bims-celmim Biomed News
on Cellular and mitochondrial metabolism
Issue of 2026–03–15
fifteen papers selected by
Marc Segarra Mondejar, AINA
  1. In vivo imaging of metabolic heterogeneity across three endpoints relevant to aggressive breast cancer.
  2. The impact of dendritic mitochondrial heterogeneity on synapse function.
  3. COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function.
  4. The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.
  5. Reversible one-way lipid transfer at ER-autophagosome membrane contact sites via Atg2.
  6. Molecular insights into the regulation of GNPTαβ by LYSET.
  7. Immunometabolism in lung cancer - The link between metabolism and immune response.
  8. APOE4 drives widespread changes to the hepatic proteome and alters metabolic function.
  9. USP7 facilitates brain tumor survival upon glucose deprivation by regulating phosphofructokinase muscle-type nuclear translocation in mice.
  10. ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.
  11. NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis.
  12. Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.
  13. A lysosomal requiem for glioblastoma cells.
  14. Extending the reach of a classic oncogene.
  15. Steroidogenic compensation and lipid deficiency with enhanced NAD+ salvage in small-for-gestational-age placenta.
  1. PNAS Nexus. 2026 Mar;5(3): pgag027
    In vivo imaging of metabolic heterogeneity across three endpoints relevant to aggressive breast cancer.
    Victoria W D'Agostino, Michelle Kwan, Adelle Yong, Kira Grossman, Enakshi D Sunassee, Megan C Madonna, Matthew Hirschey, Gregory M Palmer, Nirmala Ramanujam.
      Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and a high likelihood of recurrence. Residual disease after therapy is a key predictor of recurrence, often driven by intratumoral metabolic heterogeneity. Accumulating evidence indicates that tumors are able to shift between glycolysis and oxidative metabolism and alter nutrient preferences to sustain growth and resist therapy. We have developed a in vivo microscope that enables near-simultaneous measurements of fluorescent metabolic surrogates of glucose, fatty acids, and oxidative phosphorylation through a combination of spectral separation and sequential delivery schemes. Widefield imaging with uniform illumination across the entire tumor landscape (5 mm × 5 mm) informs on the spatial distribution of these metabolic probes. We used this technology to investigate metabolic heterogeneity of a murine model of TNBC (4T1 tumor line) and normal mammary tissues that have distinctly different metabolic pathways. Mammary tissues relied primarily on oxidative metabolism and showed high levels of glucose and fatty acid uptake across the entire imaging area reflecting a single metabolic phenotype. Though tumors were predominantly glycolytic, they displayed a heterogeneous distribution of nutrient preferences with regions dominated by either fatty acid uptake, glucose uptake, or both. Taken together, this work highlights the importance of not only capturing multiple metabolic endpoints but also investigating their spatial relationships to understand heterogeneity in key substrates and metabolic pathways for energy production in vivo.
    Keywords:  breast cancer; fatty acid oxidation; fluorescence microscopy; glycolysis; tumor metabolism
    DOI:  https://doi.org/10.1093/pnasnexus/pgag027
  2. Trends Neurosci. 2026 Mar 11. pii: S0166-2236(26)00014-7. [Epub ahead of print]
    The impact of dendritic mitochondrial heterogeneity on synapse function.
    Mikel L Cawley, Shannon Farris.
      Mitochondria are energy- and metabolite-producing organelles that are differentially distributed throughout neuronal axons and dendrites to meet unique energy demands. Emerging evidence indicates that mitochondria in dendrites can be molecularly, structurally, and functionally distinct depending on cell types or even nearby synaptic inputs. This suggests that mitochondrial heterogeneity not only serves individual cell types but also plays a role in supporting the diversity of synaptic functions and connectivity patterns across different brain areas. This review highlights recent studies that contribute to our understanding of how heterogeneity in dendritic mitochondrial morphology, dynamics, and function converges to support cell- and compartment-specific metabolic demands and diverse postsynaptic properties.
    Keywords:  bioenergetics; brain; local translation; neuron; plasticity; postsynapse
    DOI:  https://doi.org/10.1016/j.tins.2026.01.011
  3. PLoS Genet. 2026 Mar;22(3): e1012076
    COG5 deficiency disrupts cellular copper homeostasis and underlies the impaired mitochondrial OXPHOS function.
    Yuwei Zhou, Keyi Li, Ruowei Zhu, Xue Ma, Xinfei Ye, Mengqing Mao, Ding Li, Xiaofei Zeng, Zhehui Chen, Jing Wu, Liqin Jin, Xiaohua Tang, Yanling Yang, Jianxin Lyu, Xiaoting Lou.
      COG5, a subunit of the conserved oligomeric Golgi (COG) complex, plays a critical role in retrograde trafficking within the Golgi apparatus. Dysfunction of COG5 is associated with various human disorders, yet the underlying pathogenic mechanisms remain poorly understood. To investigate the mechanisms, we conducted proteomic analyses using COG5-deficient and rescue cell models, which revealed a potential link between COG5 dysfunction and mitochondrial oxidative phosphorylation (OXPHOS) deficiency. Using COG5-deficient cell models and patient-derived cells harboring COG5 variants, we biochemically validated the involvement of COG5 in mitochondrial OXPHOS, particularly in the regulation of complex I content. These models also exhibited elevated cellular copper levels. Notably, the significant reduction in OXPHOS complexes could be rescued by either restoring COG5 expression or administering a copper chelator. We further demonstrated that excessive cellular copper disrupts the function of mitochondrial iron-sulfur clusters, potentially leading to complex I assembly defects. Additionally, we identified a patient with biallelic COG5 variants presenting with a distinct subtype of mitochondrial disease (Leigh syndrome), a phenotype not previously associated with COG5-related disorders. These findings provide novel mechanistic insights into the role of COG5, extending beyond its established function in Golgi-mediated glycosylation modifications. Our results underscore the importance of COG5 in mitochondrial function through a copper-dependent pathway, offering new perspectives on its contribution to cellular homeostasis and disease pathogenesis.
    DOI:  https://doi.org/10.1371/journal.pgen.1012076
  4. Front Immunol. 2026 ;17 1779543
    The "serine code" of metabolic reprogramming: multidimensional roles of the serine synthesis pathway in tumors and novel breakthroughs for targeted therapy.
    Peng Su, Ying Yang, Hong Zheng.
      As a pivotal contributor to tumor metabolism following glucose and glutamine, serine plays a crucial role in the metabolic network of tumors via its de novo synthesis pathway (SSP). The SSP is aberrantly activated in a variety of malignant tumors and promotes tumor progression through multi-dimensional mechanisms. On the one hand, it provides the material basis and one-carbon units required for the synthesis of nucleotides, proteins and phospholipids to support the rapid proliferation of tumor cells. On the other hand, it maintains cellular redox homeostasis by generating glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH). Furthermore, it regulates the tumor immune microenvironment through metabolic reprogramming, inducing macrophage polarization and modulating T-cell function, thereby shaping an immunosuppressive microenvironment. The activity and stability of key enzymes in the SSP are precisely regulated by transcription factors (such as c-Myc, HIF-1α, and NRF2), epigenetic modifications (including m5C and m6A), and post-translational modifications (such as methylation, ubiquitination, and deacetylation). Meanwhile, the SSP forms an interactive network with tumor signaling pathways including Akt, mTOR, and EGF-ERK, collectively driving metabolic reprogramming. Therapeutic strategies targeting the SSP have emerged as a research hotspot, encompassing dietary intervention, the development of inhibitors targeting key enzymes such as phosphoglycerate dehydrogenase (PHGDH), as well as combination therapies with radiotherapy, chemotherapy and immunotherapy. Notably, these strategies have shown promising potential in reversing drug resistance to BRAF inhibitors, sorafenib, 5-fluorouracil (5-FU) and other agents, providing novel strategies for pan-cancer therapy. Through a systematic and comprehensive analysis of the multi-dimensional functions, heterogeneous regulation and roles in therapeutic resistance of the SSP across cancer types, this review aims to elucidate the conserved principles and cancer-specific characteristics of the SSP as a metabolic hub. Additionally, we discuss the prospects and unique challenges of precise intervention strategies targeting the SSP in overcoming tumor heterogeneity and drug resistance.
    Keywords:  metabolic reprogramming; phosphoglycerate dehydrogenase (PHGDH); serine metabolism; serine synthesis pathway (SSP); targeted therapy; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1779543
  5. J Cell Biol. 2026 May 04. pii: e202506039. [Epub ahead of print]225(5):
    Reversible one-way lipid transfer at ER-autophagosome membrane contact sites via Atg2.
    Li Hao, Tomoki Midorikawa, Yuta Ogasawara, Takuma Tsuji, Takuma Kishimoto, Yutaro Hama, Huichao Lang, Nobuo N Noda, Kuninori Suzuki.
      Bridge-like lipid transfer proteins (LTPs) contain a repeating β-groove domain and long hydrophobic grooves that act as bridges at membrane contact sites (MCSs) to efficiently transfer lipids. Atg2 is one such bridge-like LTP essential for autophagosome formation, during which a newly synthesized isolation membrane (IM) emerges and expands through lipid supply. However, studies on Atg2-mediated lipid transfer are limited to in vitro studies due to the lack of a suitable probe for monitoring phospholipid dynamics in vivo. Here, we characterized the lipophilic dye octadecyl rhodamine B (R18), which internalizes and labels the endoplasmic reticulum (ER) in a manner that requires flippases and oxysterol-binding protein-related proteins. Using R18, we demonstrated phospholipid transfer from the ER to the IM during autophagy in vivo. Upon autophagy termination, our data suggested the reversible phospholipid flow from the IM to the ER in response to environmental changes. Our findings highlight the critical role of bridge-like LTPs in MCS-mediated phospholipid homeostasis.
    DOI:  https://doi.org/10.1083/jcb.202506039
  6. Nat Commun. 2026 Mar 11.
    Molecular insights into the regulation of GNPTαβ by LYSET.
    Xi Yang, Balraj Doray, Danielle Henn, Varsha Venkatarangan, Benjamin C Jennings, Zhongzheng Dong, Jiaxuan Liang, Weichao Zhang, Bokai Zhang, Linchen Yu, Liang Chen, Stuart Kornfeld, Ming Li.
      In vertebrates, newly synthesized lysosomal enzymes traffic to lysosomes through the mannose-6-phosphate (M6P) pathway. The Golgi membrane protein LYSET was recently discovered to regulate lysosome biogenesis by controlling the level of GlcNAc-1-phosphotransferase (GNPT). However, its working mechanism remained unclear. In this study, we demonstrate that LYSET is a two-transmembrane protein essential for GNPT stability, cleavage by Site-1 Protease (S1P), and enzymatic activity. We reconcile conflicting models by showing that LYSET enhances GNPT cleavage and prevents its mislocalization to lysosomes for degradation. We further establish that LYSET achieves this by interacting with GOLPH3 and retromer complexes to anchor the LYSET-GNPT complex at the Golgi. Alanine mutagenesis identified an F4XXR7 motif in LYSET's N-tail for GOLPH3 binding. The retromer further promotes Golgi retention by binding to the C-terminal of LYSET and recycling it from endolysosomes. Together, our findings reveal LYSET's multifaceted role in stabilizing GNPT, retaining it at the Golgi, and ensuring the fidelity of the M6P pathway, thereby providing insights into its molecular function.
    DOI:  https://doi.org/10.1038/s41467-026-70402-6
  7. iScience. 2026 Mar 20. 29(3): 115041
    Immunometabolism in lung cancer - The link between metabolism and immune response.
    Yasamin Eivazzadeh, Niloufar Orooji, Tamana Eskandari, Mahdieh Tarahomi, Fatemeh Tavassoli Razavi, Dariush Haghmorad.
      Lung cancer remains a leading cause of cancer-related mortality worldwide, characterized by complex interactions between tumor metabolism and immune evasion mechanisms. This review explores the emerging field of immunometabolism, highlighting how metabolic reprogramming within lung tumors not only fuels cancer progression but also shapes the tumor immune microenvironment (TME). Key metabolic pathways, such as glycolysis, glutaminolysis, and lipid metabolism, are extensively altered in lung cancer cells, facilitating immune suppression through mechanisms such as nutrient competition, lactate accumulation, and modulation of immune checkpoints. Immune cells, including tumor-associated macrophages (TAMs), T cells, NK cells, and dendritic cells, undergo functional impairment due to these metabolic constraints. The review further discusses therapeutic strategies targeting immunometabolic pathways, including inhibitors of glucose and amino acid transporters, lipid biosynthesis enzymes, and immune-metabolic checkpoints such as IDO and CD73. Despite promising preclinical outcomes, challenges such as metabolic plasticity, systemic toxicity, and limited biomarker availability hinder clinical translation. Future directions emphasize the integration of multi-omics, metabolic profiling, and combinatory immunotherapy to personalize treatment and overcome resistance. A deeper understanding of immunometabolic crosstalk is pivotal for advancing precision medicine in lung cancer.
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2026.115041
  8. iScience. 2026 Mar 20. 29(3): 115035
    APOE4 drives widespread changes to the hepatic proteome and alters metabolic function.
    Colton R Lysaker, Chelsea N Johnson, Vivien Csikos, Edziu Franczak, Ashley L Tetlow, Maggie Benson, John P Thyfault, Paige C Geiger, Jill K Morris, Heather M Wilkins.
      Apolipoprotein E (APOE) is essential for lipid homeostasis and has been extensively studied in Alzheimer's disease (AD). Individuals carrying an APOE4 allele have an increased risk of AD and exhibit deficits in energy metabolism, including glucose utilization and mitochondrial dysfunction. While the role of APOE in the liver is well characterized, the impact of APOE genotype on hepatic health and metabolism remains poorly understood. We sought to investigate this using young APOE3 and APOE4-targeted replacement mice and isogenic-induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iHLCs). Proteomic and functional assays show that APOE4 causes extensive changes to liver mitochondrial function in a sex-specific manner in mice and alters glucose and lipid metabolism. APOE4 also impairs mitochondrial function in iHLCs, shifts metabolism towards glycolysis, increases reliance on fatty acid utilization, and drives lipid accumulation. Together, these findings show that APOE genetic variation causes mitochondrial dysfunction and rewires hepatic metabolism.
    Keywords:  Biochemistry; Human metabolism; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2026.115035
  9. PLoS Biol. 2026 Mar;24(3): e3003698
    USP7 facilitates brain tumor survival upon glucose deprivation by regulating phosphofructokinase muscle-type nuclear translocation in mice.
    Siyang Wu, Ruixiu Cao, Xiaolan Huang, Qiongni Feng, Yajuan Zhang, Hong Gao, Bangbao Tao, Ji Liang, Weiwei Yang.
      Cancer cells reprogram the metabolic pathways to adapt to nutrient deficiency, while the underlying mechanism has not been fully understood. Phosphofructokinase 1 muscle type (PFKM) is the second rate-limiting step of glycolysis, catalyzing the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate. Here we show, using an orthotopic xenograft glioma mouse model, that PFKM is deubiquitinated and translocated into nucleus upon glucose deficiency, thereby activating fatty acid oxidation (FAO), which sustains tumor cell survival and ultimately promotes glioblastoma (GBM) development. Mechanistically, the levels of fructose-2,6-bisphosphate (F-2,6-BP) are decreased in tumor cells upon glucose deficiency, which enhances the interaction between ubiquitin carboxyl-terminal hydrolase 7 (USP7) and PFKM. USP7 removes the monoubiquitination of PFKM at lysine (K) 615, thereby promoting PFKM's translocation into the nucleus. Nuclear PFKM interacts with c-MYC, which upregulates the expression of carnitine o-palmitoyltransferase 1 muscle isoform (CPT1B) to activate FAO, thereby sustaining tumor cell survival upon glucose deficiency. Notably, USP7 inhibitor effectively dampens GBM development and extends the survival duration of the mice. The levels of nuclear PFKM correlate with the malignancy and prognosis of human GBM patients. Our findings reveal a novel mechanism through which USP7 senses fructose-2,6-bisphosphate levels to promote PFKM nuclear translocation, thereby sustaining tumor cell survival under nutrient deficiency by activating FAO. This establishes the critical role of USP7 in brain tumor development and suggests the therapeutic potential of USP7 inhibitors for treating GBM.
    DOI:  https://doi.org/10.1371/journal.pbio.3003698
  10. FASEB J. 2026 Mar 31. 40(6): e71655
    ORMDL Proteins Turnover via Proteasome and Autophagy Is Cell-Type Dependent and Tied to Ceramide Homeostasis.
    Michal Mrkacek, Magda Tumova, Alex Puskasu, Pavol Utekal, Marek Vrbacky, Ladislav Kuchar, Petr Draber, Viktor Bugajev.
      ORMDL proteins are essential negative regulators of the serine palmitoyltransferase (SPT) complex, thereby controlling the rate of de novo sphingolipid synthesis. Although mammalian ORMDLs undergo rapid turnover, the mechanisms regulating their stability remain unclear, with conflicting observations across studies. Here, we combined lipidomics, proteomics, and biochemical assays to investigate ORMDL regulation in HEK293, RPE-1, and primary mouse bone marrow-derived mast cells (BMMCs). Inhibition of SPT by myriocin or of ceramide synthases by fumonisin B1 (FB1) profoundly altered sphingolipid composition but induced minimal global proteomic changes while consistently reducing ORMDL protein levels. In contrast, overexpression of a single-chain SPT increased ORMDLs alongside elevated sphingolipids, an effect reversed by myriocin or FB1. ORMDL loss closely correlated with ceramide depletion and, in HEK293 and RPE-1 cells, was prevented by proteasome inhibition, whereas autophagy inhibition had no effect. In BMMCs, both pathways contributed to ORMDL regulation, consistent with high basal autophagy reflected by elevated LC3-II. The p97/valosin-containing protein ATPase was involved in the regulation of ORMDL turnover in all tested cell lines. Mutation of conserved asparagines (N11/N13) in ORMDL3, which mediate ceramide binding and stabilization of the inhibitory conformation, disrupted association with SPTLC1 and SPTLC2, mimicking myriocin-induced complex dissociation, while FB1 had a weaker effect. Together, these findings suggest that ceramide depletion is the primary trigger for ORMDL degradation in HEK293, RPE-1, and BMMCs and reveal a proteasome-dependent pathway that can be supplemented by autophagy in cells with high basal autophagic activity.
    Keywords:  LC3; ORMDL3; RRID; autophagy; fumonisin B1; myriocin; proteasome degradation; sphingolipid
    DOI:  https://doi.org/10.1096/fj.202502924RR
  11. Cell. 2026 Mar 09. pii: S0092-8674(26)00161-3. [Epub ahead of print]
    NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis.
    Xiaofan Jia, Teng Zhang, Chenxi Yang, Kaiyang Liu, Li Wu, Longfei Diao, Yuting Yang, Jie Wu, Yeyi Li, Weiyan Sun, Kai Zhang, Yuhui Jiang, Yuzheng Zhao, Xu Zhang, Peng Jiang, Yideng Jiang, Qiujing Yu, Song Xiang, Yuan Fu, Ting Wang.
      The regulation of nicotinamide adenine dinucleotide (NAD+) is crucial for numerous life processes. However, the mechanisms leading to NAD+ degradation in mitochondria remain insufficiently defined. Through in silico screening of potential NAD-binding proteins, we discovered a mitochondrial reaction in which NAD+ is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO (SelO), using Mn2+ as cofactor. Catalysis depends on SelO's selenocysteine-serine-serine (CSS) C-terminal residues, particularly the selenocysteine 667. In addition to broad metabolic effects, this reaction plays a pronounced role in lipid utilization via SelO directly associating with fatty acid oxidation (FAO) enzymes, and it is conserved in both mammalian cells and bacteria. This reaction is responsive to elevated matrix pH, a signal of enhanced mitochondrial respiration, and protects mitochondria from sustained metabolic overactivation. These findings reveal a conserved mechanism for spatiotemporal NAD+ regulation and highlight its physiological significance in both prokaryotes and eukaryotes.
    Keywords:  NAD; fatty acid oxidation; hydrolysis reaction; mitochondrial homeostasis; nicotinamide adenine dinucleotide; selenocysteine
    DOI:  https://doi.org/10.1016/j.cell.2026.01.033
  12. J Biol Chem. 2026 Mar 10. pii: S0021-9258(26)00227-9. [Epub ahead of print] 111357
    Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.
    Varun Ponnusamy, Deahzana R Randall, Zheng Hong Lee, Nupur K Das, Liang Zhao, Kathryn Buscher, Sumeet Solanki, Adam R Renslo, Peggy P Hsu, Yatrik M Shah.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the elevated iron must be counterbalanced given its potential to generate damaging reactive oxygen species. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. Selenoenzyme glutathione peroxidase 4 (GPX4) controls this process by reducing lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined and whether ferroptosis is accompanied by dynamic changes in the LIP is unknown. To examine this, we treated CRC cells with exogenous iron and pharmacologic ferroptosis inducers. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, by assessing expression of iron regulatory genes as well as employing two orthogonal approaches to measure labile iron, we found that the LIP did not measurably increase during ferroptosis induction with GPX4 or SLC7A11 inhibition. These findings suggest that the LIP does not expand upon pharmacologically initiated ferroptosis, despite the potentiating effect of exogenous iron supplementation.
    Keywords:  Cell Death; Colon Cancer; Iron; Lipid Peroxidation; Metabolic Regulation; Metal Homeostasis; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.jbc.2026.111357
  13. Trends Cancer. 2026 Mar 11. pii: S2405-8033(26)00025-7. [Epub ahead of print]
    A lysosomal requiem for glioblastoma cells.
    Laura Merlet, Margaux Le Guyon, Julie Gavard.
      Once viewed solely as degradative compartments, lysosomes shape cell fate through signaling, metabolism, and communication. In glioblastoma, their rewiring underlies plasticity, invasion, and resistance to therapies. This forum explores lysosomal dynamics in brain tumors and therapeutic strategies targeting lysosomal vulnerabilities, offering fresh perspectives for precision approaches in this lethal cancer.
    Keywords:  autophagy; cell death; endolysosome; glioma; organelles
    DOI:  https://doi.org/10.1016/j.trecan.2026.01.012
  14. Science. 2026 Mar 12. 391(6790): 1103-1104
    Extending the reach of a classic oncogene.
    Alexander Pfannenstein, Tobias Meyer.
      Exocytosis exposes Src at the outer surface of cancer cells, poised for therapeutic targeting.
    DOI:  https://doi.org/10.1126/science.aef9956
  15. FEBS J. 2026 Mar 10.
    Steroidogenic compensation and lipid deficiency with enhanced NAD+ salvage in small-for-gestational-age placenta.
    Serena Xodo, Lorenza Driul, Vanessa Tolotto, Eros Di Giorgio, Luigi E Xodo.
      Fetal growth restriction (FGR) affects approximately 8% of pregnancies in Western countries and is characterised by complex placental adaptations at both metabolic and transcriptional levels. In this study, we integrated RNA sequencing and metabolomic analyses to investigate alterations in steroidogenesis, NAD+ metabolism and ω-3/ω-6 polyunsaturated fatty acid (PUFA) pathways in placental biopsies and trophoblast organoids. Placentas from small-for-gestational-age (SGA10 and SGA3) infants, compared with appropriate-for-gestational-age (AGA) controls, showed increased cholesterol uptake and enhanced steroid biosynthesis. In SGA3 placentas, these changes were accompanied by activation of the NAD+ salvage pathway, supporting elevated steroidogenesis, redox balance and energy metabolism. Despite this compensatory response, concentrations of key steroid metabolites, including androstenedione sulfate and oestrogens, were reduced. Metabolomic profiling further revealed a marked depletion of lysophospholipids enriched in ω-3 and ω-6 PUFAs, along with decreased levels of free arachidonic acid (ARA), docosahexaenoic acid (DHA) and selected prostaglandins and thromboxanes. These alterations suggest mobilisation of lipid stores to counteract reduced PUFA-derived eicosanoid production, a process that may compromise placental vascular regulation and fetal neurodevelopment. Collectively, our results highlight the metabolic plasticity of the FGR placenta and identify coordinated alterations in lipid and NAD+ metabolism as key adaptive responses to placental insufficiency.
    Keywords:  NAD+ salvage pathway; SGA placenta; cholesterol uptake; steroidogenesis; ω‐3/ω‐6 PUFAs
    DOI:  https://doi.org/10.1111/febs.70475
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