bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2025–03–09
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Maternal omega-3 polyunsaturated fatty acids improved levels of DHA-enriched phosphatidylethanolamines and enriched lipid clustering in the neuronal membranes of C57BL/6 mice fetal brains during gestation.
  2. Modulating lipid droplet dynamics in neurodegeneration: an emerging area of molecular pharmacology.
  3. [18F]FDG-PET and [18F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation.
  4. Knocking down the neuronal lactate transporter MCT2 in the arcuate nucleus of female rats increases food intake and body weight.
  5. Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications.
  6. Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.
  7. Nutrient supplementation mitigates retinal dysfunction in Acox1 knockout mice with impaired peroxisomal fatty acid oxidation.
  8. NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
  9. Mitochondrial Dysfunction in Alzheimer's Disease.
  10. Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
  11. Conformational free energy landscape of a glutamate transporter and microscopic details of its transport mechanism.
  12. Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
  13. Single-nucleus RNA sequencing uncovers metabolic dysregulation in the prefrontal cortex of major depressive disorder patients.
  14. Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates.
  15. Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
  1. J Nutr Biochem. 2025 Mar 04. pii: S0955-2863(25)00054-3. [Epub ahead of print] 109891
    Maternal omega-3 polyunsaturated fatty acids improved levels of DHA-enriched phosphatidylethanolamines and enriched lipid clustering in the neuronal membranes of C57BL/6 mice fetal brains during gestation.
    Innocent Uzochukwu Okagu, Olatunji Anthony Akerele, Tiffany Fillier, Thu Huong Pham, Raymond Thomas, Katie A Wilson, Sukhinder Kaur Cheema.
      The composition of brain lipids is crucial for neurodevelopment and brain function. Diets enriched in omega (n)-3 polyunsaturated fatty acids (PUFA) can modulate brain lipid composition. However, the influence of maternal n-3 PUFA intake on fetal brain lipidome and neuronal membrane structure during gestation is not well studied. Eight-week-old female C57BL/6 mice were fed low or high n-3 PUFA semi-purified diets for two weeks before mating and during gestation. Fetal brain lipidome and neuronal membrane structure were studied at gestation day (GD) 12.5 (mid) and 18.5 (late) using liquid chromatography high-resolution accurate mass tandem mass spectrometry and computational techniques. Maternal diets high in n-3 PUFA increased fetal brain total phosphoethanolamine, phosphoinositol, phosphoglycerol, and phosphoserine glycerophospholipids, compared to the low n-3 PUFA diet. Docosahexaenoic acid (DHA, 22:6n-3)-enriched phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), and lyso-PC (LPC) fatty acyl species increased as gestation progressed in the high n-3 PUFA group, compared to low n-3 PUFA. These fatty acyl species and phospholipids promote neurotransmission, memory, and cognition. A high n-3 PUFA diet increased the area per lipid in fetal neuronal membranes as gestation progressed, indicating improved membrane fluidity. Furthermore, a high n-3 PUFA diet increased the clustering of membrane lipids associated with neurotransmission, memory, and cognition (ceramide, PE, and cholesteryl ester) as gestation progressed. Our findings show for the first time that maternal diets high in n-3 PUFA before and during gestation improve fetal brain lipidome and membrane area per lipid that may enhance brain development and function.
    Keywords:  Omega-3 polyunsaturated fatty acids; docosahexaenoic acid; fetal brain lipidome; lipidomics; molecular dynamics; neuronal plasma membrane
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.109891
  2. Mol Biol Rep. 2025 Mar 03. 52(1): 277
    Modulating lipid droplet dynamics in neurodegeneration: an emerging area of molecular pharmacology.
    Reet Verma, Prateek Sharma, Veerta Sharma, Thakur Gurjeet Singh.
      Neurodegenerative diseases (NDDs) are characterised by the progressive loss of neurons in the central nervous system (CNS), resulting in memory impairment, cognition abnormalities, and motor dysfunctions. The common pathological features include altered energy metabolism, neuroinflammation, loss of neurons, aberrant protein aggregation, and synaptic dysfunction. Lipids, fundamental components of cell membranes play a critical role in energy storage and cell signaling. The brain, comprising approximately 60% lipid content by dry weight, underscores the significance of lipid dynamics in maintaining CNS integrity. Variations in lipid distribution across brain regions further highlight their specialised functions. Dysregulation of lipid metabolism, encompassing synthesis, transport, and utilization, has been implicated in the pathogenesis of neurodegenerative diseases. Lipid droplets (LDs), key intermediates of lipid metabolism, accumulate in neurons, microglia, and astrocytes, particularly in aging brains. The deposition of these LDs disrupts cellular homeostasis and links the dynamics of LDs to pathology of disease. Therefore, this review explores the pivotal role of lipid metabolism and LDs in NDDs, providing insights into their contributions to neuronal dysfunction and potential therapeutic implications.
    Keywords:  Cellular lipid dynamics; Lipid droplets; Neurodegeneration; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-025-10381-x
  3. Sci Rep. 2025 Mar 01. 15(1): 7280
    [18F]FDG-PET and [18F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation.
    Isabel Day, Mikayla Tamboline, Lindsay Lueptow, Irina Zhuravka, Taryn Diep, Ilona Tkachyova, Shili Xu, Andreas Schulze, Gerald S Lipshutz.
      Pathogenic variants in the creatine transporter gene SLC6A8, reported to represent 2% of all intellectual disabilities in males, result in a spectrum of behavioral abnormalities including developmental delay, intellectual disability, and deficit in speech. While at present there are no effective treatments available, preclinical development and testing of gene therapy and other approaches to increase brain creatine are being actively pursued. In studying a mouse model of the disorder, [18F]fluorodeoxyglucose ([18F]FDG)-based positron emission tomography (PET)/computed tomography (CT) was performed to assess brain glucose metabolism in wild type and creatine transporter mutant mice (Slc6a8-/y). The findings demonstrate marked differences in glucose metabolism in the brains of wild type and Slc6a8-/y mice. In conducting behavioral phenotyping studies, notable abnormalities in behavior in the murine model led to additional studies in serotonin-mediated activity. Serotonergic signaling differences were detected between wild type and Slc6a8-/y mice using 4-(2'-methoxyphenyl)-1-[2'-(N-2″-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine ([18F]MPPF). These data demonstrate that [18F]FDG-PET and [18F]-MPPF-PET may serve as appropriate and sensitive biomarkers that could be used to assess the efficacy of not only new approaches in treating mutations of the creatine transporter SLC6A8 and their effectiveness in normalizing brain metabolism but also in enhancing our understanding of the mechanism of brain dysfunction that occurs in this complex brain disorder.
    Keywords:  CRT-1 transporter deficiency; Creatine; Glucose; PET-CT; SLC6A8 mutations; Serotonin; [18F]MPPF; [18F]fluorodeoxyglucose
    DOI:  https://doi.org/10.1038/s41598-025-92022-8
  4. Sci Rep. 2025 Mar 03. 15(1): 7497
    Knocking down the neuronal lactate transporter MCT2 in the arcuate nucleus of female rats increases food intake and body weight.
    Alanis Coca, Sergio López, Patricio Órdenes, Vania Sepúlveda, Diego Cuevas, Andrés Villarroel, Javiera Álvarez-Indo, Patricia V Burgos, Estefanía Tarifeño, Roberto Elizondo-Vega, María A García-Robles.
      In the arcuate nucleus of the hypothalamus, tanycyte-neuron interactions regulate glucose homeostasis and feeding behavior. Previously, we reported that monocarboxylate transporters (MCT) 1 and 4 are localized in tanycytes, whereas MCT2 is present in arcuate nucleus neurons, including orexigenic and anorexigenic neurons (POMC). MCT1 and MCT4 inhibition impacts feeding behavior, suggesting that monocarboxylate transfer between tanycytes and neurons influences food intake. Electrophysiological studies have shown that POMC neurons respond to lactate through transport and indirect signaling using astrocytic hydroxycarboxylic acid receptor 1. To investigate the role of MCT2 further, we generated MCT2 knockdown rats and analyzed their feeding behavior. Female Sprague-Dawley rats received bilateral injections in the arcuate nucleus with an adeno-associated virus (AAV) carrying a specific short hairpin RNA to inhibit MCT2 expression, thereby generating neuronal MCT2 knockdown rats. Knockdown efficiency in rat hypothalamic tissue was assessed using real-time PCR, Western Blot, and immunohistochemistry. The acute effect on feeding behavior was evaluated following 24 h of fasting, followed by 24 h of refeeding. In MCT2-knockdown rats, we observed additional inhibition of MCT1, suggesting a potential glial response to increased parenchymal lactate levels. Both macrostructure and microstructure of feeding were evaluated in MCT2-knockdown rats and compared to control AAV-injected rats. MCT2 knockdown led to a significant increase in macrostructural parameters, such as food intake and body weight. These findings underscore the importance of lactate transfer as a mechanism in tanycyte-neuron communication mediated by monocarboxylates.
    Keywords:  Arcuate nucleus; Feeding behavior; MCT2; Rats; Satiation
    DOI:  https://doi.org/10.1038/s41598-025-90513-2
  5. Mol Psychiatry. 2025 Mar 03.
    Brain O-GlcNAcylation: Bridging physiological functions, disease mechanisms, and therapeutic applications.
    Liping Chen, Huihui Jiang, Julio Licinio, Haitao Wu.
      O-GlcNAcylation, a dynamic post-translational modification occurring on serine or threonine residues of numerous proteins, plays a pivotal role in various cellular processes, including gene regulation, metabolism, and stress response. Abundant in the brain, O-GlcNAcylation intricately governs neurodevelopment, synaptic assembly, and neuronal functions. Recent investigations have established a correlation between the dysregulation of brain O-GlcNAcylation and a broad spectrum of neurological disorders and injuries, spanning neurodevelopmental, neurodegenerative, and psychiatric conditions, as well as injuries to the central nervous system (CNS). Manipulating O-GlcNAcylation has demonstrated neuroprotective properties against these afflictions. This review delineates the roles and mechanisms of O-GlcNAcylation in the CNS under both physiological and pathological circumstances, with a focus on its neuroprotective effects in neurological disorders and injuries. We discuss the involvement of O-GlcNAcylation in key processes such as neurogenesis, synaptic plasticity, and energy metabolism, as well as its implications in conditions like Alzheimer's disease, Parkinson's disease, and ischemic stroke. Additionally, we explore prospective therapeutic approaches for CNS disorders and injuries by targeting O-GlcNAcylation, highlighting recent clinical developments and future research directions. This comprehensive overview aims to provide insights into the potential of O-GlcNAcylation as a therapeutic target and guide future investigations in this promising field.
    DOI:  https://doi.org/10.1038/s41380-025-02943-z
  6. Elife. 2025 Mar 04. pii: RP100570. [Epub ahead of print]13
    Deuterium metabolic imaging phenotypes mouse glioblastoma heterogeneity through glucose turnover kinetics.
    Rui Vasco Simoes, Rafael Neto Henriques, Jonas L Olesen, Beatriz M Cardoso, Francisca F Fernandes, Mariana A V Monteiro, Sune N Jespersen, Tânia Carvalho, Noam Shemesh.
      Glioblastomas are aggressive brain tumors with dismal prognosis. One of the main bottlenecks for developing more effective therapies for glioblastoma stems from their histologic and molecular heterogeneity, leading to distinct tumor microenvironments and disease phenotypes. Effectively characterizing these features would improve the clinical management of glioblastoma. Glucose flux rates through glycolysis and mitochondrial oxidation have been recently shown to quantitatively depict glioblastoma proliferation in mouse models (GL261 and CT2A tumors) using dynamic glucose-enhanced (DGE) deuterium spectroscopy. However, the spatial features of tumor microenvironment phenotypes remain hitherto unresolved. Here, we develop a DGE Deuterium Metabolic Imaging (DMI) approach for profiling tumor microenvironments through glucose conversion kinetics. Using a multimodal combination of tumor mouse models, novel strategies for spectroscopic imaging and noise attenuation, and histopathological correlations, we show that tumor lactate turnover mirrors phenotype differences between GL261 and CT2A mouse glioblastoma, whereas recycling of the peritumoral glutamate-glutamine pool is a potential marker of invasion capacity in pooled cohorts, linked to secondary brain lesions. These findings were validated by histopathological characterization of each tumor, including cell density and proliferation, peritumoral invasion and distant migration, and immune cell infiltration. Our study bodes well for precision neuro-oncology, highlighting the importance of mapping glucose flux rates to better understand the metabolic heterogeneity of glioblastoma and its links to disease phenotypes.
    Keywords:  cancer biology; deuterium metabolic imaging; glioblastoma; glycolysis; kinetic modeling; mitochondrial metabolism; mouse
    DOI:  https://doi.org/10.7554/eLife.100570
  7. J Adv Res. 2025 Mar 04. pii: S2090-1232(25)00145-6. [Epub ahead of print]
    Nutrient supplementation mitigates retinal dysfunction in Acox1 knockout mice with impaired peroxisomal fatty acid oxidation.
    Myriam Boeck, Hitomi Yagi, Chuck T Chen, Yan Zeng, Deokho Lee, Shen Nian, Taku Kasai, Jeff Lee, Victoria Hirst, Chaomei Wang, Katherine Neilsen, Tori C Rodrick, Andrew McCutcheon, Mathew Yu, Irfan J Lodhi, Sasha A Singh, Masanori Aikawa, Richard P Bazinet, Zhongjie Fu.
       INTRODUCTION: Dyslipidemia contributes to many retinal diseases, but underlying lipid processing pathways are not fully understood. Peroxisomes oxidize very long-chain fatty acids and generate docosahexaenoic acid (DHA). Mutations in peroxisomal genes can result in severe neural retinal dysfunction. However, therapeutic approaches for peroxisomal diseases remain scarce, and dietary strategies yield inconsistent results.
    OBJECTIVES: This study sought to elucidate retinal metabolic adaptations resulting from impaired peroxisomal fatty acid oxidation and to evaluate the therapeutic potential of nutrient supplementation in peroxisomal retinal disease.
    METHODS: In mice with global knockout (KO) of acyl-coenzyme A oxidase 1 (Acox1), encoding the first and rate-limiting enzyme in peroxisomal fatty acid oxidation, the retina was characterized at postnatal day (P) 30 during development. Retinal thickness, photoreceptor structure, and function were examined. Proteome analysis was utilized for molecular mechanistic investigation. Metabolomics and fatty acid profiling were conducted to study metabolic alterations in the retina. Nutrient intervention was performed to test if providing deficient nutrients could attenuate the observed retinal dysfunction.
    RESULTS: In P30 Acox1 KO mice, we observed impaired neural retinal signaling, accompanied by reduced expression of genes involved in phototransduction. Proteomics suggested diminished glucose and mitochondrial metabolism, supported by decreased mitochondrial number and mitochondrial DNA copy number. Metabolomics showed reduced abundance of retinal pyruvate, and pyruvate supplementation from P30-P60 attenuated neural retinal dysfunction in Acox1 KO mice at P60. Furthermore, Acox1 KO mice at P30 exhibited a significant decrease in omega-3 (n-3) fatty acids and a compensatory increase in n-6 fatty acids. Dietary supplementation with DHA (n-3) or DHA plus arachidonic acid (n-6) from P30-P60 mitigated the progression of retinal dysfunction in Acox1 KO mice.
    CONCLUSION: Retinal dysfunction, decreased mitochondrial number, and metabolic imbalance were observed in mice with impaired peroxisomal fatty acid oxidation. Nutrient intervention may offer a promising therapeutic approach for peroxisomal diseases.
    Keywords:  ACOX1; DHA; Dyslipidemia; Peroxisomes; Retinal degeneration; Retinal metabolism
    DOI:  https://doi.org/10.1016/j.jare.2025.03.004
  8. Cell Death Discov. 2025 Mar 01. 11(1): 82
    NDUFB7 mutations cause brain neuronal defects, lactic acidosis, and mitochondrial dysfunction in humans and zebrafish.
    Yen-Lin Chen, Brian Hon-Yin Chung, Masakazu Mimaki, Shumpei Uchino, Yin-Hsiu Chien, Christopher Chun-Yun Mak, Steven Shinn-Forng Peng, Wei-Chen Wang, Yu-Li Lin, Wuh-Liang Hwu, Shyh-Jye Lee, Ni-Chung Lee.
      Complex I of the mitochondrial electron transfer chain is one of the largest membrane protein assemblies ever discovered. A patient carrying a homozygous NDUFB7 intronic mutation died within two months after birth due to cardiorespiratory defects, preventing further study. Here, we report another patient with compound heterozygous mutations in NDUFB7 who suffers from pons abnormality, lactic acidosis, prematurity, prenatal and postnatal growth deficiency, incomplete closure of the abdominal wall (ventral hernia), and a poorly functioning gastrointestinal tract (pseudo-obstruction). We demonstrated that the patient's skin fibroblasts are deficient in Complex I assembly and reduced supercomplex formation. This report further broadens the spectrum of mitochondrial disorders. The patient has had several surgeries. After receiving treatment with Coenzyme Q10 and vitamin B complex, she has remained stable up to this point. To further explore the functionality of NDUFB7 in vivo, we knocked down Ndufb7 in zebrafish embryos. This resulted in brain ventricle and neuronal defects, elevated lactic acid levels, and reduced oxygen consumption, indicating defective mitochondrial respiration. These phenotypes can be specifically rescued by ectopic expression of ndufb7. More importantly, Mitoquinone mesylate (MitoQ), a common remedy for mitochondrial disorders, can ameliorate these conditions. These results suggest a role for NDUFB7 in mitochondrial activity and the suitability of the zebrafish model for further drug screening and the development of therapeutic strategies for this rare disease.
    DOI:  https://doi.org/10.1038/s41420-025-02369-0
  9. Ageing Res Rev. 2025 Feb 27. pii: S1568-1637(25)00059-5. [Epub ahead of print] 102713
    Mitochondrial Dysfunction in Alzheimer's Disease.
    Maria Clara Bila D'alessandro, Salim Kanaan, Mauro Geller, Domenico Praticò, João Paulo Lima Daher.
      Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive decline and distinct neuropathological features. The absence of a definitive cure presents a significant challenge in neurology and neuroscience. Early clinical manifestations, such as memory retrieval deficits and apathy, underscore the need for a deeper understanding of the disease's underlying mechanisms. While amyloid-β plaques and tau neurofibrillary tangles have dominated research efforts, accumulating evidence highlights mitochondrial dysfunction as a central factor in AD pathogenesis. Mitochondria, essential cellular organelles responsible for energy production necessary for neuronal function become impaired in AD, triggering several cellular consequences. Factors such as oxidative stress, disturbances in energy metabolism, failures in the mitochondrial quality control system, and dysregulation of calcium release are associated with mitochondrial dysfunction. These abnormalities are closely linked to the neurodegenerative processes driving AD development and progression. This review explores the intricate relationship between mitochondrial dysfunction and AD pathogenesis, emphasizing its role in disease onset and progression, while also considering its potential as a biomarker and a therapeutic target.
    Keywords:  Mitochondrial dysfunction. Alzheimer’ disease. Pathology. Mitophagy. Neurodegeneration
    DOI:  https://doi.org/10.1016/j.arr.2025.102713
  10. Neurobiol Dis. 2025 Mar 04. pii: S0969-9961(25)00078-6. [Epub ahead of print] 106862
    Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
    Yifei Zheng, Jiahui Yang, Xuanyao Li, Linjie Qi, Zhuo Zheng, Jiming Kong, Guohui Zhang, Ying Guo.
      Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.
    Keywords:  Mitochondrial quality control; Neurodegenerative diseases; Neuron; Senescence; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.nbd.2025.106862
  11. Proc Natl Acad Sci U S A. 2025 Mar 11. 122(10): e2416381122
    Conformational free energy landscape of a glutamate transporter and microscopic details of its transport mechanism.
    Sundar Thangapandian, Ashkan Fakharzadeh, Mahmoud Moradi, Emad Tajkhorshid.
      Removing glutamate from the synaptic cleft is vital for proper function of the brain. Excitatory amino acid transporters mediate this process by uptaking the neurotransmitter from the synaptic cleft back to the cell after its release. The archaeal homolog, GltPh, an aspartate transporter from Pyrococcus horikoshii, presents the best structurally characterized model for this family of transporters. In order to transport, GltPh undergoes elevator-like conformational changes between inward-facing (IF) and outward-facing (OF) states. Here, we characterize, at an atomic level, the OF⇌IF transition of GltPh in different apo/bound states using a combination of ensemble-based enhanced sampling techniques, employing more than two thousand of coupled simulation replicas of membrane-embedded GltPh. The resulting free-energy profiles portray the transition of apo/bound states as a complex four-stage process, while sodium binding alone locks the structure in one of its states. Along the transition, the transport domain (TD) disengages from the scaffold domain (SD), allowing it to move as a piston sliding vertically with respect to the membrane during the elevator-like motion of TD. Lipid interactions with residues comprising the SD-TD interface directly influence the large-scale conformational changes and, consequently, the energetics of transport. Structural intermediates formed during the transition leak water molecules and may correlate to the uncoupled Cl- ion conductance observed experimentally in both prokaryotic and mammalian glutamate transporters. Mechanistic insights obtained from our study provide a structural framework for better development of therapeutic for neurological disorders.
    Keywords:  enhanced sampling; free energy; membrane transporter; molecular dynamics
    DOI:  https://doi.org/10.1073/pnas.2416381122
  12. Nat Commun. 2025 Feb 28. 16(1): 2053
    Neuron-specific isoform of PGC-1α regulates neuronal metabolism and brain aging.
    Dylan C Souder, Eric R McGregor, Josef P Clark, Timothy W Rhoads, Tiaira J Porter, Kevin W Eliceiri, Darcie L Moore, Luigi Puglielli, Rozalyn M Anderson.
      The brain is a high-energy tissue, and although aging is associated with dysfunctional inflammatory and neuron-specific functional pathways, a direct connection to metabolism is not established. Here, we show that isoforms of mitochondrial regulator PGC-1α are driven from distinct brain cell-type specific promotors, repressed with aging, and integral in coordinating metabolism and growth signaling. Transcriptional and proteomic profiles of cortex from male adult, middle age, and advanced age mice reveal an aging metabolic signature linked to PGC-1α. In primary culture, a neuron-exclusive promoter produces the functionally dominant isoform of PGC-1α. Using growth repression as a challenge, we find that PGC-1α is regulated downstream of GSK3β independently across promoters. Broad cellular metabolic consequences of growth inhibition observed in vitro are mirrored in vivo, including activation of PGC-1α directed programs and suppression of aging pathways. These data place PGC-1α centrally in a growth and metabolism network directly relevant to brain aging.
    DOI:  https://doi.org/10.1038/s41467-025-57363-y
  13. Sci Rep. 2025 Mar 03. 15(1): 7418
    Single-nucleus RNA sequencing uncovers metabolic dysregulation in the prefrontal cortex of major depressive disorder patients.
    Xiang-Yao Li, Yingbo Rao, Guo-Hao Li, Luxi He, Yaohan Wang, Wenli He, Ping Fang, Chenyu Pei, Lun Xi, Haiyan Xie, Yun-Rong Lu.
      Major depressive disorder (MDD) is a widespread psychiatric condition, recognized as the third leading cause of global disease burden in 2008. In the context of MDD, alterations in synaptic transmission within the prefrontal cortex (PFC) are associated with PFC hypoactivation, a key factor in cognitive function and mood regulation. Given the high energy demands of the central nervous system, these synaptic changes suggest a metabolic imbalance within the PFC of MDD patients. However, the cellular mechanisms underlying this metabolic dysregulation remain not fully elucidated. This study employs single-nucleus RNA sequencing (snRNA-seq) data to predict metabolic alterations in the dorsolateral PFC (DLPFC) of MDD patients. Our analysis revealed cell type-specific metabolic patterns, notably the disruption of oxidative phosphorylation and carbohydrate metabolism in the DLPFC of MDD patients. Gene set enrichment analysis based on human phenotype ontology predicted alterations in serum lactate levels in MDD patients, corroborated by the observed decrease in lactate levels in MDD patients compared to 47 age-matched healthy controls (HCs). This transcriptional analysis offers novel insights into the metabolic disturbances associated with MDD and the energy dynamics underlying DLPFC hypoactivation. These findings are instrumental for comprehending the pathophysiology of MDD and may guide the development of innovative therapeutic strategies.
    Keywords:  Glycolysis; KEGG; Major depressive disorder; Serum lactate; SnRNA-Seq
    DOI:  https://doi.org/10.1038/s41598-025-92030-8
  14. J Neuroinflammation. 2025 Mar 01. 22(1): 59
    Lactate accumulation from HIF-1α-mediated PMN-MDSC glycolysis restricts brain injury after acute hypoxia in neonates.
    Xiaogang Zhang, Laiqin Peng, Shuyi Kuang, Tianci Wang, Weibin Wu, Shaowen Zuo, Chunling Chen, Jiaxiu Ye, Guilang Zheng, Yuxiong Guo, Yumei He.
      Fetal intrauterine distress (FD) during delivery can cause fetal intrauterine hypoxia, posing significant risks to the fetus, mother, and newborns. While studies highlight the role of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in neonatal diseases and tumor hypoxia, their specific involvement in newborns experiencing fetal distress during delivery (FDNB) is not well understood. Here, we found elevated PMN-MDSC activation, increased glycolysis, enhanced lactate production, and upregulated HIF-1α expression in the blood of FDNB neonates compared to healthy newborns (NNB). Importantly, PMN-MDSC levels were inversely correlated with neuron-specific enolase (NSE), a marker for neurological injury. In neonatal mice subjected to acute hypoxia, a 48-h exposure led to a shift from exacerbation to amelioration of brain damage when compared with a 24-h period. This change was associated with a reduction in microglial activation, a decrease in the expression of inflammatory factors within the microglia, alongside increased peripheral PMN-MDSC activation. Depleting PMN-MDSCs led to heightened microglial activation and aggravated brain injury. Mechanistically, enhanced activation of PMN-MDSCs promotes HIF-1α accumulation while enhancing glycolysis and lactate release, thereby mitigating neonatal brain injury. Notably, lactate supplementation in hypoxic mice rescued brain damage caused by insufficient PMN-MDSC activation due to HIF-1α deficiency. Our study clarifies the role of lactate in peripheral PMN-MDSCs after acute hypoxia and its effects on microglial activation and subsequent brain injury.
    Keywords:  Fetal intrauterine distress; Glycolysis; HIF-1α; Inflammatory factors expression; Lactate; Microglial activation; Polymorphonuclear myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1186/s12974-025-03385-8
  15. Nature. 2025 Mar 05.
    Structure of mitochondrial pyruvate carrier and its inhibition mechanism.
    Zheng He, Jianxiu Zhang, Yan Xu, Eve J Fine, Carl-Mikael Suomivuori, Ron O Dror, Liang Feng.
      The mitochondrial pyruvate carrier (MPC) governs the entry of pyruvate-a central metabolite that bridges cytosolic glycolysis with mitochondrial oxidative phosphorylation-into the mitochondrial matrix1-5. It thus serves as a pivotal metabolic gatekeeper and has fundamental roles in cellular metabolism. Moreover, MPC is a key target for drugs aimed at managing diabetes, non-alcoholic steatohepatitis and neurodegenerative diseases4-6. However, despite MPC's critical roles in both physiology and medicine, the molecular mechanisms underlying its transport function and how it is inhibited by drugs have remained largely unclear. Here our structural findings on human MPC define the architecture of this vital transporter, delineate its substrate-binding site and translocation pathway, and reveal its major conformational states. Furthermore, we explain the binding and inhibition mechanisms of MPC inhibitors. Our findings provide the molecular basis for understanding MPC's function and pave the way for the development of more-effective therapeutic reagents that target MPC.
    DOI:  https://doi.org/10.1038/s41586-025-08667-y
This page is being maintained by Thomas Krichel. It was last updated on 2025‒05‒01 at 11:12.