bims-celmim 2026-02-08 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–02–08
25 papers selected by
Marc Segarra Mondejar, AINA

ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.
Pyruvate kinase muscle 2 (PKM2) promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion.
Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.
Visualization of Calcium Decoding via a FRET-Based Reporter for Calcium-Decoder Conformation.
IMP metabolic mechanisms and IMPDH targeting strategies in tumor metabolic reprogramming and therapy (Review).
Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets.
Multi-omic analysis of guided and unguided forebrain organoids reveals differences in cellular composition and metabolic profiles.
USP20-RAB8A signaling axis restricts pancreatic cancer progression by disrupting GLUT1 vesicular trafficking and inhibiting glucose uptake.
SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
Lactate transmission from hypoxic tumor cells promotes macrophage senescence and M2 polarization via the DNMT1-NHE7 axis to accelerate endometrial cancer progression.
Oncogenic functions of polypyrimidine tract-binding protein 1 in breast cancer metabolism and progression.
Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.
NMR metabolomic signatures of healthy lifestyle and incident MASLD.
An Integrated Multi-omic Analysis Reveals Novel Gene-Metabolite Relationships in Human Steatohepatitic Hepatocellular Carcinoma.
HRD1 negatively regulates autolysosome formation by inhibiting liquid-liquid phase separation of SNAP29.
Connections between physics and metabolism in brain functions.
A Dual-Organelle Fluorescent Probe for Visualizing Intracellular Microviscosity Dynamics.
Distinct sensing of BCAAs by mTOR and c-Myc governs T cell proliferation, independent of catabolism.
Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.
Fluorescence Lifetime Microscopy Methods for Studying Dynamics of Fluorescent Proteins In Vivo and In Vitro.
Mitochondrial specialization and signaling shape neuronal function.
ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.
Covalent modification of a glutamic acid inspired by HaloTag technology.
Dual-organelle-targeted near-infrared carbon dots for visualizing glucose dynamics in cellular energy metabolism with potential in exercise physiology.
Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.

Cancer Res. 2026 Feb 04. OF1-OF14

ZNF395 Is a Hypoxia-Responsive Regulator of Mitochondrial Glutaminolysis in Clear Cell Renal Cell Carcinoma.

Joanna Koh, Chengheng Liao, Michelle Shu Wen Ng, Jing Han Hong, Hong Lee Heng, Dan Y Gui, Zhenxun Wang, Benjamin Yan-Jiang Chua, Zhimei Li, Radoslaw M Sobota, Lye Siang Lee, Jabed Iqbal, Kevin Junliang Lim, Divya Bezwada, Ralph J DeBerardinis, Gertrud Steger, Jianhong Ching, Patrick Tan, Bin Tean Teh, Qing Zhang, Xiaosai Yao.

Hypoxia signaling induced by VHL deficiency fuels growth but also imposes metabolic stress on clear cell renal cell carcinomas (ccRCC). Many ccRCC cells depend on glutamine as the primary source of tricarboxylic acid (TCA) anaplerosis. Hypoxia-inducible factor α (HIFα) governs glycolysis but does not directly regulate glutamine metabolism; instead, the factor responsible for orchestrating glutamine metabolism and mitochondrial adaptations to hypoxia remains elusive. In this study, we showed that ZNF395 is a hypoxia-responsive factor that regulates glutamine metabolism in the mitochondria. When activated by a HIF2α-modulated superenhancer, ZNF395 facilitated the transcription of enzymes essential for glutaminolysis, including glutaminase (GLS) and isocitrate dehydrogenase 2. Functionally, ZNF395 depletion resulted in reduced TCA cycle intermediates and their derivatives, including amino acids, glutathione, and pyrimidine nucleotides, leading to impaired mitochondrial respiration. Restoration of mitochondrial complex I function and GLS expression partially rescued the effects of ZNF395 depletion on ccRCC tumor growth. Together, this study underscores the coordinated role of HIFα and ZNF395 in shaping metabolic adaptations in response to hypoxia in VHL-deficient ccRCCs.
SIGNIFICANCE: ZNF395 and HIF are complementary mediators of hypoxia-induced metabolic reprogramming and therapeutic targets in VHL-deficient kidney cancer, with the former regulating glutamine metabolism and the latter regulating glucose metabolism.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4745
Sci Adv. 2026 Jan 30. 12(5): eaec5092

Pyruvate kinase muscle 2 (PKM2) promotes CD4 T cell survival by regulating pyruvate oxidation during homeostasis and expansion.

Jeff J Subleski, Erika M Palmieri, Jessica F Walls, Steven Hsu, Ian A Bettencourt, Timothy R Gower, Scott K Durum, Daniel W McVicar.

Glycolysis is an essential metabolic pathway for rapidly expanding T cells, but the role of pyruvate kinase muscle 1 (PKM1) and PKM2 in regulating this process is underappreciated. Here, using a pharmacological activator and targeted deletion of PKM2 in T cells, we delineated distinct functions of PKM1 and PKM2 in regulating CD4 T cell survival during homeostasis and expansion. Expanding PKM2-deficient CD4 T cells increased PKM1 expression with associated mitochondrial reactive oxygen species-mediated cell death. Examination of T cell compartments revealed that PKM2-deficient CD4 T cells were unaltered in the thymus but were significantly reduced in peripheral tissues as mice aged. The inability of PKM1 to protect CD4 T cells in the absence of PKM2 led to less severe T cell-mediated colitis as PKM2-deficient pathogenic cells were significantly reduced compared with control cells. This study shows that PKM2 is critical for CD4 T cell survival during expansion and homeostasis.

DOI: https://doi.org/10.1126/sciadv.aec5092
bioRxiv. 2026 Jan 23. pii: 2026.01.22.701145. [Epub ahead of print]

Astrocytic response to traumatic brain injury to rescue neuronal mitochondrial dysfunction through mitochondrial transfer.

Gopal V Velmurugan, Hemendra J Vekaria, Alexander G Rabchevsky, Kai Saito, Josh M Morganti, Samir Patel, Brad Hubbard, Patrick G Sullivan.

As highly dynamic organelles, mitochondria play an essential role in neuronal survival and synaptic function. Excitotoxicity is as a critical factor that promotes mitochondrial dysfunction after traumatic brain injury (TBI). Intercellular mitochondrial transfer and exogenous mitochondrial transplantation are emerging concepts to understand mitochondrial trafficking in response to mitochondrial dysfunction; however, robust in vivo evidence remains limited on the extent of these processes in the central nervous system (CNS). There is a significant knowledge gap in our understanding of mitochondrial transfer mechanisms under both normal physiological conditions and after experimental TBI. Mouse lines expressing mitochondrial green-fluorescent dendra-2 (mtD2) and GFP (mtGFP) targeted to inner and outer mitochondrial membranes, respectively, were used to study astrocyte-specific (Aldh1l1-CreER; mtD2 f/f - AmtD2 and Aldh1l1-CreER; mtGFP f/f - AmtGFP) and neuron-specific (CamK2aCre; mtD2 f/f - NmtD2 and CamK2aCre; mtGFP f/f - NmtGFP) mitochondrial dynamics and bioenergetics in acute TBI and excitotoxicity. At 24 hrs following TBI, neurons in the NmtD2 mouse brain exhibited rapid and significant alterations in mitochondrial morphology, including changes in total mitochondrial volume, volume distribution, and sphericity. Synaptic neuronal (SN) mitochondria display robust deficits in mitochondrial bioenergetics and complex protein levels while non-synaptic neuronal (NSN) mitochondria show State III bioenergetics and complex proteins at control levels. These findings are accompanied by a marked increase in astrocyte-derived mitochondria (AmtGFP) transfer to neurons at 24 hrs post-injury, compared to control animals, but no increase in transfer to neuronal synapses. While TBI also altered astrocytic mitochondrial morphology in the cortex, astrocytic mitochondrial bioenergetics remained preserved. Single-cell RNA-seq analysis of astrocytes revealed significant transcriptional reprogramming following TBI, characterized by the upregulation of genes associated with mitochondrial homeostasis and the machinery for organelle trafficking. In vitro co-cultures of primary cortical astrocytes and neurons demonstrated that astrocytes can transfer mitochondria to neurons via direct contact and that NMDA-mediated excitotoxicity further enhanced this astrocyte-to-neuron mitochondrial transfer. Furthermore, astrocytic-derived extracellular vesicles containing mitochondria (EV-mito) deliver mitochondria to neurons and EV-mediated mitochondrial transfer significantly ameliorated NMDA-induced mitochondrial dysfunction in primary cortical neurons. Together, these findings show that astrocytes take on a TBI-related phenotype that facilitates dynamic changes in mitochondrial networks and mitochondrial trafficking to neurons. Astrocytic transfer of respiratory-competent mitochondria support is an intrinsic neuroprotective response to injury that supports mitochondrial function in neuronal soma, dendrites, and axons but not at the neuronal synapse. Finally, we show therapeutic potential of exogenous mitochondrial transfer, particularly via EV-mito, for treating neurological disorders associated with excitotoxicity, such as TBI.

DOI: https://doi.org/10.64898/2026.01.22.701145
Methods Mol Biol. 2026 ;3012 67-94

Visualization of Calcium Decoding via a FRET-Based Reporter for Calcium-Decoder Conformation.

Anja Liese, Sarah Lederer, Bernadette Eichstädt, Tina Romeis.

  Calcium sensors as tools to visualize calcium dynamics have significantly advanced our understanding of calcium signaling, but visualization of calcium decoding remains a major challenge. Towards this end, we developed the CPKaleon reporter for monitoring conformational changes of the calcium sensor-decoder family of calcium-dependent protein kinases (CPK). It enables the real-time visualization of CPK activation and inactivation in response to specific treatments. Here, detailed protocols for the in vitro characterization and in vivo imaging of CPKaleon are presented.

Keywords:  Biosensor; CPK conformational sensor; Calcium-dependent protein kinases (CPKs); Förster resonance energy transfer; Live-cell imaging; Visualization of calcium decoding

DOI:  https://doi.org/10.1007/978-1-0716-5138-4_5
Int J Mol Med. 2026 Apr;pii: 81. [Epub ahead of print]57(4):

IMP metabolic mechanisms and IMPDH targeting strategies in tumor metabolic reprogramming and therapy (Review).

Hao Zhu, Hao Wang, Xia Li, Weisong Zhang, Yihao Wang, Qingze Tan, Dongxu Ying, Zhan Shi, Jianxiang Song.

  Metabolic reprogramming is a hallmark feature of malignant tumors. These metabolic pathways are regulated in a cell‑autonomous manner by oncogenic signaling and transcriptional networks, and tracking their metabolic reprogramming is frequently used in the diagnosis, detection and treatment of cancer. There are currently promising therapeutic prospects for a variety of types targeting fixed core metabolic pathways in tumor metabolic reprogramming. Among these, inosine monophosphate (IMP) is an essential intermediate in purine nucleotide synthesis that demonstrates significant target potential. Nevertheless, further research is needed to elucidate the regulatory networks that control IMP metabolism in tumor cells. This review combines the latest insights into IMP metabolism into an interesting conceptual framework. This includes the supply of IMP precursor substrates (reprogramming of glucose metabolism, serine/one‑carbon metabolism, glutamine and mitochondrial metabolism), the dynamic regulation of important enzymes [phosphoribosyl pyrophosphate synthetase, phosphoribosyl pyrophosphate amidotransferase, IMP dehydrogenase (IMPDH)], purinosomes and signaling pathways (RAS‑ERK, PI3K/AKT‑mTORC1 and Hippo‑YAP) that ultimately regulate IMP synthesis in tumor cells. Additionally, it focused on downstream associations between IMPDH and the immune microenvironment, offering a fresh perspective for current research on tumor therapy targeting IMP metabolism.

Keywords:  IMP metabolism; IMPDH; cancer; metabolic reprogramming; purinosome; signaling pathways

DOI:  https://doi.org/10.3892/ijmm.2026.5752
Annu Rev Biophys. 2026 Feb 05.

Mitochondrial Outer Membrane Voltage-Dependent Anion Channels: Unique Structures, Distinct Functions, and Novel Therapeutic Targets.

Shashank Ranjan Srivastava, Aadish Rawat, Radhakrishnan Mahalakshmi.

Voltage-dependent anion channels (VDACs) of the outer mitochondrial membrane carry out bidirectional flux of metabolites and ions and serve as the first line of communication between the cytosol and mitochondria. They are now recognized as indispensable for mitochondrial function and cellular homeostasis, mitochondria-endoplasmic reticulum communication, lipid and cholesterol biogenesis, Ca2+ homeostasis, and mitochondria-mediated apoptosis. The unique structural features of VDACs are also important in redox regulation. VDAC dysregulation by interaction with amyloid-β, α-synuclein, Tau, or tubulin can lead to neurodegeneration. Here, we provide insights into the structures, isoform-specific molecular functions, cellular interactome, variations, and unique regulatory elements of VDACs and their direct implications in widespread burdens like cancer and neurodegeneration in humans. We discuss how deducing isoform-specific structure-function studies of VDACs has the potential for successful development of next-generation diagnostics-guided therapeutics.

DOI: https://doi.org/10.1146/annurev-biophys-061124-102155
Cell Rep Methods. 2026 Feb 04. pii: S2667-2375(25)00331-5. [Epub ahead of print] 101295

Multi-omic analysis of guided and unguided forebrain organoids reveals differences in cellular composition and metabolic profiles.

Marie Sejberg Øhlenschlæger, Pia Jensen, Jesper Foged Havelund, Sissel Ida Schmidt, Fadumo Abdullahi Mohamed, Magdalena Sutcliffe, Sofie Blomberg Elmkvist, Lucrezia Criscuolo, Steven W Wingett, Ilaria Chiaradia, Elif Bayram, Jeppe Allen Abildsten Nicolaisen, Lene Andrup Jakobsen, Jonathan Brewer, Michael Eriksen Benros, Kristine Freude, Nils Joakim Færgeman, Madeline A Lancaster, Martin Røssel Larsen, Helle Bogetofte.

  Neural organoids are invaluable model systems for studying neurodevelopment, generated by either guided or unguided approaches. Despite the importance for the field, the resulting differences between these models are unclear. To obtain an unbiased comparison, we performed a multi-omic analysis of forebrain organoids generated in parallel with two widely applied guided and unguided protocols. The guided forebrain organoids contained a larger proportion of neurons, including GABAergic interneurons, whereas the unguided organoids contained significantly more choroid plexus, radial glia, and astrocytes at later stages. Substantial differences in metabolic profiles were identified, pointing to increased levels of oxidative phosphorylation and fatty acid β-oxidation in the unguided forebrain organoids and a higher reliance on glycolysis in the guided forebrain organoids. Overall, our study comprises a thorough description of the multi-omic differences between these guided and unguided forebrain organoids and provides an important resource for the neural organoid field studying neurodevelopment and disease.

Keywords:  CP: neuroscience; CP: stem cell; brain organoids; cerebral organoids; forebrain; neural organoids; post-translational modifications; proteomics; schizophrenia; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.crmeth.2025.101295
Cancer Lett. 2026 Feb 04. pii: S0304-3835(26)00062-5. [Epub ahead of print] 218299

USP20-RAB8A signaling axis restricts pancreatic cancer progression by disrupting GLUT1 vesicular trafficking and inhibiting glucose uptake.

Yu Bai, Zixi Liu, Xiao Zhai, Di Zhang, Shiqiang Liu, Qilong Xia, Lin Chen, Yongkang Shi, Yangwei Liao, Yuhui Liu, Zhenxiong Zhang, Simiao Xu, Jun Gong, Chunle Zhao, Min Wang, Xiuhui Shi, Feng Zhu, Renyi Qin.

  Cancer cells undergo metabolic reprogramming to meet the demands of rapid proliferation, survival and chemotherapy resistance. Targeting cancer-specific metabolic vulnerabilities offers a compelling strategy for therapeutic intervention. Owing to the Warburg effect and the unique tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells exhibit a high demand for glucose to sustain their energy metabolism. Here, we identify a novel regulatory mechanism controlling the cell surface abundance of glucose transporter 1 (GLUT1), mediated by RAB8A-dependent vesicular trafficking. RAB8A, a member of the RAS oncogene family, enhances GLUT1 membrane localization and thereby increases glucose uptake in PDAC cells. Mechanistically, we demonstrate that ubiquitin-specific peptidase 20 (USP20) negatively regulates RAB8A activation by selectively removing K48-linked polyubiquitin chains from its inactive form. Functional assays in vitro and in vivo validate the tumor-suppressive role of the USP20-RAB8A signaling axis. Furthermore, using primary PDAC cells derived from KPC (KrasG12D/+; Trp53 R172Hflox/flox; Pdx1-Cre) mice, we show that dual knockdown of Rab8a and Glut1 markedly attenuates tumor-promoting effects driven by oncogenic Kras and Trp53 loss. Collectively, our findings reveal that the USP20-RAB8A-GLUT1 axis regulates glucose uptake and metabolic reprogramming in PDAC, thereby inhibiting tumor growth and metastasis. Targeting this signaling axis provides a novel insight into metabolic therapy for pancreatic cancer.

Keywords:  Deubiquitination; Glucose transport; RAB8A; USP20; Vesicular transport

DOI:  https://doi.org/10.1016/j.canlet.2026.218299
Nat Metab. 2026 Feb 06.

SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.

Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.

Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.

DOI: https://doi.org/10.1038/s42255-026-01455-6
Cell Death Dis. 2026 Jan 30. 17(1): 185

Lactate transmission from hypoxic tumor cells promotes macrophage senescence and M2 polarization via the DNMT1-NHE7 axis to accelerate endometrial cancer progression.

Shizhou Yang, Yuejiang Ma, Tingting Wu, Xiufeng Huang.

Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to produce and export more lactate. This lactate is transported to macrophages by MCT1 to drive M2 macrophage polarization. Mechanistically, lactate induces lactylation of Histone 3 in the promoter of DNA methyltransferase 1 (DNMT1) gene and activates transcription in macrophages, leading to the silencing of NHE7 gene expression, a key regulator of intracellular pH. Critically, NHE7 downregulation drives M2 polarization and senescence through the mitogen-activated protein kinase (MAPK) pathway activation in macrophages, ultimately facilitating EC progression. In vivo, we successfully established a xenograft tumor model using Ishikawa cells, and the data further confirmed that NHE7-overexpressing macrophages effectively abrogate exogenous lactate-accelerated xenograft tumor growth, as well as its M2 polarization and senescence. These findings uncover that hypoxia-mediated lactate production and transmission promote tumor-macrophage crosstalk via the DNMT1-NHE7 axis and EC progression, which offers novel therapeutic targets for EC.

DOI: https://doi.org/10.1038/s41419-026-08411-y
Biochem Biophys Rep. 2026 Mar;45 102458

Oncogenic functions of polypyrimidine tract-binding protein 1 in breast cancer metabolism and progression.

Manabu Futamura, Yoshihisa Tokumaru, Akira Nakakami, Yoshimi Niwa, Junichi Mase, Emiri Sugiyama, Mai Okawa, Kana Matsuda, Ryutaro Mori, Yukihiro Akao, Nobuhisa Matsuhashi.

  Polypyrimidine tract-binding protein 1 (PTBP1) is an RNA-binding protein that regulates alternative splicing and primarily acts as a splicing repressor. Previous studies have shown that PTBP1 is closely linked to cancer metabolism through regulation by miR-133b and miR-124, which inhibit PTBP1 expression and modulate the splicing of the pyruvate kinase muscle (PKM) gene. Increased PTBP1 expression promotes PKM2 production and enhances glycolysis-dependent metabolism, a hallmark of cancer known as the Warburg effect. Clinical and experimental analyses were conducted to investigate the role of PTBP1 in breast cancer (BC). In silico investigations using The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets revealed a significant association between PTBP1 overexpression and poor prognosis. In vitro, PTBP1 knockdown in BC cell lines (MCF7, SK-BR-3, and MDA-MB-231) increased PKM1 expression and the PKM1/PKM2 ratio, leading to reduced cell proliferation. ATP production increased in MCF7 and SK-BR-3 cells, but not in MDA-MB-231. Although NADH levels were elevated in MCF7 and MDA-MB-231 cells, lactate accumulation was most prominent in MDA-MB-231 cells. qRT-PCR analysis of surgical BC specimens confirmed significantly higher PTBP1 expression in tumour tissues than in adjacent normal breast tissues, with expression positively correlating with tumour grade. These findings collectively demonstrate that PTBP1 is overexpressed in BC and drives cancer-specific metabolic reprogramming associated with the Warburg effect. Therefore, PTBP1 may act as an oncogenic regulator of breast cancer metabolism and serve as a potential therapeutic target.

Keywords:  Breast cancer; Glycolysis; Oncogene; PKM; PTBP1; Warburg effect

DOI:  https://doi.org/10.1016/j.bbrep.2026.102458
J Biol Chem. 2026 Jan 28. pii: S0021-9258(26)00083-9. [Epub ahead of print] 111213

Mannose metabolic pathway senses glucose supply and regulates cell fate decisions.

Ziwei Wang, Yasuhide Miyamoto, Takehiro Suzuki, Miki Tanaka-Okamoto, Yu Mizote, Naoshi Dohmae, Hideaki Tahara, Naoyuki Taniguchi, Yoichiro Harada.

  Mammalian cells exploit diverse metabolic pathways to regulate cell fates during glucose deprivation. We previously reported that glucose deprivation lowers the metabolic activity of mannose pathway that is interconnected with glycolysis, leading to biosynthetic arrest and degradation of the glycan precursors for asparagine-linked glycosylation (N-glycosylation) in the endoplasmic reticulum (ER). However, the cellular role of this sequential metabolic response remains unknown, largely due to metabolic complications caused by glucose deprivation. Here, we genetically engineered cells to separate mannose pathway from glycolysis, allowing precise control of mannose pathway activity by adjusting mannose supply levels instead of changing glucose supply. Moderate decrease in mannose supply severely suppressed N-glycosylation, leading to activation of pro-survival PERK-eIF2 signals. Although further decrease in mannose supply to the minimal levels did not compromise cell survival, it depleted luminal protective glycocalyx of lysosomes and increased a risk of cell death by impairing lysosome integrity. These results indicate that low metabolic flux of glucose into mannose pathway initiates alterations in homeostasis of the ER and lysosomes, at least in part through N-glycosylation defects, leading to cell fate decisions.

Keywords:  Cell fate decision; N-glycosylation; endoplasmic reticulum; glucose deprivation; lysosomes

DOI:  https://doi.org/10.1016/j.jbc.2026.111213
Sci Rep. 2026 Feb 03.

NMR metabolomic signatures of healthy lifestyle and incident MASLD.

Xin Tang, Sihua Wen, Min Huang, Biao Tang, Zhixing Fan.

  We aimed to investigate the relationship between metabolomic signatures of healthy lifestyle with incident metabolic dysfunction-associated steatotic liver disease (MASLD) risk, and quantify the extent to metabolic signatures explain the healthy lifestyle-MASLD relationship. This prospective cohort study analyzed 179,261 UK Biobank participants with available nuclear magnetic resonance metabolomics data. Healthy lifestyle scores incorporated dietary quality, alcohol consumption, physical activity, and smoking behavior. Elastic net regularized regression identified lifestyle-associated metabolic signatures from 251 metabolic biomarkers. Cox regression models evaluated associations between lifestyle indices, metabolic profiles, and incident MASLD. Counterfactual-based mediation analysis quantified mechanistic pathways. During follow-up, 2422 participants (1.35%) developed incident MASLD. We identified a 94-metabolite signature strongly reflecting healthy lifestyle behaviors, dominated by lipoprotein subclasses (61.70%) and fatty acids (10.64%). Each 1-unit increment in the metabolic signature corresponded to 65.9% reduced MASLD risk (HR = 0.341, 95% CI 0.311-0.373). Mediation analysis revealed that metabolic alterations explained 55.80% (95% CI 47.85-85.28%) of the protective lifestyle-MASLD association, with fatty acid metabolism contributing the largest mediation effect. Addtionly, the parallel mediating effect of metabolic signatures, BMI, diabetes, and hypertension reached 86.21%. This comprehensive metabolomic signature captures healthy lifestyle behaviors and strongly predicts incident MASLD risk through metabolic reprogramming, particularly fatty acid and lipoprotein metabolism.

Keywords:  Fatty acids; Healthy lifestyle; Lipoprotein; Metabolic dysfunction-associated steatotic liver disease; Metabolomic

DOI:  https://doi.org/10.1038/s41598-026-36704-x
medRxiv. 2026 Jan 30. pii: 2026.01.28.26344977. [Epub ahead of print]

An Integrated Multi-omic Analysis Reveals Novel Gene-Metabolite Relationships in Human Steatohepatitic Hepatocellular Carcinoma.

Garrett B Anspach, Robert M Flight, Sehyung Park, Hunter N B Moseley, Robert N Helsley.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the fastest-growing etiology of hepatocellular carcinoma (HCC). A mechanistic understanding of the metabolic heterogeneity of MASLD-driven tumors is crucial to inform strategies for future treatment options.
Methods: Paired tumor (n=8) and adjacent non-tumor tissue (n=8) were collected from patients with steatohepatitic HCC at the University of Kentucky Markey Cancer Center. Hematoxylin and eosin (H&E) staining was used for pathological determination of tumor and adjacent nontumor tissue by a board-certified pathologist. Lipidomic, metabolomic, and transcriptomic analyses were performed, and data were integrated across platforms to identify novel relationships across tumor and adjacent nontumor tissue.
Results: Histological analysis by H&E showed significant lipid vacuole accumulation and inflammatory foci in HCC tumors relative to nontumor tissue. Across omics platforms, we identified 1,679 genes, 1,696 metabolites, and 292 lipids that were significantly (padj<0.01) increased or decreased in tumors relative to nontumor tissue. We identified significant reductions in total ceramides and increases in fatty acyl chain saturation in tumor tissue. Furthermore, metabolites involved in amino acid and fatty acid metabolism were largely decreased in tumors relative to nontumor tissue. We also identified a total of 303 highly significant and novel transcript-metabolite associations (117 gene-metabolite; 186 gene-lipid) across tumor and nontumor tissue.
Conclusions: Taken together, this integrative analysis reveals novel relationships between steady-state gene transcripts and specific metabolites in steatohepatitic tumors, thereby identifying new pharmacological targets that may be exploited for therapeutic benefit.

DOI: https://doi.org/10.64898/2026.01.28.26344977
Cell Rep. 2026 Jan 29. pii: S2211-1247(25)01686-9. [Epub ahead of print]45(2): 116914

HRD1 negatively regulates autolysosome formation by inhibiting liquid-liquid phase separation of SNAP29.

Wenyan Qu, Di Chen, Hongyu Zhao, Qiang Sheng, Juan Wang, Yujun Shen, Yuxian Shen.

  Autophagy is a highly conserved cellular process in which cytoplasmic contents are sequestrated by autophagosomes and delivered to lysosomes for degradation. Generation of degradative autolysosomes mediated by SNARE proteins is essential; however, the regulatory mechanisms governing this process remain underexplored. This study aimed to demonstrate that E3 ubiquitin ligase HRD1 regulates liquid-liquid phase separation (LLPS) of SNAP29, thereby modulating SNARE assembly. We found that HRD1 deficiency enhances autophagy activity and promotes autolysosome formation in a SNAP29-dependent manner. We also determined that SNAP29 forms highly dynamic condensates in in vivo and in vitro, which are crucial for the assembly of the SNARE complex. Mechanistically, HRD1 interacts with SNAP29 to suppress its condensation, whereas HRD1 depletion accelerates both SNAP29 condensate formation and SNARE complex assembly. Our findings reveal that HRD1 acts as a negative regulator in autolysosome formation by interacting with SNAP29, inhibiting its LLPS process, thereby modulating the binding affinity among SNARE components.

Keywords:  CP: Cell biology; HRD1; SNAP29; SNARE assembly; autolysosome; liquid-liquid phase separation

DOI:  https://doi.org/10.1016/j.celrep.2025.116914
iScience. 2026 Feb 20. 29(2): 114643

Connections between physics and metabolism in brain functions.

Fanny Mochel, Alfonso de Oyarzábal Sanz, Leticia Pías Peleteiro, Juliana Ribeiro-Constante, Patricia Bassereau, Kevin Chalut, Laurent Cognet, Leroy Cronin, Stuart Hameroff, Francisco J López-Murcia, Eva K Pillai, Marta Sales-Pardo, Anne Straube, Adrien Hallou, Angeles Garcia-Cazorla.

  Advances in molecular biology have shaped our understanding of cellular biology. Yet, this molecular-centric approach has overshadowed the role of physical processes governing cellular homeostasis. In genetic disorders, particularly inherited metabolic diseases, phenotypic heterogeneity cannot solely be explained by genetic variants. Mechanical properties of cells and tissues may account for this variability, given the interplay between biological and physical cues in metabolic regulations. In July 2024, we organized an international symposium with world experts in physics, chemistry, and neurobiology to explore the physical regulation of brain metabolism in health and disease. Topics included mechanotransduction in neurodevelopment and brain aging, the physics of neurotransmission and cellular trafficking, and emerging methods to model cellular metabolism, analyze single-cell mechanical and transcriptional signals, and track nanoparticles in intact brain tissue. This effort aims to foster an interdisciplinary framework for neuroscience and train scientists across disciplines, while integrating art to stimulate creativity and integrative thinking.

Keywords:  Biophysics; Cell biology; Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2026.114643
J Fluoresc. 2026 Feb 05.

A Dual-Organelle Fluorescent Probe for Visualizing Intracellular Microviscosity Dynamics.

Kaiwen Zheng, Xiang Wang, Haijiao Xie.

  Intracellular microviscosity is a key physicochemical parameter that influences molecular diffusion, signal transduction, and organelle function. However, fluorescence probes capable of selectively visualizing viscosity dynamics with high sensitivity and biological compatibility remain limited. Here, we report a dihydroxanthene-based viscosity-responsive fluorescent probe, ZKW, constructed with a D-π-A push-pull architecture and an o-bromophenyl molecular rotor. ZKW displays a pronounced viscosity-dependent fluorescence enhancement at 580 nm upon 550 nm excitation, originating from restricted intramolecular rotation and suppressed TICT processes. The probe exhibits good selectivity toward viscosity with negligible interference from polarity, pH, reactive species, metal ions, amino acids, or proteins, along with acceptable photostability and low cytotoxicity. Colocalization studies revealed preferential mitochondrial accumulation with partial lysosomal distribution, enabling simultaneous visualization of viscosity variations in these organelles. Using multiple cellular stress models-including LPS stimulation, oleic-acid treatment, nystatin exposure, and erastin-induced ferroptosis-ZKW effectively reported viscosity elevations at the subcellular level. These results establish ZKW as a robust and versatile tool for probing microviscosity heterogeneity in living cells and for facilitating studies of viscosity-associated physiological and pathological processes.

Keywords:  Cellular stress; Fluorescent probe; Intracellular microviscosity; Live-cell imaging; Lysosome; Mitochondria

DOI:  https://doi.org/10.1007/s10895-026-04714-7
bioRxiv. 2026 Jan 17. pii: 2026.01.16.699967. [Epub ahead of print]

Distinct sensing of BCAAs by mTOR and c-Myc governs T cell proliferation, independent of catabolism.

Kelly Rome, Elise Hall, Aaron Wu, Will Bailis.

The branched chain amino acids (BCAAs: leucine, isoleucine, valine) are essential amino acids that function as catabolic substrates and signaling molecules via mTORC1. While individual BCAAs have unique roles in organismal and cellular physiology, the mechanisms underlying their individual effects remain poorly understood. We demonstrate that the three BCAAs have distinct roles in T cell biology. We find that isoleucine and valine are necessary and sufficient for quiescence exit and cell division, whereas leucine is dispensable. Mechanistically, these effects are independent of their diverging catabolic fates and instead due to differential sensing of leucine and isoleucine/valine by mTOR and c-Myc. While isoleucine and valine are necessary and sufficient for c-Myc expression, mTORC1 leucine-sensing represses c-Myc and proliferation during BCAA restriction. Together, we find that the discrete sensing of the BCAAs uncouples two major anabolic regulators, mTORC1 and c-Myc, in cell growth. This provides mechanistic insight into the distinct roles of the BCAAs in cell physiology, highlighting divergent BCAA sensing rather than catabolism, and offering a new lens to appreciate their impact on immunity and pathophysiology.

DOI: https://doi.org/10.64898/2026.01.16.699967
PLoS One. 2026 ;21(2): e0340957

Quantitative and temporal analysis of autophagy: Differential Response to amino acid and glucose starvation.

Katie R Martin, Stephanie L Celano, Jessica D Guillaume, Ryan D Sheldon, Russell G Jones, Jeffrey P MacKeigan.

Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous, and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we set out to create a quantitative dataset of autophagy across multiple stages in single, living cells, measured under normal growth conditions and during nutrient starvation of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions.

DOI: https://doi.org/10.1371/journal.pone.0340957
Adv Exp Med Biol. 2026 ;1496 335-362

Fluorescence Lifetime Microscopy Methods for Studying Dynamics of Fluorescent Proteins In Vivo and In Vitro.

Bruno Pannunzio, Leonel Malacrida.

  Fluorescence-based microscopy techniques are key tools for studying protein dynamics in vivo, enabling real-time tracking of molecular interactions with high specificity and subcellular resolution. Fluorescence lifetime imaging microscopy (FLIM) provides quantitative insights into the microenvironment of fluorophores by measuring their excited-state decay times, independent of intensity-based variations such as concentration and photobleaching. The phasor approach to FLIM simplifies lifetime analysis by mapping decay dynamics onto a two-dimensional plot, eliminating complex fitting procedures and allowing real-time visualization of heterogeneous fluorescence signals. This approach enhances the detection of subtle microenvironmental changes, facilitating the study of protein interactions. This chapter explores the application of FLIM in molecular interaction studies, with a focus on Förster resonance energy transfer (FRET). Combining FLIM with FRET (FRET-FLIM) enables precise quantification of energy transfer efficiency, overcoming the limitations of intensity-based FRET measurements. Additionally, integrating FLIM with stimulated emission depletion (FLIM-STED) super-resolution microscopy extends the spatial resolution beyond the diffraction limit, allowing for the nanoscale mapping of protein distributions and interactions. Together, these advanced techniques provide powerful tools for investigating dynamic cellular processes with high temporal and spatial resolution, offering new perspectives on protein function and biomolecular mechanisms in living systems.

Keywords:  FLIM; FLIM-STED; FRET; Fluorescence lifetime imaging microscopy; Förster resonance energy transfer; Phasor approach

DOI:  https://doi.org/10.1007/978-3-032-07511-6_13
Trends Neurosci. 2026 Feb 03. pii: S0166-2236(25)00263-2. [Epub ahead of print]

Mitochondrial specialization and signaling shape neuronal function.

Benjamin Chun-Kit Tong, Francesco Gubinelli, Lena F Burbulla, Angelika B Harbauer.

  Neurons are specialized cells designed to process information and transmit it, often across long distances. In many neurons, the axonal volume far exceeds the somato-dendritic volume, creating a need for long-range transport and local polarization mechanisms. In addition, action potential firing and restoration of ionic gradients, as well as dynamic changes in synaptic plasticity, further increase the energetic demands of neurons. In this review, we highlight the roles mitochondria play in vertebrate neuronal biology and how mitochondrial functionality is tuned to support the unique demands of neurons. We cover the influence of mitochondrial positioning, ATP generation and Ca2+ buffering on neuronal function, and explore the role of mitochondria in neurotransmitter metabolism and local protein translation.

Keywords:  Ca(2+) signaling; local translation; neuronal cell biology; neurotransmitter metabolism; respiration; transport

DOI:  https://doi.org/10.1016/j.tins.2025.12.006
Nature. 2026 Feb 04.

ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.

Siva Kumar Natarajan, Joanna Lum, James Haggerty Skeans, Minal Nenwani, Sanjana Eyunni, Mateus Mota, Jill M Bayliss, Akash Deogharkar, Erin Taya Hamanishi, Matthew Pun, Stefan R Sweha, Simon Hoffman, Eleanor Young, Qiuyang Zhang, Rijul Mehta, Olamide Animasahun, Pranav Narayanan, Sushanth Sunil, Abhijit Parolia, Peter Sajjakulnukit, Pooja Panwalkar, Robert Doherty, Madison Clausen, Derek Dang, Debra Hawes, Fusheng Yang, Mariarita Santi, Alexander R Judkins, Yelena Wilson, Thomas Vigil, Andrea Franson, Richard M Mortensen, Tatsuya Ozawa, Andrea Griesinger, Eric C Holland, Nicholas K Foreman, Kulandaimanuvel Antony Michealraj, Sameer Agnihotri, Michael Taylor, Richard J Gilbertson, Carl Koschmann, Arul M Chinnaiyan, Costas A Lyssiotis, Deepak Nagrath, Sriram Venneti.

ZFTA-RELA+ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA1. Here we show that ZFTA-RELA+ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite2. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA+ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA+ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA+ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.

DOI: https://doi.org/10.1038/s41586-025-10005-1
Nat Commun. 2026 Jan 30. 17(1): 1257

Covalent modification of a glutamic acid inspired by HaloTag technology.

Ruirui Zhang, Jie Liu, Raphael Gasper, Anke Unger, Farnusch Kaschani, Markus Kaiser, Petra Janning, Herbert Waldmann.

For targeted covalent protein modification at low-reactivity aspartates and glutamates, new methods are in high demand. We report a technique inspired by the HaloTag technology, which employs nucleophilic substitution at chloroalkane-functionalised ligands by a specific aspartate residue. Embedding of alkyl bromide warheads into non-covalent inhibitors enables covalent modification of a glutamate in the lipoprotein binding chaperone - phosphodiesterase of retinal rod subunit delta (PDEδ), which shuttles prenylated lipoproteins between cellular membranes and thereby mediates their activity. Its hydrophobic ligand-binding pocket contains p.E88 as the only accessible nucleophile for covalent targeting. We show that a covalent inhibitor, termed DeltaTag, overcomes limitations of non-covalent inhibitors. DeltaTag labels PDEδ at its p.E88 under biologically relevant conditions, modulates mammalian target of rapamycin (mTOR) signalling by disrupting the PDEδ-Rheb (Ras homologue enriched in brain)-mTORC1 (mTOR complex 1) axis and inhibits cancer cell proliferation. This proof-of-concept study demonstrates that the design strategy holds promise for the covalent modification of proteins with lipophilic binding sites that lack accessible reactive amino acids but contain specific carboxylates.

DOI: https://doi.org/10.1038/s41467-026-68999-9
Anal Methods. 2026 Feb 06.

Dual-organelle-targeted near-infrared carbon dots for visualizing glucose dynamics in cellular energy metabolism with potential in exercise physiology.

XiaoWen Duan, XiaoDong Cheng.

Accurate monitoring of cellular energy metabolism is crucial for understanding exercise physiology and optimizing athlete training and recovery. However, current assessments mainly rely on macroscopic indicators such as heart rate and blood lactate, providing limited insight into intracellular glucose utilization-the key process governing energy supply and fatigue during exercise. Herein, we report the in situ synthesis of boronic acid-functionalized near-infrared (NIR) carbon dots (B-OH-CDs) from 1-methylisoquinoline and 4-formylbenzeneboronic acid under green and mild conditions. The resulting B-OH-CDs feature a graphitic carbon core and a borate-rich surface shell, exhibiting excitation-independent red emission (615 nm), high quantum yield (3.2%), and excellent photostability. Abundant boronic acid sites confer selective and sensitive fluorescence responses toward glucose (100 nM-200 µM, detection limit 85 nM). Confocal imaging reveals dual targeting of mitochondria and lysosomes, enabling real-time visualization of intracellular glucose dynamics related to cellular energy metabolism. This sustainable nanoplatform offers a new tool for exploring glucose-dependent metabolic regulation and holds potential for precision monitoring of energy balance, fatigue, and metabolic adaptation in exercise physiology.

DOI: https://doi.org/10.1039/d5ay01904d
bioRxiv. 2026 Jan 20. pii: 2026.01.20.700435. [Epub ahead of print]

Acetyl-CoA availability regulates neuronal metabolism, growth, and synaptic activity.

Eric R McGregor, Cassandra J McGill, Nicholas L Arp, Josef P Clark, Dominique A Baldwin, Di Kuang, Gonzalo Fernandez-Fuente, Yun Hwa Choi, Keenan S Pearson, Jason K Nagorski, Judith A Simcox, Jing Fan, Luigi Puglielli, Rozalyn M Anderson.

The metabolite acetyl-CoA plays a central role in cellular metabolic homeostasis. As part of the secretory pathway, acetyl-CoA is imported into the endoplasmic reticulum (ER) by a membrane-bound transporter AT-1 (SLC33A1). AT-1 has been linked to peripheral neuropathy (heterozygous mutations), developmental delay with premature death (homozygous mutations) and intellectual disability with progeria (duplication). These phenotypes can be reproduced in the mouse. Here, we show that AT-1 overexpression in primary neurons impacts diverse phenotypes related to neuronal function and plasticity. At the gene level, AT-1 induces brain aging signatures, and key differences in ribosomal and synaptic processes were identified in both the transcriptome and the proteome. Changes in mitochondria-associated pathways were reflected in an increase in expression of mitochondrial master regulator PGC-1α and its target genes. Functionally, marked differences in mitochondrial membrane potential, architecture, and respiration were detected. Tracing experiments indicated altered glucose utilization in glycogen storage and nucleotide production. Shifts in redox metabolism were linked to differences in levels of NAD-dependent SIRT1 and CtBP2, with consequences for acetylated lysine modification. Depletion of lipid stores was associated with greater plasticity in fuel substrate utilization and a major shift in cellular lipid composition. These broad-scale changes in metabolism were coincident with reduced expression of synaptic proteins and reduced activity among synaptic networks, indicating that neuronal electrophysiology and network communication are coordinated at least in part through neuronal acetyl-CoA metabolism.

DOI: https://doi.org/10.64898/2026.01.20.700435