bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–08–23
ten papers selected by
Marc Segarra Mondejar, AINA
  1. Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling.
  2. Distinct spatiotemporal immunometabolic remodeling following acute traumatic brain injury.
  3. Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.
  4. Structural rearrangements underlying the activation of STIM1 by ER calcium depletion.
  5. Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
  6. Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.
  7. ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology.
  8. A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.
  9. HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis.
  10. From NAD+ metabolism to skeletal muscle function: The emerging role of ADP-ribosylation.
  1. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2606216123
    Repression of ferroptotic cell death mediated antitumor immunity by mitochondrial calcium signaling.
    Jianwen Chen, Bao Zhao, Hong Dong, Zhiwei Liao, Shen Wang, Anjun Ma, Yajun Sun, Xiang Cheng, Shengyin Lin, Xinghui Li, Gang Xin, Kai He, Bei Liu, Yu L Lei, Qin Ma, Kymberly M Gowdy, Ruili Xie, Xiaolin Cheng, Zihai Li, Haitao Wen.
      Ferroptosis is a unique type of programmed cell death caused by excessive lipid peroxidation and represents a vulnerability in certain types of cancer. However, the signaling mechanisms that modulate ferroptosis and its functional consequence on the tumor microenvironment are poorly understood. Here, we demonstrate an inhibitory effect of mitochondrial calcium uniporter (MCU) on ferroptosis during embryogenesis and tumor development. MCU-dependent production of metabolite acetyl-coenzyme A (acetyl-CoA) supports the normal function of glutathione peroxidase 4 (GPX4), a critical gatekeeper of ferroptosis. Mechanistically, acetylation of GPX4 on lysine 90 (K90) prevents the formation of a detrimental salt bridge between K90 and aspartate 23, therefore protecting GPX4 enzymatic activity and avoiding ferroptosis. Deletion of MCU in cancer cells caused a robust antitumor T cell response and significantly blunted tumor growth. Thus, our findings indicate MCU-mediated acetyl-CoA metabolism as a critical anti-ferroptosis mechanism, which can be investigated as potential therapeutic candidate for tumor treatment.
    Keywords:  GPX4; MCU; ferroptotic cell death
    DOI:  https://doi.org/10.1073/pnas.2606216123
  2. bioRxiv. 2026 Jul 29. pii: 2026.07.28.740519. [Epub ahead of print]
    Distinct spatiotemporal immunometabolic remodeling following acute traumatic brain injury.
    Zohreh Erfani, Erin H Seeley, Erik J Plautz, Brenda L Bartnik-Olson, Jae Mo Park.
      Traumatic brain injury induces profound metabolic reprogramming across neurons, astrocytes, and microglia, yet the spatiotemporal organization of these metabolic responses remains poorly understood. Because pyruvate is uniquely positioned in cerebral metabolism by connecting glycolysis, lactate metabolism, and the tricarboxylic acid cycle, we combined matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging with in vivo administration of isotopically labeled pyruvate and immunohistochemistry to characterize cell-type-wise metabolic remodeling in a controlled cortical impact rat model during the acute and subacute phases of injury. TBI induced distinct spatiotemporal immunometabolic remodeling across neuroglial compartments. Microglia- and macrophage-enriched regions exhibited selective accumulation of citrate, succinate, and itaconate, consistent with inflammatory metabolic rewiring. In contrast, astrocyte enriched regions showed increased glutamine and malate abundance, indicative of altered neuron-astrocyte metabolic coupling such as remodeling of the glutamate-glutamine cycle and enhanced anaplerotic metabolism. These metabolic signatures evolved with distinct regional and temporal distributions, identifying compartmentalized metabolic responses. Notably, labeled isotopologues of selected metabolites, including glutamate and citrate derived from administered pyruvate, changed before the corresponding metabolite pools. Together, these findings describe the spatiotemporal landscape of immunometabolic remodeling following acute TBI, uncover metabolically distinct microglial/macrophage and astrocytic responses during secondary brain injury, and identify candidate metabolic pathways for therapeutic intervention and metabolic imaging.
    DOI:  https://doi.org/10.64898/2026.07.28.740519
  3. Nat Metab. 2026 Aug;8(8): 1772-1790
    Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism.
    Zhongchi Li, Shuchen Liu, Wenbing Jin, Leyi Xiao, Olivia Kester, Nayah Bullen, Xuanrong Chen, Un In Chan, Jude Owiredu, Zhucui Li, Rabia Khan, Jennifer Endress, Moniquetta Shafer, Vivien Low, Nikolaos Koundouros, Sungyun Cho, Christopher Barbieri, Chun-Jun Guo, John Blenis.
      Enhanced cholesterol synthesis and lipid droplet accumulation are hallmarks of aggressive prostate cancer, yet how tumour cells sense metabolic inputs to dynamically regulate cholesterol homeostasis remains poorly defined. Here we uncover a metabolic signalling mechanism in which prostate cancer cells remodel propionyl-CoA metabolism to support stress adaptation during disease progression. We show that the catabolism of branched-chain amino acid, specifically isoleucine and valine, is the primary source of intracellular propionyl-CoA in prostate cancer cells. Beyond its metabolic role, propionyl-CoA functions as a signalling molecule that stabilizes nuclear sterol regulatory element-binding protein 2 (SREBP2) through site-specific lysine propionylation, thereby enhancing its transcriptional activity. This activation promotes cholesterol biosynthesis, fuels de novo androgen production, and sustains androgen receptor signalling under metabolic and therapeutic stress, including androgen deprivation. Together, our findings establish propionyl-CoA as a key metabolic signal linking amino acid catabolism to cholesterol-driven oncogenic programmes and highlight targeting isoleucine and valine metabolism as a potential strategy to disrupt lipid reprogramming in prostate cancer.
    DOI:  https://doi.org/10.1038/s42255-026-01583-z
  4. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2602410123
    Structural rearrangements underlying the activation of STIM1 by ER calcium depletion.
    Ruoyi Qiu, Richard S Lewis.
      In resting cells, STIM1, the dimeric endoplasmic reticulum (ER) Ca2+ sensor that controls store-operated Ca2+ entry (SOCE), is held in a Ca2+-bound inactive state by multiple intramolecular restraints, or brakes. Receptor-evoked release of Ca2+ from the ER causes a large conformational change in STIM1 that releases the brakes and exposes the CRAC activation domain (CAD), enabling it to bind and open store-operated Orai1 channels in the plasma membrane. We performed single-molecule Förster resonance energy transfer (smFRET) measurements with purified STIM1 to better understand how Ca2+ release from the luminal domain of STIM1 drives the conformational changes in the cytosolic domain that underlie CAD release. We find that Ca2+ removal releases the CAD from CC1α1 (the "CC1 clamp") without obligatory formation of the CC1 coiled-coil that has been associated with CAD release in cells. Surprisingly, the CAD rearranges dramatically during release, as the two hairpin protomers that create its characteristic V-shaped structure are spread apart. Locking the two protomers together by cysteine crosslinking prevents CAD release, suggesting that the CAD must rearrange to escape the CC1 clamp. Our data support a model in which ER depletion-induced dimerization of the luminal SAM domains drives the cytosolic domain into multiple intermediate states including a 3-helix bundle of CC1α1/2/3, releasing the CC1 clamp and allowing the CAD to escape through a "fold-out" mechanism. Subsequent formation of the CC1 coiled-coil enables the CAD to revert to its original shape and extends it toward the plasma membrane to activate Orai1.
    Keywords:  STIM1; calcium signaling; single-molecule FRET; store-operated calcium entry
    DOI:  https://doi.org/10.1073/pnas.2602410123
  5. Sci Adv. 2026 Aug 21. 12(34): eaed6318
    Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
    Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.
      Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.
    DOI:  https://doi.org/10.1126/sciadv.aed6318
  6. Mol Cell. 2026 Aug 21. pii: S1097-2765(26)00517-4. [Epub ahead of print]
    Nicotinamide nucleotide transhydrogenase directly couples redox homeostasis to proline biosynthesis in human glioma.
    Lisa A Vettore, Adam Boufersaoui, Yingying Lyu, Anaïs Oudin, Keene L Abbott, Sonu Subudhi, Yetiş Gültekin, Katherine L Eales, Ishana Rajgopal, Cristina Escribano-Gonzalez, Rahatil A Chowdhury, Himani Rana, Victoria Wykes, Rakesh K Jain, Anna Golebiewska, Matthew G Vander Heiden, Daniel A Tennant.
      Cancer cell proliferation requires a precise balance between biomass production and nutrient catabolism. The pyridine nucleotide cofactors nicotinamide adenine dinucleotide NAD(H) and NAD phosphate NADP(H) are central to this process, but their compartment-specific regulation is incompletely understood. Using in vivo isotope-labeled metabolite tracing in an orthotopic xenograft model, we find that human gliomas extensively synthesize proline, an amino acid previously associated with hypoxia tolerance. In glioma cells, we identify a hypoxia-enhanced proliferative sensitivity to environmental proline dependent on NADH to NADPH transhydrogenation from a spatially compartmentalized mitochondrial pool by the enzyme nicotinamide nucleotide transhydrogenase (NNT). We demonstrate NNT-dependent generation of mitochondrial NADPH is important for proline accumulation, maintenance of antioxidant systems, and reductive metabolism in hypoxic glioma cells in vitro and tumor progression in vivo. Collectively, these results highlight proline accumulation as a marker of mitochondrial NAD(P)(H) homeostasis and NNT as a specific metabolic dependency in human glioma.
    Keywords:  NNT; glioma; hypoxia; proline; redox
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.031
  7. Mol Cell. 2026 Aug 17. pii: S1097-2765(26)00513-7. [Epub ahead of print]
    ER-liquid condensate contacts sequester FAM134B/C and RhoA to govern cell morphology.
    Natalia Jimenez-Moreno, Arianna Karageorgiou, Katie Winnington-Ingram, Jimi Wills, Chinmayi Pednekar, Melina Overhoff, Katherine Paine, Matthew Pearson, Lukas Gerasimavicius, Ann Wheeler, Natalia L Kononenko, Joseph A Marsh, Paul Verkade, Alex von Kriegsheim, Jon D Lane, Simon Wilkinson.
      Endoplasmic reticulum (ER)-phagy receptors have elusive physiological functions beyond ER remodeling. To gain insight into these, we screen for cytoplasmic interactors of well-known receptors in mouse pancreatic ductal adenocarcinoma cells. Our data subsequently reveal a non-canonical action of PRKAR1A, a subunit of protein kinase A (PKA), in binding and activating FAM134B/C. At a molecular level, an amphipathic helix in the otherwise-disordered C terminus of FAM134B directly binds PRKAR1A dimers. Multimodal imaging reveals that this interaction occurs at interorganellar contact sites between the ER and liquid-like condensates of PRKAR1A. Mechanistically, ER-condensate contacts promote clustering of FAM134B/C with LC3B and recruit lysosomes, forming degradation hubs. Unexpectedly, these structures are found to control cytoplasmic signaling through FAM134B/C-mediated lysosomal sequestration of RhoA. Underscoring the physiologic relevance of this, these cytoplasmic-facing actions of FAM134B/C result in RhoA-dependent cell morphologic and migratory control in response to cyclic AMP (cAMP) stimuli. Thus, interorganellar contacts expand the roles of FAM134B/C ER-phagy receptors beyond ER degradation.
    Keywords:  ER-phagy; LLPS; RHO GTPase; autophagy; cAMP; cancer; cell invasion; cytoskeleton; liquid-like condensate; lysosome
    DOI:  https://doi.org/10.1016/j.molcel.2026.07.027
  8. Nat Chem Biol. 2026 Aug 19.
    A chemigenetic endogenous Ras activity biosensor for live-cell pharmacology.
    Ryan Weeks, Daojia R Zhou, Michelle S Frei, Jin Zhang.
      Ras is a small GTPase that regulates cell growth and proliferation. Hyperactive Ras is prevalent in cancer and has been a therapeutic target for decades. Many lines of evidence have demonstrated that Ras signals from the plasma membrane as well as noncanonical compartments such as the Golgi, making live-cell biosensors for tracking the spatiotemporal dynamics of Ras activity a valuable approach for Ras studies. However, current biosensors are limited in their quantitative capacity for measuring endogenous Ras activity. Here we introduce a chemigenetic biosensor design, making use of circularly permuted HaloTag labeled with the fluorophore JF635, for detecting endogenous Ras activity. This HaloTag-based Ras Activity Reporter (HaloRasAR) revealed the spatiotemporal dynamics of Ras activity downstream of either growth factor signaling or protein kinase C activation. In addition, live-cell characterization of a Ras(G12C) inhibitor and a Ras GEF inhibitor revealed subcellular-specific inhibition profiles. HaloRasAR represents a major advance in spatiotemporal interrogation of Ras signaling and live-cell pharmacology.
    DOI:  https://doi.org/10.1038/s41589-026-02276-0
  9. Sci Adv. 2026 Aug 21. 12(34): eaeg3424
    HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis.
    Izadora de Souza, Izabela Amélia Marques Andrade, Florencio Porto Freitas, Ana Beatriz da Silva Teixeira, Maria Carolina Clares Ramalho, Karoline Almeida Lima, Ancely Ferreira Dos Santos, Werner Schmitz, Gholamreza Fazeli, Clarissa Ribeiro Reily Rocha, José Pedro Friedmann Angeli.
      Modulating the intracellular labile iron pool (LIP) has emerged as a promising strategy to induce ferroptosis in cancer cells, offering a way to overcome resistance to apoptosis-based therapies. One of the main contributors to LIP is heme catabolism mediated by heme oxygenase-1 (HMOX1), which promotes ferroptosis sensitivity by releasing free iron. Beyond its role as an iron donor, heme can influence diverse proteins and signaling pathways that drive tumor progression, but how heme regulates ferroptosis remains poorly understood. Here, we uncover a paradoxical, protective function of heme in the absence of HMOX1 activity. When HMOX1 is inactive, heme becomes stabilized, leading to ferritin up-regulation, suppression of ferroptosis, and rescue of cell death induced by both pharmacological and genetic inhibition of GPX4. Our findings reveal an unrecognized heme-HMOX1-ferritin axis that controls ferroptosis sensitivity. Targeting this pathway may offer a new therapeutic strategy to modulate ferroptosis in cancer.
    DOI:  https://doi.org/10.1126/sciadv.aeg3424
  10. Cell Rep. 2026 Aug 17. pii: S2211-1247(26)00944-7. [Epub ahead of print]45(8): 117866
    From NAD+ metabolism to skeletal muscle function: The emerging role of ADP-ribosylation.
    Caio Y Yonamine, Ever Espino-Gonzalez, Sheila P Aguilar Lozano, Jonas T Treebak.
      Nicotinamide adenine dinucleotide (NAD+) is a metabolic coenzyme and substrate for enzymes catalyzing post-translational modifications such as ADP-ribosylation. This reversible modification, mediated by ADP-ribosyltransferases and hydrolases, regulates cellular processes. Although studied in cancer and DNA repair, its roles in skeletal muscle remain less defined. Emerging evidence shows ADP-ribosylation modifies structural proteins like actin and desmin, affecting filament organization, contractility, and calcium signaling. It contributes to muscle regeneration by regulating satellite cell activation and differentiation, with ARTC1 implicated in myogenesis. Additionally, ADP-ribosylation intersects with insulin signaling, glycolysis, and mitochondrial function, linking it to systemic metabolism and exercise performance. Roles in extracellular matrix interactions suggest involvement in force transmission and remodeling. Advances in proteomics enable identification of ADP-ribosylation targets, offering insight into functional impact. This review aims to compile studies on ADP-ribosylation in skeletal muscle to enhance our comprehension of these mechanisms, potentially revealing new therapeutic opportunities for metabolic and skeletal muscle diseases.
    Keywords:  ADP-ribosylation; CP: metabolism; CP: molecular biology; extracellular matrix; insulin action; mitochondrial function; muscle regeneration; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117866
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