bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2026–06–07
sixty-two papers selected by
Christian Frezza, Universität zu Köln
  1. Spermine is an endogenous iron chelator that inhibits ferroptosis.
  2. LASER couples damage sensing to ESCRT assembly for lysosome repair.
  3. Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.
  4. Cancer as a window into mitochondrial biology.
  5. Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
  6. Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
  7. Clonal lineage tracing of innate immune cells in human cancer.
  8. A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
  9. Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?
  10. Reductive death is averted by a conserved de novo lipogenic switch.
  11. Pathogenesis of diffuse large B cell lymphoma proteogenotypes.
  12. Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
  13. Functional specialization within the mitochondrial network: Are all mitochondria created equal?
  14. Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.
  15. Somatic cells compartmentalise their carbohydrate metabolism to sustain germ cell survival.
  16. Regulation of mitochondrial protein translocases.
  17. Consequences of defective mitochondrial protein import: From targeting signals to pathology.
  18. DREAM repressive activity links somatic mutation, lifespan and disease.
  19. Fmp30p is a mitochondrial phosphatidylinositol hydrolase that modulates CoQ biosynthesis.
  20. Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism.
  21. Expert opinion on burning questions in cancer myeloid cell biology.
  22. Redox signals and oxidative stress in the control of mitochondrial protein import.
  23. Fueling the fire: aspartate deficiency primes and fuels STING activation.
  24. Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
  25. Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
  26. The aging genome exhibits organized vulnerability to somatic mutations.
  27. Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma.
  28. Voluntary running exercise is associated with metabolic shifts linked to adult hippocampal neurogenesis.
  29. TGFβ activity stabilizes ACC1 to increase de novo lipogenesis in metabolic liver disease.
  30. Considerations and best practices for respirometry.
  31. Mitochondria across the globe: Diverse voices, shared energy.
  32. Mitochondria across the globe: Diverse voices, shared energy.
  33. Metab8D: a metabolic regulome network from multiomics and machine learning.
  34. Mutational signatures of environmental carcinogens in human tissue organoids revealed by duplex sequencing.
  35. LKB1 inactivation elicits an NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancer.
  36. Somatic mutations reveal the ontogeny of human microglia.
  37. Effortless immortalization of primary mouse fibroblasts.
  38. Ketone bodies as guardians of leukemic stemness through ferroptosis suppression.
  39. Under pressure: peroxisomes in cancer therapy resistance.
  40. Polyendocrine metabolic ovarian syndrome - a new name for an old problem.
  41. Plasma signals of lung tumor promotion for molecular cancer prevention.
  42. Cell autonomous inflammation in VEXAS is mediated by cGAS-STING.
  43. ACLY integrates metabolism and chromatin accessibility to enable B Cell activation and humoral immunity.
  44. High level dynein impairs mitochondrial distribution and differentiation of rhabdomyosarcoma cells.
  45. RFX7 is a tumor suppressor that restricts MYC function and B cell activation.
  46. Targeting GSTZ1 sensitizes KRAS G12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring.
  47. Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.
  48. MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.
  49. High-resolution nuclear cell biology by cryo-electron tomography.
  50. Inborn errors of redox metabolism: an emerging nosology.
  51. Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.
  52. AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
  53. Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.
  54. An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma.
  55. Genome integrity, somatic mutation, and the N-of-1 imperative in aging research.
  56. Pan-cancer single-cell atlases of mouse and human tumor-associated dendritic cells.
  57. A hypothalamic circuit for anticipating future changes in energy balance.
  58. The Rising Burden of Early-Onset Cancer: Challenges and Opportunities.
  59. Cell death-induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation.
  60. Commensal-derived acetylcholine enhances mucosal immune education.
  61. FBApro: A fast, simple linear transformation for diverse metabolic modeling tasks.
  62. Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
  1. Nature. 2026 Jun 03.
    Spermine is an endogenous iron chelator that inhibits ferroptosis.
    Man Li, Xuexin Yu, Shuqin Ouyang, Xiaohong Chen, Huiqi Yu, Yuanji Liu, Ziwen Li, Chunhua Yu, Rui Kang, Christine Gaillet, Ludovic Colombeau, Raphaël Rodriguez, Libing Song, Guido Kroemer, Daolin Tang, Jun Li.
      Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation1. Here we identify spermine-a polyamine derived from spermidine2-as an endogenous iron chelator that directly suppresses ferroptosis. Integrating metabolomics, stable isotope tracing and biophysical studies of the interaction between spermine and Fe2+ ions, we demonstrate that aldehyde dehydrogenase 18 family member A1 (ALDH18A1) promotes an alternative glutamine-dependent pathway for de novo spermine synthesis. This process limits iron availability and lipid peroxidation in hepatocellular carcinoma. Genetic or pharmacological inhibition of ALDH18A1-through knockout, short hairpin RNA delivered using adeno-associated virus (AAV), or the small molecule inhibitor YG1702-triggers ferroptosis and impairs both spontaneous and chemically induced hepatocarcinogenesis. Conversely, supplementation of spermine protects against ferroptosis-associated ischaemia-reperfusion injury across multiple tissues, including the liver, intestine and kidneys. These findings uncover a pathophysiologically relevant metabolic circuit in which spermine-mediated iron chelation suppresses ferroptosis.
    DOI:  https://doi.org/10.1038/s41586-026-10597-2
  2. Nature. 2026 Jun 03.
    LASER couples damage sensing to ESCRT assembly for lysosome repair.
    Claire S Goul, Aakriti Jain, Samira Yitiz, Zahra E Soltani, Serim Yang, Simon Rapp, Martina Spacci, Scot Federman, James Sacco, Huinan Li, Lauren D Enriquez, Nalan Liv, Laralynne Przybyla, Roberto Zoncu.
      Lysosomal membrane integrity is essential for cell survival, but how damage sensing is spatiotemporally coupled to repair remains poorly understood. Recruitment and assembly of endosomal sorting complex required for transport (ESCRT) I-III rapidly counteracts membrane damage, but it is unclear how ESCRT-I recognizes defective lysosomal membranes. Here, leveraging genome-wide CRISPRi screens in a damage-sensitized genetic background, we identified LC3/GABARAP-assisted stimulator for ESCRT recruitment (LASER), a multicomponent protein assembly that forms rapidly upon calcium release from damaged lysosomes and couples sensing of lysosomal membrane damage to ESCRT-dependent repair. At the core of LASER is TFG, an endoplasmic reticulum exit-site-resident protein that translocates to damaged lysosomes by binding to ATG8 family proteins (LC3 and GABARAP) conjugated to lysosomal phospholipids. ATG8-bound TFG forms oligomeric assemblies that directly recruit the essential ESCRT-I subunit TSG101 via conserved motif recognition enhanced by avidity-driven interactions. TFG binding to TSG101 stimulates sequential ESCRT-I-II-III polymerization and promotes membrane repair. TFG mutations that drive hereditary spastic paraplegia disrupt its oligomerization and impair lysosomal ESCRT recruitment and membrane resealing, implicating defective repair as a driver of TFG-associated neurodegeneration. Thus, LASER promotes ESCRT polymerization at damaged lysosomes and couples damage sensing to membrane repair.
    DOI:  https://doi.org/10.1038/s41586-026-10604-6
  3. bioRxiv. 2026 May 21. pii: 2026.05.18.726122. [Epub ahead of print]
    Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells.
    David Sokolov, Eric Zheng, Serwah Danquah, Madeleine L Hart, Lucas B Sullivan.
      Succinate dehydrogenase (SDH) supports cancer cell proliferation by enabling oxidative biosynthesis of the amino acid aspartate, yet SDH loss can also drive tumorigenesis. To cope with SDH loss, cancer cells can engage alternative aspartate synthesis pathways; however, the variables dictating pathway usage and adaptive mechanisms involved are incompletely understood. Here, we systematically profile the adaptation of SDH-knockout cancer cells and find that cells can adapt to SDH loss via at least two distinct mechanisms: suppression of respiratory complex I or upregulation of pyruvate carboxylase. Each route gives rise to distinct metabolic states with both shared and unique dependencies, but either route allows cells to overcome aspartate limitation, improve proliferative fitness, and mitigate pyrimidine-dependent replication stress. Overall, this work provides a comprehensive view of adaptive aspartate synthesis in SDH-deficient cancer cells, highlights a remarkable redox-constrained metabolic plasticity, and nominates potential metabolic vulnerabilities likely to be shared among SDH-deficient cancer cells.
    DOI:  https://doi.org/10.64898/2026.05.18.726122
  4. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00188-9. [Epub ahead of print]38(6): 1085-1088
    Cancer as a window into mitochondrial biology.
    Thomas MacVicar, Laura C Greaves, Payam A Gammage, Stephen W G Tait, Kelsey H Fisher-Wellman, Gordon Freedman.
      Cancer has revealed that the mitochondrion is not a static organelle but a system of extraordinary plasticity. Here, we introduce fundamental mitochondrial behaviors that have been illuminated by cancer research and propose that further investigation in mitochondrial biology holds promise for oncology and beyond.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.003
  5. bioRxiv. 2026 May 22. pii: 2026.05.20.726656. [Epub ahead of print]
    Mitochondrial copper stabilizes lipoylated TCA cycle proteins to sustain metabolism and proliferation.
    Santanu Ghosh, Andrew F Jarvis, Jordi C J Hintzen, Nate R McKnight, Pedro Costa-Pinheiro, Noelle H Noughton, Yumi Kim, Alison Jaccard, Scot C Leary, Paul A Cobine, Caroline R Bartman, Gina M DeNicola, Nathaniel W Snyder, Kathryn E Wellen, George M Burslem, Donita C Brady.
      Copper (Cu) is an essential cofactor for mitochondrial cytochrome c oxidase, yet whether it directly regulates mitochondrial metabolism beyond respiration remains unclear. Here we show that mitochondrial Cu, delivered by SLC25A3, is required to maintain the stability of lipoylated TCA cycle proteins. Loss of Slc25a3 or pharmacological Cu depletion selectively destabilized the lipoylated E2 subunits of mitochondrial dehydrogenases and the lipoylation enzymes LIPT1 and LIPT2, an effect not reproduced by acute electron transport chain inhibition. Mechanistically, we find that Cu directly engages the reduced lipoyl moiety using chemical probes and synthetic peptide approaches. Cu depletion impaired PDH and OGDH activity, rewired TCA cycle metabolism, and imposed a dependence on pyruvate carboxylase for anaplerosis. This metabolic defect depleted aspartate, suppressed mTORC1 signaling, and limited proliferation. Conversely, selective delivery of Cu to the mitochondria restored lipoylation, TCA cycle function, and cell growth. Together, these findings identify mitochondrial Cu as a structural regulator of the lipoylation machinery and reveal a direct link between Cu homeostasis and central carbon metabolism.
    DOI:  https://doi.org/10.64898/2026.05.20.726656
  6. J Cancer Immunol (Wilmington). 2026 ;8(1): 17-22
    Cristae Architecture as a Metabolic Checkpoint in Effector T Cells - Implications for Cancer Immunity.
    Prakash Jeysankar, Sonal Srikanth, Beibei Wu, Yousang Gwack.
      Effector T cells rely on tightly coordinated metabolic and epigenetic programs to sustain immune function. Emerging evidence highlights a central role for mitochondria in integrating these programs through nutrient utilization and regulation of metabolite flux. The electron transport chain (ETC), localized to the inner mitochondrial membrane, directs cellular metabolism toward oxidative phosphorylation. The efficiency of ETC activity is governed by the highly folded architecture of the inner mitochondrial membrane into cristae. Although mitochondrial metabolism is well recognized as a key determinant of cellular metabolic states, the regulatory roles of cristae-organizing structural proteins, particularly in T cells, remain poorly defined. Our recent study identifies the inner mitochondrial membrane protein TMEM11 as a critical structural determinant of cristae organization and demonstrates how cristae integrity governs effector T cell function by controlling oxidative phosphorylation and metabolite flux. TMEM11 deficiency disrupts cristae architecture in T cells without affecting mitochondrial biogenesis or cell viability. Mechanistically, loss of TMEM11 impairs ETC function, leading to elevated mitochondrial reactive oxygen species (mtROS), which diverts acetyl-CoA away from histone acetylation toward fatty acid synthesis, thereby suppressing cytokine production. Collectively, these findings reveal a structural-metabolic-epigenetic axis that is essential for effector T cell immunity and suggest potential relevance for T cell-mediated cancer therapy.
    Keywords:  Cristae; Effector T cells; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.33696/cancerimmunol.8.120
  7. Cancer Cell. 2026 Jun 04. pii: S1535-6108(26)00251-5. [Epub ahead of print]
    Clonal lineage tracing of innate immune cells in human cancer.
    Vincent Liu, Katalin Sandor, Patrick K Yan, Zhuang Miao, Yajie Yin, Robert R Stickels, Andy Y Chen, Kamir Hiam-Galvez, Jacob Gutierrez, Wenxi Zhang, Sairaj M Sajjath, Raeline Valbuena, Steven Wang, Bence Daniel, Leif S Ludwig, Brooke E Howitt, Caleb A Lareau, Ansuman T Satpathy.
      Innate immune cells constitute the majority of the tumor microenvironment (TME) and mediate anti-tumor immunity and immunotherapy responses. While single-cell T and B cell receptor sequencing have revealed insights into the clonal dynamics of adaptive immunity, the lack of analogous tools has precluded similar analysis of innate immune cells. Here, we describe a method leveraging somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between cells in native human tissues. By jointly profiling single-cell chromatin accessibility and mtDNA variants, we resolve clonal dynamics of 218,715 cells from matched tumors, tissues, and blood from patients with lung and ovarian cancers. Clonal tracing reveals that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally related to circulating and tissue-infiltrating monocytes. We further identify distinct DC-biased and macrophage-biased clones, whose circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting intratumoral myeloid differentiation fate may be peripherally programmed before TME infiltration.
    Keywords:  fate bias; innate immunity; lineage tracing; single-cell multi-omics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.05.006
  8. J Cell Biol. 2026 Aug 03. pii: e202511088. [Epub ahead of print]225(8):
    A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage.
    Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, Jie Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu.
      Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.
    DOI:  https://doi.org/10.1083/jcb.202511088
  9. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00155-5. [Epub ahead of print]38(6): 1081-1084
    Intercellular mitochondrial transfer in disease: Therapeutic opportunity or driver of tumor progression?
    Gwang-Bum Im, Juan M Melero-Martin.
      Intercellular mitochondrial transfer has emerged as a key mode of metabolic communication across tissues. Its outcomes are context dependent, spanning from therapeutic benefits to pathological risks.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.017
  10. Mol Cell. 2026 Jun 02. pii: S1097-2765(26)00317-5. [Epub ahead of print]
    Reductive death is averted by a conserved de novo lipogenic 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, defense against which requires post-transcriptional protection of de novo lipogenesis. We demonstrate that biguanide treatment during impaired lipogenesis drives NADPH toxicity, leading to catastrophic elevation of NADH/GSH reducing equivalents and accelerated death across metazoans. Multiple NADPH-generating interventions require de novo lipogenesis to prevent markedly shortened survival, indicating that this defense mechanism is broadly leveraged. We propose that fatty acid biosynthesis is a tunable rheostat that can minimize biguanide-induced reductive stress while maximizing its pro-longevity outcomes and can serve as an exploitable vulnerability in reductive stress-sensitive cancers.
    Keywords:  Caenorhabditis elegans; cancer; de novo lipogenesis; eukaryotic initiation factor 3; lifespan; mRNA translation; metformin; phenformin; protein synthesis; reductive stress
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.011
  11. Cancer Cell. 2026 Jun 04. pii: S1535-6108(26)00253-9. [Epub ahead of print]
    Pathogenesis of diffuse large B cell lymphoma proteogenotypes.
    Julius C Enssle, Björn Häupl, Arber Qoku, Boya Wang, George W Wright, Sharon Barrans, Yulai Zhou, Matthew A Care, Cathy Burton, Caitlin Gribbin, Jennifer Ziello, Jason Weirather, Yibo Dai, Atish Kizhakeyil, Xubin Li, James D Phelan, Smriti Kanangat, Stephan Eckert, Sebastian Scheich, Sebastian Wolf, Da Wei Huang, Josefine Jakob, Sebastian P Perner, Andrea Di Fonzo, Martine Pape, Marion Bodach, Dominique Jahn, Uwe Plessmann, Annette M Staiger, German Ott, Philipp Berning, Georg Lenz, Daniel J Hodson, Bernhard Kuster, Roland Schmitz, Henning Urlaub, Michael R Green, Ari M Melnick, Reuben Tooze, Coraline Mlynarczyk, Giorgio Inghirami, Florian Buettner, Louis M Staudt, Thomas Oellerich.
      The clinical and molecular heterogeneity of diffuse large B cell lymphoma (DLBCL) is incompletely understood. By integrating proteomic, transcriptomic, and genomic data from 478 DLBCL tumors, we identify seven DLBCL proteogenotypes (PGs) reflecting specific pathophysiological features that span known molecular subtypes. PG4 is associated with poor outcome independent of established risk factors such as cell-of-origin, international prognostic index, or genetic features. PG4 contains activated B cell-like and germinal center B cell-like tumors and genetically unclassified cases. It shares a dark-zone-related B cell phenotype and shows enrichment for BTG1 mutations that can activate MYC. Single-cell sequencing and spatial transcriptomics reveal enhanced MYC and TCF3/4 transcriptional activity irrespective of MYC translocations. The PG4 tumor microenvironment is characterized by exhausted CD8+ T cells. Our study identifies common oncogenic themes underlying high-risk DLBCL tumors and provides a proteogenomic framework for future diagnostic and therapeutic approaches.
    Keywords:  B cell receptor; MYC; genomics; immune exhaustion; lymphoma; multi-omics data integration; protein translation; proteomics; single cell sequencing; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.05.008
  12. Nat Commun. 2026 May 30.
    Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.
    Geethu Emily Thomas, Veronique Voisin, Kazem Nouri, Rose Hurren, Karen Kai-Lin Fang, Ali Chegini, Marcela Gronda, Yongran Yan, Neil MacLean, Yulia Jitkova, Dakai Ling, Mary Ma, Xiao Ming Wang, Andrea Arruda, Vito Spadavecchio, Mark D Minden, Li Zhang, Jong Bok Lee, Aaron D Schimmer.
      Eukaryotic cells have separate genomes in the nucleus and mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA) and dsRNA as a by-product of this transcription. We demonstrate that mtRNA transcription and degradation are increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discover that the mitochondrial degradosome, SUV3 and PNPase, is upregulated in AML cells and stem cells and functionally important for degradation of mtRNA and mitochondrial dsRNA (double stranded RNA) in AML. Depleting SUV3 or PNPase impairs mtRNA degradation and promotes the accumulation of dsRNA. dsRNA that accumulates after depleting SUV3 or PNPase, stimulates IFN-I signaling that induces AML differentiation, decreases stemness and increases sensitivity to immune-mediating cytotoxicity. Thus, this work highlights mitochondrial RNA regulation in AML and identifies a mechanism by which mtRNA turnover influences AML differentiation, stem cell function, and immune sensitization.
    DOI:  https://doi.org/10.1038/s41467-026-73558-3
  13. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00184-1. [Epub ahead of print]38(6): 1089-1092
    Functional specialization within the mitochondrial network: Are all mitochondria created equal?
    Jessica B Spinelli.
      Mitochondria are classically viewed as a uniform ATP-producing network; however, a growing body of evidence suggests distinct subpopulations exist within tissues and even single cells. Here, I highlight evidence supporting the presence of functionally distinct mitochondria and propose mechanisms by which these subpopulations are formed and regulated.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.019
  14. J Clin Invest. 2026 Jun 01. pii: e199716. [Epub ahead of print]136(11):
    Aspartate deficiency amplifies cGAS-STING signaling in antitumor immunity.
    Yuheng Liao, Hanze Wang, Hengxin Liu, Xi Chen, Renqiang Sun, Xie Li, Zhen Yang, Chenying Liu, Wei Wu, Ziqian He, Yuzheng Zhao, Ying Mao, Dan Ye, Hui Yang.
      Metabolic signals critically shape innate immune responses. Through pharmacological screening of metabolic pathways, we identified aspartate metabolism as a key regulator of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling. Genetically or aminooxyacetic acid-mediated (AOA-mediated) pharmacologically reducing aspartate levels markedly potentiated the cGAS-STING pathway, leading to stronger upregulation of type I interferons and interferon-stimulated genes. Mechanistically, disruption of de novo pyrimidine synthesis, a major downstream pathway of aspartate, induced mtDNA replication stress and increased mtDNA double-strand breaks, promoting mtDNA release into the cytosol. Cytosolic mtDNA synergized with cGAS-STING agonists to upregulate Z-DNA binding protein 1 (ZBP1), which recruits RIPK1/3 to sustain IRF3 phosphorylation, forming a positive feedback loop that amplifies innate immune signaling. In immunocompetent mouse models, AOA enhanced the antitumor efficacy of STING agonists, chemotherapy, or radiotherapy, whereas aspartate supplementation abrogated these effects. Consistently, aspartate levels negatively correlated with antitumor immunity in colorectal cancer patient samples. Together, our study identifies aspartate-pyrimidine metabolism as a critical metabolic checkpoint that licenses STING signaling by enabling mtDNA stress to cooperate with agonist stimulation, driving type I interferon-dependent ZBP1 induction and feed-forward amplification of STING signaling, thus offering a promising strategy to enhance antitumor immunity.
    Keywords:  Cellular immune response; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/JCI199716
  15. EMBO J. 2026 Jun 04.
    Somatic cells compartmentalise their carbohydrate metabolism to sustain germ cell survival.
    Diego Sainz de la Maza, Holly Jefferson, Celine I Brucker, Sonia Paoli, Marc Amoyel.
      To ensure success in reproduction, organisms dedicate substantial resources to supporting the germline. In testes, somatic gonadal cells form a barrier that isolates germ cells from circulating nutrients, raising the question of how germ cell metabolism is sustained and how somatic cells ensure that sufficient resources are directed to the germline. Here, we use lineage-specific genetic manipulations and metabolite reporters to show that Drosophila somatic gonadal cells break down circulating sugars to produce and shuttle lactate to germ cells in vivo, thus sustaining their survival. Further, we uncover that somatic cells ensure the allocation of carbohydrate metabolites specifically to germ cell support and that increasing autonomous consumption of carbohydrates in somatic cells increases germ cell death. Thus, germ cell survival depends on functional metabolic compartmentalisation within gonadal somatic support cells.
    DOI:  https://doi.org/10.1038/s44318-026-00815-y
  16. Protein Sci. 2026 Jul;35(7): e70662
    Regulation of mitochondrial protein translocases.
    Lea Bertgen, Agnieszka Chacinska.
      Mitochondria are essential for cellular health, and their function is underlain by the plasticity of the mitochondrial proteome. Most mitochondrial proteins are nuclear encoded, synthesized in the cytosol, and require precise import into mitochondrial subcompartments to fulfill their proper functions. Multimeric mitochondrial translocases ensure accurate protein localization and membrane integration. Recent work has begun to reveal how translocase activity and composition are dynamically regulated within mammalian cells. This review discusses regulatory mechanisms, including phosphorylation and protein degradation, that emerge as important players in adjusting the capacity and/or selectivity of the mitochondrial translocase to metabolic demands. Particular emphasis will be placed on the TIM23 complex as an emerging regulator of the inner membrane and matrix proteome composition.
    Keywords:  TIM23 complex; TOM complex; mitochondria; mitochondrial biogenesis; proteases; protein translocases; protein turnover
    DOI:  https://doi.org/10.1002/pro.70662
  17. Biochim Biophys Acta Biomembr. 2026 Jun 03. pii: S0005-2736(26)00049-0. [Epub ahead of print] 184546
    Consequences of defective mitochondrial protein import: From targeting signals to pathology.
    Maya Cielo Cornejo, Sandy Che-Eun S Lee, Shaya Smith, Carla M Koehler.
      Cellular organelles are uniquely specialized membrane-bound structures that enable cells to organize and coordinate biochemical processes. Specifically, mitochondria are essential organelles for cellular metabolism, coordinating energy production, and connecting signaling networks for cellular homeostasis. 99% of mitochondrial proteins are encoded by nuclear genes that require precise and efficient translation and import into mitochondria for biological processes. This process is mediated by coordinated pathways involving the mitochondrial specific translocation complexes, chaperones, and specialized targeting routes. Tight regulation of these import mechanisms allows for proper protein localization, folding, and assembly. Disruptions in the mitochondrial protein import pathway compromise organelle homeostasis and activate proteostatic stress and quality control pathways. Such defects have been observed in a wide range of pathophysiological conditions, including cardiovascular disease, neurodegeneration, and cancer. The import defects destabilizing mitochondrial proteins can impair oxidative phosphorylation and metabolic signaling. In sum, defects to mitochondrial function can highlight a central role of mitochondrial protein import beyond maintaining cellular function and how defects at distinct stages of import contribute to disease, underscoring opportunities for therapeutic intervention targeting mitochondrial proteostasis.
    Keywords:  Mitochondria; Mitochondrial disorders; Mitochondrial protein import; Mitochondrial protein processing; Mitochondrial targeting sequence; Proteostasis; TIM23 complex; TOM complex
    DOI:  https://doi.org/10.1016/j.bbamem.2026.184546
  18. Nat Aging. 2026 Jun 02.
    DREAM repressive activity links somatic mutation, lifespan and disease.
    Zane Koch, Shuvro P Nandi, Kate Licon, Arturo Bujarrabal-Dueso, David H Meyer, Safa Saeed, Pirunthan Perampalam, Frederick A Dick, Björn Schumacher, Ludmil B Alexandrov, Trey Ideker.
      The DREAM complex has emerged as a central repressor of DNA repair, raising questions as to whether such repression exerts long-term effects on human health. Here we establish that DREAM-associated activity significantly impacts lifetime somatic mutation burden, and that such effects are linked to altered lifespan and age-related disease pathology. First, joint profiling of DREAM-associated activity (quantified from the expression of genes transcriptionally repressed by DREAM) and somatic mutations across a single-cell atlas of 21 mouse tissues shows that cellular niches with lower DREAM-associated activity have decreased mutation rates. Second, DREAM-associated activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species. Third, reduced DREAM-associated activity in individuals with Alzheimer's disease predicts late disease onset and decreased risk for severe neuropathology. Finally, DREAM knockout in mice protects against mutation accumulation, reducing single-base substitutions by 4.2% and insertion/deletions by 19.6% in the brain. These findings position DREAM as a key regulator of aging.
    DOI:  https://doi.org/10.1038/s43587-026-01132-z
  19. Nat Commun. 2026 May 30.
    Fmp30p is a mitochondrial phosphatidylinositol hydrolase that modulates CoQ biosynthesis.
    Zakery N Baker, Rachel M Guerra, Sean W Rogers, David J Pagliarini.
      Organellar membranes feature bespoke lipid compositions; however, the enzymes that craft these compositions and the functional implications these lipids exert on membrane protein organization and activity are insufficiently understood. Here, we discover that the inner mitochondrial membrane protein Fmp30p, a member of the metallo-β-lactamase superfamily, displays phospholipase type D activity toward phosphatidylinositol (PI)-a notable mitochondrial membrane component with unclear functional roles. FMP30 deletion caused substantial and specific elevation of PI species in purified mitochondria. Augmenting mitochondrial PI levels in this way, or by targeting established PI-modifying enzymes to the organelle, increased coenzyme Q (CoQ) biosynthesis concomitant with elevated expression of CoQ-related enzymes and enhanced CoQ metabolon formation. Collectively, our work establishes Fmp30p as a mitochondrial PI phospholipase related to CoQ biology and reveals the broader importance of inner membrane PI in regulating mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-026-73766-x
  20. bioRxiv. 2026 May 29. pii: 2026.05.22.727248. [Epub ahead of print]
    Cells Engage Endogenous Malonate Synthesis to Drive Mitochondrial Metabolism.
    Riley J Wedan, Pieter R Norden, Morgan T Canfield, Abigail E Ellis, Sanskriti Saxena, Jacob Z Longenecker, Michelle Dykstra, Ryan D Sheldon, Sara M Nowinski.
      Malonate is often described as an endogenous inhibitor of complex II of the electron transport chain. However, the cellular source of malonate is unclear, and current knowledge concerning its metabolism is limited to the action of a single enzyme, Acyl-CoA Synthetase Family Member 3 (ACSF3), which converts malonate to malonyl-CoA in the mitochondrial matrix. One potential route of malonate metabolism downstream of ACSF3 is its consumption by the mitochondrial fatty acid synthesis (mtFAS) pathway. However, studies examining the link between ACSF3 and mtFAS have yielded conflicting results. We developed a novel mass spectrometry approach to perform stable isotope tracing into products of mtFAS, and found that while malonate is in fact a carbon source for mtFAS, ACSF3 is not required for malonate incorporation into mtFAS products. Using this method to trace other nutrients into mtFAS, we also found evidence of acetyl-CoA carboxylase 1 (ACC1)-dependent malonate synthesis from glucose. We further show that ACC1 is required for optimal mtFAS activity, with downstream effects on oxidative phosphorylation. Together these findings establish the malonate as a regulated endogenous intermediate that supports mtFAS activity and mitochondrial oxidative function.
    DOI:  https://doi.org/10.64898/2026.05.22.727248
  21. J Immunother Cancer. 2026 Jun 03. pii: e015830. [Epub ahead of print]14(6):
    Expert opinion on burning questions in cancer myeloid cell biology.
    Jennifer L Guerriero, Miriam Merad, Florent Ginhoux, Renato Ostuni, Karin E de Visser, Mikael J Pittet, Sven Brandau, Taha Merghoub, Mikala Egeblad, Viktor Umansky, Lilian van Vlerken-Ysla, Thomas U Marron, Lisa M Coussens, Jelani C Zarif, Brian Ruffell, Simon T Barry, Judith A Varner, Dmitry I Gabrilovich.
      
    Keywords:  Myeloid; Neutrophil
    DOI:  https://doi.org/10.1136/jitc-2026-015830
  22. Protein Sci. 2026 Jul;35(7): e70665
    Redox signals and oxidative stress in the control of mitochondrial protein import.
    Lidwina Hasberg, Viktoria Katharina Lauterbach, Torsten Ochsenreiter, Jan Riemer.
      Mitochondrial protein import is essential for organelle biogenesis and cellular homeostasis. It operates in an environment that is intrinsically shaped by redox chemistry. Mitochondria are major sources of reactive oxygen species (ROS), which arise as by-products of oxidative phosphorylation. Cells therefore maintain sophisticated ROS-handling systems, including compartmentalized antioxidant networks, to balance redox signaling with protection from oxidative stress. Increasing evidence indicates that these redox conditions directly influence mitochondrial protein import at multiple levels. In this review, we provide an overview of ROS production, ROS signaling, and oxidative stress in relation to mitochondrial protein import. We outline the major mitochondrial protein import pathways, and discuss how their activity is modulated by redox-dependent mechanisms. A particular focus is placed on the mitochondrial disulfide relay system of the intermembrane space, which directly couples protein import to redox chemistry through oxidative folding, and how it is influenced by the local redox environment. Collectively, we propose that mitochondrial protein import is partially governed by redox-dependent mechanisms, enabling integration of metabolic state, stress responses, and signaling pathways.
    Keywords:  disulfide relay; mitochondrial protein import; oxidative stress; reactive oxygen species (ROS); redox signaling
    DOI:  https://doi.org/10.1002/pro.70665
  23. J Clin Invest. 2026 Jun 01. pii: e206431. [Epub ahead of print]136(11):
    Fueling the fire: aspartate deficiency primes and fuels STING activation.
    Haitao Jiang, Wenyan Wang, Yang-Xin Fu.
      Cytosolic DNA sensing through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a promising strategy to elicit antitumor immunity. However, clinical translation of STING agonists has been hindered by limited efficacy and dose-limiting inflammatory toxicity, highlighting that simply providing activating ligands is insufficient to achieve durable immune responses. In this issue of the Journal of Clinical Investigation, Liao et al. showed that intracellular aspartate availability critically shapes STING signaling responsiveness. Aspartate deficiency disrupted pyrimidine synthesis, induced mtDNA stress, and engaged a feed-forward Z-DNA binding protein 1 and receptor interacting serine/threonine kinase 1/3 axis. Rather than directly triggering immunity, this metabolic state primed DNA sensing and fueled downstream signaling, thereby enabling robust and sustained antitumor immune responses. Together, these findings position nucleotide metabolism as a key determinant of innate immune responsiveness and suggest that metabolic conditioning may enhance the efficacy of STING-targeted therapies.
    DOI:  https://doi.org/10.1172/JCI206431
  24. J Cell Biol. 2026 Aug 03. pii: e202409118. [Epub ahead of print]225(8):
    Asymmetric mitochondrial trafficking balances perinuclear biogenesis to maintain network morphology.
    Julius Winter, Juan C Landoni, Keaton B Holt, Sheda Ben Nejma, Emine Berna Durmus, Tatjana Kleele, Elena F Koslover, Suliana Manley.
      In functionally polarized cells, mitochondria can form distinct subpopulations, positioned at sites of varying metabolic and energetic demands. Thus far, the potential presence of such subpopulations and implications of their intracellular trafficking in immobile and proliferative cells remain largely undescribed, despite such cells serving as key models. Here, we use substrate micropatterning to create reproducible morphologies of cultured immortalized cells, enabling us to define mitochondrial subpopulations and follow their trafficking by photoactivation. We discovered that mitochondrial material is dispersed asymmetrically throughout the cell via biased anterograde transport from the perinuclear area. Combining quantitative analysis and in silico modeling, we characterize the causes and consequences of unbalanced mitochondrial trafficking. Our findings indicate that this bias is required to distribute new material resulting from perinuclear mitochondrial biosynthesis to sustain mitochondrial mass distribution across the cell and to maintain normal network connectivity.
    DOI:  https://doi.org/10.1083/jcb.202409118
  25. bioRxiv. 2026 May 23. pii: 2026.05.22.727209. [Epub ahead of print]
    Functional partitioning of lipoic acid decouples cellular abundance from mitochondrial utilization.
    Pieter R Norden, Riley J Wedan, Abigail E Ellis, Madeleine L Hart, Megan R Gendjar, Ryan D Sheldon, Sara M Nowinski.
      α-Lipoic acid (LA) is widely included in "mitochondrial cocktails" recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that LA exists in two functionally distinct cellular pools: a low-abundance free pool and a protein-bound pool generated through mitochondrial fatty acid synthesis (mtFAS). Disruption of the mtFAS pathway abolishes protein lipoylation and impairs oxidative phosphorylation without altering free LA levels. Conversely, supplementation with exogenous LA markedly increases free intracellular LA without restoring protein lipoylation, mitochondrial respiration, or cell proliferation. Instead, the cellular effects of LA supplementation resemble those of the antioxidant N-acetylcysteine. These findings clarify the mechanism of action of a widely used mitochondrial supplement and identify a fundamental disconnect between cellular LA abundance and mitochondrial utilization, challenging the rationale for using LA supplementation to restore mitochondrial function.
    DOI:  https://doi.org/10.64898/2026.05.22.727209
  26. bioRxiv. 2026 May 22. pii: 2026.05.21.726885. [Epub ahead of print]
    The aging genome exhibits organized vulnerability to somatic mutations.
    Joseph Ehlert, Ronald Cutler, Jonah Spector, Bnaya Gross, Orr Levy, Jan Vijg, Xiao Dong, Albert-László Barabási.
      Somatic mutations accumulate throughout life and have been hypothesized to drive organismal decline. Yet whether these mutations are distributed randomly or whether cells shield their most critical components has remained unresolved. Here we analyze over a million somatic mutations across thirteen human tis-sues, finding that the aging genome exhibits organized vulnerability, captured by the existence of hypo-mutated genes and longevity-associated pathways that have significantly lower mutation burden. Highly connected network hubs are systematically protected from mutation, while peripheral, condition-specific genes accumulate disproportionate burdens. We show that this organized vulnerability arises from the interplay of two independent mechanisms: transcription-coupled repair, and selective filtering. Finally, we validate our findings under experimental mutagenesis, demonstrating intrinsic mechanisms of protection rather than tissue-specific confounders. These findings reframe the somatic mutation hypothesis: organismal decline may not reflect total mutational burden, but where those mutations fall within the cellular network.
    DOI:  https://doi.org/10.64898/2026.05.21.726885
  27. Cancer Cell. 2026 Jun 04. pii: S1535-6108(26)00252-7. [Epub ahead of print]
    Hypoxia shapes both therapeutic response and resistance in metastatic clear cell renal cell carcinoma.
    Lynda Vuong, Andrew E Cornish, Jennifer Pfeil, Yash Khandwala, Hui Jiang, Doris X T Zheng, Eduardo A Mascareno, Nicole Rittenhouse, Phillip M Rappold, Josef Leibold, Erich A Sabio, Kate Weiss, Carlene Gonzalez, Liangliang Ji, Jing Zhang, Mojca Adlesic, Oguz Akin, Jessica Flynn, Chirag Krishna, Andrea Lopez Sanmiguel, Rebecca A Sager, Tiak J Tan, Alejandro Sanchez, Renzo G Di Natale, Kyle A Blum, Paul Russo, Jonathan A Coleman, Ian J Frew, Diego Chowell, Ying-Bei Chen, David B Solit, Irina Ostrovnaya, Robert J Motzer, Martin H Voss, Ritesh R Kotecha, Timothy A Chan, Hartland W Jackson, Fengshen Kuo, Ming O Li, A Ari Hakimi.
      Vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (VEGFR-TKIs) and anti-PD-1 (aPD-1) combinations are effective in multiple solid tumors, particularly in clear cell renal cell carcinoma (ccRCC), due to its characteristic pseudohypoxic, hyper-angiogenic state driven by biallelic VHL loss. However, long-term durability is inferior to dual aPD-1/anti-CTLA-4 regimens, yet the underlying mechanisms remain unclear. We investigated tumor microenvironment evolution following VEGFR-TKI, aPD-1, and combined VEGFR-TKI/aPD-1 treatment in a transgenic ccRCC mouse model. We identify hypoxia-responsive SPP1+ tumor-associated macrophages (TAMs) that infrequently infiltrate baseline pseudohypoxic tumors. This proxy of true hypoxia tracks with successful response to VEGFR-TKI/aPD-1 in mouse and human on-treatment single-cell RNA sequencing and imaging mass cytometry cohorts, reflecting treatment-induced hypoxic necrosis. Paradoxically, pretreatment hypoxia predicted worse outcomes across VEGFR-TKI/aPD-1 trials and real-world cohorts while extended exposure to hypoxia-inducing VEGFR-TKIs exacerbated metastasis in mice, highlighting the dual implications of hypoxia in ccRCC disease trajectory.
    Keywords:  GPNMB; SPP1; angiogenesis inhibitors; clear cell renal cell carcinoma; hypoxia; immune checkpoint blockade; pseudohypoxia; tumor microenvironment; tumor-associated macrophages; vascular normalization
    DOI:  https://doi.org/10.1016/j.ccell.2026.05.007
  28. Sci Rep. 2026 Jun 05.
    Voluntary running exercise is associated with metabolic shifts linked to adult hippocampal neurogenesis.
    Alejandra Vazquez-Medina, David Ruíz-Bolivar, Patricia Morales-Iglesias, Karina Marín-Hernandez, Danniela Rivera-Ortiz, Francisco Vizcarrondo-Fornaris, Briana Bello-Rivera, Brendimar Sierra-Medina, Sebastian Rodríguez-Soto, Nataliya Chorna.
      Adult hippocampal neurogenesis is a metabolically demanding process requiring tight coordination between energy production and biosynthetic flux. Although voluntary running is a potent stimulus for this plasticity, the metabolic landscape sustaining the neurogenic niche remains incompletely defined. Using untargeted gas chromatography/mass spectrometry-based metabolomics to characterize the hippocampal metabolome of mice following eight weeks of voluntary running, we identified metabolic changes consistent with coordinated metabolic reprogramming that suggest an adaptive metabolic stress response. A significant catabolic shift, marked by depletion of glutamic and aspartic acids, is associated with increased bioenergetic utilization and possible integration of neurotransmitter-derived substrates into central carbon metabolism. The exercise-induced elevation of CoA-related metabolites and tricarboxylic acid cycle intermediates is indicative of increased mitochondrial bioenergetic demand. Simultaneously, elevated nitrogenous metabolites, such as asparagine and glycine, coincide with increased availability of biosynthetic precursors for nucleotide synthesis, redox balance, and structural remodeling linked to neurogenesis. Enrichment of one-carbon metabolism is compatible with integration of metabolic pathways involved in biosynthetic and regulatory processes related to neurogenic remodeling. Together, these findings align with the interpretation that voluntary running may act as a metabolic hormetic stimulus, linked to reconfiguration of hippocampal metabolic networks to support a permissive environment for neurogenic plasticity and cognitive resilience.
    DOI:  https://doi.org/10.1038/s41598-026-54888-0
  29. Mol Metab. 2026 Jun 01. pii: S2212-8778(26)00073-6. [Epub ahead of print] 102389
    TGFβ activity stabilizes ACC1 to increase de novo lipogenesis in metabolic liver disease.
    Brent Mayfield, Yoko Yagashita, Jinku Kang, Changyu Zhu, Stefania Mira, Timothy J Kendall, Qiuyan Sun, Maria E Meincke, Domenick Raphael, Meng Li, Shuxuan Chen, Harrison Cullen, Stryder M Meadows, Luke E Berchowitz, Michele Carrer, Jonathan A Fallowfield, Robert F Schwabe, Luca Valenti, Utpal B Pajvani.
      Metabolic liver disease arises due to dysregulated signaling between hepatocytes and non-parenchymal cells (NPCs). Through parallel RNA sequencing screens in diet-induced and genetic mouse models, backdropped by human transcriptomic data, we identified latent TGFβ binding protein-3 (LTBP3) - a regulator of TGFβ secretion - as a novel contributor to metabolic liver disease pathogenesis. GalNAc-conjugated Ltbp3 ASO reduced hepatic triglyceride accumulation in diet-induced metabolic liver disease mouse models, which was phenocopied in mice lacking hepatocyte TGFβ activity, but surprisingly not in hepatocyte-specific Ltbp3 knockout mice. This discordance prompted evaluation as to whether GalNAc-based tools are hepatocyte-specific. In fact, we found that GalNAc-Ltbp3 ASO also targeted multiple NPC populations, reducing intrahepatic TGFβ activity, culminating to lowered lipid content by increased proteasomal degradation of the key lipogenic enzyme Acetyl-CoA-Carboxylase 1 (ACC1) in hepatocytes. These data reveal a previously unrecognized NPC-hepatocyte axis to regulate lipogenesis in metabolic liver disease.
    Keywords:  Lipogenesis; MASH; MASLD; TGFβ
    DOI:  https://doi.org/10.1016/j.molmet.2026.102389
  30. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00186-5. [Epub ahead of print]38(6): 1093-1096
    Considerations and best practices for respirometry.
    Andréa B Ball, Linsey Stiles, Ajit S Divakaruni.
      Oxygen consumption rate (OCR) measurements are now widely used to assess mitochondrial function and cellular metabolism. Here, we review the strengths and limitations of plate-based respirometry, propose unified reporting standards, and discuss how OCR measurements can be integrated with complementary assays to evaluate cellular energy demands and mitochondrial function.
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.001
  31. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00153-1. [Epub ahead of print]38(6): 1075-1078
    Mitochondria across the globe: Diverse voices, shared energy.
    Ichitaro Abe, Alejandro Failde Fiestras, Maia Hjerting Ekstrand, Nahid A Khan, Kenneth Bowitz Larsen, Jason Maynes, Agata M Rudolf, Francois Singh.
      Like mitochondria themselves, research on the organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology & Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.015
  32. Mol Cell. 2026 Jun 04. pii: S1097-2765(26)00287-X. [Epub ahead of print]86(11): 2038-2040
    Mitochondria across the globe: Diverse voices, shared energy.
    Tim Pflästerer, Andrea Dlasková, Stuart Caldwell, Marijana Croon, Staffan Strömblad, Jae Bum Kim.
      Like mitochondria themselves, research on this organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted Mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology and Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
    DOI:  https://doi.org/10.1016/j.molcel.2026.04.033
  33. Commun Biol. 2026 Jun 02.
    Metab8D: a metabolic regulome network from multiomics and machine learning.
    Ryan Schildcrout, Kirk Smith, Rupa Bhowmick, Yuntao Lu, Suraj Menon, Minali Kapadia, Emily Kurtz, Anya Coffeen-Vandeven, Srikar Nelakuditi, Sriram Chandrasekaran.
      To explore multiomic regulation of the metabolome, we used machine learning to predict metabolomic variation across ~1000 different cancer cell lines with matched omics data from eight biomolecular classes: genomic copy number variation, mutations, DNA methylation, histone post-translational modifications (PTMs), transcriptomics and RNA splice variants, non-coding transcriptomics (miRNA and lncRNA), proteomics, and phosphoproteomics. Overall, the metabolome is tightly associated with the transcriptome, with coding and non-coding RNAs emerging as top predictors. Peripheral metabolites are predictable via levels of corresponding enzymes, while those in central metabolism require combinatorial predictors in signaling and redox pathways, and may not reflect corresponding pathway expression. We reconstruct multiomic interaction subnetworks for highly predictable metabolites, and YAP1 signaling emerged as a top global predictor across four omic layers. We prioritize predictive multiomic features for single-cell and spatial metabolomics assays. Top predictors were enriched for synthetic-lethal interactions and synergistic combination therapies that target compensatory metabolic modulators.
    DOI:  https://doi.org/10.1038/s42003-026-10409-3
  34. Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00484-5. [Epub ahead of print]45(6): 117406
    Mutational signatures of environmental carcinogens in human tissue organoids revealed by duplex sequencing.
    Jill E Kucab, Shuvro P Nandi, Halh Al-Serori, Ellie Dunstone, Rebekah S S Beck, Angela L Caipa Garcia, Eleanor C Wilde, Safa Saeed, Hayley Francies, Mathew J Garnett, Beiyuan Fu, Fengtang Yang, Kourosh Saeb-Parsy, Meritxell Huch, Jarno Drost, Matthias Zilbauer, Laura Humphreys, Glen Kisby, Volker M Arlt, Michael R Stratton, Ludmil B Alexandrov, David H Phillips.
      Environmental exposures play a pivotal role in carcinogenesis, yet their molecular imprints in human tissues remain incompletely understood. Here, we present an extensive catalog of mutational signatures induced by a panel of environmental carcinogens using human tissue-derived organoids coupled with high-fidelity duplex sequencing (NanoSeq). This unique combination enables direct detection of mutations without clonal expansion and reveals consistent carcinogen-specific signatures across multiple organ types (i.e., colon, stomach, liver, kidney, and pancreas). We identify mutational signatures for agents such as benzo[a]pyrene, aflatoxin B1, aristolochic acid I, and alkylating agents, some of which show strong concordance with known tumor signatures (e.g., SBS4, SBS11, SBS22, and SBS24) and previous experimentally-derived signatures. Our findings validate organoid models as physiologically relevant platforms for chemical mutagenesis and provide a foundational resource for decoding the environmental origins of human cancer.
    Keywords:  CP: cancer; CP: genomics; carcinogen; colon; duplex sequencing; kidney; liver; mutation; organoid; pancreas; signature; stomach
    DOI:  https://doi.org/10.1016/j.celrep.2026.117406
  35. Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00565-6. [Epub ahead of print]45(6): 117487
    LKB1 inactivation elicits an NNMT-mediated methyl sink and confers dependence on PRMT5 in lung cancer.
    Wen Mi, Xinyi Xia, Yun Xue, Liucheng Li, Li Yang, Xincheng Yang, Jie Xu, Xinlei Cai, Yijia Zhou, Lingzhi Zhu, Guanlin Wang, Fei Li, Hongbin Ji, Xinyuan Tong, Pingyu Liu, Fuming Li.
      The protein arginine methyl transferase 5 (PRMT5) emerges as a therapeutic target in S-methyl-5'-thioadenosine phosphorylase (MTAP)-deleted cancers, where 5'-methylthioadenosine (MTA) accumulation partially inhibits its activity. However, it remains unclear whether other genetic alterations can dictate PRMT5 activity in cancer. Here, we identify liver kinase B1 (LKB1) as an alternative predictor of PRMT5 inhibition in lung cancer independent of MTAP. Mechanistically, LKB1 loss activates salt-inducible kinase 1/2 (SIK1/2)-cAMP response element-binding protein-regulated transcription coactivator 2 (CRTC2) signaling to upregulate nicotinamide N-methyltransferase (NNMT), creating a "methyl sink" that lowers the S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) ratio and attenuates PRMT5 activity. NNMT overexpression is sufficient to induce this hypomorphic PRMT5 state and heighten sensitivity to PRMT5 inhibitors. Functionally, PRMT5 inhibition induces senescence in LKB1-deficient cells and confers vulnerability to navitoclax, synergistically blunting tumor growth in vivo. Collectively, we identify PRMT5 as an actionable therapeutic vulnerability in LKB1-deficient lung cancer, and propose LKB1 status/NNMT expression as potential biomarkers for PRMT5 inhibition. These findings may expand the clinical utility of PRMT5-targeted therapies beyond MTAP-deleted cancers.
    Keywords:  CP: cancer; LKB1; NNMT; PRMT5; methyl sink; senescence
    DOI:  https://doi.org/10.1016/j.celrep.2026.117487
  36. bioRxiv. 2026 May 20. pii: 2026.05.19.726366. [Epub ahead of print]
    Somatic mutations reveal the ontogeny of human microglia.
    Julia A Belk, Yaowen Zhang, Quanming Shi, Lisa Ma, Raja Kalluru, Alejandro Medina Enciso, Emily E Reilly, Jacob Weiss, Rui Li, Anna E Eastman, Nicole Womack-Gambrel, Debasmita Paul, Arnav Chakravarthy, Syed Bukhari, Dipabarna Bhattacharya, Suyash Raj, Daniel Richard, Simone Brioschi, Matthew R Chrostek, Daniel C Nachun, Christopher M Arends, Jayakrishnan Gopakumar, Isak W Tengesdal, Ademar Bynum, Shaneice Mitchell, Katalin Sandor, Badri N Vardarajan, Inma Cobos, Donald E Born, Anne Brunet, Marco Colonna, Hannes Vogel, Thomas J Montine, Jody E Hooper, Irving L Weissman, C Dirk Keene, Howard Y Chang, Siddhartha Jaiswal.
      Microglia are the resident hematopoietic cells of the central nervous system 1 . In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult hematopoiesis 2-4 . The origins of human microglia are less clear, but recent evidence suggests that marrow-derived cells may be able to supplement the human microglial pool in certain individuals 5,6 . Here, to investigate the ontogeny of human microglia, we develop a method that uses the collection of accumulated somatic mutations which uniquely labels each clone of cells to track the infiltration of marrow-derived cells into the human brain. Applying this method to 20 aged individuals, we find evidence of an influx of marrow-derived cells into the brain in all examined individuals. Single cell analysis, including single cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are nearly identical to microglia and can comprise a large fraction of the microglial pool. Analysis of large-scale sequencing cohorts demonstrates a protective association between most types of clonal hematopoiesis and Alzheimer's disease. In sum, this work uncovers a widespread influx of myeloid cells into the healthy human brain which serves to reinforce the pool of human microglia and becomes common with aging.
    DOI:  https://doi.org/10.64898/2026.05.19.726366
  37. Nat Rev Mol Cell Biol. 2026 Jun 02.
    Effortless immortalization of primary mouse fibroblasts.
    Alain Nepveu.
      
    DOI:  https://doi.org/10.1038/s41580-026-00984-y
  38. Cell Stem Cell. 2026 Jun 04. pii: S1934-5909(26)00162-1. [Epub ahead of print]33(6): 901-903
    Ketone bodies as guardians of leukemic stemness through ferroptosis suppression.
    Xi Zhao, Li Zhuang, Boyi Gan.
      Leukemia stem cells exploit cell-intrinsic ketogenesis to suppress ferroptosis and sustain disease propagation. In this issue, Han et al.1 uncover a β-hydroxybutyrate-epigenetic-lipid remodeling axis that protects stemness by restraining ferroptosis, revealing a metabolic vulnerability with therapeutic potential.
    DOI:  https://doi.org/10.1016/j.stem.2026.04.022
  39. Trends Mol Med. 2026 Jun 03. pii: S1471-4914(26)00110-3. [Epub ahead of print]
    Under pressure: peroxisomes in cancer therapy resistance.
    Nicla Lorito, Francesca Bonechi, Elisabetta Romano, Alfredo Smiriglia, Andrea Morandi.
      Therapy resistance is a major obstacle to durable clinical responses. While genetic alterations and signalling rewiring are primary drivers of resistance, metabolic adaptation, which is closely intertwined with these processes, enables tumour persistence under therapeutic pressure and directly contributes to resistance. Peroxisomes are metabolic organelles with a role in controlling lipid metabolism, together with redox signalling and homeostasis-processes that intersect with pathways governing cancer behaviour and therapy response. Indeed, peroxisomal functions are remodelled to support metabolic plasticity and redox buffering under therapeutic stress. In this review, we synthesise emerging evidence linking peroxisome biology to resistance to chemotherapy, targeted therapies, radiotherapy, and immunotherapy and discuss how peroxisomal pathways may be exploited therapeutically or as biomarkers to overcome cancer therapy resistance.
    Keywords:  PPAR; ether phospholipids; fatty acid oxidation; pexophagy; redox homeostasis; therapy resistance
    DOI:  https://doi.org/10.1016/j.molmed.2026.05.001
  40. Nat Metab. 2026 Jun 03.
    Polyendocrine metabolic ovarian syndrome - a new name for an old problem.
    Pawel Kordowitzki, Helena Teede.
      
    DOI:  https://doi.org/10.1038/s42255-026-01552-6
  41. Cell. 2026 Jun 04. pii: S0092-8674(26)00522-2. [Epub ahead of print]
    Plasma signals of lung tumor promotion for molecular cancer prevention.
    Tej Pandya, Maria Zagorulya, Michelle M Leung, Marcellus Augustine, Lydia Y Liu, Aino-Maija Leppä, Ulysse Baruchel, Sin Wi Ng, Tamara Klockner, Miriam Mugabo, Anthony J Griffen, Oleg Blyuss, Chrysante S Iliakis, Amalie Grenov, Kerstin Haase, David C Muller, Ka Hung Chan, Jincheng Wu, Vernon A Burk, Neil Wright, Alix Le Marois, Ekaterina Pazukhina, Sophia Ward, Hubert Slawinski, Marc Pelletier, Cian Murphy, Matthew D Park, Thomas Snoeks, Alejandro Suarez-Bonnet, Simon L Priestnall, Alexandros Hardas, Charlotte Grieco, Ami Archer, Alpkaan Celik, Alejandro Jimenez-Sanchez, Rachel Scott, Hana Zahed, Léa Montégut, Rafael Meza, Clinton H Durney, Stephen Lam, Takahiro Karasaki, Roel C H Vermeulen, Huilei Xu, Pablo Serrano-Fernandez, Tatjana Crnogorac-Jurcevic, Usha Menon, Sophia Apostolidou, Alexey Zaikin, Richard Gunu, Harry J Whitwell, Zhe Huang, Zonglun Li, Xin Hu, Bo Zhu, Liming Li, María-Dolores Chirlaque, Marcela Guevara, P Martijn Kolijn, Aghiles Guenoun, Neeloffer Mookherjee, Mattias Johansson, Ziqiao Wang, Nilanjan Chatterjee, Chao-Hua Chiu, Zhengming Chen, Dana Pe'er, Erik Sahai, Saskia Freytag, Andreas Wack, Marc J Gunter, Miriam Merad, Jianjun Zhang, Christopher Carlsten, Pan-Chyr Yang, Hsuan-Yu Chen, Elizabeth A Platz, Lindsay M LaFave, Karl Smith-Byrne, Mariam Jamal-Hanjani, Kevin Litchfield, Nuno R Nene, Nicholas McGranahan, Eva Grönroos, William Hill, Clare E Weeden, Charles Swanton.
      Predicting lung cancer risk would enhance prevention trials. Although the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial demonstrated reduced lung cancer incidence with interleukin (IL)-1β inhibition, the high number needed to treat (NNT) to prevent lung cancer limits its use in unselected populations. Using machine learning, we identified a 14-protein plasma signature predicting lung cancer more than 5 years before diagnosis. The signature, validated across eight cohorts, was elevated in current smokers and individuals exposed to particulate matter (PM) and linked to lung myeloid and alveolar cells. In epidermal growth factor receptor (EGFR)-driven lung adenocarcinoma, diverse epithelial lineages converged on a keratin8+/claudin4+ alveolar transitional state (KAC), whose transcriptional programs correlated with signature emergence. Components of the signature were induced by PM, oncogenic EGFR, or IL-1β, whereas IL-1β inhibition restrained PM-driven KAC expansion and early tumorigenesis. In CANTOS, the signature identified individuals who seemed to benefit more from anti-IL-1β therapy, lowering the NNT threshold and nominating circulating signals of tumor promotion for prevention.
    Keywords:  cancer cell of origin; cancer prevention; lung adenocarcinoma; lung cancer initiation; lung cancer prevention; lung cancer risk; plasma proteomics; secretory alveolar niche; tumor promotion
    DOI:  https://doi.org/10.1016/j.cell.2026.05.005
  42. bioRxiv. 2026 May 29. pii: 2026.05.26.727520. [Epub ahead of print]
    Cell autonomous inflammation in VEXAS is mediated by cGAS-STING.
    Samuel J Magaziner, Jason C Collins, Brecca Miller, Patrick Zheng, Amy K Wang, Jerome Hadjadj, Juan Carlos Baladrán, Maria Sirenko, Maya English, James Bertlin, Rebecca Murray, Peter H Whitney, Tania J González-Robles, Deborah Rivera, Yan Wang, Duy T Tran, Zulfeqhar A Syed, Valentina Baena, Timothee Lionnet, Kelly V Ruggles, Iannis Aifantis, Dan A Landau, Achim Werner, David B Beck.
      VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe adult-onset inflammatory disease caused by somatic mutations that reduce cytoplasmic activity of UBA1, the primary initiating enzyme for ubiquitylation. How this hypomorphic state drives cell-intrinsic immune activation in mature myeloid cells is unknown. Using unbiased multi-omic, biochemical, and cell biological analyses of model systems and patient-derived cells, we show that loss of cytoplasmic UBA1 activity convergently disrupts endoplasmic reticulum- associated degradation (ERAD) and mitochondrial homeostasis. ERAD failure arises from preferential under-charging of ERAD E2 enzymes, explaining hallmark VEXAS features, including ER-derived vacuoles and unfolded protein response activation, and promotes accumulation of the ERAD substrate STING. Simultaneously, mitochondrial dysfunction drives cytosolic leakage of mitochondrial DNA, inducing cGAS-dependent STING signaling and inflammatory cytokine production. STING inhibition or reversal of mitochondrial DNA leakage resolves multi-cytokine inflammation in VEXAS models and patient myeloid cells, establishing the cGAS-STING pathway as a therapeutically actionable vulnerability.
    DOI:  https://doi.org/10.64898/2026.05.26.727520
  43. bioRxiv. 2026 May 27. pii: 2026.05.24.727510. [Epub ahead of print]
    ACLY integrates metabolism and chromatin accessibility to enable B Cell activation and humoral immunity.
    Meilu Li, Zhiqiang Zhang, Xian Zhou, Yanfeng Li, Xingxing Zhu, Aditya Bhagwate, Nagaswaroop Kengunte Nagaraj, Hu Zeng.
      B cell activation and differentiation into antibody-secreting cells require extensive metabolic and epigenetic remodeling, yet the molecular mechanisms that integrate these programs remain incompletely understood. ATP-citrate lyase (ACLY) links glucose metabolism to acetyl-CoA production, supporting lipid biosynthesis and protein acetylation. However, its role in humoral immunity has not been fully defined. Here, using genetic and integrated multi-omics approaches, we show that B cell activation is accompanied by coordinated metabolic, transcriptional, and epigenetic reprograming. Although ACLY is dispensable for B cell development and homeostasis, it is required to establish chromatin accessibility programs in activated B cells, with a more pronounced impact on the epigenetic landscape than on transcriptional output. ACLY-deficient B cells exhibit profound defects in TLR and BCR elicited activation, survival and metabolic fitness ex vivo . In vivo , B cell-intrinsic loss of ACLY results in impaired antigen-specific antibody production, associated with reduced germinal center and plasmablast formation, but normal homeostatic proliferation. Deletion of ACLY after B cell activation reduces plasmablast generation in vivo , indicating a continued requirement for ACLY beyond the initial activation phase. Together, these findings identify ACLY as a central regulator that links metabolism to epigenetic programing that supports B cell activation and humoral immunity.
    DOI:  https://doi.org/10.64898/2026.05.24.727510
  44. iScience. 2026 Jun 19. 29(6): 116057
    High level dynein impairs mitochondrial distribution and differentiation of rhabdomyosarcoma cells.
    Ting-Ling Ke, Linyi Chen.
      Rare disease rhabdomyosarcoma-derived RD cells and RH30 cells are defective in myogenesis. In this study, we demonstrate that mitochondria in these cells are enlarged and display a perinuclear distribution. Given that impaired mitochondrial morphology, trafficking, and activity are implicated in many human diseases, characterizing the link between these phenotypes and their physiological outcomes is essential. We found that RD cells had reduced levels of the myosin motor MYO19 and elevated levels of the dynein motor and MIRO1/2 adaptors. Our findings indicate that impaired local actin-based anterograde transport, together with enhanced microtubule-based retrograde transport, drives this perinuclear mitochondrial clustering. Overexpression of MYO19 in RD cells partially rescued this phenotype, while dynein inhibition altered mitochondrial distribution and restored myogenic differentiation in both RD and RH30 cells. Collectively, these findings reveal an intricate interplay among mitochondrial morphology, distribution, and myoblast fusion that underlies both normal physiology and disease.
    Keywords:  Cell biology; Molecular biology; Specialized functions of cells
    DOI:  https://doi.org/10.1016/j.isci.2026.116057
  45. Nat Immunol. 2026 Jun 02.
    RFX7 is a tumor suppressor that restricts MYC function and B cell activation.
      
    DOI:  https://doi.org/10.1038/s41590-026-02533-3
  46. Cancer Res Commun. 2026 May 20.
    Targeting GSTZ1 sensitizes KRAS G12C-mutant lung cancer cells by overcoming glutathione and glycolysis pathway rewiring.
    Yi Liao, Xueli Li, Min Liu, Vanessa C Fernandes, Derek Duckett, Eric B Haura, Andrii Monastyrskyi, Uwe Rix.
      KRAS mutations are prevalent in lung cancer, but KRAS G12C inhibitors exhibit limited efficacy, partly due to metabolic adaptations, such as enhanced glutathione metabolism and increased glycolysis. Glutathione S-Transferase Zeta 1 (GSTZ1) is a metabolic enzyme that regulates cell metabolism; however, its role in KRAS-driven lung cancer remains underexplored. We recently reported that targeting GSTZ1 significantly enhances the efficacy of FDA-approved KRAS G12C inhibitors in non-small cell lung cancer cells. Untargeted metabolomics now revealed significant alterations in glutathione and glycolytic pathways, marked by lowered lactate levels and increased oxidized glutathione following GSTZ1 ablation. Moreover, pharmacological inhibition of glutathione synthesis and glucose uptake mimicked the sensitizing effects of GSTZ1 targeting. These metabolic shifts were accompanied by increased AMPK phosphorylation and reduced AKT phosphorylation, two key mediators of the response to KRAS G12C inhibition. Our data reveal GSTZ1‑associated metabolic and signaling alterations that contribute to drug resistance and identify GSTZ1 as a potential complementary target to sensitize KRAS mutant NSCLC to KRAS‑directed treatments.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0698
  47. Nat Commun. 2026 Jun 06.
    Structural basis for a filamentous morpheein model of human cystathionine beta-synthase.
    Inayathulla Mohammed, Ela Mijatovic, Thilo Magnus Philipp, Lucia Janickova, Kelly Ascencao, Francisco J Asturias, Luis Alfonso Martinez-Cruz, Csaba Szabo, Henning Stahlberg, Tomas Majtan.
      Human cystathionine beta-synthase (CBS) is a vital enzyme that regulates sulfur amino acid metabolism, hydrogen sulfide production, and cellular redox balance. Using a multidisciplinary approach, we demonstrate that CBS functions as a filamentous morpheein, with its stability, turnover, and activity governed by dynamic quaternary structural transitions. Three distinct filamentous assemblies were resolved by cryo-EM and are mediated by the oligomerization loop (residues 516-525): (i) ligand-free trans-dimers that form trans-basal filaments with basal stability and activity, (ii) adenosylornithine-bound cis-dimers that assemble into stabilized cis-basal filaments and (iii) S-adenosylmethionine-bound allo-dimers, which, together with cis-dimers, form highly stable, allo-activated stacked filaments. These reversible filamentous assemblies redefine CBS biology by integrating oligomerization and allosteric regulation within a morpheein framework. These findings provide a transformative perspective on CBS function and open avenues for pharmacological targeting of dysregulated CBS in various diseases including homocystinuria, cancer, and Down syndrome.
    DOI:  https://doi.org/10.1038/s41467-026-73198-7
  48. Hum Mol Genet. 2026 Jun 01. pii: ddag042. [Epub ahead of print]35(10):
    MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.
    Ruth I C Glasgow, Finn Lennartsson, Snjolaug Arnardottir, Dmitrii Igorevich Shiriaev, Sandrina P Correia, Marco Moedas, Lucía Peña-Pérez, Martin Paucar, Karin Naess, Helene Bruhn, Nicole Lesko, Rolf Wibom, Joanna Rorbach, Christoph Freyer, Anna Wedell, Sofia Ygberg, Erik A Eklund, Anna Wredenberg.
      Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.
    Keywords:  MRPS22; adult-onset; mS22; mitochondrial ribosome; translation
    DOI:  https://doi.org/10.1093/hmg/ddag042
  49. Nucleus. 2026 Dec;17(1): 2675754
    High-resolution nuclear cell biology by cryo-electron tomography.
    Zanetta Kechagia, Ohad Medalia.
      The nucleus is a structurally diverse and dynamic organelle that anchors chromatin and orchestrates a large number of essential processes, including transcription, replication, ribosome biogenesis, and nucleocytoplasmic transport. Understanding how nuclear macromolecular assemblies are organized and coordinate these processes requires high-resolution imaging methods, capable of achieving sub-molecular resolution while preserving native cellular structures. Cryo-electron tomography (cryo-ET) now provides unprecedented three-dimensional views of nuclear architecture in situ, up to sub-nanometer resolution. In this review, we discuss how cryo-ET has reshaped our understanding of nuclear biology including chromatin organization, nuclear pore complex (NPC) architecture and dynamics, and chromatin - lamina interactions. We highlight how these insights have resolved long-standing debates in biology, linked nuclear structure to function, and set the stage for future developments that will bridge molecular and cellular scales.
    Keywords:  Cryo-ET; chromatin; nuclear lamina; nuclear pore complex; nucleus
    DOI:  https://doi.org/10.1080/19491034.2026.2675754
  50. Trends Endocrinol Metab. 2026 Jun 02. pii: S1043-2760(26)00124-4. [Epub ahead of print]
    Inborn errors of redox metabolism: an emerging nosology.
    Philip T Drell, Lea-Sophie Berendes, Julien Park.
      Inborn errors of redox metabolism (IERM) are a growing yet poorly defined group of disorders, limiting understanding and treatment. We propose a dichotomous classification: primary IERM, involving genetic defects in redox pathways, and secondary IERM, where reactive oxygen species-mediated damage arises from other metabolic defects. This framework aims to guide future research.
    Keywords:  ROS; classification; inborn errors of redox metabolism; redox signalling
    DOI:  https://doi.org/10.1016/j.tem.2026.05.005
  51. Cell Metab. 2026 Jun 04. pii: S1550-4131(26)00191-9. [Epub ahead of print]
    Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.
    Drew Adler, Alejandro Martín-Ávila, Evan Cheng, Mauricio M Oliveira, Muxian Zhang, Harrison T Evans, Deliang Yuan, Richard Sam, Nicole D Zhang, Maria Clara Selles, Olivia Mosto, Wendy J Liu, Victor T Wu, Amy X Guo, Shane A Liddelow, Robert C Froemke, Moses V Chao, Wen-Biao Gan, Eric Klann.
      De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here, we demonstrate that microglia, the resident macrophages of the brain, are required for metabolic coupling between endothelial cells, astrocytes, and neurons, which fuels protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, which increases glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit that is required for on-demand protein synthesis in mouse motor cortex.
    Keywords:  astrocyte-neuron-lactate-shuttle; brain immunometabolism; brain metabolism; immunometabolism; mRNA translation; microglia; microglia-endothelial interaction; microglia-neuron interaction; microglial-metabolic coupling; neuroimmunology; protein synthesis
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.006
  52. Nat Commun. 2026 Jun 05.
    AMC-F1 regulates mitochondria-autophagy crosstalk independent of nutrient stress.
    Yuqin Wang, Raksha K Rao, Trung Vu, Ayano Sekine, Zhengmei Mao, Nami McCarty.
      Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling becomes essential during stress adaptation. In an acute liver-injury model, Amcf1 knock-in mice were fully protected, exhibiting elevated OPA1, reduced caspase-3 and PARP activation, and preserved Beclin 1. This functional duality reflects AMC-F1's ability to modulate the mitochondrial integrated stress response (mtISR), enabling adaptive ATF4 signaling while preventing maladaptive responses when stress exceeds a threshold. Autophagy upregulation by AMC-F1 is critical for fine-tuning the ISR and preserving cellular resilience. Together, our findings position AMC-F1 as a stress-responsive gatekeeper and a novel coordinator of mitochondrial-autophagy crosstalk, defining a cellular state primed for stress adaptation.
    DOI:  https://doi.org/10.1038/s41467-026-73841-3
  53. Redox Biol. 2026 Jun 02. pii: S2213-2317(26)00243-0. [Epub ahead of print]95 104245
    Nitric oxide-driven Warburg reprogramming at the NOS2-COX2 axis: An integrative engine of cancer hallmarks.
    Leandro L Coutinho, Erika M Palmieri, Lisa A Ridnour, Robert Y S Cheng, William F Heinz, Stephen K Anderson, Timothy R Billiar, Jenny Chang, Stephen J Lockett, M Cristina Rangel, Douglas D Thomas, Daniel W McVicar, David A Wink.
      Nitric oxide synthase 2 (NOS2) and cyclooxygenase 2 (COX2) lie at a critical intersection between inflammation, metabolism, and oncogenic signaling, where they cooperatively promote and establish a Nitric Oxide (NO)-driven Warburg phenotype in advanced cancers. Early work in macrophages established NOS2-derived NO as both a signaling molecule and metabolic stressor that inhibits oxidative phosphorylation (OXPHOS) by targeting iron-sulfur enzymes and respiratory complexes, forcing neighboring cells to rewire metabolism. In human tumors, sustained NOS2 expression in cancer cells and tumor-associated macrophages (TAMs) enforces a Warburg-like state characterized by high glycolytic flux, glutamine dependence, and enhanced NADPH production, supporting proliferation, biosynthesis, and resistance to oxidative stress. At nitrosative-signaling concentrations (≈100-500 nM), NO breaks carbon entry into the TCA cycle at aconitase and pyruvate dehydrogenase, progressively disables dehydrogenase complexes containing dihydrolipoamide dehydrogenase (DLD) and electron-transport complexes (ETCs), and activates hypoxia-inducible factor 1-alpha (HIF-1), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), extracellular signal-regulated kinase (ERK)/pyruvate kinase M2 (PKM2)/c-Myc signaling axis, nuclear factor erythroid 2-related factor 2 (Nrf2), and transforming growth factor Beta (TGF-β)/SMAD pathways. These biochemical and signaling effects convert transient glycolytic adaptation into chemically enforced dependency, further stabilized by metabolite-driven inhibition of ten-eleven translocation (TET) and Jumonji demethylases, creating an "epigenetic lock" that maintains oncogenic transcriptional programs. NOS2 and COX2 form a reciprocal feed-forward circuit in which NO, prostaglandin E2 (PGE2), interleukin (IL)-6, and IL-8 reinforce one another, driving tumor-promoting inflammation, immunosuppression, angiogenesis, and metastasis while depleting nutrients and acidifying the tumor interstitial fluid. Spatially, NOS2/COX2 niches at the tumor-stroma interface and within immune deserts generate gradients of NO, PGE2, oxygen, and metabolites that partition tumors into microdomains with distinct metabolic states, immune composition, and therapeutic vulnerabilities. Integrating these insights with Hanahan's updated hallmarks of cancer, we propose that NOS2-derived NO functions as a node synchronizing deregulated energetics, inflammation, immune evasion, plasticity, and therapy resistance within the tumor microenvironment (TME). Targeting the NOS2-COX2 axis and its downstream NO-iron-epigenetic circuitry may therefore disrupt multiple hallmarks and reveal combinatorial strategies to exploit NO-induced metabolic liabilities in cancer.
    Keywords:  COX2-PGE(2) signaling; Metabolic reprogramming; Nitric oxide synthase 2 (NOS2); Tumor microenvironment (TME); Warburg effect
    DOI:  https://doi.org/10.1016/j.redox.2026.104245
  54. Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00542-5. [Epub ahead of print]45(6): 117464
    An orally active dual CBP/p300 degrader targets core dependencies of multiple myeloma.
    Praveen Kumar Tiwari, Bomin Ku, Drew A Harrison, Sarah Rizvi, Samuel Ojeda, Jessica Duffy, Leonie Cluse, Jennifer R Devlin, Nenad Bartonicek, Olga Motorna, Ann-Sophie Koglin, Barbara Karakyriakou, Kaitlyn Gagnon, Ramya S Iyer, Regina Egan, Pat Greninger, Lauren Benz, Caroline Greco, Julia Norton, Amruth Kumar, Eric F Zaniewski, Soroush Hajizadeh, Robert Morris, Genna Mullen, Ajinkya S Kawale, Sangwon Min, Sai Reddy Doda, Raghu Vannam, Lee Zou, Wilhelm Haas, Abner Louissaint, Ricky W Johnstone, Christopher J Ott.
      The enhancer lysine acetyltransferases CBP/p300 are compelling targets for multiple myeloma therapy. Chemical inhibition of these multidomain factors, either through the bromodomain or the catalytic acetyltransferase domain, show promising activity in pre-clinical models. Chemical degradation is the only modality that can completely disrupt all functional domains. Our previous attempts to induce CBP/p300 targeted degradation led to a potent tool compound, dCBP-1. Here we comprehensively demonstrate across a large panel of cell lines how CBP/p300 degradation compares to inhibition, with pronounced selective antiproliferative activity toward multiple myeloma. We use chemical linker optimization strategies to create a compound with better pharmacokinetic properties. Through these we define an advanced analog of dCBP-1, dCBP-30, that has improved potency and improved in vivo properties including oral bioavailability. dCBP-30 led to potent and sustained loss of CBP and p300, potent inhibition of several myeloma-specific dependency programs, and elicits tumor reduction in xenograft models.
    Keywords:  CBP; CP: cancer; CP: genomics; KAT; degrader; enhancer; histone acetyltransferase; lysine acetyltransferase; multiple myeloma; near-linkerless PROTAC; p300
    DOI:  https://doi.org/10.1016/j.celrep.2026.117464
  55. Biogerontology. 2026 Jun 04. pii: 109. [Epub ahead of print]27(3):
    Genome integrity, somatic mutation, and the N-of-1 imperative in aging research.
    Diddahally R Govindaraju, Gil Atzmon, Hideki Innan, Reiner A Veitia.
      Aging research has made remarkable progress in describing aging through the genetic architecture of longevity, epigenetic clocks, proteomic signatures, and systems-level analyses. Yet a critical dimension remains underrepresented: the role of genome integrity, germline and somatic mutation accumulation in individual-specific vulnerability, frailty, and multimorbidity across the life course. The need for individual-level thinking has deep roots, from Darwin's emphasis on individual variation in natural selection, to Garrod's chemical individuality, to Lewontin's genotype-phenotype (G-P) map and reaction norms. This tradition in evolutionary biology and medicine treats the individual as a primary unit of both selection and intervention. Here, we argue for an N-of-1 framework in aging research. Population-level epidemiology and genetics of aging based on means and variances can produce a "curse of the average," obscuring the individual genetic variation that impacts relative aging among individuals. The individual-centered N-of-1 framework would integrate longitudinal tracking of mutation accumulation ranging from individual cells, tissues, and organs into comprehensive individual aging profiles aligned with the G-P map concept. The emerging idea of "mosaic aging" further emphasizes that cells, cell types, tissues, organs, and organ systems within an individual reflect heterogeneous aging trajectories. We discuss how somatic mutations, operating through Muller's ratchet-like dynamics in stem cell populations, generate hierarchical vulnerabilities across biological scales. The extreme rarity of centenarians who may maintain superior genome integrity illustrates the relevance of this framework. We suggest that an integrated G-P map approach, grounded in evolutionary genetics, would advance both precision medicine and geroscience.
    Keywords:  Centenarians; Frailty; Genome integrity; Genotype–phenotype (G–P) map; Mosaic aging; Muller’s ratchet; N-of-1 in aging; Precision geroscience; Somatic mutation burden; Units of selection; Wright–Waddington landscape
    DOI:  https://doi.org/10.1007/s10522-026-10451-y
  56. Nat Commun. 2026 May 30.
    Pan-cancer single-cell atlases of mouse and human tumor-associated dendritic cells.
    Aarushi A Caro, Daliya Kancheva, Eva Hadadi, Bram Boeckx, Clint De Nolf, Pauline M R Bardet, Kevin Verstaen, Luqing Li, Lobna Oueslati, Nil Figueras-Duch, Yvon Elkrim, Niels Vandamme, Sofie Deschoemaeker, Arnaud Blomme, Pierre Close, Sophie Janssens, Michele De Palma, Diether Lambrechts, An Coosemans, Damya Laoui.
      Dendritic cells (DCs) are critical inducers of anti-tumor immunity. To achieve a comprehensive mapping of mouse and human DC subsets and states in a cancer context, here we generate pan-cancer mouse and human tumor-associated DC (TADC) scRNA-seq atlases, encompassing 14 mouse tumor models and 10 human cancer types, within which we identify several lineage-defined DC subsets along with maturation/functional states. We show that TADCs acquire an inflammatory profile with tumor progression and that tumor-mediated reprogramming occurs within the DCs from lymph nodes of tumor-bearing mice. Importantly, we demonstrate that TADCs are broadly conserved between mice and humans, although species-specific differences may exist in some subsets and states. Moreover, we present a comprehensive assessment of how different human TADC clusters associate with patient survival outcomes. Overall, we provide an in-depth characterization of the TADC compartment in mouse and human cancers, which can improve our understanding of the tumor microenvironment and contribute to the development of new anti-cancer therapies.
    DOI:  https://doi.org/10.1038/s41467-026-73721-w
  57. Neuron. 2026 Jun 03. pii: S0896-6273(26)00381-8. [Epub ahead of print]
    A hypothalamic circuit for anticipating future changes in energy balance.
    Samuel J Walker, Elijah D Lowenstein, Amelia M Douglass, Callum M P Thomas, Joseph C Madara, Hakan Kucukdereli, Eunice A Barbosa-Meillon, Jenkang Tao, Jon M Resch, Bradford B Lowell.
      AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons since cues that predict future food intake rapidly inhibit AgRP neurons, but is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here, we show in mice that such rapid fasting activation of AgRP neurons does occur. This rapid activation is driven by excitatory input from paraventricular hypothalamic (PVH) neurons expressing Sim2, which are bidirectionally sensitive to predictions of future energy state. Thus, cognitively processed contextual information conveyed by PVHSim2 neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVHSim2 neurons causes persistent hypophagia. This PVHSim2-to-AgRP-neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.
    Keywords:  AGRP neurons; appetite; energy balance; feeding; food intake; homeostasis; hunger; hypothalamus; metabolism; neuroscience
    DOI:  https://doi.org/10.1016/j.neuron.2026.05.010
  58. Cancer Discov. 2026 Jun 01. 16(6): 1050-1054
    The Rising Burden of Early-Onset Cancer: Challenges and Opportunities.
    Andrea Cercek, Daniel J Zabransky, Gianluca Mauri, Elizabeth M Jaffee, Alberto Bardelli, Timothy R Rebbeck.
      Early-onset cancers are increasing globally, yet traditional research frameworks have yet to inform the epidemiologic and biological underpinnings of this trend. This perspective summarizes the current state of knowledge and prospects for a research agenda spanning epidemiology, exposure science, mechanistic studies, and federated infrastructures to address this emerging challenge.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0328
  59. Cell Death Differ. 2026 Jun 03.
    Cell death-induced release of the pro-aging protein acyl CoA binding protein (ACBP) into the circulation.
    Yan Rong, Flavia Lambertucci, Yaning Yang, Vincent Carbonnier, Hui Chen, Yanbing Dong, Silvia Mingoia, Sijing Li, Omar Motiño, Léa Montégut, Adrien Joseph, Lucille Ferret, Ester Gloria Saavedra Díaz, Stephane Isnard, Jean-Pierre Routy, Mojgan Djavaheri-Mergny, Maria Castedo, Alexander Fuerlinger, Mahmoud Abdellatif, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer.
      Acyl-CoA-binding protein (ACBP, encoded by diazepam binding inhibitor, DBI) is an abundant intracellular regulator of lipid metabolism that also circulates systemically, yet the mechanisms governing its release and its relationship to organ injury remain unresolved. Herein, we combine human multi-omics, mechanistic mouse models and controlled cell death assays to identify cell death-driven liberation of intracellular ACBP/DBI as a unifying mechanism underlying its elevation in disease. In a cohort of 1198 hospitalized adults, among whom 75% were acutely infected by SARS-CoV-2, plasma ACBP/DBI tightly correlated with inflammatory markers and biochemical signatures of cardiac, hepatic, renal, metabolic and hematologic dysfunction. SomaScan proteomics further revealed that ACBP/DBI co-varies with organ-enriched proteins, particularly those originating from skeletal muscle and pancreas, implicating tissue injury as a major determinant of its circulating abundance. Multiple forms of acute organ damage in mice, including hepatic or renal ischemia-reperfusion, bile duct ligation, pancreatitis and rhabdomyolysis, triggered rapid and robust increases in plasma ACBP/DBI. Using defined in vitro paradigms, we demonstrate that apoptosis, ferroptosis and necroptosis each cause loss of intracellular ACBP/DBI and its release upon plasma membrane permeabilization, independent of the upstream lethal pathway. These mechanistic insights translated in vivo: hepatocyte apoptosis, ferroptosis and necroptosis each elevated circulating ACBP/DBI in a manner attenuated by pathway-specific inhibitors. Finally, meta-analysis of >100,000 individuals across diverse populations revealed that elevated plasma ACBP/DBI consistently associates with systemic and organ-specific disease and predicts future morbidity. Together, our findings identify cell death-driven ACBP/DBI release as a conserved mechanism linking organ injury to increased plasma ACBP/DBI, positioning this molecule as an integrative biomarker of tissue damage across species, organs, and cell death modalities.
    DOI:  https://doi.org/10.1038/s41418-026-01775-w
  60. Nature. 2026 Jun 03.
    Commensal-derived acetylcholine enhances mucosal immune education.
    Deguang Song, Brianna Duncan-Lowey, Varnica Khetrapal, Randy Hamchand, Tong Deng, Hailey Brown, Anchi Wu, Anjelica L Martin, Kaylyn M Bauer, Yanyu Zhao, Mytien T Nguyen, Nicole D Sonnert, Shana R Leopold, Qihao Wu, Jason M Crawford, Noah W Palm.
      The microbiota produces thousands of potentially bioactive small molecules1-3. High-throughput bioactivity screens of in vitro commensal cultures have exposed microbiota metabolites that shape host physiology by activating diverse G-protein-coupled receptors (GPCRs)4-7. However, owing to technical limitations, the GPCRome-wide bioactivities of in vivo metabolomes, which result from complex diet-microorganism-host interactions, remain unclear. Here we used a multiplexed GPCR screening technology to assess GPCRome-wide bioactivities of 100 commensal strains grown in vivo in monoassociated germ-free mice or in vitro in bacterial culture medium. In vivo and in vitro commensal metabolomes exhibited distinct GPCR activation patterns due to (1) host-mediated metabolite degradation; (2) in vivo microbial metabolic reprogramming; and (3) biotransformation of dietary substrates. Notably, we found that multiple commensal strains produced acetylcholine (ACh) in vivo through the conversion of dietary choline, including select Bifidobacterium strains that dominate the microbiome in early life and a probiotic Pediococcus strain. Mechanistically, we identified and characterized the bacterial enzymes that mediate this biotransformation in Bifidobacterium breve and Pediococcus pentosaceus, and generated an isogenic mutant B. breve strain lacking ACh production. Mice colonized with ACh-producing B. breve exhibited enhanced intestinal immunoglobulin A (IgA) production, altered microbiota composition and increased resistance to enteric infection. These findings underscore the profound impacts of the in vivo environment on microbiota metabolism and reveal a diet-microbiome-host axis that strengthens mucosal immune defences and reinforces host-microbiota mutualism.
    DOI:  https://doi.org/10.1038/s41586-026-10592-7
  61. ArXiv. 2026 May 21. pii: arXiv:2601.14577v2. [Epub ahead of print]
    FBApro: A fast, simple linear transformation for diverse metabolic modeling tasks.
    Ariel Bruner, Mona Singh.
      Constraint-based metabolic modeling is the predominant framework for simulating cellular metabolism. The central assumption of these models is that metabolism operates at a steady state, meaning that the production and consumption rates of each metabolite are balanced. This assumption imposes linear constraints on the fluxes of biochemical reactions. Flux Balance Analysis (FBA), a fundamental method in the field, is formulated as an optimization problem maximizing a cellular objective (e.g., growth) over the resulting linear subspace of steady state fluxes. Many other methods in the field are expressed either as a modification to FBA, or use FBA as a black box within an algorithm. Here, we propose a general alternative to optimization called FBApro. For any given vector of reference fluxes, FBApro finds the closest flux vector within the steady-state subspace, and accounts for both partially given reference fluxes and exact constraints on reactions. While FBApro is the solution to a quadratic program, we show that it can be implemented as a single linear operation using orthogonal projections to corresponding affine spaces and sets of linear equations. The overall approach is computationally efficient, does not require a cellular objective, and is easy to implement. We formally derive the closed-form expressions for FBApro and simpler variants, and validate it on both synthetic and real cancer cell line data.
  62. Cell Death Dis. 2026 Jun 05.
    Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation.
    Daniel Lagos, Pamela R de Santiago, Nicolás Pérez-Bravo, Benjamín Cartes-Saavedra, Josefa Vial-Brizzi, Diego Troncoso-Chandía, Oliver Podmanicky, Rita Horvath, Verónica Eisner.
      Mitochondria undergo fusion and fission. While DRP1 regulates fission, fusion is controlled by OPA1, MFN1, and MFN2. The balance between these processes and the crosstalk between machineries remains poorly understood. MFN2 mutations cause Charcot-Marie-Tooth disease type 2 A (CMT2A), affecting mitochondrial fusion and morphology. However, their role in fission is unclear. Using skin fibroblasts from CMT2A patients (L248H and M376V MFN2 mutations) and wild-type mouse embryonic fibroblasts expressing these variants, we studied how MFN2 mutations impact mitochondrial dynamics beyond fusion. We analyzed mitochondrial morphology and dynamics by live-cell confocal microscopy and tested fusion/fission protein levels, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits. MFN2 mutations impaired mitochondrial fusion and displayed distinct effects on fission and cellular metabolism. L248H-expressing cells showed hyper-elongated mitochondria, impaired fission, and increased OCR, while M376V cells exhibited fragmentation, enhanced fission, and elevated ECAR. These effects correlated with differential Drp1 phosphorylation. Our findings demonstrate that MFN2 mutants differentially influence fission and metabolism, highlighting the need to consider these effects in therapies aimed at modulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41419-026-08838-3
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