochondrial unfolded protein response (UPRmt), a stress activated pathway of mitochondrial proteases and chaperones that maintains protein solubility and prevents the formation of toxic aggregates. The UPRmt protease LONP1 (Lon Peptidase 1) was upregulated in AML and positively correlated with increased mitochondrial protein import and UPRmt. Genetically or chemically inhibiting the LONP1 ATPase domain induced mitochondrial protein aggregation and selectively killed AML cells with high LONP1 expression while sparing AML cells with low LONP1 expression and normal hematopoietic cells in vitro and in vivo. Thus, we uncovered a critical role of the UPRmt protease LONP1 in buffering stress from mitochondrial protein import in AML.
    Keywords:  Cancer; Cell biology; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI196687
  7. Annu Rev Genomics Hum Genet. 2026 Jun 15.
    Common Principles Underlie Mitochondrial DNA Heteroplasmy Dynamics in the Germline and Soma.
    Cameron Ryall, Patrick F Chinnery, Jelle van den Ameele.
      Heteroplasmy is the mixture of mutant and wild-type mitochondrial DNA (mtDNA) within each of our cells. Heteroplasmy levels in cells, tissues, and organisms change over time, thus contributing to mitochondrial disease, aging, and evolution. Germline and pedigree studies first revealed heteroplasmy shifts between generations and have long offered a window into the dynamics of mtDNA inheritance through single oocytes. Single-cell technologies are now uncovering similar mechanisms that operate in somatic tissues throughout life. Stochastic processes (relaxed replication and vegetative segregation, enhanced through genetic bottlenecks) generate cell-to-cell variation, while selection mechanisms such as intercellular competition, mitophagy, and preferential replication allow or drive directional shifts. Single-cell sequencing, mtDNA imaging, and genetic screening, combined with mtDNA-editing technology and heteroplasmic model systems, have transformed our ability to dissect these processes, revealing heteroplasmy dynamics at molecular resolution. These approaches are uncovering quantifiable principles governing heteroplasmy across cell types and life stages, transforming our understanding from descriptive observations to predictive mechanistic models and novel therapeutic avenues.
    DOI:  https://doi.org/10.1146/annurev-genom-120324-032239
  8. NPJ Aging. 2026 Jun 18.
    Uncovering senescent fibroblast heterogeneity connects DNA damage response to idiopathic pulmonary fibrosis.
    Jun-Wei B Hughes, Akshay Pujari, Anja Sandholm, Duncan Croll, Lea Baskin Monk, Isaac Joshua, Rachel Butterfield, Corrigan Horton, Kevin Schneider, Fiona Senchyna, Ian Brown, Zhixin A Zhang, Ana L Coelho, Tsung-Che Ho, Hideto Deguchi, Ryo Higuchi-Sanabria, Claude Jourdan Le Saux, Stefanie Deinhardt-Emmer, Lisa M Ellerby, Alberto C Vitari, David Furman, Cory M Hogaboam, Alex Laslavic, Pierre-Yves Desprez, Marco Quarta, Judith Campisi.
      Cellular senescence is a highly heterogeneous state of cell stress response that deleteriously accumulates with age and contributes to age-related dysfunction. While the heterogeneity across cell types is well documented, variation within the same cell type is only beginning to be understood. Here, we show primary human lung fibroblasts from either 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 and cytokine and chemokine responses. We combine our healthy and IPF senescent gene expression datasets to develop a novel gene signature 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 targets, and expand our understanding of how a dysregulated DDR contributes to senescent cell heterogeneity in IPF.
    DOI:  https://doi.org/10.1038/s41514-026-00388-4
  9. Bone. 2026 Jun 16. pii: S8756-3282(26)00206-1. [Epub ahead of print] 117980
    Metabolic flexibility secures skeletal progenitor function upon reduced glycolysis driven by PFKFB3 loss.
    Lore Rosseels, Ingrid Stockmans, Karen Moermans, Lina Blockx, Pieter-Jan Coolen, Gabriele Ferrari, Ruslan I Dmitriev, Peter Carmeliet, Geert Carmeliet, Steve Stegen.
      Glycolysis is widely considered as a major metabolic pathway in several bone-residing cell types, including skeletal stem and progenitor cells (SSPCs) that are essential for bone development, maintenance, and regeneration. However, the contribution of glycolysis to the in vivo function of SSPCs remains unknown. To examine how reduced glycolysis affects SSPC biology, we conditionally deleted phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), a key regulator of glycolytic flux. PFKFB3 deletion decreased glycolytic flux by at least 30%, but also reduced glucose‑carbon incorporation into glycolysis-branching pathways and tricarboxylic acid (TCA) cycle intermediates. Despite this overall attenuation of glucose metabolism, PFKFB3-deficient SSPCs maintained metabolic homeostasis and their functional properties. Bone mass was also preserved in mutant mice, even under anabolic conditions that are associated with increased glycolytic demand. Mechanistically, metabolic profiling revealed that PFKFB3 knockout SSPCs compensated for reduced glucose utilization by increasing the uptake of amino acids and pyruvate, with pyruvate‑carbon contributing to TCA cycle anaplerosis and amino acid synthesis. Together, these findings demonstrate that SSPCs possess substantial metabolic flexibility, allowing them to adapt to reductions in glucose metabolism by rerouting alternative nutrients to biosynthetic and bioenergetic pathways. This metabolic reprogramming likely represents an adaptive mechanism that helps preserve bone formation under metabolic stress.
    Keywords:  Cell metabolism; Glycolysis; Metabolic flexibility; PFKFB3; Pyruvate; Skeletal stem/progenitor cell
    DOI:  https://doi.org/10.1016/j.bone.2026.117980
  10. Mol Cell. 2026 Jun 18. pii: S1097-2765(26)00322-9. [Epub ahead of print]86(12): 2237-2239
    An aminoacyl-tRNA synthetase governs dsRNA-mediated trade-off between longevity and innate immunity.
    Haruka Ozaki, Nobunari Sasaki, Shunsuke Kitajima.
      In this issue of Molecular Cell, Sohn et al.1 explore how endogenous dsRNAs influence organismal aging and identify an unexpected function of the aminoacyl-tRNA synthetase FARS-1/FARSA in regulating mitochondrial dsRNA homeostasis to balance longevity and innate immunity.
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.016
  11. J Lipid Res. 2026 Jun 19. pii: S0022-2275(26)00109-4. [Epub ahead of print] 101083
    Rewiring Mitochondrial Phosphatidylethanolamine Metabolism Identifies New and Unaccounted Trafficking Steps.
    Rashima Prem, Erica Avery, Juliana M Marquez, Chi Xie, Steven M Claypool.
      The distinct compositions of the two mitochondrial membranes are generated through a combination of phospholipids that mitochondria can make and those they take; both processes depend on a series of distinct lipid trafficking steps. Mitochondria make phosphatidylethanolamine (PE) through the action of the phosphatidylserine decarboxylase Psd1, an intermembrane space (IMS)-facing integral inner membrane (IM) protein. Psd1 has been proposed to act on its endoplasmic reticulum-derived substrate, phosphatidylserine (PS), after its transport to the mitochondrial outer membrane (OM) and either following its Ups2/Mdm35-mediated transport across the IMS to the IM or instead, on the IMS-side of the OM in a process enabled by the mitochondrial contact site and cristae organizing system (MICOS). Here, we implement a two-pronged Psd1 rewiring-based strategy predicted to either 1) circumvent the need for Ups2/Mdm35 and/or MICOS; or 2) selectively ablate the ability of Psd1 to work in trans. Our results with yeast harboring Psd1 targeted to the OM demonstrate that, with respect to mitochondrial PE production, Ups2/Mdm35 and MICOS indeed function within the IMS. Using yeast expressing a topologically inverted Psd1 chimera that faces the matrix, we identify previously unappreciated transbilayer lipid trafficking steps within the IM and show that Psd1 does not operate via a MICOS-organized in trans mechanism. Further, retained flux through inverted Psd1 when both Ups2/Mdm35 and MICOS are absent strongly implicates the existence of a major, yet presently unknown, mediator(s) of lipid movement across the IMS. Collectively, these data suggest a new model of how mitochondrial membrane diversity is established and maintained.
    Keywords:  Glycerophospholipids; membrane diversity; metabolic rewiring; mitochondria; phospholipids; phospholipids/biosynthesis; phospholipids/metabolism; phospholipids/trafficking
    DOI:  https://doi.org/10.1016/j.jlr.2026.101083
  12. Mol Metab. 2026 Jun 13. pii: S2212-8778(26)00084-0. [Epub ahead of print] 102400
    Cross-talk between glycosylation pathways: Mechanistic insights and implications for human diseases.
    Ninon Very, Ikram El Yazidi-Belkoura.
      Glycosylation encompasses a broad spectrum of post-translational modifications (PTMs) that shape protein stability, spatial organization, and function. Traditionally, it is classified into two major categories: complex glycosylation within the secretory pathway - including N-glycosylation, mucin-type O-glycosylation, glycosaminoglycans (GAGs), and glycolipids - which generate structurally stable and long-lived modifications; and O-GlcNAcylation, a highly dynamic modification of nucleocytoplasmic and mitochondrial proteins that rapidly responds to metabolic and environmental cues. While this dichotomous framework has guided our understanding of glycan biology, emerging evidence now reveals that glycosylations are functionally interconnected through shared metabolic substrates, and regulatory circuits. Here, we revisit this classical classification and integrate it into a modern, systems-level view of glycosylation. We highlight the nucleotide sugar UDP-N-acetylglucosamine (UDP-GlcNAc) as a metabolic node reflecting cellular nutrient status and fuelling both complex glycan synthesis and O-GlcNAcylation. UDP-GlcNAc pool fluctuations drive coordinated remodeling across glycosylation pathways, and dysregulation of this hub is associated with diverse human diseases. We discuss how O-GlcNAcylation functions as a supplementary regulatory PTM, modulating glycosylation-related enzymes and proteins through both direct effects on their interactions, stability, localisation and activity, and via broader transcriptional and epigenetic programs, thereby dynamically controlling otherwise stable glycosylation processes. Examples from metabolic, cardiovascular, neurological diseases, cancer and congenital disorders of glycosylation (CDGs) illustrate how perturbations in one glycosylation pathway propagate through the glycosylation network, reshaping cellular identity and disease trajectories. We support a paradigm in which glycosylation operates as an integrated regulatory framework linking metabolism, signaling, and extracellular architecture, providing new perspectives for disease stratification and therapeutic intervention.
    Keywords:  Glycosylation network; Human diseases; Metabolic regulation; O-GlcNAcylation; UDP-GlcNAc
    DOI:  https://doi.org/10.1016/j.molmet.2026.102400
  13. Neuron. 2026 Jun 17. pii: S0896-6273(26)00325-9. [Epub ahead of print]114(12): 2073-2075
    Limiting neurodegeneration in ALS: A phosphatase paves the way.
    Elena I Rugarli, Thomas Langer.
      Zheng et al. identify phosphatase PGAM5 as a novel promising target for the treatment of different amyotrophic lateral sclerosis subtypes. PGAM5 dephosphorylates and activates the stress-regulated mitochondrial peptidase OMA1, which elicits a maladaptive mitochondrial integrated stress response in motor neurons.
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.030
  14. Nat Commun. 2026 Jun 17.
    Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
    Yuhan Zhou, Jing Li, Fangfang Liu, Yuan Gao, Songlin Yin, Liguo Yang, Xiaoxiao Li, Junhong Lin, Yan Li, Haotian Shang, Xiang Cheng, Tengfei Chao, Qian Chu, Fujia Lu, Weimin Wang.
      Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.
    DOI:  https://doi.org/10.1038/s41467-026-74430-0
  15. EMBO Mol Med. 2026 Jun 17.
    Activation of AMPK as a therapeutic strategy for FBXL4-related mitochondrial DNA depletion syndrome.
    Aniketh Bishnu, Juan Zapata-Muñoz, Robert W Taylor, Kei Sakamoto, Ian G Ganley.
      Distinct mitophagy pathways can eliminate not only damaged mitochondria but also healthy ones. In Mitochondrial DNA Depletion Syndrome 13 (MTDPS13), dysregulated BNIP3/NIX-driven mitophagy of functional mitochondria is thought to be the key pathological driver. Patient mutations in the E3 ubiquitin ligase FBXL4 impair the proteasomal degradation of the mitophagy receptors BNIP3 and NIX, causing their accumulation and excessive mitophagy. As a result, mitochondrial content and oxidative phosphorylation decline sharply across multiple tissues, leading to early mortality, with no effective treatments currently existing. Here, we build on our work showing that AMPK can inhibit mitophagy via sequestration of the ULK1 autophagy-initiating kinase ULK1 and demonstrate that it is also critically relevant for mitophagy induced by FBXL4 disruption. Using FBXL4-deficient cells, as well as fibroblasts derived from MTDPS13 patients and a chemically-induced mouse model, we show that small molecule AMPK activation inhibits BNIP3/NIX-mediated mitophagy and recovers functional mitochondrial content. This work therefore validates AMPK as a realistic target in treating MTDPS13.
    DOI:  https://doi.org/10.1038/s44321-026-00471-z
  16. Nat Aging. 2026 Jun;6(6): 1244-1266
    Aging disrupts spatiotemporal coordination in the cycling murine ovary.
    Tammy C T Lan, Alison Kochersberger, Ruth Raichur, Sophia Szady, Hien Tran, Radiana Simeonova, Ashley Helmuth, Andrew Minagar, Maria José Orozco Fuentes, Vipin Kumar, Giovanni Marrero, Irving Barrera, Sarah Mangiameli, Alex K Shalek, Pardis C Sabeti, Fei Chen, David S Fischer, Jennifer L Garrison, Hattie Chung.
      Throughout the female reproductive lifespan, the ovary undergoes hundreds of cycles of follicle development, ovulation and tissue regeneration. How aging disrupts the coordination of such precise, multicellular interactions across time and space is not well understood. Using Slide-seq, a near-cellular spatial transcriptomics method, here we profile 22 mouse ovaries across the reproductive cycle and chronological ages, capturing 610,620 spots across 69 spatial profiles. We develop a novel segmentation pipeline to examine the multicellular dynamics of 358 oocytes, 668 follicles and 236 corpora lutea to find that aging impairs the spatial and temporal coordination required for folliculogenesis even before reproductive cycles cease. These disruptions are characterized by altered immune cell dynamics, inflammatory signaling and global tissue disorganization, which impair the cyclic remodeling required for ovarian function. Our findings reveal how multicellular niches orchestrate ovarian function and demonstrate that age-related breakdown in tissue organization precedes the end of fertility.
    DOI:  https://doi.org/10.1038/s43587-026-01140-z
  17. Trends Immunol. 2026 Jun 19. pii: S1471-4906(26)00139-0. [Epub ahead of print]
    Metabolic regulatory nodes of the inflammasome and inflammatory cell death.
    Ein Lee, Minh Quan Nguyen, Suyeong Im, Rajendra Karki.
      Inflammation is a metabolically intensive and tightly regulated process, driven primarily by innate immune cells. Cellular metabolism actively instructs immune signaling and cell fate decisions. Bioenergetic pathways, including glycolysis, mitochondrial respiration, and the tricarboxylic acid cycle, reshape cytokine production and regulate inflammatory cell death pathways. In this review, we synthesize emerging evidence on how metabolic intermediates and pathways regulate inflammasome signaling and the execution of diverse inflammatory cell death modalities, including pyroptosis, necroptosis, PANoptosis, and ferroptosis. We propose that metabolic inputs-including redox balance, mitochondrial dynamics, and lipid modifications-constitute an interconnected metabolic regulatory network that determines the threshold and outcome of inflammatory signaling. This framework offers new insights into immunometabolic dysregulation and therapeutic strategies in inflammatory, infectious, and neoplastic diseases.
    Keywords:  PANoptosis; ferroptosis; inflammation; metabolic nodes; necroptosis; pyroptosis
    DOI:  https://doi.org/10.1016/j.it.2026.06.002
  18. Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2612098123
    SLC25A3 exports mitochondrial copper to metalate cytochrome c oxidase and prevent cuproptosis.
    Mohammad Zulkifli, Ifrah Farid, Laura E Oldfather, Vinit C Shanbhag, Scot C Leary, Michael J Petris, Paul A Cobine, Vishal M Gohil.
      Copper (Cu) is an essential cofactor for cytochrome c oxidase (CcO), a mitochondrial respiratory chain enzyme that is metalated in the intermembrane space (IMS) primarily using Cu derived from the mitochondrial matrix pool. While Cu import into the matrix depends on the inner membrane carrier SLC25A3, the route by which matrix Cu is exported to the IMS for insertion into CcO has remained a major, unresolved step in intramitochondrial Cu trafficking. Here, we leveraged our recent discovery that the Cu ionophore elesclomol (ES) releases Cu directly into the mitochondrial matrix to show that SLC25A3 is required for exporting Cu to the IMS for CcO metalation. Loss of SLC25A3 decreases mitochondrial Cu content and CcO activity as expected. Strikingly, bypassing the loss of SLC25A3 with ES-mediated Cu delivery to the matrix fails to restore CcO function; rather, it drives toxic Cu retention and triggers cuproptosis, revealing that SLC25A3-facilitated Cu export is the limiting determinant of CcO metalation. Heterologous expression in Lactococcus lactis confirms that SLC25A3 can mediate Cu export. These results suggest that SLC25A3 is the long-sought mitochondrial Cu exporter with a dual role in enabling CcO metalation and gating susceptibility to cuproptosis.
    Keywords:  SLC25A3; copper; cuproptosis; cytochrome c oxidase; elesclomol
    DOI:  https://doi.org/10.1073/pnas.2612098123
  19. Nat Commun. 2026 Jun 19.
    Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer.
    Sirui Weng, Lachlan Cain, James Comben, Yangyi Zhang, Timothy Semple, Sara Alaei, David Yoannidis, Luciano Martelotto, Catherine Mitchell, Anupama Pasam, Richard J Young, Benjamin Blyth, Joy Hendley, Yuzhou Feng, Heather Thorne, Roslyn Wallace, Joanna Chan, Julia Como, Lisa Devereux, Himisha Beltran, Daniel Wetterskog, Scott Williams, Anthony T Papenfuss, Belinda Parker, Paul Neeson, Gerhardt Attard, David Quigley, David L Goode, Richard B Pearson, Luc Furic, Anna S Trigos, Shahneen Sandhu.
      The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41467-026-74334-z
  20. Nat Commun. 2026 Jun 16.
    Fibroblastic aspartoacylase suppresses TGFβ-mediated responses and cancer progression.
    Ianire Astobiza, Catalina Capó-Serra, Cristina Viera, Javier Rodríguez, Patricia Carnicero, Miguel Juliá, Ainara Martinez, Carmen Pérez-López, María Subijana, Carolina Ortiz-Sanz, Saioa Garcia-Longarte, Isabel Mendizabal, Emily J Kay, Carla Riera-Domingo, Silvia Rivis, Onintza Carlevaris, Leire Egia-Mendikute, Sara Cascais, Natalia Martín-Martín, Sonia Fernandez-Ruiz, Veronica Torrano, Jana R Crespo, Mikel Pujana-Vaquerizo, Elisa Espinet, Andreas Trumpp, Noemi Eiro, Francisco J Vizoso, Ana Vivancos, Joan Seoane, David Gonzalo, Sofia Rey, Aida Santos-Martin, Aitziber Ugalde-Olano, Claudia Manini, Jose I Lopez, Diana Cabrera, Sebastian M Van Liempd, Juan M Falcon-Perez, Roger R Gomis, Asís Palazon, Christian Frezza, Mireia Castillo-Martin, Sara Zanivan, Massimiliano Mazzone, Miguel Unda, Ana Loizaga-Iriarte, Arkaitz Carracedo, Fernando Calvo.
      Metabolic reprogramming is a hallmark of cancer, and the field has predominantly focused on investigating metabolic alterations in tumour cells. However, the relevance, mechanism and consequences of metabolic adaptations in stromal cells remain understudied. Here, we identify aspartoacylase (ASPA) as a metabolic enzyme consistently repressed in tumour stroma and cancer-associated fibroblasts (CAFs). Importantly, we report a reciprocal crosstalk between ASPA and Transforming Growth Factor Beta (TGFβ) signalling that influences fibroblast behaviour. TGFβ suppresses ASPA expression in fibroblasts, whereas ASPA restrains TGFβ-dependent myofibroblast conversion, extracelullar cell matrix (ECM) remodelling, angiogenesis and pro-tumoral macrophage phenotypes. Analyses of human specimens revealed a strong negative prognostic value for ASPA in different tumour types, associated with TGFβ signalling levels and the generation of aggressive pro-tumoral responses. Our findings unveil ASPA expression in fibroblasts as a gatekeeper of TGFβ responses and activation in cancer progression.
    DOI:  https://doi.org/10.1038/s41467-026-73002-6
  21. Cell Rep. 2026 Jun 19. pii: S2211-1247(26)00652-2. [Epub ahead of print]45(7): 117574
    The pyruvate transporter hermes regulates autophagy and health by modulating ROS production.
    Panagiotis D Velentzas, Fei Chai, Eric H Baehrecke.
      Autophagy is a catabolic process that degrades cytoplasmic materials and is controlled by nutrient availability and signaling. The plasma membrane-associated pyruvate-solute carrier hermes (hrm) is required for regulation of the mechanistic target of rapamycin (mTOR) signaling and the activation of autophagy during development. Here, we screen for pyruvate-influencing genes that suppress the hrm mutant phenotype. We show that the inhibitory effect of hrm loss on autophagy depends on pyruvate transport into mitochondria and the Krebs cycle. Loss of hrm results in an increase in reactive oxygen species (ROS), and attenuation of the increase in ROS is sufficient to suppress the effects of hrm loss on autophagy and mTOR signaling. Importantly, we show that in adult animals, loss of hrm results in decreased lifespan, with defects in autophagy in intestine tissues. These results link a plasma membrane pyruvate carrier to mitochondrial pyruvate metabolism, ROS, autophagy, and organismal health.
    Keywords:  CP: cell biology; CP: metabolism; Drosophila; autophagy; development; hermes; metabolism; pyruvate; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.celrep.2026.117574
  22. Curr Opin Cell Biol. 2026 Jun 17. pii: S0955-0674(26)00052-9. [Epub ahead of print]101 102664
    Substrate selectivity as a paradigm shift in mTORC1 signaling.
    Jiyoung Pan, Stephanie A Fernandes, Riko Hatakeyama, Constantinos Demetriades.
      mTORC1 is a central regulator of cell growth and metabolism, classically viewed as a binary switch that promotes anabolic programs while suppressing catabolic pathways. Recent work advances this simplified model by revealing that mTORC1 signaling is highly substrate-specific, with distinct classes of substrates differentially regulated according to their modes of recruitment and subcellular localization. In this review, we discuss emerging evidence demonstrating that mTORC1 activity and its lysosomal localization can be functionally uncoupled, enabling selective phosphorylation of lysosomal versus non-lysosomal targets. We highlight how upstream regulatory pathways and post-translational modifications shape these substrate-specific outputs, and consider the implications of downstream uncoupling for the fundamental understanding of mTORC1 biology as well as human health and disease.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102664
  23. Cell Rep. 2026 Jun 17. pii: S2211-1247(26)00577-2. [Epub ahead of print]45(6): 117499
    A multi-organ metabolomics atlas reveals molecular dysregulations in Alzheimer's disease mouse models.
    Alzheimer Gut Microbiome Project Consortium
      The etiology of Alzheimer's disease (AD) remains unclear but is likely driven by gene-environment interactions. We present a multi-organ untargeted metabolomics atlas (n = 2,271) paired with metagenomics data (n = 666) from two AD transgenic mouse models (3xTg and 5xFAD) under colonized and germ-free conditions. Systems-level analyses revealed clusters of dysregulated molecules across tissues, including carnitines, bile acids, B vitamins, neurotransmitters, and N-acyl lipids. Metabolic shifts were associated with the depletion of Akkermansia muciniphila and enrichment of Mucispirillum schaedleri in the 3xTg model. We identify previously unexplored carnitines linked to microbial metabolism of phenylalanine. Using tissueMASST-a mass spectrometry search tool we developed to translate animal-model findings into a human clinical context-we trace phenylacetyl-carnitine in human plasma and serum samples (n = 1,470) from independent cohorts, revealing associations with aging, cognitive impairment, and diminished memory performance. This public resource and associated tools will aid future research in AD etiology.
    Keywords:  3xTg; 5xFAD; Alzheimer's disease; CP: metabolism; CP: neuroscience; metagenomics; tissueMASST; untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2026.117499
  24. Nat Commun. 2026 Jun 20.
    ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
    Jacklyn M Huhn, Liana Valin, Mary Basse, Judith Sokei, Nishanth Gabriel, Esteban Martinez, Joice S Kanefsky, Stephanie Stransky, Adrienne Dorrance, Ramiro Garzon, Daniela Di Marcantonio, Tomasz Skorski, Aaron R Goldman, Hsin-Yao Tang, Samuele Cortellazzi, Orsola di Martino, John Krais, Simone Sidoli, Francesca Ferraro, David L Wiest, Stephen M Sykes.
      Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.
    DOI:  https://doi.org/10.1038/s41467-026-74324-1
  25. mBio. 2026 Jun 15. e0093326
    Arginine metabolism supports de novo pyrimidine biosynthesis to block DNA damage and maintain Epstein-Barr virus latency.
    Shaowen White, Yifei Liao, Yin Wang, Shunji Li, Eric M Burton, John M Asara, Benjamin E Gewurz.
      Incompletely understood mechanisms serve to maintain Epstein-Barr virus (EBV) latency, in which viral oncogene(s) are expressed, but lytic antigens are not expressed. Shortly after the discovery of EBV and even before it was named, Werne and Gertrude Henle identified that restriction of extracellular arginine induces EBV lytic antigens within Burkitt lymphoma tumor cells. However, for nearly 60 years, it has remained unknown how arginine metabolism supports EBV latency. To gain insights, we performed an amino acid restriction screen in EBV+ Burkitt cell lines. This confirmed that arginine restriction was sufficient to trigger EBV reactivation in Burkitt B cells and in gastric carcinoma models. Arginine restriction strongly impaired de novo pyrimidine biosynthesis, and CRISPR- or chemical genetic-blockade of pyrimidine biosynthesis enzymes induced EBV immediate-early and early lytic gene expression. However, arginine restriction blocked EBV lytic DNA replication and, consequently, also late gene expression, suggesting an abortive lytic cycle. By contrast, chemical or CRISPR blockade of the de novo pyrimidine biosynthesis pathway rate-limiting enzyme CAD reactivated a full EBV lytic cycle, suggesting specific arginine restriction roles in support of lytic DNA replication. Arginine restriction caused DNA damage, which was a driver of EBV reactivation. Arginine restriction and DNA hypomethylation additively reactivated EBV. Together, our results highlight arginine and pyrimidine metabolism as potential targets for EBV lytic antigen induction therapy in B-cell and epithelial-cell contexts.
    IMPORTANCE: Altered metabolism is a hallmark of cancer, frequently increasing transformed cell dependence on extracellular amino acid supply. Despite current interest in Epstein-Barr virus (EBV) lytic antigen induction therapy, in which viral lytic reactivation sensitizes tumors to the highly cytotoxic effects of the antiviral ganciclovir, there has been no systematic study of extracellular amino acids that control EBV latency. We identified that arginine uptake was important for the maintenance of EBV latency in both Burkitt lymphoma and gastric carcinoma contexts. Metabolic pathway analyses highlighted that arginine uptake and metabolism were required to supply pyrimidines. Disruption of arginine metabolism or de novo pyrimidine synthesis caused DNA damage. Arginine restriction also triggered Burkitt DNA hypermethylation. Building upon this, we provide evidence that the combination of arginine restriction and DNA hypomethylation, either by decitabine or by CRISPR approaches, induced EBV reactivation more strongly than either alone, suggesting a therapeutic approach..
    Keywords:  DNA damage; de novo pyrimidine synthesis; double-stranded DNA virus; epigenetic; lytic cycle; metabolism; nucleotide biosynthesis; nucleotide metabolism; reactivation; viral latency
    DOI:  https://doi.org/10.1128/mbio.00933-26
  26. Sci Adv. 2026 Jun 19. 12(25): eaec4450
    Abiotic sources of fixed nitrogen sustained early ecosystems for several hundred million years after the origin of life.
    Joanne S Boden, Zhanghan Ni, Rika E Anderson, Eva E Stüeken.
      Nitrogen (N) plays a crucial role in controlling biological productivity. However, it remains unknown how Earth's earliest ecosystems accessed bioavailable forms of nitrogen. Here, we present genomic evidence that the last universal common ancestor (LUCA) had genes for importing ammonium into the cell, but the first organisms with all three catalytic nitrogen fixing genes emerged at least 1 billion years later. Similarly, enzymatic pathways for accessing nitrogen from urea and nitriles appear to predate biological N2 fixation. Our results imply that Earth's earliest biosphere was maintained by environmental sources of ammonium and other N-bearing compounds, possibly derived from a combination of processes such as hydrothermal activity, photochemistry, rock weathering, lightning, or impact events. Biological N2 fixation may have emerged in response to an increase in biological nutrient demand or due to declining abiotic supplies of ammonium, urea, and nitriles.
    DOI:  https://doi.org/10.1126/sciadv.aec4450
  27. Nat Med. 2026 Jun;32(6): 1985-1986
    Blood signatures of cell type-specific aging forecast disease risk and resilience.
      By measuring thousands of proteins in blood samples from over 60,000 people, we built molecular 'clocks' to estimate how fast cells age. Our analyses show that cell types age at different rates within the same person. Accelerated aging of specific cell types is associated with increased disease risk, whereas slower aging of others is linked to protection and improved survival.
    DOI:  https://doi.org/10.1038/s41591-026-04447-x
  28. Curr Med Chem. 2026 Jun 10.
    Metabolic Reprogramming and Molecular Mechanisms in Renal Cell Carcinoma: Therapeutic Implications and Future Perspectives.
    Ferdos Faghihkhorasani, Guodong Zhu.
      Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy with distinct metabolic dependencies that differentiate it from many other solid tumors. Despite recent advances in targeted therapies and immunotherapies, therapeutic resistance and variable clinical responses remain major challenges, underscoring the need for a deeper understanding of RCC-specific metabolic vulnerabilities. Current evidence indicates that metabolic reprogramming is a central driver of RCC progression, involving enhanced glycolysis, glutaminolysis, one-carbon metabolism, altered lipid metabolism, and mitochondrial adaptations. These metabolic shifts are largely regulated by dysregulated oncogenic signaling, constitutive activation of hypoxia-inducible factors (HIFs), and dynamic interactions within the tumor microenvironment. Key metabolic regulators and enzymes, including HIF-2α, glutaminase (GLS), fatty acid synthase (FASN), and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), have emerged as clinically relevant targets with therapeutic potential. In this review, we synthesized current knowledge on RCC metabolism while highlighting features that distinguish RCC from other malignancies, particularly its HIF-driven metabolic landscape and pronounced microenvironmental influences. Importantly, we extended descriptive metabolism by focusing on clinically actionable pathways, biomarker-driven patient stratification, and rational combination strategies integrating metabolic inhibitors with immunotherapy or targeted agents. We also discussed some emerging methodologies, including metabolic imaging and spatial profiling approaches, to address intratumoral metabolic heterogeneity. Overall, this review emphasizes how leveraging RCC-specific metabolic vulnerabilities can inform precision medicine approaches and improve therapeutic outcomes for patients with RCC.
    Keywords:  HIF-2α inhibitors; VHL-HIF axis; glutamine metabolism; lipid metabolism.; tumor microenvironment
    DOI:  https://doi.org/10.2174/0109298673461719260530152756
  29. J Immunol. 2026 Jun 07. pii: vkag120. [Epub ahead of print]215(6):
    Mitochondrial potential reflects T cell fitness and function during cancer immunotherapy.
    Paul L Lindau, Alex V Nesta, Caroline E Roe, Madelyn D Landis, Zaid Hatem, Allison E Sewell, Allison K Blount, Jackie E Bader, Reddy Anupama, W Kimryn Rathmell, Jonathan M Irish, Jeffrey C Rathmell, Kathryn E Beckermann.
      Checkpoint inhibitors have transformed cancer treatment, yet predicting responses remains challenging. Mitochondrial quality decreases in tumor infiltrating lymphocytes and correlates with impaired antitumor immunity in animal models. Mitochondrial membrane potential (MMP) increases with T cell activation and may also indicate cellular dysfunction. Here, we assessed the MMP of tumor-associated T cells as an indicator of cell phenotypes and immunotherapy responses in non-small cell lung carcinoma and clear cell renal cell carcinoma patients. Primary tumors were collected followed by analysis of peripheral blood mononuclear cells prior to and after 3 wk on treatment with immune checkpoint inhibitors (ICIs). Peripheral blood mononuclear T cells were analyzed for MMP using tetramethylrhodamine ethyl ester (TMRE) and sorted into high and low populations. TCRβ and single-cell RNA sequencing of primary tumors identified and characterized peripheral blood T cell clones associated with the tumor microenvironment. As anticipated, ICI therapy increased the frequency of effector T cells in patients who experienced clinical benefit. TMREhigh peripheral blood T cells with tumor-matching TCRβ sequences had elevated oxidative phosphorylation gene signatures. Gene signatures of stress and exhaustion, such as Tigit and Cmc1, were also elevated in the TMREhigh CD8 T cell populations, while gene expression patterns in TMRElow cells suggested mitochondrial fitness and cell longevity. Importantly, clinical benefit from ICIs was negatively correlated with the TMREhigh CD8 T cell gene expression signature. These findings highlight a T cell population characterized by elevated MMP that correlates with exhaustion-like transcriptional states and poor response to immunotherapy.
    Keywords:  T cells; checkpoint inhibitor; kidney cancer; lung cancer; metabolism; mitochondria
    DOI:  https://doi.org/10.1093/jimmun/vkag120
  30. Sci Adv. 2026 Jun 19. 12(25): eaec3505
    NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
    Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.
      Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.
    DOI:  https://doi.org/10.1126/sciadv.aec3505
  31. Anal Chem. 2026 Jun 19.
    Cell-Resolved Mass Spectrometry Imaging Integrated with Isotope Tracing Elucidates Macrophage Polarization-Specific Metabolic Reprogramming.
    Min Li, Junjie Ge, Bangzhen Ma, Shiping Chen, Hongya Zhao, Mengxuan Li, Xiutong Zhang, Junwen Shi, Xiao Wang, Panpan Chen, Quanbo Wang, Chenglong Sun.
      Tumor-associated macrophages, pivotal regulators of antitumor immunity, exert dual functions through their tumoricidal M1 and tumor-promoting M2 phenotypes, which are closely linked to their metabolic states. While conventional mass spectrometry imaging (MSI) can characterize the metabolic features of macrophages, it fails to capture dynamic metabolic activity and real-time substrate utilization within individual cells. In this research, we present an integrated approach that couples cell-resolved matrix-assisted laser desorption/ionization (MALDI)-MSI with stable isotope tracing to visualize dynamic metabolic heterogeneity across individual macrophage phenotypes in situ. Using isotopically labeled fatty acids as metabolic tracers, we revealed that M1 macrophages exhibit significantly enhanced synthesis of phospholipids, including phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidic acid (PA), compared to M2 macrophages, highlighting a polarization-specific metabolic signature linked to their antitumor function. Moreover, we observed that coculture with tumor cells markedly downregulated the levels of newly labeled phospholipids in M1 macrophages. Critically, the pharmacological inhibition of cPLA2, a key enzyme in the phospholipid metabolic pathway, significantly impaired the antitumor efficacy of M1 macrophages. These findings collectively demonstrate the functional importance of phospholipid metabolism in sustaining macrophage-mediated antitumor immunity. We envision that this spatially resolved metabolic tracing strategy will open new avenues for investigating cell-resolved metabolic crosstalk in complex biological environments.
    DOI:  https://doi.org/10.1021/acs.analchem.6c02192
  32. Dev Cell. 2026 Jun 16. pii: S1534-5807(26)00195-4. [Epub ahead of print]
    P5CS represses tumor progression via inhibiting assembly of 48S pre-translation initiation complex.
    Qingqing Zhang, Shuwen Cheng, Yinmin Gu, Yongbo Pan, Xiaofeng Zhu, Jinghan Sun, Ya Wen, Shan Gao.
      Δ1-Pyrroline-5-carboxylate synthase (P5CS), therate-limiting enzyme in the proline biosynthesis, has been implicated in diverse physiology and pathology, including cancer. However, whether P5CS exerts functions beyond its enzymatic activity has remained unclear. Here, we identify P5CS as a non-canonical RNA-binding protein that inhibits cancer cell growth and metastasis by inhibiting translation initiation in an enzyme-activity-independent manner in human cancer cells and cell-derived xenograft mouse models. Mechanistically, P5CS binds to the 5' untranslated region (UTR) of oncogenic mRNAs and disrupts the recruitment of eukaryotic translation initiation factor (eIF) 3a/3d-containing 43S preinitiation complex to cap-binding complex eIF4F, thereby blocking 48S assembly and subsequent global protein synthesis. Loss of P5CS accelerates the translational efficiency of IGF1R and promotes tumor progression. Collectively, our study highlights a non-canonical function of P5CS in translational regulation and the emerging non-metabolic functions of metabolic enzymes in tumorigenesis.
    Keywords:  43/48S; P5CS; RNA-binding protein; eIF3a/3d; translation regulation
    DOI:  https://doi.org/10.1016/j.devcel.2026.05.011
  33. Trends Genet. 2026 Jun 18. pii: S0168-9525(26)00138-1. [Epub ahead of print]
    Rethinking mitochondrial metabolism: Intraindividual variability meets population constraints.
    José L Cabrera-Alarcón, José A Enríquez.
      Recent advances integrating high-resolution 3D structures with population genetics and comparative evolutionary analyses indicate that mitochondrial DNA (mtDNA) acts as a primary evolutionary engine driving nuclear coadaptation. This process reflects a trade-off between individual heterozygosity and mtDNA-driven variability, which together expand the mitonuclear haplotype pool within species.
    Keywords:  OxPhos; mitonuclear evolution
    DOI:  https://doi.org/10.1016/j.tig.2026.05.011
  34. Cell Death Dis. 2026 Jun 17.
    Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.
    Sara Verdura, Àngela Llop-Hernández, Travis Van der Steen, José Antonio Encinar, Begoña Martin-Castillo, Elisabet Cuyàs, Ruth Lupu, Javier A Menendez.
      Therapy-induced senescence (TIS) in cancer cells can be triggered by radiotherapy, chemotherapy, and certain targeted therapeutics. Here, we demonstrate that a new form of TIS, termed fatty acid synthesis therapy-induced senescence (FASTIS), can be induced by pharmacologically targeting de novo lipogenesis. Cancer cells can evade the anti-proliferative effects of clinically relevant inhibitors of core lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), by entering in a senescence-like state. FASTIS cancer cells acquire the classical senescence hallmarks, such as cytomorphological remodeling, increased senescence-associated beta-galatosidase (SA-β-gal) activity, activation of cell cycle arrest markers, and hypersensitivity to IFNγ-induced activation of the immune checkpoint PD-L1. mRNA sequencing reveals an FASTIS-associated transcriptomic profile that overlaps between ACC and FASN inhibitors yet differs significantly from that of other mechanistically diverse TIS inducers, including bleomycin, alisertib, doxorubicin, and palbociclib. The FASTIS-encoding transcriptome is characterized by the activation of cholesterol- and acetyl-CoA-related lipogenic pathways, as well as cell-intrinsic innate immune responses. This profile is characterized as highly senescent (≥0.95) by the machine learning-based senescence predictor SENCAN. Mapping the metabolome and lipidome in FASTIS cells reveals a significant sterol lipid enrichment, including substantial increases in intracellular cholesterol levels. Pharmacological blockade of cholesterol synthesis or promotion of lysosomal cholesterol accumulation, prevents or potentiates the occurrence of SA-β-gal+ FASTIS cells, respectively. Cytokine arrays and miR-146a reporter-based screens revealed that the FASTIS-associated secretory phenotype (FASASP) is highly enriched in immunomodulatory factors but not in inflammatory components. FASTIS cancer cells exhibit an increased overall level of mitochondrial priming, making them highly susceptible to targeted senolysis by BCL-xL-targeting BH3 mimetics and cytokine-activated T cells. The FASTIS phenomenon is a therapeutic outcome through which cancer cells adapt to survive clinical-grade lipogenesis inhibitors. The cholesterol-addicted FASTIS fate can be rationally exploited as a collateral sensitivity in "one-two punch" senogenic-(immuno)senolytic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-08992-8
  35. Nat Aging. 2026 Jun;6(6): 1208-1226
    Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.
    Xue Hao, Bo Zhao, Qingqing Yan, Mitsutake Yano, Ayumu Matsuoka, Yuan Qi, Liping Liao, Rafal J Zielinski, Hsin-Yao Tang, Andrew V Kossenkov, M Anna Zal, Kavitha Sarma, Rugang Zhang.
      Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS-STING innate immune pathway to drive the SASP. We identify the exportin-1 (XPO1)-DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.
    DOI:  https://doi.org/10.1038/s43587-026-01147-6
  36. J Nutr Biochem. 2026 Jun 13. pii: S0955-2863(26)00190-7. [Epub ahead of print] 110448
    Moderate iron restriction improves metabolism via epigenetic regulation of GDF15.
    Jinying Yang, Limin Shi, Anna L Cubito, Akshaya Govarthanan, Jian S Sabripour, Karen Scott, Annette de Kloet, Feng Yue, Bin Liu, Larissa J Strath, Eric Krause, James F Collins, Zhiyong Cheng.
      Iron overload disrupts endocrine function and metabolic health, while iron chelation and phlebotomy enhance metabolic fitness in humans and mice. However, the working mechanism of iron-lowering strategies remains largely undefined, and it is unclear whether dietary iron restriction can serve as a new strategy to treat metabolic syndrome. Here we show that 20-ppm iron (i.e., iron moderately restricted) diet increased insulin sensitivity, adipose mitochondrial biogenesis, and energy expenditure compared to 50-ppm iron (i.e., iron adequate) diet in mice. By contrast, severe iron restriction (5-ppm iron diet) caused anemia, underweight and metabolic disorder. Mechanistically, moderate iron restriction induced a condition of subcellular "iron deficiency" due to iron redistribution into mitochondria in adipose tissues, which augmented H3K4 methylation possibly by suppressing iron-dependent histone demethylase like JARID. Enriched H3K4 methylation upregulated the expression of GDF15, a nutrient sensor that promotes adipose browning and metabolic enhancement. Pharmacological inhibition of H3K4 methylation or knockdown of GDF15 prevented iron restriction-induced enhancement of insulin sensitivity. Our study reveals a potential strategy targeting dietary iron to prevent metabolic disorder. It provides the first line of evidence of epigenetic regulation of GDF15 via an iron restriction-H3K4 methylation cascade. Future studies of the H3K4 methylation-GDF15 axis may fuel developing therapeutic options or dietary interventions for metabolic disease.
    Keywords:  GDF15; adipose browning; epigenetic regulation; metabolic health; moderate iron restriction
    DOI:  https://doi.org/10.1016/j.jnutbio.2026.110448
  37. Redox Biol. 2026 Jun 15. pii: S2213-2317(26)00262-4. [Epub ahead of print]95 104263
    Compensation for impaired sensing of selenoprotein deficiency by alternative cysteine residues in KEAP1.
    Miu Sato, Takuya Iijima, Takafumi Suzuki, Masayuki Yamamoto.
      The KEAP1-NRF2 system is a master regulator of cellular defense against oxidative and electrophilic stresses. Cysteine residues within KEAP1 function as critical stress sensors. While KEAP1-Cys151 is a well-established sensor for electrophilic NRF2 activators, its contribution to the oxidative stress response remains unclear. Here, we investigated NRF2 activation in Cys151-deficient mice under hepatocyte-specific disruption of selenoprotein synthesis, a condition associated with profound redox imbalance. NRF2 activation and hepatic homeostasis were preserved in these mice, indicating that Cys151 is dispensable for sensing of selenoprotein deficiency. Conversely, loss of Cys226/Cys613-mediated sensing impaired NRF2 activation, leading to severe liver injury and lethality. Importantly, treatment with the Cys151-dependent electrophilic activator CDDO-Im restored NRF2 activity and improved survival in mice lacking functional Cys226/Cys613 sensing. Together, these findings demonstrate that individual KEAP1 cysteine residues have distinct functional roles in stress sensing, yet their signals converge on a common pathway to regulate NRF2 activation.
    Keywords:  Electrophile; KEAP1; NRF2; Selenoprotein deficiency; Stress sensor
    DOI:  https://doi.org/10.1016/j.redox.2026.104263
  38. Nat Rev Mol Cell Biol. 2026 Jun 19.
    Regulation and function of specialized membrane protrusions in intercellular communication.
    Shiyu Liu, Christina A Daly, Stacey K Ogden, Chiara Zurzolo.
      Cells use specialized membrane extensions that enable the exchange of signals, organelles and other cargo to support long-range communication within complex tissues. Among these, tunnelling nanotubes, cytonemes and migrasomes have emerged as key contributors to development, immune responses and disease. Growing evidence has revealed that these structures are more prevalent and functionally diverse than previously appreciated, prompting a re-evaluation of how cells coordinate behaviour across space. In this Review, we discuss recent advances in understanding the formation, regulation and specificity of these dynamic connections, with an emphasis on tunnelling nanotubes and cytonemes, and highlight common principles underlying their architecture and cargo transfer. We further explore how their dysregulation contributes to pathology, underscoring the need to integrate these structures into current models of tissue organization.
    DOI:  https://doi.org/10.1038/s41580-026-00982-0
  39. Nat Commun. 2026 Jun 15.
    Tumor suppressor genotype influences the extent and mode of immunosurveillance in lung cancer.
    Keren M Adler, Haiqing Xu, Amy C Gladstein, Valerie M Irizarry-Negron, Maggie R Robertson, Katherine R Doerig, Dmitri A Petrov, Monte M Winslow, David M Feldser.
      The impact of cancer driving mutations on immunosurveillance throughout tumor development remains poorly understood. To better understand the contribution of tumor genotype to immunosurveillance, we generated and validated lentiviral-based vectors that create increasingly immunogenic neoantigens. This vector system is compatible with autochthonous Cre-regulated cancer models, CRISPR/Cas9-mediated somatic genome editing, and tumor barcoding. Here, we show that in the context of oncogenic KRAS-driven lung cancer and strong neoantigen expression, tumor suppressor genotype dictates the degree of immune cell recruitment, positive selection of tumors with neoantigen silencing, and tumor outgrowth. By quantifying the impact of 11 commonly inactivated tumor suppressor genes on tumor growth across neoantigenic contexts, we show that the growth-promoting effects of tumor suppressor gene inactivation correlate with increasing sensitivity to immunosurveillance. Importantly, some genotypes also dramatically changed sensitivity to immunosurveillance independently of their growth-promoting effects. We propose a model of immunoediting in which tumor suppressor gene inactivation works in tandem with neoantigen expression to shape tumor immunosurveillance and immunoediting such that the same neoantigens uniquely modulate tumor immunoediting depending on the genetic context.
    DOI:  https://doi.org/10.1038/s41467-026-74023-x
  40. Nat Commun. 2026 Jun 15.
    Single-cell map of the healthy human immune system across the lifespan reveals unique infant immune signatures.
    Djamel Nehar-Belaid, Asa Thibodeau, Alper Eroglu, Radu Marches, Giray Eryilmaz, Titas Grabauskas, Luke Trinity, Derya Unutmaz, Chris P Verschoor, Jinghua Gu, Uthra Balaji, Asunción Mejías, Virginia Pascual, George A Kuchel, Octavio Ramilo, Jacques F Banchereau, Duygu Ucar.
      The human immune system undergoes dynamic remodeling from infancy through old age. We profiled PBMCs from 167 healthy individuals (ages 2 months to 105 years): infants (n = 36), children (n = 26), adolescents (n = 20), young adults (n = 24), middle‑aged (n = 16), older adults (n = 33) and oldest old (n = 12) using scRNA‑seq and snATAC‑seq (n = 23). MAIT and γδ T cells showed a "rise and fall" pattern, rising in childhood, peaking in young adulthood, and declining with age. Conventional CD8⁺ T cells were most profoundly altered with age, with decreasing naïve and increasing GZMK⁺ and TEMRA cells. The oldest old had increased TEMRA, adaptive NK, and KLRF1⁺ γδ T cells. Infants showed increased CD16⁺ monocytes and pDCs, constitutive interferon‑stimulated gene expression, and expanded SOX4⁺ naïve T cells. Inflammatory and stress‑response pathways increased with age, while interferon pathways declined. This map provides insights into human immune system dynamics across the human lifespan, emphasizing unique features of the infant immune system.
    DOI:  https://doi.org/10.1038/s41467-026-73729-2
  41. Neuron. 2026 Jun 16. pii: S0896-6273(26)00371-5. [Epub ahead of print]
    Mitochondria and brain aging: From cell-specific dysfunction to intercellular cooperation.
    Amandine Grimm, Undine Lang, Anne Eckert.
      Mitochondria are essential for brain energy metabolism and are increasingly recognized as key contributors to brain aging. Although neurons are exceptionally vulnerable to age-related mitochondrial decline, emerging evidence reveals that glial and vascular cells also exhibit distinct mitochondrial impairments. This review synthesizes recent advances in our understanding of mitochondrial dysfunction across specific brain regions and diverse cell types, highlighting subcellular compartmentalization and metabolic rewiring. We further explore intercellular mitochondrial transfer as a novel form of metabolic cooperation, as well as the therapeutic potential of mitochondrial transplantation. Finally, we highlight recent clinical trials evaluating mitochondria-targeted interventions aimed at preserving brain function in older adults. Together, these findings reposition mitochondria as both integrators and amplifiers of brain aging processes across diverse cell populations. By broadening the focus beyond neurons and emphasizing translational efforts, we offer a comprehensive framework for understanding and therapeutically targeting mitochondrial dysfunction in age-related cognitive decline and neurodegeneration.
    Keywords:  aging; astrocytes; blood-brain barrier; brain; intercellular mitochondrial transfer; microglia; mitochondria; mitochondrial transplantation; neurons; oligodendrocytes
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.048
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