bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–01–04
seventeen papers selected by
Marc Segarra Mondejar, AINA
  1. Mitochondrial calcium shapes B cell signaling and mitochondrial function.
  2. Pexophagy meets physiology.
  3. Hippocampal cell- and circuit-specific differences in mitochondrial form and function.
  4. Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia.
  5. Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
  6. In vivo mapping of peroxisome dynamics and pexophagy using PO-TRG and CA-PO-TRG reporter mice.
  7. Fluorescence Lifetime Imaging Application to Probe GTPase Activation in Macrophage Cell Line, Using the Time-Domain FastFLIM Modality.
  8. A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
  9. Assessing Intracellular Metabolism of Immune Cells In Situ in Live Zebrafish Larvae by Autofluorescence Lifetime Imaging Microscopy of NAD(P)H and FAD.
  10. Molecular pathways of oxidative stress in diabetes: redox imbalance and insulin pathway dysregulation.
  11. Competition between a transmembrane helix on Scap and a membrane cholesterol regulates Scap-Insig interaction and SREBP activation.
  12. Regulatory T Cell Metabolism in Cancer.
  13. Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments.
  14. Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression.
  15. ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
  16. Protocol to assess retinal metabolic flux of mice via stable isotope-resolved metabolomics.
  17. Precision acoustofluidics for high-throughput mechanobiology in suspension cells.
  1. Front Immunol. 2025 ;16 1710128
    Mitochondrial calcium shapes B cell signaling and mitochondrial function.
    Hakan Taskiran, Elena Czeslik, Leonhard Stark, Kathrin Kläsener, Theresa Elisa Schnalzger, Jürgen Ruland, Michael Reth, Julia Jellusova.
       Introduction: Calcium (Ca2+) signaling plays a pivotal role in determining B cell fate, shaping processes such as activation, differentiation, anergy or apoptosis. Upon B cell antigen receptor activation, Ca2+ is rapidly mobilized from the endoplasmic reticulum and supplemented by Ca2+ influx from the extracellular space, ultimately driving activation of various signaling pathways required for appropriate B cell responses. Although mitochondria also harbor significant levels of Ca2+, how mitochondrial Ca2+ dynamics are regulated in B cells in response to activation or other cues remains unknown, as do the functional consequences of altered mitochondrial Ca2+ levels.
    Methods: Chemical dyes as well as a genetically encoded Ca2+ sensor with a mitochondrial targeting sequence were used to study mitochondrial Ca2+ dynamics in response to various stimuli. Proximity ligation assays were performed to assess interaction between mitochondria and the endoplasmic reticulum. Primary mouse B cells and the Burkitt lymphoma cell line Ramos were used to study functional consequences of the loss of the Mitochondrial Calcium Uniporter.
    Results: Here, we show that mitochondrial Ca2+ levels dynamically respond to cell activation, stress and metabolic cues and that mitochondrial Ca2+ uptake is largely dependent on the Mitochondrial Calcium Uniporter. Reduced mitochondrial Ca2+ uptake has a negative impact on mitochondrial activity and also affects cell signaling. These findings demonstrate that changes in mitochondrial Ca2+ contribute to shaping functional B cell responses.
    Discussion: The spatial and temporal dynamics of Ca2+ accumulation within distinct subcellular compartments, particularly the cytosol, endoplasmic reticulum and mitochondria, are essential for translating extracellular and intracellular signals into specific cellular outcomes. Our study provides new insights into the regulation of Ca2+ homeostasis in B cells.
    Keywords:  B lymphocyte; calcium; metabolism; mitochondria; signaling
    DOI:  https://doi.org/10.3389/fimmu.2025.1710128
  2. J Cell Biol. 2026 Feb 02. pii: e202511183. [Epub ahead of print]225(2):
    Pexophagy meets physiology.
    Michael J Clague.
      In this issue, Xiong et al. (https://doi.org/10.1083/jcb.202503169) introduce mouse models that enable tissue-resolved mapping of peroxisome turnover and pexophagy across development, metabolism, and disease. This study reveals striking cell type-specific differences in peroxisome dynamics and establishes a versatile platform for dissecting how pexophagy integrates with mitochondrial quality control and whole-body metabolic homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202511183
  3. bioRxiv. 2025 Dec 17. pii: 2025.12.16.694759. [Epub ahead of print]
    Hippocampal cell- and circuit-specific differences in mitochondrial form and function.
    Mayd Alsalman, Lucy Turner, Katy Pannoni, Renesa Tarannum, Rutvi Desai, Sharon A Swanger, Shannon Farris.
      Mitochondrial morphology varies by neuronal cell type and subcellular compartment; however, the functional significance of these differences is unclear. Hippocampal CA2 neurons are enriched for genes encoding mitochondrial proteins compared to CA1 neurons, suggesting a difference in metabolic demand across hippocampal circuits. However, whether CA2 neuron mitochondria are structurally or functionally distinct to support circuit-specific energy demands is unknown. Here we compared mitochondrial morphology, protein expression, and calcium levels across CA1 and CA2 circuits. We found mitochondria in CA2 dendrites were larger than mitochondria in CA1 dendrites. However, both subregions harbored larger mitochondria in the entorhinal cortex (EC)-contacting distal dendrites compared to CA3-contacting proximal dendrites. Together, these data demonstrate both cell type- and input-specific regulation of mitochondrial morphology that likely influences the function of these distinct circuits. To determine whether differences in mitochondrial fission or fusion account for cell and/or layer specific differences in morphology, we immunostained for OPA1 and MFF, which showed a general enrichment in distal dendrites relative to proximal dendrites, and an unexpected increase in CA1 distal dendrites compared to CA2 distal dendrites. To show whether these morphological differences result in functionally distinct mitochondria, we measured mitochondrial calcium levels in live slices. We found a striking enrichment of mitochondrial calcium levels in CA2 distal dendrites relative to proximal dendrites, and this layer-specific effect was significantly different from that in CA1 dendrites at baseline and after activity. Collectively, these findings reveal discrete morphological and functional differences in mitochondria across hippocampal subregions and dendritic layers, which likely confer unique circuit properties and/or vulnerabilities to disease.
    DOI:  https://doi.org/10.64898/2025.12.16.694759
  4. Elife. 2025 Dec 29. pii: RP100129. [Epub ahead of print]13
    Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia.
    Naidi Sun, Yu-Yo Sun, Rui Cao, Hong-Ru Chen, Yiming Wang, Elizabeth Fugate, Marchelle R Smucker, Yi-Min Kuo, Ellen P Grant, Diana M Lindquist, Chia-Yi Kuan, Song Hu.
      Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO2), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO2. Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO2 in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO2, it sparks a prolonged CMRO2-surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis-indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO2-surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hr post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO2-surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO2 measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.
    Keywords:  CMRO2; OXPHOS; cerebral metabolic rate of oxygen; hypothermia; medicine; mouse; neonatal hypoxia-ischemia; neuroscience; oxidative phosphorylation; photoacoustic microscopy
    DOI:  https://doi.org/10.7554/eLife.100129
  5. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2508911123
    Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts.
    Isidora Molina-Riquelme, Gonzalo Barrientos, Leonhard Breitsprecher, Wileidy Gómez, Francisco Díaz-Castro, Silke Morris, Gonzalo Almarza, Andrea Del Campo, Luis Garrido-Olivares, Hugo E Verdejo, Olympia Ekaterini Psathaki, Karin B Busch, Verónica Eisner.
      Aging is closely associated with cardiovascular diseases, the leading cause of mortality worldwide. Mitochondrial dysfunction is a hallmark of cardiovascular aging. Most of the heart's ATP is produced at the cristae, specialized subcompartments where oxidative phosphorylation (OXPHOS) takes place. In this study, we used multiple-scale electron microscopy approaches to evaluate age-related mitochondrial and ultrastructural alterations of cristae in human and mouse hearts. We found that aged patients' hearts displayed reduced cristae density as seen by transmission electron microscopy (TEM), even before any significant decline in the expression of cristae-shaping proteins. Similarly, a multiscale approach that included TEM and serial block-face scanning electron microscopy (SBF-SEM) showed that in aged mice's hearts, cristae undergo ultrastructural remodeling processes, resulting in a decrease in cristae density and width. Electron tomography suggests an apparent decline in cristae connectivity and an increase in fenestration size. These changes were linked to Opa1 downregulation, accompanied by reduced maximal OXPHOS respiration, but unrelated to alterations in the abundance of OXPHOS core subunits and ATP synthase assembly. Altogether, this indicates that alterations in cristae structure alone are sufficient to impair oxidative metabolism, which highlights its potential as an early signal of cardiac aging, even before noticeable changes in mitochondrial morphology occur.
    Keywords:  Opa1; aging; cristae; heart; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2508911123
  6. J Cell Biol. 2026 Feb 02. pii: e202503169. [Epub ahead of print]225(2):
    In vivo mapping of peroxisome dynamics and pexophagy using PO-TRG and CA-PO-TRG reporter mice.
    Yue Xiong, Weihua Gao, Zelai Wu, Rongbin Ding, Hangbin Ma, Jiahua Zheng, Boran Li, Yongjuan Sang, Lingling Zhang, Weihua Gong, Wei Liu, Xiukui Gao, Qiming Sun.
      Maintaining peroxisome homeostasis is crucial for cellular function and its disruption links to metabolic and neurodegenerative disorders. We developed PO-TRG mice ubiquitously expressing RFP-GFP-SKL to enable in vivo pexophagy monitoring. The probe was validated through cellular assays, immunostaining, autophagy perturbation, and age-dependent stability assessments. The model revealed tissue-specific basal pexophagy and dynamic changes during development. High-fat diet-induced obesity significantly reduced hepatic pexophagy, demonstrating metabolic sensitivity. Comparative analysis with mitophagy reporters showed both coordinated and distinct spatiotemporal patterns. We also created an inducible model (CA-PO-TRG) that eliminated cardiac artifacts and enabled neuronal analysis. These models provide robust tools for investigating pexophagy in physiological and pathological contexts.
    DOI:  https://doi.org/10.1083/jcb.202503169
  7. Methods Mol Biol. 2026 ;2983 275-289
    Fluorescence Lifetime Imaging Application to Probe GTPase Activation in Macrophage Cell Line, Using the Time-Domain FastFLIM Modality.
    Veronika Miskolci, Maíra de Assis Lima, Dianne Cox, Louis Hodgson.
      The p21 Rho family of small GTPases, RhoA, Rac1, and Cdc42, play vital roles in regulating actin dynamics and cell motility. These GTPases alternate between active (GTP-bound) and inactive (GDP-bound) states to modulate downstream signaling pathways that control cellular behavior. Monitoring their activation dynamics is essential for understanding cell morphodynamics and physiology, particularly in hematopoietic cells like monocytes and macrophages that are highly motile. Fluorescence resonance energy transfer (FRET)-based biosensors enable real-time visualization of Rho GTPase activities, but conventional ratiometric approaches can be limiting due to nonlinearity, making data interpretation challenging. Fluorescence lifetime imaging microscopy (FLIM) offers a quantitative alternative by directly measuring the change in donor fluorophore lifetime during FRET, circumventing acceptor imaging and ratiometric limitations. However, traditional FLIM methods can be technically challenging due to high photon demands and complex equipment. We discuss an alternative method of FLIM imaging using a time-domain FastFLIM system that supports rapid, sub-second imaging with reduced photon requirements, enabling visualization and quantification of FRET in a macrophage cell line. We demonstrate the utility of FastFLIM in RAW264.7/LR5 macrophages expressing a single-chain Rac GTPase FRET biosensor, showing Rac1 activation in response to mCSF1 (murine colony-stimulating factor 1) stimulation. This approach provides quantitative FRET data on GTPase dynamics, and we discuss herein practical guidance for researchers employing FastFLIM to study cell signaling.
    Keywords:  Biosensor; CSF1; FRET; FastFLIM; Macrophage; RhoGTPase
    DOI:  https://doi.org/10.1007/978-1-0716-4901-5_24
  8. bioRxiv. 2025 Dec 19. pii: 2025.12.17.694756. [Epub ahead of print]
    A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
    Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.
      Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.
    DOI:  https://doi.org/10.64898/2025.12.17.694756
  9. Methods Mol Biol. 2026 ;2983 169-192
    Assessing Intracellular Metabolism of Immune Cells In Situ in Live Zebrafish Larvae by Autofluorescence Lifetime Imaging Microscopy of NAD(P)H and FAD.
    Rupsa Datta, Melissa C Skala, Veronika Miskolci.
      Understanding the dynamic changes in the intracellular metabolism of immune cells has become fundamental to understanding the regulation of their effector functions. Optical metabolic imaging, consisting of optical redox ratio and fluorescence lifetime imaging microscopy of endogenous coenzymes NAD(P)H and FAD, offers a label-free and non-invasive approach to assess intracellular metabolism at the single-cell level. The major advantage of optical metabolic imaging is that it can assess heterogeneity in the sample with spatiotemporal resolution. While this approach has been mainly used to perform metabolic imaging on in vitro samples, studies have demonstrated that it also performs well in live, intact animals, and is sensitive to dynamic changes in immune cell activation. This chapter describes protocols for performing optical metabolic imaging of innate immune cells at the caudal fin wound microenvironment of larval zebrafish following sterile injuries. However, the protocol can be readily applied to other cell types and in different biological contexts.
    Keywords:  FAD; FLIM ; Immune cells; Metabolism; NAD(P)H; Optical metabolic imaging; Zebrafish
    DOI:  https://doi.org/10.1007/978-1-0716-4901-5_16
  10. Mol Biol Rep. 2025 Dec 29. 53(1): 222
    Molecular pathways of oxidative stress in diabetes: redox imbalance and insulin pathway dysregulation.
    Zahid Ahmad Wani, Asvene Kumar Sharma, Showkeen Muzamil, Mehak Nasser Mir, Ishfaq Ahmad Malik, Rayees Ahmad Naik, Shuja Shafi Malik, Irfan Ashraf Badroo, Aabid Rashid Hurra, Yaqoob Lone.
      Oxidative stress plays a pivotal role in the pathogenesis of diabetes mellitus, primarily triggered by hyperglycaemia-induced activation of various metabolic pathways such as glycolytic, hexosamine, PKC, polyol, and AGE pathways. A critical event in this process is the inhibition of GAPDH mediated by PARP-1, leading to the accumulation of glyceraldehyde-3-phosphate, which subsequently promotes the formation of AGE through methylglyoxal, augments PKC signalling, and enhances flux through the polyol and hexosamine pathways. This oxidative imbalance disrupts the IRS-PI3K-GLUT signalling axis, resulting in diminished glucose uptake and contributing to systemic insulin resistance and β-cell damage. Genetic and epigenetic variations, coupled with compromised antioxidant defences, exacerbate susceptibility to oxidative stress, while the Keap1-Nrf2-ARE pathway emerges as a crucial mechanism for reinstating redox equilibrium.
    Keywords:  Beta cell dysfunction; GAPDH; GLUT; Hyperglycaemia; IRS; Insulin signalling; Nrf2; Oxidative stress; PARP-1; PI3K/Akt pathway
    DOI:  https://doi.org/10.1007/s11033-025-11389-z
  11. Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2525043123
    Competition between a transmembrane helix on Scap and a membrane cholesterol regulates Scap-Insig interaction and SREBP activation.
    Blake C Williams, Daniel L Kober, Xiao-Chen Bai, Daniel M Rosenbaum, Arun Radhakrishnan.
      Cholesterol homeostasis in mammalian cells relies on the interaction between two endoplasmic reticulum (ER) sterol-sensing membrane proteins, Scap and Insig. Their interaction regulates activation of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control genes for cholesterol biosynthesis and uptake. Previous studies suggested a model where cholesterol sensing by Scap involves communication across the ER membrane between two functional domains, a cholesterol-binding domain on the luminal side and a COPII-binding domain on the cytosolic side. When ER cholesterol is low, Scap binds COPII adapter proteins to facilitate ER-to-Golgi transport and proteolytic activation of SREBPs. When ER cholesterol is above a threshold concentration, this transport is blocked, a process that requires Insigs. However, the precise molecular mechanisms by which cholesterol and Insigs control the conformations of Scap remain unknown. Here, we elucidate the 3.2 Å cryo-EM structure of a Scap/Insig complex in the presence of saturating amounts of cholesterol. Structure-guided mutagenesis of the Scap/Insig interface indicates that Scap's transmembrane helix 7 (TM7) plays a critical role in transducing conformational changes between the luminal and cytosolic sides of the ER membrane to control Scap/SREBP transport from ER to Golgi. An intramembrane cholesterol bound at the Scap/Insig interface competes with the intramolecular interaction of Scap's TM7 at this interface to modulate cholesterol sensing. These results further advance our understanding of how Scap senses cholesterol and provides additional targets for controlling cholesterol and lipid synthesis in the context of metabolic diseases and even some cancers.
    Keywords:  SREBP; Scap; cholesterol; lipid metabolism
    DOI:  https://doi.org/10.1073/pnas.2525043123
  12. Immunology. 2025 Dec 28.
    Regulatory T Cell Metabolism in Cancer.
    Keywan Mortezaee.
      Regulatory T cells (Tregs) display metabolic fitness to adopt tumour microenvironment (TME), characterized by hypoxia, acidity and metabolic depletion/competition, in order to impair anti-tumour immunity and allow metastasis. Tregs and other TME immune cells interact metabolically, with glycolysis supporting proliferation of Tregs along with cancer cells and CD8+ T cells and a basal oxidative phosphorylation (OXPHOS) promoting Treg and CD8+ T cell activity. Lactate is a glycolysis byproduct that its accumulation creates acidosis within TME, and its uptake provides a fuel source for Treg activity and fosters their persistence in the hypoxic TME. Itaconate and hypoxic TME increase succinate accumulation, but they take complex roles on Tregs and T cells. Hypoxia and hypoxia inducible factor-1 (HIF-1) activity induce lactate release and Treg recruitment/accumulation via stimulating glycolysis path and extracellular adenosine aggregation. Knockout of HIF-1α although reduces lactate, it secondarily induces OXPHOS to fulfil Treg immunosuppressive function. FOXP3 is stabilized by mitochondrial transcription factor A (Tfam) and induces Treg CD36 and OXPHOS, which can be disturbed by nucleus accumbens-associated protein 1 (NAC1). Liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) although induce FOXP3 stability and OXPHOS in Tregs, their activities downregulate programmed death-1 (PD-1) in such cells. OXPHOS augmentation (by α-ketoglutarate [αKG]) or suppression (by metformin) disrupt Treg metabolism. Finally, indoleamine 2,3-dioxygenase (IDO) seems to affect Tregs and can be a promising target in advanced immunotherapy naïve cancer patients. The focus of this review is to describe Treg metabolic regulators/connectome and opportunities they bring about in cancer therapy.
    Keywords:  adenosine; aryl hydrocarbon receptor (AHR); glycolysis; hypoxia inducible factor (HIF); lactate; liver kinase B1 (LKB1); metformin; oxidative phosphorylation (OXPHOS); regulatory T cell (Treg); α‐Ketoglutarate (αKG)
    DOI:  https://doi.org/10.1111/imm.70096
  13. J Cell Biol. 2026 Mar 02. pii: e202505059. [Epub ahead of print]225(3):
    Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments.
    Michaela Medina, Ya-Ting Chang, Hamidreza Rahmani, Mark Frank, Zidan Khan, Daniel Fuentes, Frederick A Heberle, M Neal Waxham, Benjamin A Barad, Danielle A Grotjahn.
      Lipid bilayers form the basis of organellar architecture, structure, and compartmentalization in the cell. Decades of biophysical, biochemical, and imaging studies on purified or in vitro-reconstituted liposomes have shown that variations in lipid composition influence the physical properties of membranes, such as thickness and curvature. However, similar studies characterizing these membrane properties within the native cellular context have remained technically challenging. Recent advancements in cellular cryo-electron tomography (cryo-ET) imaging enable high-resolution, three-dimensional views of native organellar membrane architecture preserved in near-native conditions. We previously developed a "Surface Morphometrics" pipeline that generates surface mesh reconstructions to model and quantify cellular membrane ultrastructure from cryo-ET data. Here, we expand this pipeline to measure the distance between the phospholipid head groups of the membrane bilayer as a readout of membrane thickness. Using this approach, we demonstrate thickness variations both within and between distinct organellar membranes. We show that organellar membrane thickness positively correlates with other features, such as membrane curvedness, in cells. Further, we show that subcompartments of the mitochondrial inner membrane exhibit varying membrane thicknesses that are independent of whether the mitochondria are in fragmented or elongated networks. We also demonstrate that our technique, when applied to three-dimensional data, yields results that match existing measurements obtained from two-dimensional data of in vitro samples. Finally, we demonstrate that large membrane-associated macromolecular complexes exhibit distinct density profiles that correlate with local variations in membrane thickness. Overall, our updated Surface Morphometrics pipeline provides a framework for investigating how changes in membrane composition in various cellular and disease contexts affect organelle ultrastructure and function.
    DOI:  https://doi.org/10.1083/jcb.202505059
  14. bioRxiv. 2025 Dec 19. pii: 2025.12.17.694916. [Epub ahead of print]
    Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression.
    Julia Ugras, Noah Nelson, Samuel A Kerk, Damien Sutton, Lin Lin, Peter Sajjakulnukit, Teresa Dombrowski, Gillian Davidson, Brooke Lavoie, Dominik Awad, Alberto Olivei, Wei Yan, Christopher Strayhorn, Megan Radyk, Matthew Perricone, Marina Pasca di Magliano, Filip Bednar, Timothy Frankel, Yatrik M Shah, Costas A Lyssiotis.
      Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States. This is due in part to the limited availability of effective treatment options for patients, highlighting a significant need for new targets and approaches. Deregulated metabolism is a hallmark feature of PDA that has gained attention as a promising inroad for therapy. The aspartate transaminases ( g lutamate o xaloacetate transaminases, cytosolic GOT1 and mitochondrial GOT2) have several important metabolic functions, including maintaining energy and redox balance and generating aspartate, an essential building block in protein and nucleotide biosynthesis. Previous studies of GOT proteins in preclinical tumor transplant models have yielded conflicting results regarding the requirement of GOT1 and GOT2 for PDA tumor growth. To assess the role of GOT proteins in tumor development and tumor maintenance, we generated conditional knockout mice for Got1 and Got2 and crossed these into pancreas-specific models. Whereas loss of either Got does not impact pancreas development, double Got1 and Got2 knockout results in markedly reduced pancreas size and cellularity without overtly impacting endocrine or exocrine function. In genetically engineered cancer models, single Got loss does not impact lesion formation, tumor size, animal survival, or the composition of the tumor microenvironment. Identical results were also observed in orthotopic allograft mouse models. Together, these findings add to a growing body of work illustrating the adaptability of metabolism in cancer. They also emphasize the importance of model selection, the use of multiple independent models, and the in vivo context when studying the role of metabolic programs in cancer.
    DOI:  https://doi.org/10.64898/2025.12.17.694916
  15. Front Neurosci. 2025 ;19 1665272
    ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
    Chaitanya Kunja, Vaishali Kumar, Pradeep Kodam, Chamundeshwari Devi Gopu, Shuvadeep Maity.
      The endoplasmic reticulum (ER) and mitochondria are essential organelles that interact closely at specialized sites known as ER-mitochondria-associated membranes (MAMs). MAM is enriched with proteins from both the ER and mitochondria. ER stress sensors-inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) - are traditionally recognized for their roles in the unfolded protein response (UPR), which mitigates proteotoxic stress. However, recent studies reveal their non-canonical functions at MAMs, where they regulate calcium signaling, mitochondrial dynamics, and apoptosis through interactions with MAM-resident proteins. Disruption of these pathways is implicated in various diseases, particularly neurodegenerative disorders. This review highlights the emerging roles of IRE1 and PERK in preserving mitochondrial function and their relevance to neurodegeneration. It also examines pharmacological strategies targeting these proteins, which influence both UPR signaling and ER-mitochondrial communication, offering a comprehensive perspective on their roles in health and disease.
    Keywords:  ER stress sensors; ER-mitochondrial interactions; IRE1; UPR signaling; mitochondrial health; neurodegenerative diseases; pERK
    DOI:  https://doi.org/10.3389/fnins.2025.1665272
  16. STAR Protoc. 2025 Dec 26. pii: S2666-1667(25)00658-6. [Epub ahead of print]7(1): 104252
    Protocol to assess retinal metabolic flux of mice via stable isotope-resolved metabolomics.
    Georgy Komissarov, Kriti Pandey, Nicholas D Nolan, Thomas Winogrodzki, Daniel T Hass, Aykut Demirkol, Brian M Robbings, James B Hurley, Stephen H Tsang.
      Here, we present a protocol for evaluating glucose metabolism in mouse retinas and retinal pigment epithelium (RPE)-choroid tissue by tracking the incorporation of 13C6 from U-13C6-glucose with gas chromatography-mass spectrometry (GC-MS). We describe steps for incubating tissues in Krebs-Ringer bicarbonate solution and homogenizing tissues. We then detail procedures for extracting metabolites and determining isotopic labeling of intermediates in glycolysis and the tricarboxylic acid (TCA) cycle using GC-MS. The approach has been adapted to study glucose metabolism in various tissues, animal models, and genetic conditions. For complete details on the use and execution of this protocol, please refer to Nolan et al.1.
    Keywords:  Mass spectrometry; Metabolism; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2025.104252
  17. Sci Adv. 2026 Jan 02. 12(1): eady1136
    Precision acoustofluidics for high-throughput mechanobiology in suspension cells.
    Kaichun Yang, Ruoyu Zhong, Ke Li, John Mai, Pengzhan Liu, Ye He, Joseph Rich, Ying Chen, Janna Wang, Zhiteng Ma, Xianchen Xu, Qian Wu, Tony Jun Huang.
      Mechanomodulation, the process of altering cellular behavior through applied mechanical forces, plays a critical role in physiological processes and has substantial implications for cancer therapy, immunology, and drug development. However, precise and efficient stimulation of nonadherent cells remains a major challenge, limiting the investigation of mechanotransduction pathways and the development of targeted therapeutics. Here, we developed an acoustofluidic platform named Suspension-cell Targeted Response to Excitation via Acoustofluidic Mechanomodulation (STREAM) to enable precise, high-throughput stimulation of suspension cells. STREAM accomplishes this using 101.14-megahertz high-frequency surface acoustic waves to deliver controlled mechanical stimulation at a throughput of 500,000 cells per minute. STREAM modulates intracellular calcium ion (Ca2+) signaling by activating mechanosensitive ion channels, triggering mitochondrial membrane disruption and tunable K562 leukemia cell apoptosis rates from 5.15 to 47.1%. STREAM provides a scalable, precise tool for studying mechanotransduction in suspension cells, with broad applications in cancer research, immunotherapy, and high-throughput drug screening.
    DOI:  https://doi.org/10.1126/sciadv.ady1136
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