bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–07–05
27 papers selected by
Marc Segarra Mondejar, AINA
  1. Post-translational modifications as hubs of amino acid metabolism in cancer: From oncogenic signaling to therapeutic targeting.
  2. Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
  3. Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
  4. BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.
  5. Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
  6. Dissecting autonomous enzymatic variability in single cells.
  7. Mitochondrial quality control in human ageing and longevity.
  8. Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.
  9. Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
  10. Immune cell landscape and metabolic gene activity distinguish triple negative from luminal A-like ductal carcinoma in situ.
  11. A targetable FTO/SLC7A11/CBS/CTH axis controls cysteine metabolism, growth and survival in NSCLC.
  12. Targeting amino acid metabolism in hepatocellular carcinoma.
  13. Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.
  14. Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.
  15. Metabolic profiling of human melanoma cell lines with high and low metastatic capacity by 1H-NMR spectroscopy.
  16. Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
  17. A Super-Resolution Approach for Astrocyte-Specific Molecular Imaging Reveals the Nanoscale Distribution of Monoacylglycerol Lipase, the Metabolic Node Between Endocannabinoid and Prostaglandin Signaling.
  18. Sex-specific mitochondrial dysregulation and metformin response in Wilson disease.
  19. Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts.
  20. COPII meets autophagy at the ER membrane.
  21. Beyond fat storage: neuronal lipid droplets regulate whole-body metabolism.
  22. A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.
  23. Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
  24. RAEM: random-access electron microscopy for revisitable 3D imaging.
  25. Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism.
  26. Key molecular mechanisms of mitochondrial metabolic pathways in specific cell subpopulations of pancreatic cancer based on scRNA-seq and bulk RNA-seq.
  27. Complete enzyme clustering enhances coenzyme Q biosynthesis via substrate channeling.
  1. Biochim Biophys Acta Rev Cancer. 2026 Jul 01. pii: S0304-419X(26)00125-3. [Epub ahead of print]1881(4): 189653
    Post-translational modifications as hubs of amino acid metabolism in cancer: From oncogenic signaling to therapeutic targeting.
    Nuo Xu, Jiayu Shao, Lihan Jiang, Hui Zhao, Wenjie Zheng.
      Metabolic reprogramming is a hallmark of cancer, characterized by significant alterations in amino acid metabolism to support rapid proliferation and survival. Post-translational modifications (PTMs) have become key regulatory centers that convert oncogenic signals into metabolic changes. This review systematically examines the interplay between canonical PTMs, including phosphorylation, ubiquitination, acetylation, and methylation, and recently recognized metabolite-sensitive PTMs, including O-GlcNAcylation, lactylation, succinylation, crotonylation, and β-hydroxybutyrylation, in regulating key enzymes and transporters involved in amino acid metabolism. We describe how oncogenic pathways such as PI3K/AKT/mTOR and MYC induce metabolic changes through PTMs, and how amino acid-derived metabolites, in turn, feedback to influence signaling through "metabolite/PTM/signal" loops. Additionally, we emphasize how the PTM-amino acid metabolism axis influences the tumor microenvironment, particularly regarding immune suppression and the remodeling of the extracellular matrix. Finally, we review current clinical and preclinical therapeutic strategies that target PTM-modifying enzymes and PTM-dependent metabolic pathways. Although there are technical and biological challenges, focusing on this axis offers a promising avenue for developing personalized cancer treatments.
    Keywords:  Amino acid metabolism; Immune escape; Metabolic reprogramming; Post-translational modifications (PTMs); Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189653
  2. Sci Adv. 2026 Jul 03. 12(27): eaee5417
    Loss of heterozygosity exposes germline mutations in complex I and drives Warburg metabolism in oncocytic carcinoma of the thyroid.
    Celia de la Calle Arregui, Anderson R Frank, Kelvin Mun, Jiwoong Kim, Kuntal Majmudar, Justin A Bishop, Cheryl Lewis, Yang Xie, David G McFadden.
      Oncocytic (Hürthle cell) carcinoma of the thyroid (OCT) is characterized by widespread loss of heterozygosity (LOH), mitochondrial accumulation, and recurrent mitochondrial DNA mutations leading to impairment of complex I. Here, we establish and characterize a novel OCT cell line, UT946, which displays severe mitochondrial electron transport chain dysfunction and a Warburg metabolic phenotype. Using a series of cytoplasmic hybrids, we establish that the complex I defect in UT946 stems from a nuclear-encoded loss-of-function mutation in the complex I subunit NDUFS1. To our surprise, the mutation in NDUFS1 was inherited as a recessive germline allele that underwent LOH in the tumor to expose functional loss of complex I. A reanalysis of 91 OCT tumor genomes revealed that LOH-driven exposure of recessive germline mutations in complex I subunits was a recurrent mechanism underlying complex I inactivation in OCT. These findings unveil a previously unidentified germline-driven mechanism of complex I loss and metabolic reprogramming in cancer and provide further evidence of the selective pressure for complex I impairment in OCT.
    DOI:  https://doi.org/10.1126/sciadv.aee5417
  3. Cell Rep. 2026 Jul 02. pii: S2211-1247(26)00707-2. [Epub ahead of print]45(7): 117629
    Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
    Johanna M Anttila, Mariel Savelius, Linda Id, Daniel Nicorici, Juhi Somani, Antti O Hiltunen, Pauliina M Munne, Aino Peura, Martina Peltonen, July Aung, Ryan Awadhpersad, Ellisiv Nyhamar, Bina Prajapati, Hanna Ala-Hongisto, Prson Gautam, Mika J Välimäki, Topi A Tervonen, Karina Šapovalovaitė, Raman Devarajan, María Victoria Ruiz Pérez, Minna Mutka, Panu Kovanen, Laura Niinikoski, Tuomo Meretoja, Johanna Mattson, Päivi Heikkilä, Krister Wennerberg, Marie Arsenian-Henriksson, Jukka Westermarck, Tero Aittokallio, Andrei Goga, Christopher B Jackson, Anni I Nieminen, Juha Klefström.
      In many cancers, stably elevated MYC levels drive sustained activation of anabolic programs and the cell cycle, creating opportunities for the synthetic-lethal targeting of MYChigh tumors. Enhanced mitochondrial respiration is a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+ through complex I-mediated oxidation of NADH, supporting the anabolic demand of MYC-driven cells. Metabolic carbon tracing reveals that MYC shifts the TCA cycle carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors promotes MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChigh tumors, combined inhibition of complex I and glutaminolysis produces persistent suppression of tumor growth. Altogether, the elevated respiration of MYChigh cells supports a glutamine carbon-enriched TCA cycle that meets anabolic demand, rendering MYChigh tumors selectively vulnerable to mitochondrial respiration and glutaminolysis inhibitors.
    Keywords:  CP: cancer; CP: metabolism; MYC; TCA cycle; breast cancer; cancer; complex I; glutamine; metabolism; mitochondria; mitochondrial respiration
    DOI:  https://doi.org/10.1016/j.celrep.2026.117629
  4. J Biochem. 2026 Jun 30. pii: mvag048. [Epub ahead of print]
    BNIP3/NIX-dependent mitophagy: molecular mechanisms and physiological roles.
    Tamara Ginevskaia, Takayuki Mito, Keiichi Inoue, Tomotake Kanki.
      Mitochondria are essential for cellular metabolism and homeostasis, and their quality and quantity must therefore be tightly controlled. Mitophagy, a selective form of autophagy targeting mitochondria, contributes to this control by eliminating damaged or superfluous mitochondria. Among the known mitophagy pathways, BNIP3/NIX-dependent mitophagy has emerged as a key mechanism, particularly under hypoxic and metabolic stress. Recent studies have provided important insights into how BNIP3 and NIX are transcriptionally induced, post-translationally regulated, and functionally coupled to the core autophagy machinery. These studies have also clarified their roles in isolation membrane tethering, membrane elongation, and mitophagosome formation. Beyond its molecular basis, accumulating evidence indicates that BNIP3/NIX-dependent mitophagy contributes to mitochondrial homeostasis, redox balance, and cellular stress adaptation. This review summarizes recent progress in understanding the molecular mechanisms and physiological significance of BNIP3/NIX-dependent mitophagy.
    DOI:  https://doi.org/10.1093/jb/mvag048
  5. Front Immunol. 2026 ;17 1737175
    Glucose metabolic reprogramming: mechanisms and therapeutic implications in neuroinflammation.
    Lan Zhang, Xinyue Yang, Xiaolin Ai.
      Microglia play dual and context-dependent roles in the central nervous system, contributing both to the maintenance of brain homeostasis and the propagation of neuroinflammatory responses. Under pathological conditions, microglia undergo profound glycolytic reprogramming, characterized by a shift from oxidative phosphorylation to enhanced aerobic glycolysis. This review focuses on the glucose-glycolysis-lactate metabolic axis and its pivotal role in microglial immunometabolism. We elucidated how key glycolytic enzymes (e.g., HK2, PKM2) and metabolites (e.g., lactate, pyruvate, ATP) regulate microglial function through both metabolic and non-metabolic mechanisms. Furthermore, therapeutic strategies that target this glycolytic shift to alleviate neuroinflammation were discussed. A deeper understanding of microglial glycolytic reprogramming may provide critical insights for developing novel therapies for neurodegenerative diseases.
    Keywords:  glycolysis; metabolic reprogramming; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1737175
  6. Nat Commun. 2026 Jul 02. pii: 5788. [Epub ahead of print]17(1):
    Dissecting autonomous enzymatic variability in single cells.
    Christian Gnann, Alina Sigaeva, Trang Le, Anthony J Cesnik, Sanem Sariyar, Diana Mahdessian, Rutger Schutten, Preethi Raghavan, Manuel D Leonetti, Cecilia Lindskog, Mathias Uhlén, Ulrika Axelsson, Emma Lundberg.
      Metabolic enzymes perform life-sustaining functions in various cellular compartments. Anecdotally, metabolic activity is observed to vary between genetically identical cells, which impacts drug resistance, differentiation, and immune cell activation. However, no large-scale resource systematically reporting metabolic cellular heterogeneity exists. Here, we leverage imaging-based single-cell spatial proteomics to reveal the extent of non-genetic variability of the human enzymatic proteome, as a proxy for metabolic states. Nearly two fifths of enzymes exhibit cell-to-cell variable expression, and half localize to multiple cellular compartments. Metabolic heterogeneity arises largely autonomously of cell cycling, and individual cells reestablish these myriad metabolic phenotypes over several cell divisions. We reveal through multiplexed imaging that metabolic states are continuous and that the correlation between metabolic pathways is metabolic state dependent. These results establish cell-to-cell enzymatic heterogeneity as an organizing principle of cell biology that may rewire our understanding of drug resistance, treatment design, and other aspects of medicine.
    DOI:  https://doi.org/10.1038/s41467-026-74172-z
  7. Nat Metab. 2026 Jun 29.
    Mitochondrial quality control in human ageing and longevity.
    Anna Picca, Luigi Ferrucci.
      Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.
    DOI:  https://doi.org/10.1038/s42255-026-01563-3
  8. iScience. 2026 Jul 17. 29(7): 116449
    Mitophagy interacts with mitochondrial dynamics and biogenesis, acting as a double-edged sword in digestive cancer.
    Enming Qiu, Guoqing Lv, Jianing Hou, Zhou Li, Gang Wang.
      Mitophagy is a selective autophagy that degrades dysfunctional mitochondria to maintain cellular homeostasis. Mitophagy is functionally coordinated with and regulated by mitochondrial biogenesis and mitochondrial dynamics, which include mitochondrial fusion, mitochondrial fission, and mitochondrial trafficking. Furthermore, researches have demonstrated that mitophagy plays a critical role in the occurrence and development of digestive cancer. Nonetheless, the mechanism of how mitophagy modulates digestive cancer and the mechanism of how mitochondrial biogenesis and dynamics influence mitophagy warrant more investigations. This review summarizes the current understanding of the regulatory mechanism of mitophagy and outlines recent advances from investigations that explore how mitochondrial biogenesis and dynamics coordinate with mitophagy. Additionally, this review provides a comprehensive view about how mitophagy could regulate the occurrence and development of digestive cancer. A deeper understanding about the role of mitophagy in regulation of digestive cancer benefits the development of more efficient therapeutic strategies for patients.
    Keywords:  Biological sciences
    DOI:  https://doi.org/10.1016/j.isci.2026.116449
  9. J Gen Physiol. 2026 Sep 07. pii: e202613979. [Epub ahead of print]158(5):
    Label-free real-time imaging of mitochondrial matrix volume changes and permeability transition in living cells.
    Yaw Akosah, Ioannis Azoidis, Dane D Jensen, Paolo Bernardi, Evgeny V Pavlov.
      Along with the membrane potential and respiration, mitochondrial matrix volume is a critical parameter that determines mitochondrial function. Mitochondria undergo constant changes in matrix volume and crista dynamics, and in processes that are critical for normal metabolic rates and pathophysiological responses. Changes in matrix volume cannot be easily measured by conventional fluorescence imaging techniques due to the size of the suborganellar structures, which are below resolution. This challenge was successfully resolved in studies of isolated mitochondria with the use of scattered light. Here, we use dark-field imaging, which relies on scattered light contrast, to measure matrix volume dynamics in living cells. We demonstrate that mitochondrial volume changes can be easily detected as changes in intensity of the scattered light following matrix volume modulation with K+ ionophores or by onset of the permeability transition. Specifically, we found that stimulation of K+ influx leads to an increase in mitochondrial matrix volume, while stimulation of K+ efflux leads to matrix shrinkage, and that activation of the permeability transition leads to high-amplitude mitochondrial swelling in wild-type but not in cells lacking subunit c of ATP synthase. These results directly demonstrate the dynamic nature of mitochondrial matrix volume and its link to physiological and pathological ion transport.
    DOI:  https://doi.org/10.1085/jgp.202613979
  10. Sci Rep. 2026 Jul 01.
    Immune cell landscape and metabolic gene activity distinguish triple negative from luminal A-like ductal carcinoma in situ.
    Jens Henrik Norum, Hossein Schandiz, Torill Sauer, Jürgen Geisler, Lorant Farkas, Neda Hekmati, Carina Strell, Helga Bergholtz, Therese Sørlie.
      Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer, and up to 50% of the lesions remain non-invasive even if untreated. Both tumor and microenvironmental features are associated with disease progression, but the cellular interactions are poorly understood. We investigated DCIS of the clinical breast cancer subtypes; Triple Negative (TN) and Luminal A (LumA)-like, presumed to represent lesions with the most contrasting invasive potential, using spatial transcriptomic and multiplex immunofluorescence analyses. In the intraductal cancer cells, we found significant differences between the two subtypes in expression of genes related to energy metabolism and secreted proteins. In the periductal space, we found differences in the absolute density of CD4+ T cells, CD8+ T cells, and B cells between TN and LumA-like DCIS. Spatial cellular neighborhood analyses revealed an inverse relationship between CD4+ T cells and B cells. These data suggest specific biological properties of TN and LumA-like DCIS that might underpin differences in progression potential.
    DOI:  https://doi.org/10.1038/s41598-026-60008-9
  11. Sci Adv. 2026 Jul 03. 12(27): eaed6463
    A targetable FTO/SLC7A11/CBS/CTH axis controls cysteine metabolism, growth and survival in NSCLC.
    Nishanth Kuganesan, Margaret Pan, Haowen Jiang, Stavros Melemenidis, Jiangbin Ye, Sara Richter, Maximillian Diehn, Kerriann M Casey, Edward E Graves, Quynh Thu Le, Erinn B Rankin.
      Cysteine metabolism plays a crucial role in the growth and survival of non-small cell lung cancer (NSCLC), although the mechanisms governing its regulation are not fully understood. Here, we demonstrate that the RNA demethylase FTO is a therapeutic target that drives cysteine metabolism in NSCLC cells. Genetic or pharmacologic inhibition of FTO reduced cystine uptake and transsulfuration activity, leading to depleted intracellular glutathione, elevated reactive oxygen species (ROS), and ROS-mediated DNA damage and cell death. Mechanistically, FTO promotes the expression of the cystine uptake transporter SLC7A11 and the transsulfuration enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH) to promote NSCLC cystine uptake, transsulfuration activity, and survival. FTO inhibition increased lipid peroxidation, reduced tumor growth, and resulted in additive therapeutic benefit in combination with radiotherapy in multiple NSCLC xenograft models. Collectively, our study reveals a role for FTO in cysteine metabolism and highlights the therapeutic potential of targeting cancer epitranscriptomics and cysteine metabolism for NSCLC therapy.
    DOI:  https://doi.org/10.1126/sciadv.aed6463
  12. Trends Mol Med. 2026 Jul 02. pii: S1471-4914(26)00138-3. [Epub ahead of print]
    Targeting amino acid metabolism in hepatocellular carcinoma.
    Yibing Wu, Carmen Chak-Lui Wong.
      Hepatocellular carcinoma (HCC) remains lethal due to its high refractoriness to standard treatment, which is contributed to by factors including adaptive metabolic reprogramming of HCC cells and pre-existing liver diseases that compromise liver function. Abnormal tumor vasculature creates a nutrient-deprived microenvironment, intensifying competition between HCC cells and immune cells and impairing antitumor immunity. Among the complex metabolic network, amino acid (AA) metabolism emerges as a critical player and an attractive therapeutic target. This review first examines how dysregulated AA metabolism supports HCC hallmarks, including metabolic reprogramming and immune evasion. We discuss the translational potential of therapies targeting AA metabolism in HCC, ranging from pharmacologic inhibition to dietary AA intervention, which can be further integrated with existing HCC treatments to improve clinical outcomes.
    Keywords:  amino acid metabolism; amino acid-targeted therapy; hepatocellular carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molmed.2026.06.002
  13. bioRxiv. 2026 Jun 17. pii: 2026.06.14.732179. [Epub ahead of print]
    Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.
    Esraa Gabal, Thi Kim Oanh Nguyen, Tetiana Kovalenko, Huanyao Gao, Noa Rappaport, Cory Funk, Priyanka Baloni, Eugenia Trushina.
      Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.
    DOI:  https://doi.org/10.64898/2026.06.14.732179
  14. FASEB J. 2026 Jul 15. 40(13): e72089
    Raptor and Drp1 Function Synthetically to Control Hypoxic Death and the Mitochondrial Network in Caenorhabditis elegans.
    Julien Goldstick, Diego Compte, Chun-Ling Sun, Alison E Ritter, C Michael Crowder.
      Hypoxia induces mitochondrial fragmentation. Whether this fragmentation promotes or prevents cell death and whether the mitochondrial dynamics machinery plays a role are unresolved. To address these questions, we measured the effect of hypoxia on mitochondrial morphology in a Caenorhabditis elegans Raptor mutant resistant to hypoxic death and in mutants with disrupted mitochondrial fission and fusion. The Raptor loss-of-function mutant reduced hypoxia-induced mitochondrial fragmentation and death. However, forcing mitochondrial fragmentation prior to hypoxia by combining the Raptor mutation with a loss-of-function mutation in mitofusin did not increase hypoxic death. A loss-of-function mutation in drp-1, which is required for mitochondrial fission, did not block hypoxia-induced mitochondrial fragmentation nor enhance Raptor hypoxia resistance; rather, drp-1(lf) was surprisingly mildly hypoxia resistant and partially suppressed the high-level hypoxia resistance of the Raptor mutant. Likewise, loss of DRP-1 function interacted synthetically with the Raptor(lf) mutant to produce tangled mitochondria, demonstrating a role of Raptor in maintenance of the mitochondrial network. Vitamin B12 supplementation and feeding with a bacterial strain replete in vitamin B12 mitigated hypoxia-induced mitochondrial fragmentation. Our results demonstrate that fragmented mitochondria do not necessarily promote hypoxic cell death, and hypoxia-induced mitochondrial fragmentation is mechanistically distinct from physiological mitochondrial fission.
    DOI:  https://doi.org/10.1096/fj.202601561R
  15. PLoS One. 2026 ;21(7): e0352639
    Metabolic profiling of human melanoma cell lines with high and low metastatic capacity by 1H-NMR spectroscopy.
    Nima Rezvani Kakhki, Zita Hegedűs, József Tóvári, Arash Mirzahosseini, Béla Noszál, Márta Kraszni.
       BACKGROUND: Melanoma is one of the most aggressive forms of skin cancer due to its high metastatic potential and mortality rate. Although understanding of metabolic reprogramming in melanoma has advanced, the connection between metabolic alterations and metastatic capacity remains incomplete.
    AIM: This study aimed to characterize the metabolic profiles of human melanoma cell lines with high (HT168-M1) and low (WM983B) metastatic potential, and to compare them with each other and also with the metabolic profile of normal human fibroblasts (MRC-5), in order to identify key metabolites and metabolic pathways associated with metastatic behavior.
    METHODS: Non-targeted metabolomic profiling using ¹H-NMR spectroscopy was applied to hydrophilic extracts of the three cell lines. Multivariate statistical analyses (PCA and PLS-DA) were used to identify discriminating metabolites, and pathway analysis was performed to determine altered metabolic networks.
    RESULTS: Several metabolic pathways were significantly altered in melanoma cells compared to fibroblasts, including starch and sucrose metabolism, alanine, aspartate and glutamate metabolism, and glutathione metabolism. Metabolites showing more than two-fold differences included elevated UDP-glucose, ATP, glycerophosphocholine, GTP, creatine and glutathione in the melanoma cells, and reduced glucose, glutamine and 1-methylnicotinamide in fibroblasts. Comparison of the metabolites of melanoma cell lines with differing metastatic potential revealed changes in taurine and hypotaurine, β-alanine-, glutathione-, and amino acid metabolism. Metabolites showing the largest concentration changes were UDP-glucose, glutathione, NAD+, alanine and β-alanine.
    CONCLUSION: Metabolomic profiling revealed distinct metabolic reprogramming between melanoma and normal fibroblasts, characterized by enhanced glycolysis and glutathione-dependent antioxidant defense. Highly metastatic melanoma cells demonstrated stronger redox adaptation and altered amino acid utilization, with elevated glutathione and glutamate and reduced NAD⁺ and pyruvate, indicating a metabolic shift toward oxidative stress resistance.
    DOI:  https://doi.org/10.1371/journal.pone.0352639
  16. Nat Commun. 2026 Jul 01.
    Nuclear-specific reductive carboxylation of alpha-ketoglutarate fuels histone acetylation to induce chromatin accessibility and gene activation.
    Abhisha Sawant Dessai, Nadya A Elhalawany, Tao Dai, Justine J Jacobi, Christian Prechtl, Alphonse N Dimeck, Sierra R Morton, Mark D Long, Prashant K Singh, Nagireddy Putluri, Mariana Lopes, Song Liu, Dominic J Smiraglia, Katerina V Gurova, Peder J Lund, Leah A Gates, Sung Yun Jung, Subhamoy Dasgupta.
      Mitochondria remain at the core of cell metabolism, whereas the nucleus integrates cellular and environmental signals to activate genes. However, the mechanisms that directly link cellular metabolism to gene regulation are not well understood. Here we show, a metabolic pathway in the nucleus controls acetylation of histones by nuclear localization of mitochondrial enzymes aconitase (ACO2) and isocitrate dehydrogenase (IDH2). Metabolic tracing studies show that IDH2 and ACO2 catalyze reductive carboxylation of α-ketoglutarate to rapidly synthesize citrate to increase nuclear acetyl-CoA pool. Genetic and proteomic analyses reveal nuclear IDH2 and ACO2 form a complex with KAT2A/GCN5 for acetylation of histones to increase chromatin accessibility and activation of proliferative genes. Robust nuclear expressions of ACO2 and IDH2 drive aggressive tumors indicating the tumorigenic potential of IDH2-ACO2-KAT2A axis. Altogether, our work reveals a paradigm coupling a nuclear metabolic pathway with histone acetylation to control of gene expression that accentuates hyperproliferative phenotype in tumors.
    DOI:  https://doi.org/10.1038/s41467-026-74786-3
  17. Glia. 2026 Sep;74(9): e70186
    A Super-Resolution Approach for Astrocyte-Specific Molecular Imaging Reveals the Nanoscale Distribution of Monoacylglycerol Lipase, the Metabolic Node Between Endocannabinoid and Prostaglandin Signaling.
    Miklós Zöldi, István Katona.
      Astrocytes play essential roles in brain function and disorders. Yet, compared to neurons, our knowledge of the physiological and pathological signaling mechanisms in astrocytes remains limited. As a major challenge, the ultrathin (~10-100 nm) processes of astrocytes render high-throughput quantitative molecular imaging within well-defined cellular contexts very difficult. Here, we introduce a single-molecule localization microscopy-based methodology that achieves unprecedented resolution of the intricate astrocytic arbor in intact brain circuits. Postnatal tagging of the plasma membrane by electroporation in mice resulted in selective and sparse labeling of hippocampal astrocytes and enabled the complete visualization of individual astrocytes with nanoscale precision by using STochastic Optical Reconstruction Microscopy (STORM). We also developed high-yield and easy-to-implement approaches to segment, measure, analyze, and visualize nanoscale molecular information within astrocytic compartments. As a proof-of-concept, we could readily differentiate between synaptic and astrocytic proteins by using dual-color STORM super-resolution imaging. Moreover, we identified cell-type-specific differences in the distribution of monoacylglycerol lipase (MAGL), an enzyme regulating synaptic plasticity in neurons and coupling endocannabinoid signaling to prostaglandin signaling in astrocytes. Our findings demonstrate the feasibility of nanoscale molecular measurements within ultrathin astrocytic processes. Moreover, the results provide insights into the synapse-independent nanoscale arrangement of the astrocytic MAGL pool that controls neuroinflammatory processes.
    Keywords:  MAGL; STORM; astrocyte; endocannabinoid; mgll; prostaglandin; super‐resolution imaging
    DOI:  https://doi.org/10.1002/glia.70186
  18. Sci Rep. 2026 Jun 27.
    Sex-specific mitochondrial dysregulation and metformin response in Wilson disease.
    Valentina Medici, Noreene Shibata, Aldo Vorkapich, Jennifer Dang, Rida Mullah, Atena Tork, Isabel F Snodgrass, Dohee Kim, John W Newman, Zoe Lee Greenblatt, Huy-An Tran, Ieleen Li, Keren Sierra, Qixuan Gong, Cecilia Giulivi.
      Wilson disease (WD) is an inherited disorder of copper metabolism characterized by hepatic copper accumulation, mitochondrial injury, and systemic metabolic dysfunction. Metformin is a widely used antihyperglycemic agent with known effects on mitochondrial metabolism and cellular redox state. We tested whether metformin modifies hepatic mitochondrial abnormalities in a mouse model of WD, stratified by sex. Adult male and female Atp7b-/- mice were treated with metformin in drinking water (500 mg/kg/day) or water alone for 2 weeks. Liver mitochondria were evaluated by transmission electron microscopy and quantitative morphometry, respiratory chain enzyme activities, reactive oxygen species production, hepatic and mitochondrial copper and iron content, and targeted glucocorticoid and bile acid profiling. At baseline, female Atp7b-/- mice exhibited greater mitochondrial ultrastructural injury, smaller mitochondrial size, and higher hepatic and mitochondrial copper and iron levels compared with males. Metformin exposure was higher in females and was associated with marked changes in mitochondrial morphology, including increased size and more regularized structural features, along with alterations in respiratory enzyme activities, reduced oxidative stress, and changes in glucocorticoid and bile acid profiles. In contrast, males showed more limited structural and biochemical changes following treatment. These findings identify sex as an important determinant of mitochondrial phenotype and response to metformin in WD and support further investigation of sex-informed therapeutic strategies.
    Keywords:  Chelating agents; Copper toxicosis; Glucocorticoids; Lipidomics; Liver; Mitochondrial ultrastructure; Oxidative stress
    DOI:  https://doi.org/10.1038/s41598-026-58720-7
  19. Nat Commun. 2026 Jul 02. pii: 5784. [Epub ahead of print]17(1):
    Comparative analysis of Cdc48-dependent proteolysis at the ER, mitochondria and chloroplasts.
    Anne Sophie Lau, Sreedhar Nellaepalli, R Paul Jarvis.
      The ubiquitin-proteasome system (UPS) is the preeminent proteolytic system in eukaryotes. While soluble nucleocytosolic proteins are readily accessed by the UPS, organelle-localised proteins present major, membrane-related accessibility challenges. Cells overcome this problem by employing the conserved AAA+ ATPase Cdc48 to extract organellar proteins to the cytosol, thereby enabling proteasomal degradation. Major Cdc48-dependent proteolytic systems exist at the endoplasmic reticulum, mitochondria and chloroplasts, and are uniquely adapted to deliver protein homeostasis within the respective organelles. We provide a focused comparison of these systems, analysing similarities and differences between them. Better understanding of underlying principles has important implications spanning human health and agriculture.
    DOI:  https://doi.org/10.1038/s41467-026-74728-z
  20. Nat Rev Mol Cell Biol. 2026 Jun 30.
    COPII meets autophagy at the ER membrane.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-026-00997-7
  21. Trends Endocrinol Metab. 2026 Jul 02. pii: S1043-2760(26)00148-7. [Epub ahead of print]
    Beyond fat storage: neuronal lipid droplets regulate whole-body metabolism.
    Diana U Rodrigues, Julie Jacquemyn, Maria S Ioannou.
      Lipid droplets are dynamic organelles long thought to form in neurons only during disease. However, a study by Manceau et al. discovered that lipid droplets are not only present in healthy neurons but also regulate whole-body metabolism when formed in hunger-responsive neurons in the brain.
    Keywords:  activity; energy; lipid droplets; metabolism; neuron; sex-effect
    DOI:  https://doi.org/10.1016/j.tem.2026.06.004
  22. Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00080-2. [Epub ahead of print]91 102190
    A neuronal model of mtDNA disease reveals an ineffective reprogramming of the electron transfer chain during neuronal maturation.
    Shane Thomas Bell, Rebeca Acín-Pérez, Iffath Ghouri, Jon Meyrick, Robert Lightowlers, Oliver Russell.
      Large-scale mitochondrial DNA (mtDNA) deletions can result in deficiency of oxidative phosphorylation and subsequent mitochondrial dysfunction, ultimately leading to mitochondrial disease. To investigate effective treatments, we report a characterised heteroplasmic iPSC-derived neuronal model with a single, large scale ∼6 kb mtDNA deletion. While mtDNA heteroplasmy remains stable during iNGN2-induced neuronal differentiation from iPSCs, the presence of this mtDNA deletion results in an upregulation of mtDNA copy number and compensatory adaptation of oxidative phosphorylation (OXPHOS) machinery. Despite this increase, mitochondrial dysfunction and reduced oxygen consumption is prevalent. Furthermore, as differentiated neurons mature over time, mitochondrial supercomplexes and isolated complex II diminish, suggesting an increase of severity of the mitochondrial dysfunction. In summary, this study provides insight into a novel compensatory mechanism during iPSC differentiation to bypass mitochondrial dysfunction, and how this response exacerbates dysfunction during culture of mature neurons.
    Keywords:  Complex II; Copy number; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Mitochondrial supercomplexes; iPSC-derived neurons
    DOI:  https://doi.org/10.1016/j.mito.2026.102190
  23. J Biol Chem. 2026 Jun 29. pii: S0021-9258(26)02178-2. [Epub ahead of print] 113306
    Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
    Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.
      Cardiolipin (CL) is a four-acyl chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-acyl chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of IMM structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.
    Keywords:  Barth syndrome; Cardiolipin; Lipid saturation; Mitochondria; Tafazzin
    DOI:  https://doi.org/10.1016/j.jbc.2026.113306
  24. bioRxiv. 2026 Jun 23. pii: 2026.06.18.732873. [Epub ahead of print]
    RAEM: random-access electron microscopy for revisitable 3D imaging.
    Ishaan Singh Chandok, Milan Patel, Yuelong Wu, Daniel Berger, Richard Schalek, Jeff W Lichtman, Aravinthan D T Samuel, Yaron Meirovitch.
      Volume electron microscopy is essential for understanding cells, tissues, and neural circuits in their native 3D context, but many biological specimens are too large to image exhaustively at nanometer resolution. Researchers therefore must choose between broad anatomical context and ultrastructural detail. We introduce random-access electron microscopy (RAEM), a framework for studying fixed tissue repeatedly across scales rather than imaging it once at a single resolution. RAEM first builds a lower resolution 3D survey of the specimen, then uses accumulated human or AI-derived knowledge of that volume to guide the microscope back to selected physical sites for high resolution imaging. By linking reconstructed 3D coordinates to precise electron-beam positions on the original sections, RAEM enables targeted imaging of membranes, vesicles, and other nanoscale structures within specimens that would be impractical to image exhaustively. We demonstrate RAEM with vesicle-resolved imaging of synaptic boutons in human cortex, targeted imaging of more than one million human cortical mitochondria, hierarchical imaging of a nematode nervous system, and retrospective targeting of a previously published petabyte-scale human cortical volume. RAEM turns serial-section EM into a query-driven, multi-resolution approach for scalable biomedical discovery.
    DOI:  https://doi.org/10.64898/2026.06.18.732873
  25. Proc Natl Acad Sci U S A. 2026 Jul 07. 123(27): e2524943123
    Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism.
    Biyi Chen, Jinxi Wang, Qingwen Qian, Guangqin Zhang, Yihui Wang, Mark Li, Rubin Tan, Zhuoying Yang, Weiyang Zhao, Grace Ciampa, Daniela Sarahi Yang Bennett, Yixi Liu, Qi Zhu, Zhiyong Zhu, Sepiso K Masenga, Zer Vue, Han Le, Qian Shi, Leonid V Zingman, Antentor O Hinton, Duane D Hall, E Dale Abel, Ling Yang, Long-Sheng Song.
      Dysfunctional adipocyte calcium handling is implicated in obesity and thermogenesis. Junctophilins (JPs) stabilize calcium microdomain junctions between the plasma membrane and endoplasmic reticulum, but whether JPs are required for adipocyte function is not known. We show that JP2 is enriched in thermogenic brown adipose tissue (BAT) relative to other fat depots and is downregulated under conditions of nutrient overload. Conditional knockdown of JP2 in adipocytes, and more selectively in BAT, exacerbates cold intolerance and susceptibility to diet induced obesity. Mechanistically, JP2-depleted brown adipocytes exhibit calcium handling dysfunction with elevated cytosolic calcium levels at baseline but diminished norepinephrine-induced calcium transients, reduced store-operated calcium entry. Basal cytosolic calcium overload accounts for an increase in calpain activation and ensuing downregulation of STIM1 and hormone-sensitive lipase in JP2-depleted cells. Furthermore, JP2 silencing in brown adipocytes reduced oxygen consumption rates and compromised mitochondrial structure and quality. Together, these findings demonstrate that JP2 is essential for normal calcium homeostasis in brown adipocytes and reveal a critical role for JP2 in thermogenesis and resistance to diet-induced metabolic dysregulation.
    Keywords:  Junctophilin-2; brown adipose tissue; calcium regulation; metabolism; thermogenesis
    DOI:  https://doi.org/10.1073/pnas.2524943123
  26. PLoS One. 2026 ;21(7): e0351701
    Key molecular mechanisms of mitochondrial metabolic pathways in specific cell subpopulations of pancreatic cancer based on scRNA-seq and bulk RNA-seq.
    Jianping Liu, Tao Liu, Le Yang, Yi Hu, Chao Luo, Dan Wu, Xingjian Yang.
       BACKGROUND: Pancreatic cancer (PC) is a highly malignant tumor with increasing incidence, mortality, and a low five-year survival rate. Mitochondrial metabolic reprogramming plays a crucial role in tumor development, but the molecular mechanisms in different cell subpopulations of PC remain unclear. This study aims to integrate single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq to explore mitochondrial metabolism in PC.
    METHODS: Transcriptome datasets (GSE183795, GSE16515, GSE197177, and TCGA-PAAD) were downloaded from the GEO and TCGA databases. Differentially expressed genes (DEGs) were identified using the limma package for bulk RNA-seq and the Seurat package for scRNA-seq. Weighted gene co-expression network analysis (WGCNA) was performed to identify key modules and hub genes. Machine learning algorithms screened key genes, and functional enrichment analysis was conducted using clusterProfiler. PPI, ceRNA, and transcription factor networks explored gene regulation. Immune infiltration analysis, drug prediction, and molecular docking were conducted on key genes. The prognostic value of the key genes was evaluated using clinical data from TCGA.
    RESULTS: A total of 1238 bulk RNA-DEGs and 8231 scRNA-DEGs in fibroblasts were identified. Integration of both datasets revealed 536 DEGs. WGCNA identified 6 modules associated with PC. By intersecting DEGs, hub genes, and mitochondrial metabolism-related genes, 18 candidate genes were obtained. These genes were enriched in glucose metabolism and mitochondrial outer membrane pathways. Three key genes (IFI27, PKM, and RSAD2) were selected using machine learning. PPI, ceRNA, and transcription factor networks provided regulatory insights. Immune infiltration analysis showed significant differences in immune cells, particularly in T cells CD4 memory resting and macrophages M2. Drug prediction and molecular docking identified potential drugs for these genes. Survival analysis indicated that high expression of these genes correlated with poor prognosis.
    CONCLUSION: This study integrates scRNA-seq and bulk RNA-seq data to identify three key genes (IFI27, PKM, and RSAD2) and their immune-related mechanisms in PC. These findings offer new insights into the pathogenesis and potential therapeutic targets for PC.
    DOI:  https://doi.org/10.1371/journal.pone.0351701
  27. Nat Commun. 2026 Jun 29.
    Complete enzyme clustering enhances coenzyme Q biosynthesis via substrate channeling.
    Dianzhuo Wang, Andrea Gottinger, Jio Jeong, Callum R Nicoll, Junlang Liu, Tereza Kadavá, Domiziana Cecchini, Marco Malatesta, Albert J R Heck, Andrea Mattevi, Eugene I Shakhnovich.
      Metabolons - transient assemblies of sequential metabolic enzymes - facilitate the reactions of multi-step metabolic pathways, yet, how they mechanistically bolster metabolic flux remains unknown. Here, we investigate the molecular determinants of metabolon formation in coenzyme Q (CoQ) biosynthesis using coarse-grained molecular dynamics simulations and biochemical experiments. We show that the COQ metabolon forms at the critical region of a phase transition, where both metabolon clustering and metabolic flux exhibit coordinated sigmoidal responses to changes in protein-protein interaction strength. These complete metabolons enable substrate channeling between sequential enzymes, leading to a crucial enhancement of CoQ production efficiency. Selectively disrupting protein-protein interactions and randomly shuffling the interaction network demonstrate that protein-proximity rather than a defined spatial organization of the metabolon clusters is imperative for substrate channeling. Grounded in both experiments and simulations, these findings provide a framework for understanding the organization and function of metabolons across diverse metabolic pathways.
    DOI:  https://doi.org/10.1038/s41467-026-74806-2
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