bims-medebr 2025-03-23 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–03–23
seventeen papers selected by
Regina F. Fernández, Johns Hopkins University

Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis.
Quantitative mapping of key glucose metabolic rates in the human brain using dynamic deuterium magnetic resonance spectroscopic imaging.
The Effects and Mechanisms of n-3 and n-6 Polyunsaturated Fatty Acids in the Central Nervous System.
Do microglia metabolize fructose in Alzheimer's disease?
Effects of pharmacological inhibition of FABP4 during gestation and lactation on offspring neurodevelopment and behavior.
Cholesterol Sulfate as a Negative Regulator of Cellular Cholesterol Homeostasis.
Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy.
Brain glucose metabolism in patients with traumatic brain injury undergoing rehabilitation: a longitudinal 18F-FDG PET study.
Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus.
Chromogen-based double immunohistochemical detection of mitochondrial respiratory chain deficiencies in human brain tissue.
Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.
Visualize neuronal membrane cholesterol with split- fluorescent protein tagged YDQA sensor.
Emerging Approaches for Studying Lipid Dynamics, Metabolism, and Interactions in Cells.
Comprehensive review of the expanding roles of the carnitine pool in metabolic physiology: beyond fatty acid oxidation.
International Union of Basic and Clinical Pharmacology: Fundamental insights and clinical relevance regarding the carnitine palmitoyltransferase family of enzymes.
Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide.

ACS Chem Neurosci. 2025 Mar 17.

Exploring Human Brain Metabolism via Genome-Scale Metabolic Modeling with Highlights on Multiple Sclerosis.

Mustafa Sertbas, Kutlu O Ulgen.

  Cerebral dysfunctions give rise to a wide range of neurological diseases due to the structural and functional complexity of the human brain stemming from the interactive cellular metabolism of its specific cells, including neurons and glial cells. In parallel with advances in isolation and measurement technologies, genome-scale metabolic models (GEMs) have become a powerful tool in the studies of systems biology to provide critical insights into the understanding of sophisticated eukaryotic systems. In this study, brain cell-specific GEMs were reconstructed for neurons, astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells by integrating single-cell RNA-seq data and global Human1 via a task-driven integrative network inference for tissues (tINIT) algorithm. Then, intercellular reactions among neurons, astrocytes, microglia, and oligodendrocytes were added to generate a combined brain model, iHumanBrain2690. This brain network was used in the prediction of metabolic alterations in glucose, ketone bodies, oxygen change, and reporter metabolites. Glucose supplementation increased the subsystems' activities in glycolysis, and ketone bodies elevated those in the TCA cycle and oxidative phosphorylation. Reporter metabolite analysis identified L-carnitine and arachidonate as the top reporter metabolites in gray and white matter microglia in multiple sclerosis (MS), respectively. Carbamoyl-phosphate was found to be the top reporter metabolite in primary progressive MS. Taken together, single and integrated iHumanBrain2690 metabolic networks help us elucidate complex metabolism in brain physiology and homeostasis in health and disease.

Keywords:  brain metabolism; flux balance analysis; genome-scale metabolic modeling; multiple sclerosis; reporter metabolites

DOI:  https://doi.org/10.1021/acschemneuro.5c00006
PNAS Nexus. 2025 Mar;4(3): pgaf072

Quantitative mapping of key glucose metabolic rates in the human brain using dynamic deuterium magnetic resonance spectroscopic imaging.

Xin Li, Xiao-Hong Zhu, Yudu Li, Tao Wang, Guangle Zhang, Hannes M Wiesner, Zhi-Pei Liang, Wei Chen.

  Deuterium (2H) magnetic resonance spectroscopic imaging (DMRSI) is a newly developed technology for assessing glucose metabolism by simultaneously measuring deuterium-labeled glucose and its downstream metabolites (1) and has a potential to provide a powerful neurometabolic imaging tool for quantitative studies of cerebral glucose metabolism involving multiple metabolic pathways in the human brain. In this work, we developed a dynamic DMRSI method that combines advanced radiofrequency coil and postprocessing techniques to substantially improve the imaging signal-to-noise ratio for detecting deuterated metabolites and enable robust dynamic DMRSI of the human brain at 7 T with very high resolution (HR; 0.7 cc nominal voxel and 2.5 min/image) and whole-brain coverage. Utilizing this capability, we were able to map and differentiate metabolite contents and dynamics throughout the human brain following oral administration of deuterated glucose. Furthermore, by introducing a sophisticated kinetic model, we demonstrated that three key cerebral metabolic rates of glucose consumption (CMRGlc), lactate production (CMRLac), and tricarboxylic acid (TCA) cycle (V TCA), as well as the maximum apparent rate of forward glucose transport (T max) can be simultaneously imaged in the human brain through a single dynamic DMRSI measurement. The results clearly show that the glucose transport, neurotransmitter turnover, CMRGlc, and V TCA are significantly higher in gray matter than in white matter in the human brain; and the mean metabolic rates and their ratios measured in this study are consistent with the values reported in the literature. The HR dynamic DMRSI methodology presented herein is of great significance and value for the quantitative assessment of human brain glucose metabolism, aerobic glycolysis, and metabolic reprogramming under physiopathological conditions.

Keywords:  Biological; Health; aerobic glycolysis; and Medical Sciences/neuroscience; cerebral glucose metabolism; dynamic DMRSI; imaging human brain glucose metabolic rates

DOI:  https://doi.org/10.1093/pnasnexus/pgaf072
Cell Mol Neurobiol. 2025 Mar 17. 45(1): 25

The Effects and Mechanisms of n-3 and n-6 Polyunsaturated Fatty Acids in the Central Nervous System.

Jiajia Tian, Yating Zhang, Xudong Zhao.

  The brain is rich in fatty acids (FAs), with polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (C22:6n-3, DHA) and arachidonic acid (C20:4n-6, ARA), and the former predominantly stored in the form of phosphatidylcholine, phosphatidyl ethanolamine (PE, diacyl and plasma phospholipid proform), and phosphatidylserine (PS), while the latter is mainly found in ethanolamine phosphoglycerides (EPG) and contributes to constitute most of phosphoglycerides. When required by the body, PUFAs are liberated from membrane phospholipids (either directly or via their metabolites, which are generated by a series of enzymatic reactions) to participate in various cerebral physiological processes. PUFAs and their derivatives play crucial roles in modulating numerous bodily functions, including neuronal signal transmission, neurogenesis, neuroinflammation, and glucose uptake in the brain, thereby sustaining fundamental brain function. Although PUFAs have been implicated in a spectrum of neurological disorders, including acute brain injury (TBI), multiple sclerosis (MS), and neurodegenerative diseases, their role in conditions such as depression, Alzheimer's disease (AD), and Parkinson's disease (PD) is particularly noteworthy. These disorders are closely linked to critical brain functions, including cognition, memory, and inflammatory processes. Given the substantial body of research elucidating the involvement of PUFAs in the pathogenesis and progression of these diseases, this review will specifically concentrate on their impact within these contexts.

Keywords:  Central nervous system; Effects; Mechanisms; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1007/s10571-025-01543-3
J Neuroinflammation. 2025 Mar 15. 22(1): 85

Do microglia metabolize fructose in Alzheimer's disease?

Annalise M Sturno, James E Hassell, Miguel A Lanaspa, Kimberley D Bruce.

  Alzheimer's disease (AD) is an age-associated neurodegenerative disorder with a complex etiology. While emerging AD therapeutics can slow cognitive decline, they may worsen dementia in certain groups of individuals. Therefore, alternative treatments are much needed. Microglia, the brain resident macrophages, have the potential to be novel therapeutic targets as they regulate many facets of AD, including lipid droplet (LD) accumulation, amyloid beta (Aβ) clearance, and neuroinflammation. To carry out such functions, microglia undergo phenotypic changes, which are linked to shifts in metabolism and substrate utilization. While homeostatic microglia are driven by oxidative phosphorylation (OXPHOS) and glycolysis, in aging and AD, microglia shift further towards glycolysis. Interestingly, this "metabolic reprogramming" may be linked to an increase in fructose metabolism. In the brain, microglia predominantly express the fructose transporter SLC2A5 (GLUT5), and enzymes involved in fructolysis and endogenous fructose production, with their expression being upregulated in aging and disease. Here, we review evidence for fructose uptake, breakdown, and production in microglia. We also evaluate emerging literature targeting fructose metabolism in the brain and periphery to assess its ability to modulate microglial function in AD. The ability of microglia to transport and utilize fructose, coupled with the well-established role of fructose in metabolic dysfunction, supports the notion that microglial fructose metabolism may be a novel potential therapeutic target for AD.

Keywords:  Fructose; Immunometabolism; Metabolic reprogramming; Microglia; Neurodegeneration

DOI:  https://doi.org/10.1186/s12974-025-03401-x
Neurosci Lett. 2025 Mar 14. pii: S0304-3940(25)00087-4. [Epub ahead of print]853 138199

Effects of pharmacological inhibition of FABP4 during gestation and lactation on offspring neurodevelopment and behavior.

Sun Zhengkang, Hinako Kirikae, He Xiaofeng, Fumiko Yoshimachi, Minori Ikuta, Tetsuo Ohnishi, Yui Yamamoto, Hirofumi Miyazaki, Yoshiyuki Kasahara, Mai Sakai, Zhiqian Yu, Noriko Osumi, Hiroaki Tomita, Yuji Owada, Motoko Maekawa.

  Fatty acid-binding protein 4 (FABP4), a key regulator of lipid metabolism and inflammation, has been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). This study investigated the effects of FABP4 inhibition during gestation and lactation on offspring neurodevelopment using the selective FABP4 inhibitor BMS309403. Female mice received BMS309403 (15 mg/kg) via oral gavage from two weeks before mating to postnatal day 28 (P28). Administration of BMS309403 to mouse dams resulted in autism-like phenotypes in male offspring (behavioral tests: n = 7-10 per group; spine analysis: 6 mice per group, n = 26-38 dendrites per group), characterized by increased dendritic spine density in the prefrontal cortex, impaired vocal communication, increased repetitive behaviors, and depression-like symptoms. Fatty acid analysis (n = 4-6 per group) revealed significant alterations in maternal and fetal lipid profiles, including elevated arachidonic acid levels in maternal plasma and increased n6PUFAs in the fetal brain, suggesting a pro-inflammatory lipid environment. Principal component analysis demonstrated distinct clustering of lipid profiles between control and BMS309403-treated groups. Cytokine analysis (n = 6 per group) indicated reductions in IL-10 and IL-12(p40) in maternal plasma and decreased TNFα in the fetal plasma, suggesting dysregulation in systemic inflammatory signaling. These findings suggest that FABP4 inhibition during the perinatal period perturbs lipid metabolism and may influence neurodevelopment through systemic metabolic changes. Although the direct effects of BMS309403 on the fetal brain cannot be excluded, alteration in maternal metabolism and placental function may have contributed to the observed neurodevelopmental changes in offspring.

Keywords:  Autism spectrum disorder; Brain development; Fatty acid binding protein 4; Lipid metabolism

DOI:  https://doi.org/10.1016/j.neulet.2025.138199
Mol Cells. 2025 Mar 13. pii: S1016-8478(25)00033-0. [Epub ahead of print] 100209

Cholesterol Sulfate as a Negative Regulator of Cellular Cholesterol Homeostasis.

Le Ba Nam, Sung-Jin Kim, Tan Khanh Nguyen, Chang-Yun Jeong, June-Yong Lee, Jun-Seok Lee, Jeong Taeg Seo, Seok Jun Moon.

  Cholesterol sulfate (CS), one of the most abundant cholesterol derivatives, recently emerged as a key regulatory molecule in several physiological processes. Here, we demonstrate multiple mechanisms by which CS reduces intracellular cholesterol levels. CS promotes the proteasomal degradation of HMG-CoA reductase (HMGCR) by enhancing INSIG-mediated ubiquitination, thereby inhibiting cholesterol synthesis. In addition, CS blocks low-density lipoprotein (LDL) receptor endocytosis, reducing LDL cholesterol (LDL-C) uptake. CS further suppresses the proteolytic activation of sterol regulatory element-binding protein 2 (SREBP2), a master transcription factor governing cholesterol synthesis and uptake. Using in vitro and in vivo models, we show that CS lowers cholesterol by targeting both the cholesterol synthesis and uptake pathways, while also modulating an important feedback loop via SREBP2. These findings highlight the potential of CS as a modulator of cholesterol metabolism, offering new therapeutic insights into cholesterol-related disorders.

Keywords:  Cholesterol; Cholesterol homeostasis; Cholesterol sulfate; HMGCR; LDLR; SREBP2

DOI:  https://doi.org/10.1016/j.mocell.2025.100209
Nat Commun. 2025 Mar 19. 16(1): 2685

Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.

Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.

Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.

DOI: https://doi.org/10.1038/s41467-025-57439-9
J Neurochem. 2025 Mar;169(3): e70044

Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy.

Kota Furukawa, Yoko Ikoma, Yusuke Niino, Yuichi Hiraoka, Kohichi Tanaka, Atsushi Miyawaki, Johannes Hirrlinger, Ko Matsui.

  The dynamics of energy molecules in the mouse brain during metabolic challenges induced by epileptic seizures were examined. A transgenic mouse line expressing a fluorescence resonance energy transfer (FRET)-based adenosine triphosphate (ATP) sensor, selectively expressed in the cytosol of neurons, was used. An optical fiber was inserted into the hippocampus, and changes in cytosolic ATP concentration were estimated using the fiber photometry method. To induce epileptic neuronal hyperactivity, a train of electrical stimuli was delivered to a bipolar electrode placed alongside the optical fiber. Although maintaining a steady cytosolic ATP concentration is crucial for cell survival, a single episode of epileptic neuronal hyperactivity drastically reduced neuronal ATP levels. Interestingly, the magnitude of ATP reduction did not increase with the exacerbation of epilepsy, but rather decreased. This suggests that the primary consumption of ATP during epileptic neuronal hyperactivity may not be solely directed toward restoring the Na+ and K+ ionic imbalance caused by action potential bursts. Cytosolic ATP concentration reflects the balance between supply and consumption. To investigate the metabolic flux leading to neuronal ATP production, a new FRET-based pyruvate sensor was developed and selectively expressed in the cytosol of astrocytes in transgenic mice. Upon epileptic neuronal hyperactivity, an increase in astrocytic pyruvate concentration was observed. Changes in the supply of energy molecules, such as glucose and oxygen, due to blood vessel constriction or dilation, as well as metabolic alterations in astrocyte function, may contribute to cytosolic ATP dynamics in neurons.

Keywords:  ATP; astrocyte; blood vessels; epilepsy; fiber photometry; pyruvate

DOI:  https://doi.org/10.1111/jnc.70044
Front Neurol. 2025 ;16 1556427

Brain glucose metabolism in patients with traumatic brain injury undergoing rehabilitation: a longitudinal 18F-FDG PET study.

Valeria Pingue, Irene Bossert, Daniela D'Ambrosio, Antonio Nardone, Giuseppe Trifirò, Nicola Canessa, Diego Franciotta.

   Background: Measuring 18F-FDG PET-detected brain glucose uptake provides reliable information on metabolic tissue abnormalities, cells dysfunction, and neurovascular changes after traumatic brain injury (TBI).
Objectives: We aimed to study the relationship between post-traumatic brain glucose metabolism and functional outcomes in the so far unexplored field of longitudinally 18F-FDG PET-monitored patients undergoing rehabilitation after moderate-to-severe TBI.
Methods: Fourteen patients consecutively admitted to our unit in the post-acute phase after TBI underwent 18F-FDG-PET scans performed before and 6 months after inpatient rehabilitation program. The Glasgow Coma Scale (GCS) for neurological status, and the Functional Independence Measure (FIM) plus the Glasgow Outcome Scale-Extended (GOSE) scales for the rehabilitation outcome, were applied on admission and discharge. Voxel-wise analyses were performed, with the Statistical Parametric Mapping (SPM12) software, to investigate pre- vs. post-rehabilitation changes of brain metabolism, and their relationships with clinical indices.
Results: In the whole sample, 18F-FDG uptake significantly increased in the following five regions that were hypometabolic before rehabilitation: inferior frontal gyrus bilaterally, alongside right precentral gyrus, inferior parietal lobule, and cerebellum. However, only for the right precentral gyrus the median voxel peak-value at baseline resulted a significant predictor of both cognitive (FIM cognitive subscale, p = 0.012), and functional (GOS-E, p = 0.02; post- vs. pre-treatment GOS-E difference, p = 0.009) improvements. ROC curve analysis showed that a peak voxel-value of 1.7998 was the optimal cut-off for favorable rehabilitation outcome. Unfavorable functional outcomes were predicted by increased 18F-FDG uptake in the inferior frontal gyrus (GOS-E, p = 0.032) and precentral gyrus (FIM cognitive subscale, p = 0.017; GOS-E, p = 0.015).
Conclusion: This proof-of-principle study enlightens the metabolic changes occurring in moderate-to-severe TBI course. Notably, such changes preferentially involve definite frontal brain areas regardless of TBI localization and entity. These findings pave the way for further studies with translational purposes.

Keywords:  PET scanning; neuroplasticity; rehabilitation; traumatic brain injury; voxel-wise analyses

DOI:  https://doi.org/10.3389/fneur.2025.1556427
Front Cell Neurosci. 2025 ;19 1551700

Acetoacetate, a ketone body, attenuates neuronal bursts in acutely-induced epileptiform slices of the mouse hippocampus.

Hao Wen, Nagisa Sada, Tsuyoshi Inoue.

  The ketogenic diet increases ketone bodies (β-hydroxybutyrate and acetoacetate) in the brain, and ameliorates epileptic seizures in vivo. However, ketone bodies exert weak or no effects on electrical activity in rodent hippocampal slices. Especially, it remains unclear what kinds of conditions are required to strengthen the actions of ketone bodies in hippocampal slices. In the present study, we examined the effects of acetoacetate on hippocampal pyramidal cells in normal slices and epileptiform slices of mice. By using patch-clamp recordings from CA1 pyramidal cells, we first confirmed that acetoacetate did not change the membrane potentials and intrinsic properties of pyramidal cells in normal slices. However, we found that acetoacetate weakened spontaneous epileptiform bursts in pyramidal cells of epileptiform slices, which were acutely induced by applying convulsants to normal slices. Interestingly, acetoacetate did not change the frequency of the epileptiform bursts, but attenuated individual epileptiform bursts. We finally examined the effects of acetoacetate on excitatory synaptic barrages during epileptiform activity, and found that acetoacetate weakened epileptiform bursts by reducing synchronous synaptic inputs. These results show that acetoacetate attenuated neuronal bursts in epileptiform slices, but did not affect neuronal activity in normal slices, which leads to seizure-selective actions of ketone bodies.

Keywords:  epilepsy; hippocampus; ketogenic diet; ketone body; patch-clamp recording; slice physiology

DOI:  https://doi.org/10.3389/fncel.2025.1551700
Acta Neuropathol Commun. 2025 Mar 20. 13(1): 63

Chromogen-based double immunohistochemical detection of mitochondrial respiratory chain deficiencies in human brain tissue.

Tale L Bjerknes, Anna Rubiolo, Omnia Shadad, Ole-Bjørn Tysnes, Charalampos Tzoulis.

  Studies of the mitochondrial respiratory chain (MRC) have given important insights into the pathology of mitochondrial and neurodegenerative disorders. Immunohistochemical methods for staining MRC complexes are particularly valuable for assessing quantitative changes in situ, especially in complex tissues with cellular heterogeneity, such as the brain. However, traditional approaches have notable limitations. Chromogen-based staining, while preserving tissue morphology, has been restricted to a single antigen per section, preventing co-assessment of MRC complexes and mitochondrial mass on the same section. Immunofluorescence, which allows multiplex staining of multiple targets, partially addresses this limitation but compromises tissue morphology and can be highly variable in postmortem brain samples. To address these challenges, we have established a dual-antigen, chromogen-based immunohistochemical method that allows simultaneous assessment of each MRC complex and the mitochondrial marker voltage-dependent anion channel 1 (VDAC1) on the same section. As proof of concept, we apply this method on brain tissue from patients with neurological disease caused by mutations in the mitochondrial DNA polymerase gamma (POLG). Our findings demonstrate that this approach is both reliable and robust. Moreover, this method enables more precise identification of MRC deficiencies in neurons and significantly reduces the amount of tissue required for analysis, a critical advantage when working with scarce human brain samples.

Keywords:  Human brain; Immunohistochemistry; Mitochondria; Mitochondrial respiratory chain

DOI:  https://doi.org/10.1186/s40478-025-01980-7
J Inherit Metab Dis. 2025 Mar;48(2): e70019

Glycerophospholipids: Roles in Cell Trafficking and Associated Inborn Errors.

Foudil Lamari, Francis Rossignol, Grant A Mitchell.

  Glycerophospholipids (GPLs) are the main lipid components of cellular membranes. They are implicated in membrane structure, vesicle trafficking, neurotransmission, and cell signalling. GPL molecules are amphiphilic, organized around the three carbons of glycerol. Positions sn-1 and sn-2 are each esterified to a fatty acid (FA). At position sn-3, a phosphate group is linked, which in turn can bind a polar head group, the most prevalent classes being phosphatidic acid (PA, phosphate alone as head group), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and cardiolipin (CL). Pathways of GPL biosynthesis span several cell compartments (endoplasmic reticulum (ER), Golgi mitochondria). Particularly important are mitochondria-associated membranes (MAMs), where the ER and mitochondrial outer membrane are in proximity. After synthesis, GPLs continuously undergo remodelling by FA hydrolysis and re-esterification. Esterification with different FAs alters membrane properties. Many steps in GPL synthesis and remodelling can be mediated by more than one enzyme, suggesting complexity that requires further exploration. The 38 known GPL-related inborn errors are clinically diverse. 23 (61%) have neurologic features, sometimes progressive and severe, particularly developmental delay/encephalopathy in 16 (42%) and spastic paraplegia in 12 (32%). Photoreceptor/neuroretinal disease occurs in 14 (37%). Three present skeletal dysplasias (8%). Most GPL inborn errors have been diagnosed by broad molecular testing. Lipidomics holds promise for diagnostic testing and for the discovery of functionally relevant metabolite profiles for monitoring natural history and treatment response.

Keywords:  Glycerophospholipid; biosynthesis; cell trafficking; inborn errors of metabolism; remodelling

DOI:  https://doi.org/10.1002/jimd.70019
J Lipid Res. 2025 Mar 19. pii: S0022-2275(25)00041-0. [Epub ahead of print] 100781

Visualize neuronal membrane cholesterol with split- fluorescent protein tagged YDQA sensor.

Yi Xu, Saixuan Li, Yiran Xu, Xiaoqin Sun, Yuqing Wei, Yuejun Wang, Shuang Li, Yongqi Ji, Keyi Hu, Yuxia Xu, Cuiqing Zhu, Bin Lu, Dandan Wang.

  Cholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer's disease (AD). However, in vivo visualization of cholesterol has remained challenging, hindering a comprehensive understanding of AD pathology. In this study, we generated a new sensor combining the split-fluorescent protein tags with YDQA, a derivate of cholesterol-dependent cytolysin PFO. Through a series of validations in cell and C. elegans models, we demonstrate that the new sensor (name as sfPMcho) efficiently detects neuronal PM cholesterol. We further applied this sensor in 5X FAD and APOE KO mice models and revealed the cholesterol changes within neurons. PM cholesterol became sparse and locally aggregated in neuron bodies but significantly accumulated in nerve fibers. Collectively, this study provides a new tool for detecting neuronal PM cholesterol in vivo and uncovers cholesterol abnormalities in AD-related pathology at the cellular level. Further development based on this sensor or the similar strategy are to be expected.

Keywords:  Alzheimer’s disease; Cholesterol; plasma membrane; sensor

DOI:  https://doi.org/10.1016/j.jlr.2025.100781
Annu Rev Biochem. 2025 Mar 18.

Emerging Approaches for Studying Lipid Dynamics, Metabolism, and Interactions in Cells.

Lin Luan, Nathan P Frederick, Jeremy M Baskin.

Lipids are a major class of biological molecules, the primary components of cellular membranes, and critical signaling molecules that regulate cell biology and physiology. Due to their dynamic behavior within membranes, rapid transport between organelles, and complex and often redundant metabolic pathways, lipids have traditionally been considered among the most challenging biological molecules to study. In recent years, a plethora of tools bridging the chemistry-biology interface has emerged for studying different aspects of lipid biology. Here, we provide an overview of these approaches. We discuss methods for lipid detection, including genetically encoded biosensors, synthetic lipid analogs, and metabolic labeling probes. For targeted manipulation of lipids, we describe pharmacological agents and controllable enzymes, termed membrane editors, that harness optogenetics and chemogenetics. To conclude, we survey techniques for elucidating lipid-protein interactions, including photoaffinity labeling and proximity labeling. Collectively, these strategies are revealing new insights into the regulation, dynamics, and functions of lipids in cell biology.

DOI: https://doi.org/10.1146/annurev-biochem-083024-110827
J Transl Med. 2025 Mar 14. 23(1): 324

Comprehensive review of the expanding roles of the carnitine pool in metabolic physiology: beyond fatty acid oxidation.

Feng Xiang, Zhimin Zhang, Jingchen Xie, Suhui Xiong, Chen Yang, Duanfang Liao, Bohou Xia, Limei Lin.

  Traditionally, the carnitine pool is closely related to fatty acid metabolism. However, with increasing research, the pleiotropic effects of the carnitine pool have gradually emerged. The purpose of this review is to comprehensively investigate of the emerging understanding of the pleiotropic role of the carnitine pool, carnitine/acylcarnitines are not only auxiliaries or metabolites of fatty acid oxidation, but also play more complex and diverse roles, including energy metabolism, mitochondrial homeostasis, epigenetic regulation, regulation of inflammation and the immune system, tumor biology, signal transduction, and neuroprotection. This review provides an overview of the complex network of carnitine synthesis, transport, shuttle, and regulation, carnitine/acylcarnitines have the potential to be used as communication molecules, biomarkers and therapeutic targets for multiple diseases, with profound effects on intercellular communication, metabolic interactions between organs and overall metabolic health. The purpose of this review is to comprehensively summarize the multidimensional biological effects of the carnitine pool beyond its traditional role in fatty acid oxidation and to summarize the systemic effects mediated by carnitine/acylcarnitine to provide new perspectives for pharmacological research and treatment innovation and new strategies for the prevention and treatment of a variety of diseases.

Keywords:  Acylcarnitine; Carnitine; Carnitine transport; Fatty acid oxidation; Metabolism; Mitochondrial

DOI:  https://doi.org/10.1186/s12967-025-06341-5
Pharmacol Rev. 2025 Feb 25. pii: S0031-6997(25)07459-9. [Epub ahead of print]77(3): 100051

International Union of Basic and Clinical Pharmacology: Fundamental insights and clinical relevance regarding the carnitine palmitoyltransferase family of enzymes.

Rosalía Rodríguez-Rodríguez, Miguel Baena, Sebastián Zagmutt, West Kristian Paraiso, Ana Cristina Reguera, Rut Fadó, Núria Casals.

The carnitine palmitoyltransferases (CPTs) play a key role in controlling the oxidation of long-chain fatty acids and are potential therapeutic targets for diseases with a strong metabolic component, such as obesity, diabetes, and cancer. Four distinct proteins are CPT1A, CPT1B, CPT1C, and CPT2, differing in tissue expression and catalytic activity. CPT1s are finely regulated by malonyl-CoA, a metabolite whose intracellular levels reflect the cell's nutritional state. Although CPT1C does not exhibit significant catalytic activity, it is capable of modulating the functioning of other neuronal proteins. Structurally, all CPTs share a Y-shaped catalytic tunnel that allows the entry of 2 substrates and accommodation of the acyl group in a hydrophobic pocket. Several molecules targeting these enzymes have been described, some showing potential in normalizing blood glucose levels in diabetic patients, and others that, through a central mechanism, are anorexigenic and enhance energy expenditure. However, given the critical roles that CPTs play in certain tissues, such as the heart, liver, and brain, it is essential to fully understand the differences between the various isoforms. We analyze in detail the structure of these proteins, their cellular and physiological functions, and their potential as therapeutic targets in diseases such as obesity, diabetes, and cancer. We also describe drugs identified to date as having inhibitory or activating capabilities for these proteins. This knowledge will support the design of new drugs specific to each isoform, and the development of nanomedicines that can selectively target particular tissues or cells. SIGNIFICANCE STATEMENT: Carnitine palmitoyltransferase (CPT) proteins, as gatekeepers of fatty acid oxidation, have great potential as pharmacological targets to treat metabolic diseases like obesity, diabetes, and cancer. In recent years, significant progress has been made in understanding the 3-dimensional structure of CPTs and their pathophysiological functions. A deeper understanding of the differences between the various CPT family members will enable the design of selective drugs and therapeutic approaches with fewer side effects.

DOI: https://doi.org/10.1016/j.pharmr.2025.100051
RSC Chem Biol. 2025 Mar 13.

Ganglioside lipids inhibit the aggregation of the Alzheimer's amyloid-β peptide.

Zenon Toprakcioglu, Akhila K Jayaram, Tuomas P J Knowles.

The aggregation of the amyloid-β (Aβ) peptides (Aβ42/Aβ40) into amyloid fibrils and plaques is one of the molecular hallmarks in dementia and Alzheimer's disease (AD). While the molecular mechanisms behind this aggregation process are not fully known, it has been shown that some biomolecules can accelerate this process whereas others can inhibit amyloid formation. Lipids, which are ubiquitously found in cell membranes, play a pivotal role in protein aggregation. Here, we investigate how ganglioside lipids, which are abundant in the brain and in neurons, can influence the aggregation kinetics of both Aβ42 and Aβ40. We employ a variety of biophysical assays to characterise the effect ganglioside lipids have on the aggregation of Aβ. Through kinetic analysis, we show that the primary nucleation rate is greatly affected by the addition of gangliosides and that these lipids impair Aβ42 aggregation, while completely inhibiting Aβ40 aggregation. Furthermore, we find that an Aβ-ganglioside complex is formed, which potentially disrupts the aggregation pathway and results in delayed kinetics. Taken together, our results provide a quantitative description of how lipid molecules such as gangliosides can inhibit the aggregation of Aβ and shed light on the key factors that control these processes. In view of the fact that declining levels of gangliosides in neurons have been associated with ageing, our findings could be instrumental towards establishing new approaches in the prevention of amyloid-β aggregation.

DOI: https://doi.org/10.1039/d4cb00189c