bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–04–19
thirteen papers selected by
Marc Segarra Mondejar, AINA
  1. Super resolution microscopy-based assessment of organellar redox-active iron transfer and its relevance for ferroptosis.
  2. SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
  3. PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming.
  4. Sensing succinate: SUCNR1 as a context-dependent metabolic and cellular signal integrator.
  5. A photodynamically activated nanoplatform relieves glucose-driven immunosuppression to potentiate STING immunotherapy in triple-negative breast cancer.
  6. FAAH initiates a positive feedback loop to promote lung adenocarcinoma progression through inhibition of ferroptosis.
  7. Targeting mitochondria in triple-negative breast cancer: Emerging therapeutic and drug development strategies.
  8. Genetically encoded lockdown of SERCA in the endoplasmic reticulum membrane arrests Ca2+ signaling through proximity-covalent crosslinking.
  9. Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.
  10. Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
  11. SARM1 executes neuronal parthanatos and promotes excitotoxic cell death.
  12. Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer's disease model.
  13. Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
  1. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00005-1. [Epub ahead of print]205 85-105
    Super resolution microscopy-based assessment of organellar redox-active iron transfer and its relevance for ferroptosis.
    Francesca Rizzollo, Charlotte Cresens, Benjamin Pavie, Pablo Hernandez-Varas, Patrizia Agostinis.
      Intracellular iron is essential for numerous biological processes, yet its redox activity makes it potentially cytotoxic. Because of this, a tight regulation of its cellular compartmentalization is required. Lysosomes and mitochondria play central roles in iron metabolism. Lysosomes are crucial for iron redistribution after its endocytosis, while mitochondria utilize it for heme and Fe-S cluster synthesis. Disruption of the functional crosstalk between these two organelles can lead to iron dyshomeostasis and ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation. Recent evidence highlights the importance of mitochondria-lysosome contact sites (MLCs) in mediating iron trafficking, particularly under pathological conditions. However, studying these nanoscopic, dynamic structures poses significant technical challenges. Here, we describe a novel live-cell imaging protocol combining super-resolution structured illumination microscopy (SIM) with organelle-specific dyes and a selective mitochondrial Fe(II) probe to visualize MLC formation and track iron transfer in real time. This approach enables the precise investigation of subcellular iron dynamics and their implications for ferroptosis and disease.
    Keywords:  Inter-organelle iron transfer; Iron; Lysosomes; Melanoma; Mitochondria; Mitochondria-lysosomes contact sites; Super-resolution structured illumination microscopy
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.005
  2. bioRxiv. 2026 Apr 07. pii: 2026.04.03.716311. [Epub ahead of print]
    SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity.
    Dingcheng Sun, Guangrui Ding, Haonan Lin, Guo Chen, Chun-Chin Wang, Seema Bachoo, Sarah E Bohndiek, Ji-Xin Cheng.
      Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.
    DOI:  https://doi.org/10.64898/2026.04.03.716311
  3. Oncol Rep. 2026 Jun;pii: 112. [Epub ahead of print]55(6):
    PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming.
    Zong Jin Guo, Qian Yu, Rui Sha, Wei Li, Hui Juan Dai.
      Breast cancer is a predominant cause of cancer‑related mortality among women, particularly aggressive subtypes such as triple‑negative breast cancer (TNBC), which currently lack effective targeted therapies. While PTEN‑induced kinase 1 (PINK1) is known for its role in maintaining mitochondrial homeostasis via mitophagy, its specific contributions to breast cancer progression and metabolic regulation remain poorly defined. The present study aimed to investigate the oncogenic potential of PINK1 and its influence on metabolic reprogramming. To achieve this, the PINK1 expression levels in breast cancer tissues and cell lines were assessed. Gain‑ and loss‑of‑function methodologies were employed in luminal (MCF‑7) and TNBC (MDA‑MB‑231) cells. Then, mitophagy was evaluated by measuring LC3‑II levels, Parkin expression and utilizing transmission electron microscopy. Glucose uptake assays and metabolite quantification (including pyruvate and acetyl‑CoA) were conducted. Reverse transcription‑quantitative polymerase chain reaction identified phosphoglycerate kinase 2 (PGK2) as a downstream target of PINK1. Functional assays were then performed to examine the proliferation, migration and invasion of cells with PINK1 overexpression. The results demonstrated that PINK1 overexpression increased mitophagy and induced a glycolytic phenotype, characterized by enhanced glucose uptake and elevated PGK2 levels. Elevated concentrations of pyruvate and acetyl‑CoA indicated increased metabolic flux. Functionally, PINK1 promoted proliferation, migration and invasion in both cell types. Knockdown of PGK2 reversed these effects, underscoring its critical role in PINK1‑mediated metabolic reprogramming. Transcriptomic data obtained from online databases revealed a correlation between high PINK1 expression and immunosuppressive tumor microenvironments, as well as poor prognosis. The PINK1‑PGK2 axis constitutes a critical mechanism linking mitophagy to glycolytic reprogramming in breast cancer, representing a novel therapeutic target, particularly for TNBC. Targeting this axis may yield new strategies for addressing treatment‑resistant, metabolically adaptive breast cancer.
    Keywords:  PTEN‑induced kinase 1‑phosphoglycerate kinase 2 axis; breast cancer; glycolysis; mitophagy; therapeutic target
    DOI:  https://doi.org/10.3892/or.2026.9117
  4. Front Mol Biosci. 2026 ;13 1815835
    Sensing succinate: SUCNR1 as a context-dependent metabolic and cellular signal integrator.
    Aenne-Dorothea Liebing, Claudia Stäubert.
      Succinate (SUC), a central intermediate in the mitochondrial tricarboxylic acid (TCA) cycle, functions not only as a metabolic substrate but also acts as the endogenous ligand for succinate receptor 1 (SUCNR1), a Gi- and Gq protein-coupled receptor. SUC accumulates when energy demand exceeds oxygen supply or during metabolic rewiring, including hypoxia, endurance exercise, inflammation, and tumor progression. SUC can be released into the extracellular space, reaching levels sufficient to activate SUCNR1. SUCNR1 is expressed in various tissues, including the kidney, liver, and adipose tissue, as well as in immune cells and cancer subtypes. Rather than functioning as a simple pro- or anti-inflammatory receptor, SUCNR1 acts as a metabolic signal integrator whose output is determined by G protein preferences, receptor trafficking, and the balance between intra- and extracellular SUC pools. In immune cells, particularly macrophages, SUCNR1 signaling promotes either inflammatory activation or resolution depending on the metabolic state. In metabolic tissues and cancer, SUCNR1 coordinates adaptive responses to nutrient and oxygen stress while shaping the tissue microenvironment. Here, we review recent advances in SUC-SUCNR1 signaling across immune and metabolic systems, discuss unresolved controversies regarding signaling selectivity and spatial encoding, and evaluate the therapeutic opportunities and challenges of targeting this metabolic checkpoint.
    Keywords:  G protein-coupled receptor (GPCR); cancer; metabolism; pro- and anti-inflammatory immune responses; signal selectivity; signal transduction; succinate; succinate receptor 1 (SUCNR1)
    DOI:  https://doi.org/10.3389/fmolb.2026.1815835
  5. Mater Today Bio. 2026 Jun;38 103071
    A photodynamically activated nanoplatform relieves glucose-driven immunosuppression to potentiate STING immunotherapy in triple-negative breast cancer.
    Yongxuan Long, Jinlin Li, Menghan Chang, Huihui Zhu, Xu Yang, Yinhua Lv, Yi Sun, Yongqiang Yu, Weijie Zhang.
      Triple-negative breast cancer (TNBC) carries a poor prognosis due to its high invasiveness, strong tendency toward metastasis and recurrence, and limited treatment options. Metabolic reprogramming, particularly abnormal glucose metabolism, is a hallmark of TNBC. This dysregulated metabolic pattern is closely associated with the establishment of an immunosuppressive tumor microenvironment (TME). We designed a self-assembling nanoparticle, DI/Ce6@STF, integrating photodynamic therapy (PDT), glucose metabolism intervention, and cGAS-STING pathway activation to achieve synergistic antitumor effects. Under 660 nm laser irradiation, DI/Ce6@STF NPs induce immunogenic cell death (ICD) while releasing the STING agonist DIABZI, the GLUT1 inhibitor STF-31, and reactive oxygen species (ROS) causing oxidative damage. STF-31-mediated glucose uptake inhibition not only reduces energy supply but also synergistically enhances tumor response to DIABZI-induced cGAS-STING activation, significantly improving the TME. Collectively, DI/Ce6@STF induces potent ICD, promotes dendritic cell maturation, and enhances intratumoral infiltration of CD8+ T cells, thereby reprogramming the immunosuppressive TME. In vivo, DI/Ce6@STF nanoparticles demonstrated not only excellent biocompatibility but also highly efficient tumor targeting and enrichment capabilities. They significantly inhibited tumor growth and effectively activated the body's antitumor immune response. By synergistically modulating tumor metabolism and innate immunity, this nanoplatform offers a promising strategy for overcoming therapeutic resistance in TNBC.
    Keywords:  Glut1; Immunotherapy; Photodynamic; STING; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103071
  6. Cell Death Differ. 2026 Apr 17.
    FAAH initiates a positive feedback loop to promote lung adenocarcinoma progression through inhibition of ferroptosis.
    Xinyi He, Cheng Tang, Tongtong Jiang, Chaohao Yang, Xiang Zhang, Zhuan Ju, Jiuzhou Zhao, Renji Wei, Ting Wang, Yanlu Xiong, Lintao Jia, Xiao Zhang.
      Ferroptosis represents an iron-dependent form of cell death characterized by accumulation of lipid peroxides. However, it is largely elusive how authentic lipid metabolites contribute to ferroptosis, and whether this is dysregulated in malignant cells due to metabolic rewiring. Here, we identify fatty acid amide hydrolase (FAAH) as a crucial ferroptosis regulator in lung adenocarcinoma (LUAD). FAAH is upregulated and correlated with poor prognosis of LUAD patients. FAAH overexpression inhibits ferroptosis, whereas FAAH knockdown robustly enhances ferroptosis of LUAD cells. Mechanistically, FAAH promotes the palmitoylation of STAT3 through converting N-palmitoylethanolamine to palmitic acid. Palmitoylated STAT3 undergoes cytomembrane translocation and phosphorylation by JAK2, and transcriptionally activates GPX4 to suppress ferroptosis. Concomitantly, activated STAT3 licenses FAAH transcription, thus forming a positive feedback loop in LUAD cells. FAAH targeting represses tumor growth and boosts the anti-tumor efficacy of cisplatin in vivo. These findings uncover a novel regulatory circuit of ferroptosis driven by a saturated fatty acid, and demonstrate the applicability of targeting FAAH to overcome ferroptosis resistance in LUAD therapy.
    DOI:  https://doi.org/10.1038/s41418-026-01742-5
  7. Biochim Biophys Acta Rev Cancer. 2026 Apr 14. pii: S0304-419X(26)00063-6. [Epub ahead of print] 189591
    Targeting mitochondria in triple-negative breast cancer: Emerging therapeutic and drug development strategies.
    Ziyue Yuan, Dan Mu, Xiya Chen, Qianqian Yang, Jin Zhang, Lan Zhang.
      Mitochondria are essential regulators of cell metabolism, apoptosis, and oxidative stress, rendering them critical targets for cancer therapy. This review systematically dissects the multifaceted roles of mitochondrial dysfunction in triple-negative breast cancer (TNBC), including its contributions to tumor initiation, progression, metabolic reprogramming, immune evasion, and programmed cell death, as well as its communication with other organelles. We summarize the current landscape of mitochondria-targeted therapeutic strategies for TNBC, encompassing direct targeting of mitochondrial proteins, indirect modulation of mitochondrial function via signaling pathways, mitochondrial-targeted modification, and drug combination regimens. Additionally, we examine emerging approaches such as nanoparticle delivery systems and clinical compounds with mitochondrial regulatory effects. This review aims to provide a comprehensive framework for advancing the development of more precise and effective mitochondria-targeted therapies against TNBC.
    Keywords:  Mechanism; Mitochondria; Small-molecule compounds; TNBC
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189591
  8. FEBS Lett. 2026 Apr 15.
    Genetically encoded lockdown of SERCA in the endoplasmic reticulum membrane arrests Ca2+ signaling through proximity-covalent crosslinking.
    Yiying Li, Kozo Hamada.
      Reversible conformational dynamics of membrane proteins are essential for intracellular signaling, but no method enables their irreversible arrest in living cells. Here, we developed a genetically encoded proximity-based lockdown enzyme derived from an engineered transglutaminase catalytic core (TGC) that covalently crosslinks membrane proteins. By fusing TGC to the endoplasmic reticulum (ER)-resident microprotein ALN encoded by a short open reading frame (sORF), we created an organelle-specific module that selectively catalyzes covalent crosslinking within the SERCA Ca2+ pump, strongly suppressing its ATP-dependent pump activity and arresting ER Ca2+ signaling. This engineered lockdown enzyme remodels ER membrane protein architecture and restricts conformational dynamics, providing a versatile platform for long-term covalent control of intracellular signaling and a foundation for future therapeutic cellular applications. Impact statement Our proximity-based lockdown enzyme, engineered from microbial transglutaminase, provides a new strategy to covalently arrest the conformational states of organelle-resident membrane proteins in living cells, enabling long-term control of intracellular signaling and establishing a foundation for next-generation cellular therapeutics.
    Keywords:  calcium ATPase; calcium homeostasis; calcium signaling; endoplasmic reticulum; microprotein; transglutaminase
    DOI:  https://doi.org/10.1002/1873-3468.70342
  9. Amino Acids. 2026 Apr 14.
    Reprogramming of nitrogen metabolism in tumors: mechanisms and therapeutic implications.
    Jiaqi Fang, Jing Ling, Xinyue Liu, Yanbin Wang, Yongbiao Huang, Zhe Cao, Yanmei Zou, Hua Xiong.
      Nitrogen metabolism plays a key role in maintaining normal physiological functions of the organism and cell proliferation and differentiation. Nitrogen metabolism in normal human body maintains a dynamic balance to meet the body's demand for synthesis of biological macromolecules such as proteins and nucleic acids. However, in the process of tumor development, the nitrogen metabolism of tumor cells is reprogrammed to meet the demand of rapid proliferation, showing significantly different metabolic characteristics from normal cells. Key enzymes in the tumor microenvironment affect nitrogen metabolism through multiple mechanisms, providing essential nitrogen sources and energy for tumor cells. In-depth exploration of the regulatory mechanisms of tumor nitrogen metabolism not only helps to reveal the molecular basis of tumor development, but also provides a theoretical basis for the development of new tumor therapeutic strategies. In this paper, the relationship between nitrogen metabolism and tumors is systematically elaborated from the characteristics of nitrogen metabolism in normal people, the reprogramming of nitrogen metabolism in tumor patients, the influence of key enzymes on nitrogen metabolism in the tumor microenvironment, as well as the mechanism of tumor nitrogen metabolism regulation, etc., so as to provide references for the related research.
    Keywords:  Ammonia; CPS1; GLS1; Nitrogen metabolism; Tumor
    DOI:  https://doi.org/10.1007/s00726-026-03517-1
  10. Nat Rev Immunol. 2026 Apr 15.
    Metabolite and nutrient regulation of macrophages in obesity and metabolic disease.
    Neil T Sprenkle, Evanna L Mills.
      Tissue-resident macrophages are crucial sentinel cells of the innate immune system that sense nutrient fluctuations and orchestrate adaptive responses to support steady-state metabolic homeostasis. When dysregulated, these cells have major roles in the pathogenesis of numerous diseases, including obesity-associated metabolic diseases such as type 2 diabetes, metabolic dysfunction-associated fatty liver disease and atherosclerotic cardiovascular disease. Cellular and phenotypic remodelling of macrophage populations in response to metabolic alterations linked to obesity perturbs homeostatic interactions and promotes low-grade sterile tissue inflammation, which propagates tissue dysfunction. Much of the seminal initial work in the field of 'immunometabolism' explored the role of metabolic pathways in the regulation of distinct immune cell types. More recently, however, it has become appreciated that intermediary metabolites can function as signals that regulate macrophages at the level of the whole tissue or organism. As we discuss here, recent work has identified intermediary metabolites such as lactate, succinate and itaconate, and nutrients including glucose, amino acids and free fatty acids, as crucial regulatory signals that control macrophage function in obesity and metabolic disease.
    DOI:  https://doi.org/10.1038/s41577-026-01292-4
  11. Neuron. 2026 Apr 16. pii: S0896-6273(26)00218-7. [Epub ahead of print]
    SARM1 executes neuronal parthanatos and promotes excitotoxic cell death.
    Tong Wu, Liya Yuan, Yo Sasaki, Si Jia Chen, William Buchser, A Joseph Bloom, Aaron DiAntonio, Jeffrey Milbrandt.
      The nicotinamide adenine dinucleotide (NAD+) hydrolase sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is the central executioner of pathological axon degeneration and is allosterically activated by an increased nicotinamide mononucleotide (NMN)/NAD+ ratio. DNA damage induces NAD+ loss and an increased NMN/NAD+ ratio by hyperactivating poly(ADP-ribose) polymerase 1 (PARP1), which triggers the parthanatos cell death pathway. Multiple mechanistically distinct DNA-damaging agents activate SARM1 and induce axon degeneration following PARP1 activation. Remarkably, SARM1 is required for key steps downstream of hyperactivated PARP1, which are pathognomonic of parthanatos, including mitochondrial depolarization, nuclear translocation of apoptosis-inducing factor (AIF), and cell death. Hence, SARM1 is an essential component of neuronal parthanatos. Moreover, complex neurodegenerative stimuli whose mechanisms include activation of parthanatos, such as 1-methyl-4-phenyl-pyridinium (MPP+) dopaminergic neuron toxicity and N-methyl-D-aspartate (NMDA) excitotoxicity, are potently protected by SARM1 inhibition. These findings place SARM1 at the nexus of multiple mechanisms driving neuronal cell death, thereby greatly expanding the potential clinical utility of SARM1 inhibitors beyond diseases of axon loss.
    Keywords:  ALS; NAD⁺ metabolism; Parkinson’s disease; SARM1; dopaminergic neurons; excitotoxicity; iPSC; neurodegeneration; parthanatos; stroke
    DOI:  https://doi.org/10.1016/j.neuron.2026.03.027
  12. Nat Commun. 2026 Apr 14.
    Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer's disease model.
    Yiannis Poulot-Becq-Giraudon, Océane Guillemaud, Elisa Degl'Innocenti, Vivien Letenneur, Karouna Bascarane, Tony Barbay, Mie Møller Clausen, Céline Derbois, Martine Guillermier, Ludmila Juricek, Miriam Riquelme-Perez, Tom Lakomy, Lucile Benhaim, Noëlle Dufour, Pauline Gipchtein, Fanny Petit, Léa Siron, Gwennaëlle Aurégan, Nathalie Dechamps, Marie-Claude Gaillard, Alexis-Pierre Bemelmans, Rémi Bos, Maria-Angeles Carrillo-de Sauvage, Giampaolo Milior, Nathalie Rouach, Solène Brohard, Kevin Muret, Eric Bonnet, Carole Escartin.
      Astrocytes are key partners for neurons and can impact diseases such as Alzheimer's disease (AD), as they exhibit multiple reactive changes. Recent single cell/nucleus genomics analyses evidence astrocyte subpopulations coexisting in normal and AD brains. However, the signaling cascades controlling them, their functional characteristics and roles in AD are still unknown. Here, thanks to astrocyte-specific reporters for STAT3 and NF-kB signaling pathways, two regulators of astrocyte reactivity, we report the presence of three astrocyte subpopulations defined by their signaling activity, in the prefrontal cortex of male APP/PS1dE9 mice. These subpopulations are not triggered by amyloid deposition and are also observed in wild-type mice. They show distinct morphologies, molecular signatures and functional profiles. While NF-kB+ astrocytes have larger territories and higher lysosomal activity, STAT3+ astrocytes display enhanced hemichannel activity. Specific inhibition of these subpopulations reduces amyloid plaque size and impacts anxiety, social preference and social memory in AD but not wild-type mice. Our results show how innate signaling shapes astrocyte subpopulations in the mouse cortex, with distinct functions in health and disease.
    DOI:  https://doi.org/10.1038/s41467-026-71826-w
  13. EMBO Rep. 2026 Apr 14.
    Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
    Manami Tanaka, Takako Hishiki, Tomomi Matsuura, Masato Yasui, Shunsuke Chikuma, Mariko Hara-Chikuma.
      Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes.　In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.
    Keywords:  Glycerol; Inflammation; Macrophage; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/s44319-026-00747-y
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