bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–02–22
thirteen papers selected by
Marc Segarra Mondejar, AINA
  1. Protocol for live-cell imaging of mitochondrial dynamics in adult Drosophila oenocytes.
  2. The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.
  3. DAPL1 restrains RPE PANoptosis in experimental AMD by inhibiting GRP75-mediated mitochondria-associated endoplasmic reticulum membranes.
  4. BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
  5. Decoding cancer across scales with metabolomics.
  6. Core principles of autophagy initiation mechanisms.
  7. KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
  8. CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis.
  9. Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
  10. Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair.
  11. Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.
  12. Cellular mechanisms of brain lipid metabolism in health and disease.
  13. Covalent capture and genetic code expansion enables chemoproteomic profiling and functional characterization of lysine acetoacetylation.
  1. STAR Protoc. 2026 Feb 16. pii: S2666-1667(26)00023-7. [Epub ahead of print]7(1): 104370
    Protocol for live-cell imaging of mitochondrial dynamics in adult Drosophila oenocytes.
    Ankur Kumar, Hua Bai.
      Mitochondrial dynamics are essential for cellular homeostasis and can be visualized in adult Drosophila oenocytes using live-cell confocal imaging. Here, we present a protocol for live-cell imaging of mitochondrial dynamics in adult Drosophila oenocytes. We describe steps for fly preparation, dissection of abdominal cuticle to expose oenocytes, and mounting. We then detail procedures for time-lapse acquisition of mitochondria labeled with mitoGFP. Optimized imaging parameters enable reproducible visualization of mitochondrial morphology stably for longer durations.
    Keywords:  Cell Biology; Genetics; Microscopy; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2026.104370
  2. FEBS J. 2026 Feb 18.
    The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.
    Michaela Veliova, Caroline M Ferreira, Katrina P Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Anthony E Jones, Linsey Stiles, Ajit S Divakaruni, Marc Liesa, Orian S Shirihai, Marcus F Oliveira.
      Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD+ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle (GPSh), and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh, namely the oxoglutarate carrier (Ogc) and aspartate-glutamate carrier (Aralar1), had no apparent effects on respiratory rates. However, silencing either Ogc or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.
    Keywords:  energy; heat; metabolism; obesity; redox; thermogenesis
    DOI:  https://doi.org/10.1111/febs.70461
  3. Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2511926123
    DAPL1 restrains RPE PANoptosis in experimental AMD by inhibiting GRP75-mediated mitochondria-associated endoplasmic reticulum membranes.
    Yan Li, Meiyu Jing, Wanxiao Wang, Wanzhen Lin, Yingxin Zhang, Tianyin Nie, Pingping Liu, Wan-Ni Lu, Yu Chen, J Fielding Hejtmancik, Qinxiang Zheng, Ling Hou, Xiaoyin Ma.
      Retinal pigment epithelium (RPE) cell damage is a critical factor of age-related macular degeneration (AMD), the leading cause of blindness among the aged population. This study focuses on the AMD susceptible gene, Death associated protein like 1 (DAPL1), and provides insights with significant therapeutic implications. DAPL1-deficient mice exhibit dry AMD-like pathological features, a phenomenon whose mechanisms have remained largely unknown. Here, we reveal that DAPL1 deficiency promotes the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to cause mitochondrial Ca2+ overload and dysfunction, which triggers the activation of inflammasomes, leading RPE cells to RIPK1-mediated PANoptosis, an inflammatory programmed cell death, in an experimental dry AMD (dAMD) mouse model. Knockdown of Ripk1 in the Dapl1-/- mice RPE inhibits RPE cell PANoptosis and ameliorates the severity of dAMD pathological features. Conversely, overexpression of DAPL1 inhibits MAM formation and protects RPE cells from PANoptosis in the model. Mechanistically, DAPL1 suppresses MAM formation by downregulating GRP75 expression. This disrupts the formation of the VDAC-GRP75-IP3R axis, which comprises critical tethering proteins responsible for endoplasmic reticulum to mitochondria coupling and Ca2+ trafficking. Knockdown of Grp75 inhibits the formation of MAM and prevents mitochondrial Ca2+ overload, improving mitochondrial quality and inhibiting PANoptosis in RPE cells, thereby interrupting the progression of experimental dAMD in Dapl1-deficient mice. These results unveil the role of MAMs regulated by DAPL1 in RPE cell PANoptosis and AMD progression, highlighting targeting MAM formation as a potential therapeutic strategy for treating dAMD.
    Keywords:  AMD; GRP75; PANoptosis; RPE; mitochondria-associated ER membrane
    DOI:  https://doi.org/10.1073/pnas.2511926123
  4. Mol Cell. 2026 Feb 13. pii: S1097-2765(26)00032-8. [Epub ahead of print]
    BRD4-mediated ER membrane contact creates functionally distinct mitochondrial subtypes.
    Brandon Chen, Drew C Stark, Pankaj V Jadhav, Theophilus M Lynn-Nguyen, Benjamin S Halligan, Nicholas J Rossiter, Nicole Sindoni, Myungsun Shin, Joao A Paulo, Matthew Chang, Imhoi Koo, Sergei Koshkin, Sanjana Eyunni, Paolo Ronchi, Michelle T Paulsen, Harrison S Greenbaum, Mariana T Ruckert, Pietro Morlacchi, David A Hanna, Jason Lin, Rachel M Guerra, Tao Liu, David J Pagliarini, Ruma Banerjee, Abhijit Parolia, Mats E Ljungman, Andrew D Patterson, Joseph D Mancias, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.
      Inter-organellar communication is critical for cellular metabolism. One of the most abundant inter-organellar interactions occurs at the endoplasmic reticulum and mitochondria contact sites (ERMCSs). However, an understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism is limited by a lack of tools that permit temporal induction and reversal. Through screening approaches, we identified fedratinib, an FDA-approved drug that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology, induces a distinct ER-mitochondria envelopment structure, and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondrial electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCSs revealed common mechanisms of induction and function, providing clarity to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCSs and cellular metabolism.
    Keywords:  bromodomain protein; endoplasmic reticulum-mitochondria contact sites; high-throughput screening; mitochondrial electron transport chain
    DOI:  https://doi.org/10.1016/j.molcel.2026.01.012
  5. Nat Rev Cancer. 2026 Feb 20.
    Decoding cancer across scales with metabolomics.
    Joe L Rowles, Gary J Patti.
      It is well established that malignant cells alter their metabolism to support proliferation, but the nutrients required to meet the anabolic demands of different cancers located at various anatomical sites throughout the body remain largely unknown. Moreover, the extent to which nutrients are supplied by neighbouring stromal cells or distant tissues, possibly due to metabolic reprogramming, is poorly understood. Metabolomics provides a unique biochemical approach to address these gaps in our knowledge, but cancer studies require careful consideration because it is challenging to identify appropriately matched control samples for comparison. Here, we detail a collection of metabolomics workflows designed to interrogate cancer across three discrete scales. First, we describe experiments to define the nutrient demands of cancer cells themselves. Second, we focus on identifying metabolic relationships between neighbouring cells in the tumour microenvironment. Finally, we highlight strategies to explore the metabolic crosstalk between cancer cells and distant tissues in the tumour macroenvironment. The approaches outlined span cells in culture, animal models and human specimens from patients with cancer. Special emphasis is dedicated to the application of emerging technologies and computational pipelines in the field of mass spectrometry that enable global profiling of metabolites and lipids.
    DOI:  https://doi.org/10.1038/s41568-026-00908-0
  6. Nat Struct Mol Biol. 2026 Feb 20.
    Core principles of autophagy initiation mechanisms.
    Tetsuya Kotani, Hitoshi Nakatogawa.
      Autophagy is a conserved intracellular degradation system essential for maintaining cellular homeostasis and adapting to a variety of environmental or metabolic cues. Different types of autophagy are induced in response to various physiological signals through distinct mechanisms. In this Review, we highlight recent advances in understanding the molecular mechanisms that induce autophagic degradation of cytoplasmic material in bulk upon nutrient or energy deprivation, and those that trigger the selective autophagic removal of specific cellular components for their quality or quantity control. We discuss mechanistic principles shared across different types of autophagy, such as phase-separation-mediated assembly and activation of related factors, and the coordination between cargo recognition and membrane biogenesis, delineating how diverse mechanisms converge on core principles to ensure context-specific control of autophagy initiation.
    DOI:  https://doi.org/10.1038/s41594-026-01752-4
  7. EMBO Mol Med. 2026 Feb 18.
    KRAS-dependent glycolytic reprogramming of endothelial cells in sporadic arteriovenous malformations.
    Ruilin Wu, Negar Khosraviani, Ann Mansur, Emilie Boudreau, Gabrielle E Largoza, Suejean Park, Dakota Gustafson, Sneha Raju, Crizza Ching, Amira Klip, Thomas Wälchli, Kathryn L Howe, Ivan Radovanovic, Joshua D Wythe, Jason E Fish.
      Somatic activating KRAS mutations in endothelial cells are the predominant cause of sporadic brain arteriovenous malformations (bAVMs) and also occur in sporadic extracranial AVMs. We found that KRASG12V expression in the endothelium increased angiogenesis, which was accompanied by enhanced glucose uptake and glycolytic flux. Mechanistically, this increase in glycolysis was facilitated by enhanced membrane localization of glucose transporters (e.g., GLUT1) and induction of hexokinase-2 (HK2) expression. Importantly, RNA-sequencing and proteomics revealed that HK2 appeared to be the only glycolytic component elevated. Analysis of single-cell RNA-sequencing data and immunofluorescence staining confirmed that HK2 was elevated in mouse and human bAVMs. Critically, either pharmacologic inhibition of glycolytic flux or knockdown of HK2 suppressed sprouting angiogenesis in cultured KRASG12V endothelial cells. Glycolysis inhibition also reversed arteriovenous shunts and potentiated the effect of MEK inhibition in a KRAS-mutant zebrafish model. Finally, combined glycolysis and MEK inhibition suppressed angiogenesis in patient-derived bAVM primary endothelial cells. Together, our findings show that KRAS-driven reprogramming of endothelial metabolism represents a potential therapeutic vulnerability for sporadic AVMs.
    Keywords:  Arteriovenous Malformations; Endothelial Glycolysis; KRAS Signaling; Metabolic Regulation; Targeted Therapeutics
    DOI:  https://doi.org/10.1038/s44321-026-00383-y
  8. Adv Sci (Weinh). 2026 Feb 17. e02239
    CypD Dependent mPTP Opening Is Crucial for Oxidized Mitochondrial DNA Release in Ferroptosis.
    Hong Zhou, Wan Fu, Shizuo Liu, Zili Zhang, Hanyan Luo, Qing Zhong.
      Ferroptosis is a type of regulated cell death characterized by the accumulation of lipid peroxides that damage cell membranes specifically. Mitochondrial swelling and dysfunction are hallmarks of ferroptosis; however, what causes mitochondrial swelling and the consequences of mitochondrial swelling in ferroptotic signal transduction remain poorly understood. Our study found that mitochondrial permeability transition pore (mPTP) opening is essential for mitochondrial swelling and ferroptosis activation. During ferroptosis, oxidized mitochondrial DNAs (mtDNAs) are released through the mPTP. These oxidized mtDNAs activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, promoting ferroptosis through activating ferrotinophagy. Consistently, inhibition of mtDNA-repair enhances cellular sensitivity to ferroptosis and therefore synergizes with ferroptosis inducer in suppressing tumorigenesis in mouse xenograft tumor models. This study provides a fundamental understanding of how mPTP engages in ferroptosis by releasing mitochondrial DNAs as crucial messengers to activate ferroptotic signaling.
    Keywords:  cGAS‐STING; ferroptosis; mPTP; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/advs.202502239
  9. Nat Metab. 2026 Feb 17.
    Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
    Andrea Curtabbi, Sara Natalia Jaroszewicz, Rocío Sanz-Cortés, Rebeca Acín-Pérez, Dimitrios Prymidis, Maksym Cherevatenko, Raquel Martínez-de-Mena, María Jesús Esteban-Amo, Miguel A de la Fuente, Christian Frezza, José Antonio Enríquez.
      Dihydroorotate dehydrogenase is a rate-limiting enzyme of de novo pyrimidine synthesis. In most eukaryotes, this enzyme is bound to the inner mitochondrial membrane, where it couples orotate synthesis to ubiquinone reduction. As ubiquinone must be regenerated by respiratory complex III, pyrimidine biosynthesis and cellular respiration are tightly coupled. Consequently, inhibition of respiration suppresses DNA synthesis and cell proliferation. Here we show that expression of the Saccharomyces cerevisiae URA1 gene (ScURA) in mammalian cells uncouples pyrimidine biosynthesis from mitochondrial electron transport. ScURA forms a homodimer in the cytosol that uses fumarate as an electron acceptor instead of ubiquinone, enabling respiration-independent pyrimidine biosynthesis. Cells expressing ScURA are resistant to drugs that inhibit complex III and the mitochondrial ribosome. Additionally, ScURA enables growth of mitochondrial-DNA-lacking ρ0 cells in uridine-deficient medium and ameliorates the phenotype of cellular models of mitochondrial diseases. Overall, this genetic tool uncovers the contribution of pyrimidine biosynthesis to the phenotypes arising from electron transport chain defects.
    DOI:  https://doi.org/10.1038/s42255-026-01454-7
  10. Cell Rep. 2026 Feb 18. pii: S2211-1247(26)00079-3. [Epub ahead of print]45(3): 117001
    Glutamine metabolism tunes myeloid responses to drive resolution of inflammation during skin repair.
    Yiting Xu, Maria Fernanda Forni, Abigail Benvie, Nicole Castano, Diane King, Qiushi Sun, Stephan Siebel, Van Anh Tran, Richard G Kibbey, Kathryn Miller-Jensen, Valerie Horsley.
      Tissue repair requires inflammation resolution, but the molecular mechanisms involved in vivo are not fully understood. Here, we show that glutamine metabolism suppresses neutrophil recruitment to abrogate inflammation and drive skin wound repair. Integrated metabolomic and transcriptional profiling identified glutamine metabolism as enriched in macrophages during resolution. Dietary depletion studies and conditional deletion of glutaminase, the enzyme essential for glutamine metabolism, in mouse myeloid cells revealed that macrophages suppress neutrophil recruitment genes during tissue resolution to promote repair. We also found that these genes are upregulated in macrophages in patients with diabetes. Mechanistically, our data reveal that glutamine metabolism in macrophages induces suppressive chromatin remodeling of neutrophil recruitment genes, including Ccl ligands, during resolution of inflammation. These findings highlight the ability of specific metabolites to control cellular communication during tissue repair, with glutamine specifically to suppress neutrophil recruitment to advance inflammation resolution.
    Keywords:  CP: immunology; CP: metabolism; glutamine; immunology; inflammation; macrophages; metabolism; neutrophils; resolution; skin; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.celrep.2026.117001
  11. Sci Adv. 2026 Feb 20. 12(8): eadx7815
    Disrupted energy metabolism is associated with retinal ganglion cell degeneration in autosomal dominant optic atrophy.
    Eugene Yu-Chuan Kang, Yun-Ju Tseng, Wei-Hao Peng, Hui-Chuan Hung, Pei-Hsuan Lin, Katrina P Montales, Emmet Sherman, John Peregrin, Ethan Hunghsi Wang, Chunya Kang, Yu-Chuan Teng, Chen-Yang Huang, Chia-Lung Tsai, Ian Yi-Feng Chang, Jiazhang Chen, Gülgün Tezel, Ye He, Tai-De Li, Linsey Stiles, Orian Shirihai, Stephen H Tsang, Chi-Chun Lai, Chi-Neu Tsai, Chyuan-Sheng Lin, Nan-Kai Wang.
      Autosomal dominant optic atrophy (ADOA) is a hereditary optic neuropathy caused by OPA1 variants, leading to retinal ganglion cell (RGC) degeneration and vision loss. The mechanisms behind RGC vulnerability to mitochondrial dysfunction remain unclear. We developed a patient-specific Opa1V291D/+ knock-in mouse model to investigate mitochondrial dysfunction and retinal metabolism in ADOA. We observed that Opa1V291D/+ mice exhibited anatomical and functional RGC abnormalities recapitulating the ADOA phenotypes. Reduced optic atrophy 1 (OPA1) protein levels were noted in Opa1V291D/+ mice, accompanied by decreased protein stability. Moreover, mitochondrial function was compromised, as indicated by reduced Complex I activity, increased oxidative stress, and diminished adenosine triphosphate production in the retinas of Opa1V291D/+ mice. Spatial metabolomics revealed energy deficits in the inner retina and heightened glycolysis in the outer retina. Immunostaining showed decreased expression of glycolytic proteins in the ganglion cell layer. Single-nucleus RNA sequencing disclosed significant down-regulation of energy-production genes in RGCs, while other retinal cell types remained unaffected. These findings emphasize the specific vulnerability of RGCs to bioenergetic crises, connecting disrupted energy homeostasis to their degeneration. By increasing the nicotinamide adenine dinucleotide (NAD+)/reduced form of NAD+ (NADH) redox ratio through the overexpression of mitochondrial-targeted Lactobacillus brevis NADH oxidase (MitoLbNOX) in RGCs, we demonstrated improved RGC function and survival through enhanced energy metabolism and reduced oxidative stress. These findings confirm that disrupted energy metabolism leads to RGC degeneration and emphasize the enhancement of the NAD+/NADH redox ratio as a promising treatment strategy to protect RGCs from degeneration in ADOA.
    DOI:  https://doi.org/10.1126/sciadv.adx7815
  12. Nat Cell Biol. 2026 Feb 20.
    Cellular mechanisms of brain lipid metabolism in health and disease.
    Francesco Petrelli, Carlotta Gilardi, Carla Marie Igelbüscher, Diana Panfilova, Alicia Rey, Rosa Chiara Paolicelli, Marlen Knobloch.
      Lipid metabolism has recently regained considerable attention in neuroscience, as disturbances in lipid metabolic pathways have been linked to neurodevelopmental and neurodegenerative diseases. Here we examine brain lipid metabolism from a cellular perspective, focusing on lipid uptake, de novo synthesis, storage, breakdown and intercellular transfer. We cover the recent literature showing how these processes are important during brain development and how they occur in diverse brain cell types, including astrocytes, oligodendrocytes, neural stem and progenitor cells, microglia and neurons in the adult brain. We further discuss the consequences of disrupted lipid metabolism and highlight emerging insights into neuron-glia lipid exchange, as well as the importance of lipid droplets for brain health and disease.
    DOI:  https://doi.org/10.1038/s41556-026-01880-5
  13. Sci Adv. 2026 Feb 20. 12(8): eaeb5106
    Covalent capture and genetic code expansion enables chemoproteomic profiling and functional characterization of lysine acetoacetylation.
    Xiaohan Song, Yuhan Lu, Xinlong Guo, Yanan Zheng, He Huang.
      Lysine acetoacetylation (Kacac) driven by metabolite acetoacetic acid represents a molecular mechanism by which ketone bodies regulate cellular functions beyond energy provision. However, comprehensive characterization of Kacac has been hindered by technical limitations in detection and functional validation. Here, we report an integrated platform for systematic Kacac investigation. Exploiting the unique reactive ketone carbonyl moiety, we developed Aca-Bio, a hydroxylamine-based probe enabling specific enrichment of Kacac peptides through ketone-targeted covalent labeling and pH-controlled reversible enrichment. Application to mouse liver identified 260 Kacac sites across 125 proteins, revealing notable enrichment in metabolic pathways. Concurrently, we established a genetic code expansion system enabling site-specific Kacac incorporation. Using this approach, we demonstrated that K310acac in HMGCS2 substantially attenuates catalytic activity through impaired substrate binding. This dual-platform approach establishes a comprehensive framework for global profiling and site-specific functional characterization of Kacac, thereby facilitating systematic exploration of its physiological roles and pathological implications.
    DOI:  https://doi.org/10.1126/sciadv.aeb5106
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