bims-celmim 2025-08-10 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2025–08–10
25 papers selected by
Marc Segarra Mondejar

Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.
Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.
Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors.
The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.
Metabolic alterations associated with epileptic seizures detected by NMR spectroscopy.
NADH reductive stress drives metabolic reprogramming.
Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
Impacts of aging on brain metabolism.
Quantitative profiling of lipid transport between organelles enabled by subcellular photocatalytic labelling.
Metabolic dynamics of human external urethral sphincter myoblast differentiation and the effects of tricarboxylic acid cycle inhibition.
Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.
Targeting SREBP2 in cancer progression: Molecular mechanisms, oncogenic crosstalk, and therapeutic interventions.
Assessing cellular metabolic dynamics with NAD(P)H fluorescence polarization imaging.
Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.
Cradles of cellular architecture: ER nests as hubs for organelle birth.
Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
Reprogramming of amino acid metabolism in breast cancer.
Lysosomal membrane homeostasis and its importance in physiology and disease.
Nicotinamide phosphoribosyltransferase in NAD+ metabolism: physiological and pathophysiological implications.
Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide.
A cholesterol-dependent switch controls organ-specific metastasis in pancreatic cancer.
Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.
Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.
Glucose Metabolism echoes Long-Range Temporal Correlations in the Human Brain.
Yeast adapts to diverse ecological niches driven by genomics and metabolic reprogramming.

bioRxiv. 2025 Jul 31. pii: 2025.07.28.667250. [Epub ahead of print]

Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.

Simon Couly, Yuko Yasui, Ioannis Grammatikakis, Yuriko Kimura, Josh Hinkle, Juan Gomez, Hsiang-En Wu, Ghosh Paritosh, Ashish Lal, Michael Michaelides, Brandon Harvey, Tsung-Ping Su.

Sigma-1 receptor (S1R) is a Ca 2+ sensitive, ligand-operated receptor chaperone protein present on the endoplasmic reticulum (ER) membrane and more specifically at the mitochondria-associated ER membrane (MAM). Upon activation by ER calcium depletion or ligand binding, S1R can increase calcium efflux from the ER into the mitochondria by chaperoning IP3 receptor type3 (Ip3R3). Mitochondrial metabolism has an intricate relationship with glycolysis. Despite S1R affecting mitochondria, the relevance of S1R to glycolysis and its impact on the overall cellular energy metabolism is not known. This study utilizes wild-type (Wt) and S1R knockout (S1R KO) Neuro2a (N2a) cells and Wt and S1R KO mice for primary culture of cortical neurons studies and longitudinal in-vivo imaging. In this manuscript we describe the fundamental functions of S1R on glycolysis, mitochondrial activity and NAD + /NADH metabolism, keystone coenzymes essential for glycolysis and for mitochondrial activity. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 but no change in mitochondrial oxygen consumption. Furthermore, we observed an increased NAD + /NADH ratio in S1R KO condition. Positron emission tomography revealed decreased [ 18 F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking down GRIM19 in S1R KO condition rescued the glycolysis deficit. Altogether, these data show for the first time that S1R modulates glycolysis and NAD metabolism in various neuronal systems. This new insight on the S1R function may lead to new therapeutic applications of S1R ligands where compromised glycolysis and cellular NAD+/NADH ratios occur such as aging and neurodegeneration.

DOI: https://doi.org/10.1101/2025.07.28.667250
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667736. [Epub ahead of print]

Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.

Johnathon Sturgis, Ke Jiang, Stephanie A Hagstrom, Maya Moorthy, Vera L Bonilha.

Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet to be thoroughly explored. Our previous studies focused on the retinal phenotype observed in the PolgD257A mutator mice (D257A), revealing the effects of aging and mtDNA mutation accumulation in the retina. We have reported that this model exhibited significant morphological and functional deficits in the retina by 6 months of age, with notable alterations in the retinal pigment epithelium (RPE) occurring as early as 3 months, including changes in the cristae density and reduction in length of mitochondria. This study investigated how mtDNA mutations affect the metabolic interaction between the retina and RPE in young (3 months) and old (12 months) wild-type (WT) and D257A mice. We assessed cellular energy production using freshly dissected retina samples from both groups through Seahorse analysis, immunofluorescence, and Western blot experiments. The analysis of aged D257A retina punches revealed significantly reduced basal and maximal mitochondrial respiration, along with increased mitochondrial reserve capacity compared to WT. However, glycolytic flux, measured as a function of extracellular acidification rate (ECAR), did not differ between WT and D257A mice. Both D257A retina and RPE exhibited decreased expression of essential electron transport proteins involved in oxidative phosphorylation. Additionally, we observed a reduction in the expression of glucose transporter 1 (GLUT-1) and lactate transporter (MCT1) at the apical surface of the RPE. Enzymes associated with glycolysis, including hexokinase II and lactate dehydrogenase A, were significantly lower in the aged D257A retina, while hexokinase I and pyruvate kinase 2 were upregulated in the RPE. These findings indicate that the accumulation of mtDNA mutations leads to impaired metabolism in both the retina and RPE. Furthermore, it suggests that glucose from the choroidal blood supply is being utilized by the RPE rather than being transported to the neural retina. Mitochondrial dysfunction in RPE promotes a glycolytic state in these cells, leading to reduced availability of metabolites and, consequently, diminished overall retinal function. These results are essential for advancing our understanding of the mechanisms underlying retinal degeneration and provide a new perspective on the role of mtDNA mutations in these diseases.

DOI: https://doi.org/10.1101/2025.07.30.667736
Front Immunol. 2025 ;16 1595162

Research progress on the interaction between glucose metabolic reprogramming and lactylation in tumors.

Yi Yang, Yi Wu, Hui Chen, Zehai Xu, Ruisi Lu, Sijie Zhang, Rui Zhan, Qinghua Xi, Yunfeng Jin.

  Glucose metabolic reprogramming describes the alterations in intracellular metabolic pathways in response to variations in the body's internal environment. This metabolic reprogramming has been the subject of extensive research. The primary function is to enhance glycolysis for rapid ATP production, even with sufficient oxygen, leading to a significant accumulation of lactic acid, which subsequently affects the functions of tumor cells and immune cells within TME. Lactylation represents a newly identified post-translational modification (PTM) that occurs due to lactate accumulation and is observed in various proteins, encompassing both histone and non-histone types. Lactylation alters the spatial configuration of proteins, influences gene transcription, and thereby regulates gene expression. This modification serves as a significant epigenetic regulatory factor in numerous diseases. Glucose metabolic reprogramming and lactylation are intricately linked in the process of tumorigenesis. Glucose reprogramming activates essential enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), through transcription factors such as HIF-1α and c-Myc, thereby enhancing glycolysis and lactate accumulation. Lactate functions as a metabolite and signaling molecule, acting as a substrate for lactylation facilitated by histone acetyltransferases such as CBP/p300. This epigenetic modification inhibits antitumor immunity through the upregulation of oncogenic signaling pathways, the induction of M2-type macrophage polarization, and the dysfunction of T-cells. Glucose metabolic reprogramming not only influences lactate synthesis but also provides sufficient substrates for lactate modification. The two factors jointly affect gene expression and protein function, acidify the tumor microenvironment, regulate immune evasion, and promote carcinogenesis. This review systematically details the mechanisms of lactylation and glucose metabolic reprogramming, their impacts on immune cells within the tumor microenvironment, and their interrelations in tumor progression, immunity, and inflammation.

Keywords:  glucose metabolic reprogramming; immune cells; lactate; lactylation; macrophage; posttranslational modification; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1595162
Annu Rev Cell Dev Biol. 2025 Aug 06.

The AMPK Pathway: Molecular Rejuvenation of Metabolism and Mitochondria.

Nazma Malik, Reuben J Shaw.

Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.

DOI: https://doi.org/10.1146/annurev-cellbio-120420-094431
Sci Rep. 2025 Aug 08. 15(1): 29119

Metabolic alterations associated with epileptic seizures detected by NMR spectroscopy.

Juan C Avalos, Leonardo Pellizza, Martin Aran.

  Epilepsy affects over 50 million individuals worldwide. Despite the availability of anti-seizure medications, approximately 30% of patients remain drug-resistant, emphasizing the pressing need for alternative therapeutic strategies. In recent years, NMR-based metabolomics has emerged as a robust platform to investigate metabolic disturbances in neurological disorders, potentially improving diagnostic precision and explore individualized treatment options.In this study, we analysed serum metabolomics profiles from 32 patients with epilepsy, evaluated both at baseline and shortly after seizure episodes, and 28 healthy controls. Using an untargeted NMR-based metabolomics approach combined with multivariate and statistical analyses, we identified significant metabolic alterations and assessed their diagnostic potential. A total of 14 metabolites differed significantly between patients and controls. Among these, citrate, glutamate, proline, 3-methyl-2-oxovalerate, and glucose showed strong potential as biomarkers. Post-seizure samples revealed alterations in seven metabolites, including hippurate, pyroglutamate, isovalerate, creatinine, threonine, 3-methyl-2-oxovalerate, and 2-oxoisocaproate. Notably, we observed distinct metabolic signatures distinguishing focal from generalized seizures.To our knowledge, this is the first comprehensive serum metabolomics study using NMR to evaluate both basal and post-seizure states in epilepsy. Our findings highlight key alterations in energy metabolism, oxidative stress, and amino acid pathways, offering promising leads for improving clinical assessment and tailoring therapeutic strategies in epilepsy care.

Keywords:  Biomarkers; Epilepsy; NMR-metabolomics; Seizure-specific metabolic signatures

DOI:  https://doi.org/10.1038/s41598-025-14718-1
Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]

NADH reductive stress drives metabolic reprogramming.

Ronghui Yang, Zihao Guo, Binghui Li.

  Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.

Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress

DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
bioRxiv. 2025 Jul 24. pii: 2025.07.23.666448. [Epub ahead of print]

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.

Milan R Savani, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Bingbing Li, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Tracey Shipman, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

Conventional stable isotope tracing assays track one or several metabolites. However, cells use an array of nutrients to sustain nitrogen metabolic pathways. This incongruency hampers a system level understanding of cellular nitrogen metabolism. Therefore, we created a platform to simultaneously trace 30 nitrogen isotope-labeled metabolites. This platform revealed that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine despite expressing de novo pathway enzymes. This link between cell state and pyrimidine synthesis routes persisted in physiological contexts, including primary murine and human tissues and tumor xenografts. Mechanistically, we found that Ser1900 phosphorylation of CAD, the first enzyme of the de novo pathway, was enriched in primitive cells and that mimicking this modification in differentiated cells abrogated their preference for pyrimidine salvage. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

DOI: https://doi.org/10.1101/2025.07.23.666448
Prog Brain Res. 2025 ;pii: S0079-6123(25)00067-6. [Epub ahead of print]295 9-38

Impacts of aging on brain metabolism.

Bianca Andrade Rodrigues, Thays Calista Santiago Pretes, Josiane do Nascimento Silva.

  Changes in energy homeostasis in aging have significant implications for brain health. Decreased glucose utilization efficiency, mitochondrial dysfunction, loss of metabolic flexibility, and increased oxidative stress can compromise cognitive functions and increase vulnerability to neurodegenerative diseases. Understanding these changes provides valuable insights for prevention and treatment strategies, such as dietary interventions, physical exercise, and pharmacological therapies, aimed at restoring or preserving energy homeostasis in the brain and thus improving cognitive health throughout life. This chapter explores the metabolic changes in the brain associated with aging, examining the underlying biochemical and molecular mechanisms, as well as therapeutic strategies that may alleviate the detrimental effects of brain aging.

Keywords:  Brain aging; Brain metabolism; Energy homeostasis; Glucose; Ketone bodies; Metabolic flexibility; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/bs.pbr.2025.05.009
Nat Chem. 2025 Aug 06.

Quantitative profiling of lipid transport between organelles enabled by subcellular photocatalytic labelling.

Xi Chen, Ru He, Haolin Xiong, Ruohong Wang, Yandong Yin, Yiyun Chen, Zheng-Jiang Zhu.

Subcellular lipid composition and transport substantially influence the physiological and pathological functions of both cells and organelles. However, lipid transport and turnover between organelles remain poorly understood due to a lack of methods for selectively labelling lipids in organelles. Here we develop a subcellular photocatalytic labelling strategy that enables organelle-selective lipid analysis by mass spectrometry and the quantitative profiling of lipid transport between organelles. We use this approach to quantitatively characterize fatty-acyl-dependent transport of phosphatidylethanolamine and phosphatidylserine lipids between the endoplasmic reticulum and mitochondria, the nucleus or lysosomes. Further experiments revealed the relative contributions of various biosynthesis pathways to the phosphatidylethanolamine and phosphatidylserine lipid compositions in the mitochondria, nucleus and lysosomes. Lysosome-specific photocatalytic labelling revealed the impact of the mTOR kinase pathway on lysosomal lipid metabolism. Together, this subcellularly localized photocatalytic labelling of lipids quantitatively deciphers the subcellular lipid composition and transport, enhancing our understanding of lipid metabolism in living organisms.

DOI: https://doi.org/10.1038/s41557-025-01886-w
Sci Rep. 2025 Aug 07. 15(1): 28987

Metabolic dynamics of human external urethral sphincter myoblast differentiation and the effects of tricarboxylic acid cycle inhibition.

Hironori Kai, Shinro Hata, Noriko Hamamatsu, Mayuka Shinohara, Keiko Matsuura, Hiromitsu Mimata, Toshitaka Shin.

  Stress urinary incontinence commonly arises with aging or following prostatectomy, yet its underlying mechanisms remain unclear. To address this, we investigated the role of metabolic pathways-particularly the tricarboxylic acid (TCA) cycle-in the differentiation of human external urethral sphincter myoblasts. Immortalized sphincter cells (US2-KD) were induced to differentiate over 192 h. Metabolomic profiling using gas chromatography-mass spectrometry, along with pathway enrichment analysis, identified key metabolic changes. Inhibition of mitochondrial pyruvate transport with UK5099 markedly suppressed TCA cycle metabolites, including citrate, α-ketoglutarate, fumarate, and malate. This inhibition also significantly reduced MYH7 expression and intracellular adenosine triphosphate levels throughout the differentiation period. These results demonstrate that the TCA cycle plays a critical role in both energy metabolism and the differentiation of urethral sphincter myoblasts. This study is the first to suggest that impaired TCA cycle activity may contribute to the pathogenesis of Stress urinary incontinence and represents a potential therapeutic target. Our findings offer new insight into age-related metabolic decline associated with Stress urinary incontinence and support the development of therapies that combine metabolic modulation with regenerative approaches.

Keywords:  External urethral sphincter; Metabolomic pathways; Myoblast differentiation; Stress urinary incontinence; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1038/s41598-025-13764-z
Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00300-6. [Epub ahead of print]37(8): 1630-1632

Insulin signaling in microglia: A metabolic switch controlling neuroinflammation and amyloid pathology in Alzheimer's disease.

Eugenio Barone, D Allan Butterfield.

Insulin resistance is a risk factor for Alzheimer's disease (AD). Chen et al.1 show that microglial insulin signaling is essential for metabolic homeostasis and immune regulation, while insulin resistance impairs Aβ clearance and promotes neuroinflammation in AD. Their findings reframe AD pathogenesis through a cell-type-specific lens.

DOI: https://doi.org/10.1016/j.cmet.2025.06.005
Cell Signal. 2025 Aug 04. pii: S0898-6568(25)00459-0. [Epub ahead of print]135 112044

Targeting SREBP2 in cancer progression: Molecular mechanisms, oncogenic crosstalk, and therapeutic interventions.

Rajan Radha Rasmi, Rachel Kovatich, Alyssa Farley, Kunnathur Murugesan Sakthivel, Vinita Takiar, Mathieu Sertorio.

  Cholesterol, an essential membrane component and a precursor for steroid hormones and bile acids, plays a vital role in various cellular processes. Cancer cells, in particular, exhibit a heightened demand for cholesterol to support their proliferation. This increased cholesterol requirement can be attributed to the upregulation of cholesterol biosynthesis or enhanced cholesterol uptake. Metabolic reprogramming in cancer cells allows them to sustain the energy demands associated with their aberrant growth characteristics. In normal cells, cholesterol uptake and synthesis are tightly regulated through various mechanisms within the cholesterol metabolism pathway. SREBP2 (Sterol Regulatory Element Binding Protein 2) is a critical master regulator of cholesterol homeostasis in normal cells. Dysregulation of cholesterol metabolism is intricately linked with the development of malignant phenotypes. Furthermore, emerging evidence highlights the crosstalk between SREBP2 and aberrant signaling pathways, such as PI3K/AKT/mTORC1, p53, TGF-β, c-Myc, Hippo, and FoxM1, which promote tumorigenesis. Understanding these molecular interactions between SREBP2 and signaling pathways is crucial for unraveling the mechanisms underlying cancer development. Identifying combinatorial treatment strategies targeting cholesterol metabolism holds great promise in deciphering mechanistic insights into metabolic vulnerabilities in cancer cells. Such strategies have the potential to enhance the efficacy of standard chemo/radiotherapy approaches for highly resistant cancer types. This review explores the regulation of SREBP2 in cancer and elucidates its role in dysregulated cholesterol metabolism. A detailed discussion on the implications of targeting cholesterol metabolism as a therapeutic approach for cancer treatment has also been elucidated.

Keywords:  Cancer; Cholesterol; Combinatorial targeted therapeutics; Sterol regulatory element binding protein 2 (SREBP2)

DOI:  https://doi.org/10.1016/j.cellsig.2025.112044
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667273. [Epub ahead of print]

Assessing cellular metabolic dynamics with NAD(P)H fluorescence polarization imaging.

Lu Ling, Jack C Crowley, Matthew L Tan, Jennie A M R Kunitake, Adrian A Shimpi, Rebecca M Williams, Lara A Estroff, Claudia Fischbach, Warren R Zipfel.

Altered metabolism enables adaptive advantages for cancer, driving the need for improved methods for non-invasive long-term monitoring of cellular metabolism from organelle to population level. Here we present two-photon steady-state fluorescence polarization ratiometric microscopy (FPRM), a label-free imaging method that uses nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) autofluorescence as a functional readout of cellular metabolism. The method is simple to implement and operates an order of magnitude faster than the NAD(P)H-fluorescence lifetime imaging microscopy (FLIM) imaging modality, reducing cytotoxic stress while providing long-term monitoring capacity. FPRM enables high-resolution dynamic tracking of NAD(P)H signals with subcellular details and we have established a set of instrument-independent ratiometric parameters that correlates NAD(P)H signals with metabolic status during pharmaceutical and environmental perturbations. We further integrated FPRM readouts with other parameters such as cell shape and migration on 2D and 3D collagen matrices, demonstrating the technique's versatility across bioengineered platforms for cancer metabolism research.

DOI: https://doi.org/10.1101/2025.07.28.667273
Nat Commun. 2025 Aug 04. 16(1): 7174

Unequal segregation of mitochondria during asymmetric cell division contributes to cell fate divergence in sister cells in vivo.

Ioannis Segos, Jens Van Eeckhoven, Simon Berger, Nikhil Mishra, Eric J Lambie, Barbara Conradt.

The unequal segregation of organelles has been proposed to be an intrinsic mechanism that contributes to cell fate divergence during asymmetric cell division; however, in vivo evidence is sparse. Using super-resolution microscopy, we analysed the segregation of organelles during the division of the neuroblast QL.p in C. elegans larvae. QL.p divides to generate a daughter that survives, QL.pa, and a daughter that dies, QL.pp. We found that mitochondria segregate unequally by density and morphology and that this is dependent on mitochondrial dynamics. Furthermore, we found that mitochondrial density in QL.pp correlates with the time it takes QL.pp to die. We propose that low mitochondrial density in QL.pp promotes the cell death fate and ensures that QL.pp dies in a highly reproducible and timely manner. Our results provide in vivo evidence that the unequal segregation of mitochondria can contribute to cell fate divergence during asymmetric cell division in a developing animal.

DOI: https://doi.org/10.1038/s41467-025-62484-5
Dev Cell. 2025 Aug 04. pii: S1534-5807(25)00445-9. [Epub ahead of print]60(15): 2027-2028

Cradles of cellular architecture: ER nests as hubs for organelle birth.

Dibyayan Maity, Amit S Joshi.

In this issue of Developmental Cell, Wright et al. uncover discrete ER subdomains termed "ER nests" as sites for peroxisomes and lipid droplet (LD) biogenesis in Arabidopsis seedlings. ER nests are enriched in lipid biosynthetic enzymes, COPII components, and ER-shaping proteins that coordinate the biogenesis and contact between peroxisomes and LDs.

DOI: https://doi.org/10.1016/j.devcel.2025.07.007
Cell Metab. 2025 Jul 30. pii: S1550-4131(25)00333-X. [Epub ahead of print]

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.

Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Nicole M Foy, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.

  Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-beyond energy production-that is required for CD8+ T cell responses in vivo.

Keywords:  CD8(+) T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.07.006
Biochim Biophys Acta Rev Cancer. 2025 Aug 06. pii: S0304-419X(25)00154-4. [Epub ahead of print] 189412

Reprogramming of amino acid metabolism in breast cancer.

Meijin Wang, Yunlu Zhang, Zhenhua Li, Li Fu.

  Breast cancer is one of the most prevalent malignant tumours, representing a significant health risk for women. Subtyping of breast cancer is based on gene expression profiles, with five distinct subtypes identified Luminal A, Luminal B, HER2-positive, basal-like and normal-like. The heterogeneity of breast cancer represents a significant challenge to its treatment, while drug resistance limits the effectiveness of existing therapies. There is widespread amino acid metabolic reprogramming in breast cancer, and the altered amino acid metabolism observed in breast cancer cells exhibits a heterogeneous metabolic phenotype that differs from normal cells. Consequently, targeting the metabolic differences between breast and normal cells may represent a promising novel anti-cancer strategy. In this article, we review the alterations in the metabolism of amino acids such as glutamine, cystine, serine, glycine, tryptophan and arginine in breast cancer and explore the specific mechanisms by which the aberrant expression of various amino acid metabolism-related enzymes leads to alterations in the proliferative, invasive and metastatic capacities of cancer cells. Finally, we summarise the drugs targeting amino acid metabolism in breast cancer that are currently in preclinical and clinical trials, providing a theoretical basis for targeted therapy of amino acid metabolism.

Keywords:  Amino acid metabolic reprogramming; Breast cancer; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189412
Nat Rev Mol Cell Biol. 2025 Aug 04.

Lysosomal membrane homeostasis and its importance in physiology and disease.

Maja Radulovic, Chonglin Yang, Harald Stenmark.

Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell. The integrity of their membrane is crucial for lysosomes to function as hubs for the regulation of cell metabolism. Various agents, including pathogens, nanoparticles and drugs, can compromise lysosomal membrane integrity. Membrane permeabilization causes leakage of proteases and cations into the cytosol, which can induce cell death pathways and innate immunity signalling. Multiple pathways repair damaged lysosomes, and severely damaged lysosomes are degraded by an autophagic process, lysophagy. Moreover, lysosome damage activates transcriptional programmes that orchestrate lysosome biogenesis to replenish the cellular lysosome pool. In this Review, we discuss recent insights into the mechanisms that ensure the maintenance of lysosomal membrane homeostasis, including novel mechanisms of lysosomal membrane repair and the interplay between lysosome damage, repair, lysophagy and lysosome biogenesis. We highlight the importance of lysosomal membrane homeostasis in cell function, physiology, disease and ageing, and discuss the potential for therapeutic exploitation of lysosomal membrane permeabilization.

DOI: https://doi.org/10.1038/s41580-025-00873-w
Cell Death Discov. 2025 Aug 08. 11(1): 371

Nicotinamide phosphoribosyltransferase in NAD+ metabolism: physiological and pathophysiological implications.

Weijia Zhang, Haoyu Ren, Wangwang Chen, Bo Hu, Chao Feng, Peishan Li, Yufang Shi, Jiankai Fang.

Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration pathway. This review summarizes the multiple roles of NAMPT in both physiological and pathological states, particularly in cellular stress, aging, metabolic disorders, and cancer. We first describe the central role of NAMPT in NAD⁺ synthesis and explore how NAD⁺ levels are regulated through NAMPT to control cellular functions and metabolic adaptation. Second, we analyze the pathological roles of NAMPT in aging and related diseases, highlighting how NAD⁺ depletion leads to mitochondrial dysfunction, DNA damage, and immune system dysregulation. Notably, NAMPT exacerbates cancer immune evasion mechanisms by influencing immune cell functions and the metabolic environment of tumors. We also discuss the potential of NAMPT as a therapeutic target, particularly through NAD⁺ precursor supplementation or the use of NAMPT activators and inhibitors to modulate NAD⁺ metabolism in aging, metabolic diseases, and cancer. Future research should focus on exploring the functional differences of NAMPT in various tissues and its therapeutic potential in disease treatment.

DOI: https://doi.org/10.1038/s41420-025-02672-w
Nat Metab. 2025 Aug 04.

Classically activated macrophages undergo functionally significant nucleotide metabolism remodelling driven by nitric oxide.

Steven V John, Gretchen L Seim, Billy J Erazo-Flores, James A Votava, Uzziah S Urquiza, Nicholas L Arp, John Steill, Jack Freeman, Lauren N Carnevale, Isaiah Roberts, Xin Qing, Stuart A Lipton, Ron Stewart, Laura J Knoll, Jing Fan.

During an immune response, macrophages specifically reprogramme their metabolism to support functional changes. Here, we revealed that nucleotide metabolism is one of the most significantly reprogrammed pathways upon classical activation. Specifically, de novo synthesis of pyrimidines is maintained up to uridine monophosphate, but blocked at cytidine triphosphate and deoxythymidine monophosphate synthesis; de novo synthesis of purines is shut off at the last step (catalysed by AICAR transformylase/IMP cyclohydrolase, ATIC), and cells switch to increased purine salvage. Nucleotide degradation to nitrogenous bases is upregulated but complete oxidation of purine bases (catalysed by xanthine oxidoreductase, XOR) is inhibited, diverting flux into salvage. Mechanistically, nitric oxide was identified as a major regulator of nucleotide metabolism, simultaneously driving multiple key changes, including the transcriptional downregulation of Tyms and profound inhibition of ATIC and XOR. Inhibiting purine salvage using Hgprt knockout or inhibition alters the expression of many stimulation-induced genes, suppresses macrophage migration and phagocytosis, and increases the proliferation of the intracellular parasite Toxoplasma gondii. Together, these results thoroughly uncover the dynamic reprogramming of macrophage nucleotide metabolism upon classical activation and elucidate the regulatory mechanisms and functional significance of such reprogramming.

DOI: https://doi.org/10.1038/s42255-025-01337-3
Dev Cell. 2025 Aug 04. pii: S1534-5807(25)00439-3. [Epub ahead of print]60(15): 2029-2031

A cholesterol-dependent switch controls organ-specific metastasis in pancreatic cancer.

Julie Haenlin, Almut Schulze.

As different organs offer distinct chemical microenvironments, cancer cells require unique metabolic adaptation to colonize distant sites. In a recent issue of Nature, Rademaker et al. identify PCSK9 as a predictive factor for metastatic colonization of different organs, showing adaptation of cancer cells to different environments by regulating cholesterol metabolism.

DOI: https://doi.org/10.1016/j.devcel.2025.07.001
Cancer Res. 2025 Aug 07.

Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.

Mohamed Faisal Kassir, Han Gyul Lee, Natalia V Oleinik, Wyatt Wofford, Chase Walton, Firdevs Cansu Atilgan, Alhaji H Janneh, Paramita Chakraborty, Kubra Calisir, Elif Percin, Silvia G Vaena, Kalyani Sonawane, Ashish Deshmukh, Narayan R Bhat, Kumar Sambamurti, Onder Albayram, Ozgur Sahin, Shikhar Mehrotra, Besim Ogretmen.

Alzheimer's disease (AD) patients have a decreased incidence of cancer., with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD compared to AD patients. Here, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress-mediated hyperactive mitophagy in aging T-cells, improving their anti-tumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer (ACT)-based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T-cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving anti-tumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T-cells, enhancing their anti-tumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched AD patients. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance anti-tumor functions.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4740
bioRxiv. 2025 Aug 01. pii: 2025.07.29.667471. [Epub ahead of print]

Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer.

Tonatiuh Montoya, Joyce V Lee, Longhui Qiu, Abigail Krall, Nedas Matulionis, Yurim Seo, Brian N Finck, Robin K Kelley, Heather Christofk, Andrei Goga.

Liver cancer is a leading cause of cancer-related death world-wide in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and especially difficult to treat subset of patients. Given MYC's ability to reprogram cancer cell metabolism, and the liver's role as a coordinator of systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate liver tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner to sustain their growth. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited MYC-driven liver tumorigenesis. In vivo isotope tracing studies uncovered a role for alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle, nucleotide production, and amino acid synthesis. Treating transgenic MYC-driven liver tumor mouse models with L-Cycloserine, a compound that inhibits GPT2, was sufficient to diminish the frequency of mouse tumor formation and attenuate growth of established human liver tumors. Thus, we identify a new targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

DOI: https://doi.org/10.1101/2025.07.29.667471
bioRxiv. 2025 Jul 30. pii: 2025.07.29.667370. [Epub ahead of print]

Glucose Metabolism echoes Long-Range Temporal Correlations in the Human Brain.

Massimiliano Facca, Anna Ridolfo, Miriam Celli, Claudia Tarricone, Ilaria Mazzonetto, Tommaso Volpi, Andrei G Vlassenko, Manu S Goyal, Maurizio Corbetta, Alessandra Bertoldo.

Intrinsic brain activity is characterized by pervasive long-range temporal correlations. While these scale-invariant dynamics are a fundamental hallmark of brain function, their implications for individual-level metabolic regulation remain poorly understood. Here, we address this gap by integrating resting-state functional Magnetic Resonance Imaging (fMRI) and dynamic [ 18 F]FDG Positron Emission Tomography (PET) data acquired from the same cohort of participants. We uncover a systematic relationship between long-range temporal correlations, quantified via the Hurst exponent, and glucose metabolism. Our findings reveal that persistent temporal dependencies impose a measurable metabolic cost, with brains exhibiting higher long-range temporal correlations incurring greater energetic demands. Beyond glucose metabolism, we also show that these dynamics are likely supported by continuous biosynthetic processes, such as protein synthesis, which are critical for neural circuit maintenance and remodeling. Overall, our results suggest that a significant fraction of the brain's so-called "Dark Energy" is actively spent to power spontaneous long-range temporal correlations.

DOI: https://doi.org/10.1101/2025.07.29.667370
Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2502044122

Yeast adapts to diverse ecological niches driven by genomics and metabolic reprogramming.

Haoyu Wang, Jens Nielsen, Yongjin J Zhou, Hongzhong Lu.

  The famous model organism Saccharomyces cerevisiae is widely present in a variety of natural and human-associated habitats. Despite extensive studies of this organism, the metabolic mechanisms driving its adaptation to varying niches remain elusive. We here gathered genomic resources from 1,807 S. cerevisiae strains and assembled them into a high-quality pangenome, facilitating the comprehensive characterization of genetic diversity across isolates. Utilizing the pangenome, 1,807 strain-specific genome-scale metabolic models (ssGEMs) were generated, which performed well in quantitative predictions of cellular phenotypes, thus helping to examine the metabolic disparities among all S. cerevisiae strains. Integrative analyses of fluxomics and transcriptomics with ssGEMs showcased ubiquitous transcriptional regulation of metabolic flux in specific pathways (i.e., amino acid synthesis) at a population level. Additionally, the gene/reaction inactivation analysis through the ssGEMs refined by transcriptomics showed that S. cerevisiae strains from various ecological niches had undergone reductive evolution at both the genomic and metabolic network levels when compared to wild isolates. Finally, the compiled analysis of the pangenome, transcriptome, and metabolic fluxome revealed remarkable metabolic differences among S. cerevisiae strains originating from distinct oxygen-limited niches, including human gut and cheese environments, and identified convergent metabolic evolution, such as downregulation of oxidative phosphorylation pathways. Together, these results illustrate how yeast adapts to distinct niches modulated by genomic and metabolic reprogramming, and provide computational resources for translating yeast genotype to fitness in future studies.

Keywords:  Saccharomyces cerevisiae; environmental adaptation; metabolic reprogramming; pangenome; strain-specific genome-scale metabolic model

DOI:  https://doi.org/10.1073/pnas.2502044122