bims-medebr 2025-02-02 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–02–02
29 papers selected by
Regina F. Fernández, Johns Hopkins University

Glucose Transporter 1 Deficiency Impairs Glucose Metabolism and Barrier Induction in Human Induced Pluripotent Stem Cell-Derived Astrocytes.
Lipidome disruption in Alzheimer's disease brain: detection, pathological mechanisms, and therapeutic implications.
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.
APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease.
Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a DNA Repair-Deficient 3xTg/POLβ+/- Alzheimer Disease Mouse Model.
Oxyglutamate Carrier Alleviates Cerebral Ischaemia-Reperfusion Injury by Regulating Mitochondrial Function.
Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson's disease patients mutated in TMEM175.
Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease.
Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content.
Cellular Cholesterol Loss Impairs Synaptic Vesicle Mobility via the CAMK2/Synapsin-1 Signaling Pathway.
Improvement of lactic acidosis in pyruvate dehydrogenase complex deficiency using custom-made amino acid-based dialysate for peritoneal dialysis.
Task activation results in regional 13C-lactate signal increase in the human brain.
Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.
The lactate metabolism and protein lactylation in epilepsy.
The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease.
Mitochondria as a Therapeutic Target: Focusing on Traumatic Brain Injury.
The protective efficacy of omega-3 polyunsaturated fatty acids on oxidative stress, inflammation, neurotransmitter perturbations, and apoptosis induced by monosodium glutamate in the brain of male rats.
Impact of the Ketogenic Diet on Neurological Diseases: A Review.
The Circulatory Arrest Recovery Ammonia Problem (CARAP) Hypothesis: a 1H-MRS study of brain metabolism during neonatal cardiopulmonary bypass surgery.
Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.
Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment.
SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.
The measurement, regulation and biological activity of FAHFAs.
7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease.
LPCAT1, the Enzyme Responsible for Converting LPC to PC, Promotes OPC Differentiation In Vitro.
VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.
Long-chain acyl-CoA synthetase regulates systemic lipid homeostasis via glycosylation-dependent lipoprotein production.
Cholesterol affects the binding of proteins to phosphatidic acid without influencing its ionization properties.

J Cell Physiol. 2025 Jan;240(1): e31523

Glucose Transporter 1 Deficiency Impairs Glucose Metabolism and Barrier Induction in Human Induced Pluripotent Stem Cell-Derived Astrocytes.

Iqra Pervaiz, Yash Mehta, Abraham Jacob Al-Ahmad.

  Glucose is a major source of energy for the brain. At the blood-brain barrier (BBB), glucose uptake is facilitated by glucose transporter 1 (GLUT1). GLUT1 Deficiency Syndrome (GLUT1DS), a haploinsufficiency affecting SLC2A1, reduces glucose brain uptake. A lot of effort has been made to characterize GLUT1DS at the BBB, but the impact on astrocytes remains unclear. In this study, we investigated the impact of GLUT1DS on astrocyte differentiation and function in vitro, using human induced pluripotent stem cells GLUT1DS (GLUT1DS-iPSCs) differentiated into astrocyte-like cells (iAstros). GLUT1 expression is decreased during the differentiation of iPSCs into astrocytes, with neural progenitor cells showing the lowest expression. The presence of a truncated GLUT1 did not compromise the differentiation of iPSCs into iAstros, as these cells could express several key markers representative of the astrocyte lineage. GLUT1DS-iAstros failed to express full-length GLUT1 at protein levels while showing no signs of impaired GLUT4 expression. However, GLUT1DS-iAstros showed decreased glucose uptake and lactate production compared to control-iAstros, reduced glycolysis, and mitochondrial activity as well as ATP deficit. In addition to reduced energy production, astrocytes displayed a reduced extracellular glutamate release. As previously observed, one iAstros clone (C7) showed the most severe phenotype from all groups. Our study provides an insightful view of the contribution of GLUT1 in astrocytes' energetic metabolism and raises the possible contribution of these cells in the astrocyte-neuron metabolic coupling. Our future direction is to understand better how GLUT1DS impacts astrocytes and neurons within their metabolic coupling.

Keywords:  GLUT1; GLUT1DS; astrocytes; metabolism; stem cells

DOI:  https://doi.org/10.1002/jcp.31523
Mol Neurodegener. 2025 Jan 27. 20(1): 11

Lipidome disruption in Alzheimer's disease brain: detection, pathological mechanisms, and therapeutic implications.

Sijia He, Ziying Xu, Xianlin Han.

  Alzheimer's disease (AD) is among the most devastating neurodegenerative disorders with limited treatment options. Emerging evidence points to the involvement of lipid dysregulation in the development of AD. Nevertheless, the precise lipidomic landscape and the mechanistic roles of lipids in disease pathology remain poorly understood. This review aims to highlight the significance of lipidomics and lipid-targeting approaches in the diagnosis and treatment of AD. We summarized the connection between lipid dysregulation in the human brain and AD at both genetic and lipid species levels. We briefly introduced lipidomics technologies and discussed potential challenges and areas of future advancements in the lipidomics field for AD research. To elucidate the central role of lipids in converging multiple pathological aspects of AD, we reviewed the current knowledge on the interplay between lipids and major AD features, including amyloid beta, tau, and neuroinflammation. Finally, we assessed the progresses and obstacles in lipid-based therapeutics and proposed potential strategies for leveraging lipidomics in the treatment of AD.

Keywords:  Alzheimer’s disease; Lipid metabolism; Lipidome; Lipidomics

DOI:  https://doi.org/10.1186/s13024-025-00803-6
Sci Adv. 2025 Jan 31. 11(5): eads0535

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Eric D Queathem, Zahra Moazzami, David B Stagg, Alisa B Nelson, Kyle Fulghum, Abdirahman Hayir, Alisha Seay, Jacob R Gillingham, D André d'Avignon, Xianlin Han, Hai-Bin Ruan, Peter A Crawford, Patrycja Puchalska.

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry-based 13C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl-coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.

DOI: https://doi.org/10.1126/sciadv.ads0535
J Neuroinflammation. 2025 Jan 30. 22(1): 25

APOEε4 alters ApoE and Fabp7 in frontal cortex white matter in prodromal Alzheimer's disease.

Marta Moreno-Rodriguez, Sylvia E Perez, Michael Malek-Ahmadi, Elliott J Mufson.

  The ApoE ε4 allele (APOEε4) is a major genetic risk factor for sporadic Alzheimer's disease (AD) and is linked to demyelination and cognitive decline. However, its effects on the lipid transporters apolipoprotein E (ApoE) and fatty acid-binding protein 7 (Fabp7), which are crucial for the maintenance of myelin in white matter (WM) during the progression of AD remain underexplored. To evaluate the effects of APOEε4 on ApoE, Fabp7 and myelin in the WM of the frontal cortex (FC), we examined individuals carrying one ε4 allele that came to autopsy with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and mild to moderate AD compared with non-carrier counterparts. ApoE, Fabp7 and Olig2 immunostaining was used to visualize cells, whereas myelin basic protein (MBP) immunocytochemistry and luxol fast blue (LFB) histochemistry of myelin in the WM of the FC were combined with quantitative morphometry. We observed increased numbers of ApoE-positive astrocytes in the WM of both NCI and MCI APOEε4 carriers compared with non-carriers, whereas Fabp7-positive cells were elevated only in AD. Conversely, Olig2 cell counts and MBP immunostaining decreased in MCI APOEε4 carriers compared to non-carriers, while LFB levels were higher in NCI APOEε4 carriers compared to non-carriers. Although no correlations were found between ApoE, Fabp7, and cognitive status, LFB measurements were positively correlated with perceptual speed, global cognition, and visuospatial scores in APOEε4 carriers across clinical groups. The present findings suggest that the ε4 allele compromises FC myelin homeostasis by disrupting the lipid transporters ApoE, Fabp7 and myelination early in the onset of AD. These data support targeting cellular components related to WM integrity as possible treatments for AD.

Keywords:  APOEε4; Alzheimer's disease; Astrocytes; Fabp7; Mild cognitive impairment; White matter

DOI:  https://doi.org/10.1186/s12974-025-03349-y
J Neurochem. 2025 Jan;169(1): e16295

Effect of Dietary Ketosis and Nicotinamide Riboside on Hippocampal Krebs Cycle Intermediates and Mitochondrial Energetics in a DNA Repair-Deficient 3xTg/POLβ+/- Alzheimer Disease Mouse Model.

Robert Pawlosky, Tyler G Demarest, M Todd King, Darlene Estrada, Richard L Veech, Vilhelm A Bohr.

  Alzheimer disease is a neurodegenerative pathology-modifying mitochondrial metabolism with energy impairments where the effects of biological sex and DNA repair deficiencies are unclear. We investigated the therapeutic potential of dietary ketosis alone or with supplemental nicotinamide riboside (NR) on hippocampal intermediary metabolism and mitochondrial bioenergetics in older male and female wild-type (Wt) and 3xTgAD-DNA polymerase-β-deficient (3xTg/POLβ+/-) (AD) mice. DNA polymerase-β is a key enzyme in DNA base excision repair (BER) of oxidative damage that may also contribute to mitochondrial DNA repair. Metabolic alterations imparted by ketosis and/or NR were assessed in 16 male and female groups, 4 Wt and 4 AD. At 73 weeks of age, mice were divided into: (A) carbohydrate diet (Carb); (B) Carb diet with NR (Carb-NR); (C) Ket diet (Ket); and (D) Ket diet with NR (Ket-NR) groups and remained on their respective treatments for 12 weeks. Mice were euthanized and hippocampi were rapidly removed and frozen. Glycolytic and TCA cycle intermediates were determined by quantitative GC-MS and the ratios of the mitochondrial free [NADox]/[NADHred] and coenzyme ubiquinone (CoQ/CoQH2) couples and the Gibbs free energy of the Complex I-II system of the electron transport chain (ETC) ( ∆Gmitochondrial ComplexI-II'$$ \Delta {G}_{\mathrm{mitochondrial}\ \mathrm{Complex}\ \mathrm{I}-\mathrm{II}}^{\prime } $$ ) were calculated from selected metabolites. Mice in Groups C and D had elevated blood ketones (1-2 mM). In most groupings, male mice had higher concentrations of TCA cycle intermediates than females. Moreover, higher concentrations of fumarate in Wt males were associated with elevations in the ΔG' of Complex I-II compared to females. In Wt males, NR treatments were associated with elevated concentrations of α-ketoglutarate and malate and linked to increased energy of Complex I-II. In AD males, both NR treatment and dietary ketosis restored the ΔG' of Complex I-II, where the ratio of the CoQ/CoQH2 couple was oxidized and the [NADox]/[NADHred] couple was reduced. In AD females, only mice in the Ket diet group had a sufficiently reduced [NADox]/[NADHred] couple to restore the free energy profile.

Keywords:  Alzheimer disease; NAD; TCA cycle; hippocampus; ketones; mitochondrial energetics; nicotinamide riboside

DOI:  https://doi.org/10.1111/jnc.16295
Eur J Neurosci. 2025 Jan;61(1): e16659

Oxyglutamate Carrier Alleviates Cerebral Ischaemia-Reperfusion Injury by Regulating Mitochondrial Function.

Wenhao Liu, Xin Liu, Min Liu, Rui Zhao, Zhiyuan Zhao, Jingrui Xiao, Dongdong Wan, Qi Wan, Rui Xu.

  Mitochondrial dysfunction has been reported to participate in the pathophysiological processes of cerebral ischaemia-reperfusion injury, which include reduced energy homeostasis, increased generation of oxidative stress species (ROS) and the release of apoptotic factors. Oxyglutamate carrier (OGC) is an important carrier protein on the inner mitochondrial membrane that can transport metabolites from the cytoplasm to the mitochondria. The role of OGC in cerebral ischaemia-reperfusion injury (I/R) remains unknown. In this study, we found that the expression of OGC was significantly upregulated after cerebral ischaemia-reperfusion injury. Inhibiting OGC with phenylsuccinic acid (PSA) increased neuronal death after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro. Mechanistically, OGC was localized in mitochondria and could facilitate the transport of glutathione from the cytoplasm to the mitochondria to reduce ROS levels and increase ATP production after OGD/R. In addition, in vivo inhibition of OGC exacerbated brain infarction, and GSH supplementation alleviated brain infarction resulting from OGC inhibition. This study revealed the role of OGC in alleviating brain damage by regulating mitochondrial GSH transport to alleviate mitochondrial function after cerebral ischaemia-reperfusion injury, which may provide a target for alleviating ischaemic brain injury.

Keywords:  OGC; ROS; ischaemia–reperfusion injury; mitochondria; neuron

DOI:  https://doi.org/10.1111/ejn.16659
NPJ Parkinsons Dis. 2025 Jan 24. 11(1): 23

Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson's disease patients mutated in TMEM175.

Federica Carrillo, Marco Ghirimoldi, Giorgio Fortunato, Nicole Piera Palomba, Laura Ianiro, Veronica De Giorgis, Shahzaib Khoso, Tiziana Giloni, Sara Pietracupa, Nicola Modugno, Elettra Barberis, Marcello Manfredi, Teresa Esposito.

Parkinson's disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in dermal fibroblasts of PD patients carrying mutations in TMEM175 gene. We revealed a wide dysregulation of lysosome, autophagy, and mitochondrial pathways in these patients, supporting a role of this channel in regulating these cellular processes. The most significant altered lipid classes were Fatty acyls, Glycerophospholipids and Phosphosphingolipids. The plasma level of Phosphatidylcholines (PC) and Phosphatidylinositol (PI) 34:1 significantly correlated with an earlier age at onset of the disease in TMEM175 patients (p = 0.008; p = 0.006). In plasma we also observed altered amino acids metabolic pathways in PD patients. We highlighted that increased level of L-glutamate strongly correlated (p < 0.001) with the severity of motor and non-motor symptoms in PD_TMEM175 patients. In dermal fibroblasts, we disclosed alterations of proteins involved in lipids biosynthesis (PAG15, PP4P1, GALC, FYV1, PIGO, PGPS1, PLPP1), in the insulin pathway (IGF2R), in mitochondrial metabolism (ACD10, ACD11, ACADS) and autophagy (RAB7L). Interestingly, we quantified 43 lysosomal or lysosomal-related proteins, which were differentially modulated between TMEM175 patients and controls. Integrative correlation analysis of proteome and lipidome of PD_TMEM175 cellular models identified a strong positive correlation of 13 proteins involved in biosynthetic processes with PC and Ceramides. Altogether, these data provide novel insights into the molecular and metabolic alterations underlying TMEM175 mutations and may be relevant for PD prediction, diagnosis and treatment.

DOI: https://doi.org/10.1038/s41531-024-00853-5
Biomaterials. 2025 Jan 24. pii: S0142-9612(25)00061-4. [Epub ahead of print]318 123142

Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease.

Elliya Park, Chunsheng He, Azhar Z Abbasi, Meng Tian, Shudi Huang, Liting Wang, John Georgiou, Graham L Collingridge, Paul E Fraser, Jeffrey T Henderson, Xiao Yu Wu.

  The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated. To examine this, a transgenic mouse model of Alzheimer's disease (TgCRND8) in vivo were treated intravenously with beta-amyloid antibody-conjugated (Ab), blood-brain barrier-crossing terpolymer (TP) containing polymer-lipid based manganese dioxide nanoparticles (Ab-TP-MDNPs). Alterations in cerebral glucose utilization were determined by [1⁸F]FDG-PET imaging in vivo, with glucose metabolism and mitochondrial activity analyzed by biomarkers and studies with primary neurons in vitro. Synaptic function was evaluated by both biomarkers and electrophysiologic analysis. Current study shows that intravenously administered Ab-TP-MDNPs enhanced cerebral glucose utilization, improved glucose metabolism, mitochondrial activity, and increased the levels of neprilysin, O-glycosylation. The consequence of this was enhanced glucose and ATP availability, resulting in improved long-term potentiation for promoting neuronal synaptic function. This study highlights the importance of targeting the metabolism of complex disease pathologies in addressing disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease.

Keywords:  Biocompatible hybrid manganese dioxide nanoparticles; Blood brain barrier-crossing nanomedicine; Disease-modifying treatment of Alzheimer's disease; Glucose metabolism; Glucose utilization; Mitochondrial function; Synaptic function

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123142
Life Metab. 2023 Apr;2(2): load010

Ablation of Mea6/cTAGE5 in oligodendrocytes significantly impairs white matter structure and lipid content.

Tiantian Ma, Wei Mao, Shaohua Zhang, Yaqing Wang, Tao Wang, Jinghua Liu, Lei Shi, Xiang Yu, Rong Xue, Guanghou Shui, Zhiheng Xu.

  Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons. Abnormal myelin sheath is associated with many neurological diseases. Meningioma-expressed antigen 6 (Mea6)/cutaneous T cell lymphoma-associated antigen 5C (cTAGE5C) plays an important role in vesicle trafficking from the endoplasmic reticulum (ER) to Golgi, and conditional knockout (cKO) of Mea6 in the brain significantly affects neural development and brain function. However, whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear. In this study, by using different models of diffusion magnetic resonance imaging, we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter, as well as a significant decrease of cholesterol and triglycerides in brains. Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome, especially the proportion of very long chain fatty acids (VLCFAs). In particular, the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice. The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids (ELOVLs). Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath, myelin lipids, and the pathogenesis of white matter diseases.

Keywords:  Mea6; hypomyelination; myelin lipidomic analysis; oligodendrocyte

DOI:  https://doi.org/10.1093/lifemeta/load010
Front Biosci (Landmark Ed). 2025 Jan 20. 30(1): 27111

Cellular Cholesterol Loss Impairs Synaptic Vesicle Mobility via the CAMK2/Synapsin-1 Signaling Pathway.

Atikam Qurban, Mengqi Zhang, Hengbing Zu, Kai Yao.

   BACKGROUND: Neuronal cholesterol deficiency may contribute to the synaptopathy observed in Alzheimer's disease (AD). However, the underlying mechanisms remain poorly understood. Intact synaptic vesicle (SV) mobility is crucial for normal synaptic function, whereas disrupted SV mobility can trigger the synaptopathy associated with AD. In this study, we investigated whether cellular cholesterol deficiency affects SV mobility, with the aim of identifying the mechanism that links cellular cholesterol loss to synaptopathy in AD.
METHODS: Lentiviruses carrying 3β-hydroxysteroid-Δ24 reductase-complementary DNA (DHCR24-cDNA), DHCR24-short hairpin RNA (DHCR24- shRNA) or empty lentiviral vectors were transfected into SHSY-5Y cells in order to construct DHCR24 knock-down and knock-in models, along with corresponding controls. Filipin III cholesterol staining was employed to visualize membrane and intracellular cholesterol in the different cell models, and fluorescence intensity was assessed using confocal microscopy. Additionally, we performed immunoblotting to quantify the expression of DHCR24, total calmodulin-dependent protein kinase 2 (CAMK-2), p-CAMK2 (T286), caveolin-1, total synapsin-1, phosphorylated synapsin-1 (p-synapsin-1; S605), and synaptophysin in each experimental group.
RESULTS: In DHCR24-silenced cells, the loss of cellular cholesterol caused by knock-down of DCHR24 resulted in a significant decrease in the levels of phosphorylated CAMK2 (p-CAMK2) and phosphorylated synapsin-1 (p-synapsin-1) compared to control cells. The reduction in p-CAMK2 and p-synapsin-1 could disrupt SV mobility, thereby reducing replenishment of the readily releasable pool (RRP) from the reserve pool (RP). Furthermore, cells with DHCR24 knock-down showed downregulation of caveolin-1, a crucial lipid raft marker, compared to control cells. Conversely, elevated cellular cholesterol levels caused by knock-in of DHCR24 reversed the effects of cholesterol deficiency, suggesting that CAMK2-mediated synapsin-1 phosphorylation may be regulated in a lipid raft-associated manner. Additionally, we found that cellular cholesterol loss could significantly downregulate the expression of synaptophysin protein, which is vital for SV biogenesis and synaptic plasticity.
CONCLUSION: These results suggest that depletion of cellular cholesterol following knock-down of DHCR24 can decrease synaptophysin protein expression and impair SV mobility by regulating the CAMK2-meditated synapsin-1 phosphorylation pathway, potentially via a lipid raft-associated mechanism. Our study indicates a critical role for cellular cholesterol deficiency in AD-related synaptopathy, thus highlighting the potential for targeting cellular cholesterol metabolism in therapeutic strategies.

Keywords:  Alzheimer’s disease; CAMK2; DHCR24; cholesterol; synapsin-1; synaptic vesicle; synaptopathy

DOI:  https://doi.org/10.31083/FBL27111
Pediatr Nephrol. 2025 Jan 29.

Improvement of lactic acidosis in pyruvate dehydrogenase complex deficiency using custom-made amino acid-based dialysate for peritoneal dialysis.

Manson Chon In Kuok, Chi Kwan Jasmine Chow, Ngai Man Chan, Winnie Kwai Yu Chan.

  This case report presents a newborn with pyruvate dehydrogenase complex deficiency who developed significant lactic acidosis and acute kidney injury after birth. Peritoneal dialysis with glucose-based peritoneal dialysis fluid was initially started, but the patient had worsening hyperglycemia and lactic acidosis, likely related to excess glucose reabsorption with shunting to lactate due to the underlying metabolic disorder. As amino acid-based dialysis solution was not available in our formulary, a dialysis fluid was manually created with Vaminolact, which was commonly used in neonatal parenteral nutrition. Switching to the new dialysis fluid led to significant biochemical improvement.

Keywords:  Amino acid-based dialysate; Lactic acidosis; Metabolic disease; Neonate; Peritoneal dialysis

DOI:  https://doi.org/10.1007/s00467-025-06679-4
J Cereb Blood Flow Metab. 2025 Jan 25. 271678X251314683

Task activation results in regional 13C-lactate signal increase in the human brain.

Biranavan Uthayakumar, Nicole Ic Cappelletto, Nadia D Bragagnolo, Albert P Chen, Nathan Ma, William J Perks, Ruby Endre, Fred Tam, Simon J Graham, Chris Heyn, Kayvan R Keshari, Hany Soliman, Charles H Cunningham.

  Hyperpolarized-13C magnetic resonance imaging (HP-13C MRI) was used to image changes in 13C-lactate signal during a visual stimulus condition in comparison to an eyes-closed control condition. Whole-brain 13C-pyruvate, 13C-lactate and 13C-bicarbonate production was imaged in healthy volunteers (N = 6, ages 24-33) for the two conditions using two separate hyperpolarized 13C-pyruvate injections. BOLD-fMRI scans were used to delineate regions of functional activation. 13C-metabolite signal was normalized by 13C-metabolite signal from the brainstem and the percentage change in 13C-metabolite signal conditions was calculated. A one-way Wilcoxon signed-rank test showed a significant increase in 13C-lactate in regions of activation when compared to the remainder of the brain (p=0.02). No significant increase was observed in 13C-pyruvate signal (p=0.11) or 13C-bicarbonate signal (p=0.95). The results show an increase in 13C-lactate production in activated regions that is measurable with HP-13C MRI.

Keywords:  Energy metabolism; MR metabolite; MRI; lactate; molecular imaging

DOI:  https://doi.org/10.1177/0271678X251314683
Mol Biol Rep. 2025 Jan 29. 52(1): 173

Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.

Shreya Singh, Rakesh Kumar Singh.

  Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive decline. The processes underlying the pathophysiology of AD are still not fully understood despite a great deal of research. Since mitochondrial dysfunction affects cellular energy metabolism, oxidative stress, and neuronal survival, it is becoming increasingly clear that it plays a major role in the development of AD. This review summarizes the recent developments of mitochondrial dysfunction in AD, emphasizing mitochondrial biogenesis, dynamics, axonal transport, interactions between endoplasmic reticulum and mitochondria, mitophagy, and mitochondrial proteostasis. It emphasizes how tau and amyloid-beta (Aβ) proteins worsen mitochondrial and synaptic dysfunction by impairing adenosine triphosphate (ATP) synthesis, causing oxidative stress, and upsetting equilibrium. Additionally, important processes controlling mitochondrial activity and their correlation to the brain health are also discussed. One of the promising therapeutic approaches to lessen neurodegeneration and cognitive decline in AD is to improve mitochondrial activity. This study highlights possible directions for creating focused therapies to impede the advancement of AD through incorporating knowledge of mitochondrial biogenesis and its related mechanisms.

Keywords:  Alzheimer’s disease; Dementia; Mitochondrial biogenesis; Mitophagy

DOI:  https://doi.org/10.1007/s11033-025-10297-6
Front Cell Neurosci. 2024 ;18 1464169

The lactate metabolism and protein lactylation in epilepsy.

Xi Kuang, Shuang Chen, Qingmei Ye.

  Protein lactylation is a new form of post-translational modification that has recently been proposed. Lactoyl groups, derived mainly from the glycolytic product lactate, have been linked to protein lactylation in brain tissue, which has been shown to correlate with increased neuronal excitability. Ischemic stroke may promote neuronal glycolysis, leading to lactate accumulation in brain tissue. This accumulation of lactate accumulation may heighten neuronal excitability by upregulating protein lactylation levels, potentially triggering post-stroke epilepsy. Although current clinical treatments for seizures have advanced significantly, approximately 30% of patients with epilepsy remain unresponsive to medication, and the prevalence of epilepsy continues to rise. This study explores the mechanisms of epilepsy-associated neuronal death mediated by lactate metabolism and protein lactylation. This study also examines the potential for histone deacetylase inhibitors to alleviate seizures by modifying lactylation levels, thereby offering fresh perspectives for future research into the pathogenesis and clinical treatment of epilepsy.

Keywords:  epilepsy; high-mobility group box 1; histone deacetylase; hypoxia-inducible factor-1α; lactate; protein lactylation

DOI:  https://doi.org/10.3389/fncel.2024.1464169
Cell Death Dis. 2025 Jan 14. 16(1): 14

The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease.

Xudong Sha, Jiayuan Lin, Kexin Wu, Jia Lu, Zhihua Yu.

Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.

DOI: https://doi.org/10.1038/s41419-024-07328-8
J Integr Neurosci. 2025 Jan 21. 24(1): 25292

Mitochondria as a Therapeutic Target: Focusing on Traumatic Brain Injury.

Randhall Bruce Carteri.

  Mitochondria are organelles of eukaryotic cells delimited by two membranes and cristae that consume oxygen to produce adenosine triphosphate (ATP), and are involved in the synthesis of vital metabolites, calcium homeostasis, and cell death mechanisms. Strikingly, normal mitochondria function as an integration center between multiple conditions that determine neural cell homeostasis, whereas lesions that lead to mitochondrial dysfunction can desynchronize cellular functions, thus contributing to the pathophysiology of traumatic brain injury (TBI). In addition, TBI leads to impaired coupling of the mitochondrial electron transport system with oxidative phosphorylation that provides most of the energy needed to maintain vital functions, ionic homeostasis, and membrane potentials. Furthermore, mitochondrial metabolism produces signaling molecules such as reactive oxygen species (ROS), regulating calcium levels and controlling the expression profile of intrinsic pro-apoptotic effectors influenced by TBI. Hence, the set of these functions is widely referred to as 'mitochondrial function', although the complexity of the relationship between such components limits such a definition. In this review, we present mitochondria as a therapeutic target, focus on TBI, and discuss aspects of mitochondrial structure and function.

Keywords:  head injury; metabolism; neurodegeneration

DOI:  https://doi.org/10.31083/JIN25292
Metab Brain Dis. 2025 Jan 29. 40(1): 114

The protective efficacy of omega-3 polyunsaturated fatty acids on oxidative stress, inflammation, neurotransmitter perturbations, and apoptosis induced by monosodium glutamate in the brain of male rats.

Amina E Essawy, Eman M Jimmiey, Wessam M Abdel-Wahab, Rania G Ali, Saber M Eweda, Heba M Abdou.

  Exaggerated neuronal excitation by glutamate is a well-known cause of excitotoxicity, a key factor in numerous neurodegenerative disorders. This study examined the neurotoxic effect of monosodium glutamate (MSG) in the brain cortex of rats and focused on assessing the potential neuroprotective effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs). Four groups of adult male rats (n = 10) were assigned as follows; normal control, ω-3 PUFAs (400 mg/kg) alone, MSG (4 mg/g) alone, and MSG plus ω-3 PUFAs (4 mg/g MSG plus 400 mg/kg ω-3 PUFAs). Biochemical analysis, immunohistochemical, and histological examinations were conducted upon completion of the treatment protocol. Results revealed that MSG significantly increased malondialdehyde, nitric oxide, tumor necrosis factor-α, interleukin 1β, acetylcholinesterase, monoamine oxidase, and caspase-3. However, the MSG-treated group showed a decline in reduced glutathione, catalase, superoxide dismutase, dopamine, and serotonin. In addition, MSG caused histopathological changes in the cortical region which support the biochemical and immunohistochemical analysis. Supplementation of ω-3 PUFAs greatly improved the biochemical, immunohistochemical, and histopathological alterations induced by MSG administration in the brain cortex. Together, these findings revealed a neuroprotective effect of ω-3 PUFAs against MSG-induced toxicity in the brain cortex by attenuating oxidative damage, inflammation, neurochemical perturbations, and apoptosis.

Keywords:  Apoptosis; Monosodium glutamate; Neuroinflammation; Omega-3 polyunsaturated fatty acids; Oxidative stress

DOI:  https://doi.org/10.1007/s11011-025-01539-4
Life (Basel). 2025 Jan 09. pii: 71. [Epub ahead of print]15(1):

Impact of the Ketogenic Diet on Neurological Diseases: A Review.

Carmen Rubio, Alejandro López-Landa, Hector Romo-Parra, Moisés Rubio-Osornio.

   BACKGROUND: The ketogenic diet (KD), high in fat and low in carbohydrates, was introduced in the 1920s as a non-pharmacological treatment for refractory epilepsy. Although its mechanism of action is not fully understood, beneficial effects have been observed in neurological diseases such as epilepsy, Alzheimer's disease, and Parkinson's disease.
OBJECTIVE: This review examines the impact of the ketogenic diet and its molecular and neuroglial effects as a complementary therapy for neurological diseases.
DISCUSSION: KD is associated with neuroprotective and antioxidant effects that improve mitochondrial function, regulate neurotransmitter flow, and reduce neuroinflammation and oxidative stress. Glial cells play an essential role in the utilization of ketone bodies (KBs) within the central nervous system's metabolism, particularly during ketosis induced by the KD. Thus, the KD represents a broad and promising strategy that involves both neurons and glial cells, with a molecular impact on brain metabolism and neuroinflammatory homeostasis.
CONCLUSION: Multiple molecular mechanisms have been identified to explain the benefits of the KD in neurological diseases; however, further experimental and clinical studies are needed to address various molecular pathways in order to achieve conclusive results.

Keywords:  ketogenic diet; neuroglia; neuroinflammation; neurological diseases

DOI:  https://doi.org/10.3390/life15010071
J Thorac Cardiovasc Surg. 2025 Jan 22. pii: S0022-5223(25)00039-X. [Epub ahead of print]

The Circulatory Arrest Recovery Ammonia Problem (CARAP) Hypothesis: a 1H-MRS study of brain metabolism during neonatal cardiopulmonary bypass surgery.

Daniel Spielman, Meng Gu, Hunter Liu, Shie-Chau Liu, Ralph Hurd, Kirk Riemer, Kenichi Okamura, Masafumi Shibata, Paul Shuttleworth, Zachary Kleiman, Karla Epperson, Kevin Epperson, Frank Hanley.

   OBJECTIVE: Congenital heart disease affects 1% of US births, with many babies requiring major cardiothoracic surgery under cardiopulmonary bypass (CPB), exposing the more critical patients to neurodevelopmental impairment. Optimal surgical parameters to minimize neuronal injury are unknown. We used 1H MRS and blood ammonia assays in a neonatal pig model of CPB to compare two approaches, complete circulatory arrest (CA) versus antegrade cerebral perfusion (ACP).
METHODS: Two-week old piglets (N=17) were put on a CPB pump and placed in a 3T MRI to study brain metabolism during CPB. Dynamic single-voxel 1H MRS brain data were acquired while animals underwent one of four CPB protocols: ∼50 min CA at 18ºC and 28ºC or ACP at 18ºC and 28ºC, followed by a ∼1-hr recovery period. Based on 1H MRS findings suggesting the presence of brain ammonia upon reperfusion, a second cohort of piglets (N=22) underwent the same CPB conditions without MRS to allow regular venous blood sampling with ammonia assays.
RESULTS: All animals showed a transitory temperature-dependent rise in blood ammonia (p < .001) immediately following restart of whole-body perfusion . In contrast, metabolic processing of brain ammonia, as detected by an increased 1H MRS glutamine/glutamate ratio, was also temperature dependent (p =.002) but only significantly observed in the CA studies (p =.009).
CONCLUSIONS: Serial 1H-MRS and blood ammonia assays in this preclinical CPB model identified a previously unreported build-up of ammonia, hypothesized to arise from gut bacterial production, following reperfusion, that may contribute to brain injury in these pediatric surgeries.

Keywords:  Ammonia; Antegrade Cerebral Perfusion; Brain metabolism; Cardiopulmonary bypass; Deep Hyperthermic Circulatory Arrest; Magnetic Resonance Spectroscopy; Neonatal

DOI:  https://doi.org/10.1016/j.jtcvs.2025.01.016
Life Metab. 2025 Feb;4(1): loae040

Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.

Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.

  Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.

Keywords:  G6PD; NADPH; PINK1; PPP; ROS; mitophagy

DOI:  https://doi.org/10.1093/lifemeta/loae040
J Cell Sci. 2025 Jan 30. pii: jcs.263637. [Epub ahead of print]

Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.

Samruddhi S Shembekar, Petra Nikolaus, Ulrike Honnert, Marcus Höring, Aya Attia, Karin Topp, Birgit Lohmann, Gerhard Liebisch, Martin Bähler.

  The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The Mitochondrial Intermembrane Bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the MICOS system. However, the interaction between Myo19, Miro1/2, and the MIB/MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB/MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex, but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for Myo19 and Miro1/2's connection to MIB/MICOS. Deleting Miro1/2 mimics Myo19 deficiency effects on ER-mitochondria contacts and cristae structure, while Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites.

Keywords:  Cristae organization; Lipid transfer; Mitochondria; Myosin; Rho GTPases

DOI:  https://doi.org/10.1242/jcs.263637
Int J Mol Sci. 2025 Jan 10. pii: 553. [Epub ahead of print]26(2):

Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment.

Pavel E Volynsky, Anatoly S Urban, Konstantin V Pavlov, Yaroslav V Bershatsky, Olga V Bocharova, Anastasia K Kryuchkova, Veronika V Zlobina, Alina A Gavrilenkova, Sofya M Dolotova, Anna V Kamynina, Olga T Zangieva, Amir Taldaev, Oleg V Batishchev, Ivan S Okhrimenko, Tatiana V Rakitina, Roman G Efremov, Eduard V Bocharov.

  Alzheimer's disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the APP and secretase location relative to ordered or disordered membrane microdomains. We used high-resolution NMR to probe the interactions of the cholesterol analog with APP transmembrane domain in two membrane-mimicking systems resembling ordered or perturbed lipid environments (bicelles/micelles). In bicelles, spin-labeled sterol interacted with the peptide near the amphiphilic juxtamembrane region and N-terminal part of APP transmembrane helix, as described earlier for cholesterol. Upon transition into micellar environment, another interaction site appeared where sterol polar head was buried in the hydrophobic core near the hinge region. In MD simulations, sterol moved between three interaction sites, sliding along the polar groove formed by glycine residues composing the dimerization interfaces and flexible hinge of the APP transmembrane domain. Because the lipid environment modulates interactions, the role of lipids in the AD pathogenesis is defined by the state of the entire lipid subsystem rather than the effects of individual lipid species. Cholesterol can interplay with other lipids (polyunsaturated, gangliosides, etc.), determining the outcome of amyloid-β production cascades.

Keywords:  Alzheimer’s disease; NMR; alternative cleavage cascades; amyloid precursor protein; cholesterol; lipid membrane state; molecular dynamics; transmembrane domain

DOI:  https://doi.org/10.3390/ijms26020553
Nat Commun. 2025 Jan 30. 16(1): 1181

SLC29A1 and SLC29A2 are human nicotinamide cell membrane transporters.

Mingyang Chen, Luexiang Yuan, Binxin Chen, Hui Chang, Jun Luo, Hengbin Zhang, Zhongjian Chen, Jiao Kong, Yaodong Yi, Mengru Bai, Minlei Dong, Hui Zhou, Huidi Jiang.

Nicotinamide (NAM), a main precursor of NAD+, is essential for cellular fuel respiration, energy production, and other cellular processes. Transporters for other precursors of NAD+ such as nicotinic acid and nicotinamide mononucleotide (NMN) have been identified, but the cellular transporter of nicotinamide has not been elucidated. Here, we demonstrate that equilibrative nucleoside transporter 1 and 2 (ENT1 and 2, encoded by SLC29A1 and 2) drive cellular nicotinamide uptake and establish nicotinamide metabolism homeostasis. In addition, ENT1/2 exhibits a strong capacity to change the cellular metabolite composition and the transcript, especially those related to nicotinamide. We further observe that ENT1/2 regulates cellular respiration and senescence, contributing by altering the NAD+ pool level and mitochondrial status. Changes to cellular respiration, mitochondrial status and senescence by ENT1/2 knockdown are reversed by NMN supplementation. Together, ENT1 and ENT2 act as both cellular nicotinamide-level keepers and nicotinamide biological regulators through their NAM transport functions.

DOI: https://doi.org/10.1038/s41467-025-56402-y
Nat Chem Biol. 2025 Jan 28.

The measurement, regulation and biological activity of FAHFAs.

Dan Tan, Alan Saghatelian.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are bioactive lipids that are positively correlated with metabolic health in humans and mice. Since their discovery, understanding the role and regulation of FAHFAs has been a prime focus of research into these lipids. In this Review, we describe how FAHFAs are quantitatively measured from biological samples. We then highlight advances in elucidating the genes responsible for the regulation of endogenous FAHFA levels through the degradation, biosynthesis and storage of FAHFAs. We conclude by presenting several examples of antidiabetic and immunomodulatory effects of FAHFAs in cells and in vivo, including their ability to protect against type 1 diabetes. These FAHFA topics are interconnected by their reliance on chemistry and chemical biology to enlighten this frontier of lipid biology, offering new perspectives on metabolic health and potential therapeutic interventions.

DOI: https://doi.org/10.1038/s41589-024-01827-7
bioRxiv. 2025 Jan 28. pii: 2025.01.19.633810. [Epub ahead of print]

7-ketocholesterol contributes to microglia-driven increases in astrocyte reactive oxygen species in Alzheimer's disease.

Kayalvizhi Radhakrishnan, Yiyu Zhang, Oluwaseun Mustapha, Thaddeus K Weigel, Clint M Upchurch, Xiaodong Tian, Franklin Herbert, Wenyuan Huang, Norbert Leitinger, Ukpong Bassey Eyo, Huiwang Ai, Heather A Ferris.

Oxidative stress is a prominent feature of Alzheimer's disease. Within this context, cholesterol undergoes oxidation, producing the pro-inflammatory product 7-ketocholesterol (7-KC). In this study, we observe elevated levels of 7-KC in the brains of the 3xTg mouse model of AD. To further understand the contribution of 7-KC on the oxidative environment, we developed a method to express a genetically encoded fluorescent hydrogen peroxide (H2O2) sensor in astrocytes, the primary source of cholesterol in the brain. With this sensor, we discovered that 7-KC increases H2O2 levels in astrocytes in vivo, but not when directly applied to astrocytes in vitro. Interestingly, when 7-KC was applied to a microglia cell line alone or mixed astrocyte and microglia cultures, it resulted in microglia activation and increased oxidative stress in astrocytes. Depletion of microglia from 3xTg mice resulted in reduced 7-KC in the brains of these mice. Taken together, these findings suggest that 7-KC, acting through microglia, contributes to increased astrocyte oxidative stress in AD. This study sheds light on the complex interplay between cholesterol oxidation, microglia activation, and astrocyte oxidative stress in the pathogenesis of AD.

DOI: https://doi.org/10.1101/2025.01.19.633810
J Cell Mol Med. 2025 Feb;29(3): e70387

LPCAT1, the Enzyme Responsible for Converting LPC to PC, Promotes OPC Differentiation In Vitro.

Qi Shang, Xin Zhang, Yingyan Pu, Junjian Lin, Peng Ma, Yuchen Pan, Ming Zhao, Dingya Sun, Li Cao.

  Myelin is the key structure for high-speed information transmission and is formed by oligodendrocytes (OLs) which are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system. Lipid is the main component of myelin and the role of lipid metabolism-related molecules in myelination attach increasing attention. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) mediates the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC), and its role in myelination draws our interest as LPC is a classical demyelination inducer and PC is a major component of myelin. In this work, LPCAT1 is found expressed in the oligodendrocyte lineage cells during myelination. In vitro experiments showed that the expression level of LPCAT1 gradually increased along with the differentiation process from OPCs to OLs, and over-expression and interference experiments showed that LPCAT1 promoted OPCs differentiation without affecting their proliferation or apoptosis. Mechanistically, the undertaker of LPCAT1's pro-differentiation role is not PC, but the phosphorylated mTOR which is a key regulator in OPCs differentiation. RNA sequencing analysis showed LPCAT1 promoted the expression of ZBTB20 which is an important transcription factor related to lipid metabolism and regulates mTOR phosphorylation. In vivo, complex myelin tomacula involving multiple axons was formed after conditionally knocking out LPCAT1 in oligodendrocyte lineage cells, but no obvious myelin thickness abnormalities were observed. Our results indicate that LPCAT1 is an important regulator of myelination, and lipid metabolism-related molecules may be new valuable targets for the treatment of diseases with myelin abnormalities.

Keywords:  LPCAT1; OPCs; ZBTB20; lipid metabolism; myelination

DOI:  https://doi.org/10.1111/jcmm.70387
Biomolecules. 2024 Dec 30. pii: 33. [Epub ahead of print]15(1):

VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration.

Shirel Argueti-Ostrovsky, Shir Barel, Joy Kahn, Adrian Israelson.

  Voltage-Dependent Anion Channel 1 (VDAC1) is a mitochondrial outer membrane protein that plays a crucial role in regulating cellular energy metabolism and apoptosis by mediating the exchange of ions and metabolites between mitochondria and the cytosol. Mitochondrial dysfunction and oxidative stress are central features of neurodegenerative diseases. The pivotal functions of VDAC1 in controlling mitochondrial membrane permeability, regulating calcium balance, and facilitating programmed cell death pathways, position it as a key determinant in the delicate balance between neuronal viability and degeneration. Accordingly, increasing evidence suggests that VDAC1 is implicated in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and others. This review summarizes the current findings on the contribution of VDAC1 to neurodegeneration, focusing on its interactions with disease-specific proteins, such as amyloid-β, α-synuclein, and mutant SOD1. By unraveling the complex involvement of VDAC1 in neurodegenerative processes, this review highlights potential avenues for future research and drug development aimed at alleviating mitochondrial-related neurodegeneration.

Keywords:  ALS; Alzheimer’s disease; Parkinson’s disease; VDAC1; neurodegenerative diseases

DOI:  https://doi.org/10.3390/biom15010033
Life Metab. 2024 Apr;3(2): loae004

Long-chain acyl-CoA synthetase regulates systemic lipid homeostasis via glycosylation-dependent lipoprotein production.

Jie Li, Yue Dong, Tianxing Zhou, He Tian, Xiahe Huang, Yong Q Zhang, Yingchun Wang, Sin Man Lam, Guanghou Shui.

  Interorgan lipid transport is crucial for organism development and the maintenance of physiological function. Here, we demonstrate that Drosophila long-chain acyl-CoA synthetase (dAcsl), which catalyzes the conversion of fatty acids into acyl-coenzyme As (acyl-CoAs), plays a critical role in regulating systemic lipid homeostasis. dAcsl deficiency in the fat body led to the ectopic accumulation of neutral lipids in the gut, along with significantly reduced lipoprotein contents in both the fat body and hemolymph. The aberrant phenotypes were rescued by fat body-specific overexpression of apolipophorin. A multi-omics investigation comprising lipidomics, metabolomics, and proteomics in conjunction with genetic screening revealed that glycosylation processes were suppressed in dAcsl knockdown flies. Overexpression of CG9035, human ortholog of which is implicated in the congenital disorder of glycosylation, ameliorated gut lipid accumulation in Drosophila. Aberrant lipoprotein glycosylation led to accelerated proteasome-related degradation and induced ER stress in dAcsl knockdown flies, impairing lipoprotein release into the circulation which compromised interorgan lipid transport between the fat body and the gut. Inhibition of ubiquitin-proteasome-dependent degradation alleviated the phenotype of gut ectopic fat accumulation in dAcsl knockdown flies. Finally, we verified that ACSL4, the human homolog of dAcsl, also regulated lipoprotein levels in HepG2 cells, indicating that the role of dAcsl in modulating lipoprotein secretion and systemic lipid homeostasis is possibly conserved in humans.

Keywords:  apolipoprotein; glycosylation; lipid homeostasis; lipidomics; metabolomics; proteomics

DOI:  https://doi.org/10.1093/lifemeta/loae004
J Lipid Res. 2025 Jan 27. pii: S0022-2275(25)00009-4. [Epub ahead of print] 100749

Cholesterol affects the binding of proteins to phosphatidic acid without influencing its ionization properties.

Desmond Owusu Kwarteng, Alexander Wolf, Madisyn Langdon, Nawal Kassas, Nicolas Vitale, Edgar Eduard Kooijman.

  Phosphatidic acid (PA) through its unique negatively charged phosphate headgroup binds to various proteins to modulate multiple cellular events. To perform such diverse signaling functions, the ionization and charge of PA's headgroup relies on the properties of vicinal membrane lipids and changes in cellular conditions. Cholesterol has conspicuous effects on lipid properties and membrane dynamics. In eukaryotic cells, its concentration increases along the secretory pathway, reaching its highest levels towards the plasma membrane. Moreover, membrane cholesterol levels are altered in certain diseases such as Alzheimer's disease, cancer and in erythrocytes of hypercholesteremia patients. Hence, those changing levels of cholesterol could affect PA's charge and alter binding to effector protein. However, no study has investigated the direct impact of cholesterol on the ionization properties of PA. Here, we used 31P MAS NMR to explore the effects of increasing cholesterol concentrations on the chemical shifts and pKa2 of PA. We find that, while the chemical shifts of PA change significantly at high cholesterol concentrations, surprisingly, the pKa2 and charge of PA under these conditions are not modified. Furthermore, using in vitro lipid binding assays we found that higher cholesterol levels increased PA binding of the Spo20p PA sensor. Finally, in cellulo experiments demonstrated that depleting cholesterol from neurosecretory cells halts the recruitment of this sensor upon PA addition. Altogether, these data suggest that the intracellular cholesterol gradient may be an important regulator of proteins binding to PA and that a disruption of those levels in certain pathologies may also affect PA binding to its target proteins and subsequent signaling pathways.

Keywords:  Cholesterol; Lipid protein interactions; Phosphatidic acid; Signaling lipids

DOI:  https://doi.org/10.1016/j.jlr.2025.100749