bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023–04–02
forty-two papers selected by
Regina F. Fernández, Johns Hopkins University
  1. AMPK activators have compound and concentration-specific effects on brain metabolism.
  2. Regulation of neuronal energy metabolism by calcium: Role of MCU and Aralar/malate-aspartate shuttle.
  3. Large neutral amino acid levels tune perinatal neuronal excitability and survival.
  4. Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases.
  5. Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy.
  6. Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs.
  7. A Perspective on the Link between Mitochondria-Associated Membranes (MAMs) and Lipid Droplets Metabolism in Neurodegenerative Diseases.
  8. A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations.
  9. Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement.
  10. The roles of brain lipids and polar metabolites in the hypoxia tolerance of deep-diving pinnipeds.
  11. Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.
  12. Metabolic and Transcriptomic Changes in the Mouse Brain in Response to Short-Term High-Fat Metabolic Stress.
  13. Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice.
  14. Neuronal Prosurvival Role of Ceramide Synthase 2 by Olidogendrocyte-to-Neuron Extracellular Vesicle Transfer.
  15. Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations.
  16. From seconds to days: Neural plasticity viewed through a lipid lens.
  17. Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy.
  18. Neurotransmitters in Type 2 Diabetes and the Control of Systemic and Central Energy Balance.
  19. The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis.
  20. Activation of TRPV4 induces intraneuronal tau hyperphosphorylation via cholesterol accumulation.
  21. Acetyl-L-carnitine and Amyotrophic Lateral Sclerosis: current evidence and potential use.
  22. Brain metabolic signatures in patients with genetic and nongenetic amyotrophic lateral sclerosis.
  23. Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5.
  24. Microarrays, Enzymatic Assays, and MALDI-MS for Determining Specific Alterations to Mitochondrial Electron Transport Chain Activity, ROS Formation, and Lipid Composition in a Monkey Model of Parkinson's Disease.
  25. Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.
  26. Integrative analysis of metabolomics and proteomics unravels purine metabolism disorder in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
  27. Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.
  28. In vivo assessment of β-hydroxybutyrate metabolism in mouse brain using deuterium (2 H) MRS.
  29. TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1.
  30. Lipids and Amyotrophic Lateral Sclerosis: A two-sample Mendelian Randomization Study.
  31. Deciphering Complex Interactions in Bioactive Lipid Signaling.
  32. Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin.
  33. Sex differences in hippocampal-dependent memory and the hippocampal lipidome in adolescent rats raised on diets with or without DHA.
  34. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.
  35. Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis.
  36. Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes.
  37. Cytosolic and mitochondrial NADPH fluxes are independently regulated.
  38. New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia.
  39. Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity.
  40. Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6/2 HD Mice.
  41. 24-Hydroxycholesterol Induces Tau Proteasome-Dependent Degradation via the SIRT1/PGC1α/Nrf2 Pathway: A Potential Mechanism to Counteract Alzheimer's Disease.
  42. Human neurons lacking amyloid precursor protein exhibit cholesterol-associated developmental and presynaptic deficits.
  1. J Neurochem. 2023 Mar 28.
    AMPK activators have compound and concentration-specific effects on brain metabolism.
    Lavanya B Achanta, Donald S Thomas, Gary D Housley, Caroline D Rae.
      AMP-activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577, and indirectly, using AICAR and metformin. We studied the resultant metabolism of [1-13 C]glucose and [1,2-13 C]acetate using NMR spectroscopy. We found distinct activator concentration dependent effects on metabolism which ranged from decreased metabolic pool sizes at EC50 activator concentrations with no expected stimulation in glycolytic flux, to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct vs indirect activators produced distinct metabolic outcomes at both low (EC50 ) and higher (EC50 x 10) concentrations. Specific direct activation of β1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration and mechanism-dependent impact.
    DOI:  https://doi.org/10.1111/jnc.15815
  2. Biochim Biophys Acta Mol Cell Res. 2023 Mar 28. pii: S0167-4889(23)00039-3. [Epub ahead of print] 119468
    Regulation of neuronal energy metabolism by calcium: Role of MCU and Aralar/malate-aspartate shuttle.
    Araceli Del Arco, Luis González-Moreno, Irene Pérez-Liébana, Inés Juaristi, Paloma González-Sánchez, Laura Contreras, Beatriz Pardo, Jorgina Satrústegui.
      Calcium is a major regulator of cellular metabolism. Calcium controls mitochondrial respiration, and calcium signaling is used to meet cellular energetic demands through energy production in the organelle. Although it has been widely assumed that Ca2+-actions require its uptake by mitochondrial calcium uniporter (MCU), alternative pathways modulated by cytosolic Ca2+ have been recently proposed. Recent findings have indicated a role for cytosolic Ca2+ signals acting on mitochondrial NADH shuttles in the control of cellular metabolism in neurons using glucose as fuel. It has been demonstrated that AGC1/Aralar, the component of the malate/aspartate shuttle (MAS) regulated by cytosolic Ca2+, participates in the maintenance of basal respiration exerted through Ca2+-fluxes between ER and mitochondria, whereas mitochondrial Ca2+-uptake by MCU does not contribute. Aralar/MAS pathway, activated by small cytosolic Ca2+ signals, provides in fact substrates, redox equivalents and pyruvate, fueling respiration. Upon activation and increases in workload, neurons upregulate OxPhos, cytosolic pyruvate production and glycolysis, together with glucose uptake, in a Ca2+-dependent way, and part of this upregulation is via Ca2+ signaling. Both MCU and Aralar/MAS contribute to OxPhos upregulation, Aralar/MAS playing a major role, especially at small and submaximal workloads. Ca2+ activation of Aralar/MAS, by increasing cytosolic NAD+/NADH provides Ca2+-dependent increases in glycolysis and cytosolic pyruvate production priming respiration as a feed-forward mechanism in response to workload. Thus, except for glucose uptake, these processes are dependent on Aralar/MAS, whereas MCU is the relevant target for Ca2+ signaling when MAS is bypassed, by using pyruvate or β-hydroxybutyrate as substrates.
    Keywords:  Bioenergetic; Calcium signaling; Mitochondrial carriers; Neuronal activity; Neuronal metabolism; Redox shuttles; Respiration
    DOI:  https://doi.org/10.1016/j.bbamcr.2023.119468
  3. Cell. 2023 Mar 24. pii: S0092-8674(23)00215-5. [Epub ahead of print]
    Large neutral amino acid levels tune perinatal neuronal excitability and survival.
    Lisa S Knaus, Bernadette Basilico, Daniel Malzl, Maria Gerykova Bujalkova, Mateja Smogavec, Lena A Schwarz, Sarah Gorkiewicz, Nicole Amberg, Florian M Pauler, Christian Knittl-Frank, Marianna Tassinari, Nuno Maulide, Thomas Rülicke, Jörg Menche, Simon Hippenmeyer, Gaia Novarino.
      Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.
    Keywords:  SLC7A5; autism; branched-chain amino acids; lipids; metabolism; microcephaly; neurodevelopment
    DOI:  https://doi.org/10.1016/j.cell.2023.02.037
  4. Pharmacol Ther. 2023 Mar 24. pii: S0163-7258(23)00058-X. [Epub ahead of print]244 108394
    Inhibiting degradation of 2-arachidonoylglycerol as a therapeutic strategy for neurodegenerative diseases.
    Chu Chen.
      Endocannabinoids are endogenous lipid signaling mediators that participate in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid and is a full agonist of G-protein-coupled cannabinoid receptors (CB1R and CB2R), which are targets of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient in cannabis. While 2-AG has been well recognized as a retrograde messenger modulating synaptic transmission and plasticity at both inhibitory GABAergic and excitatory glutamatergic synapses in the brain, growing evidence suggests that 2-AG also functions as an endogenous terminator of neuroinflammation in response to harmful insults, thus maintaining brain homeostasis. Monoacylglycerol lipase (MAGL) is the key enzyme that degrades 2-AG in the brain. The immediate metabolite of 2-AG is arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes. Several lines of evidence indicate that pharmacological or genetic inactivation of MAGL, which boosts 2-AG levels and reduces its hydrolytic metabolites, resolves neuroinflammation, mitigates neuropathology, and improves synaptic and cognitive functions in animal models of neurodegenerative diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), and traumatic brain injury (TBI)-induced neurodegenerative disease. Thus, it has been proposed that MAGL is a potential therapeutic target for treatment of neurodegenerative diseases. As the main enzyme hydrolyzing 2-AG, several MAGL inhibitors have been identified and developed. However, our understanding of the mechanisms by which inactivation of MAGL produces neuroprotective effects in neurodegenerative diseases remains limited. A recent finding that inhibition of 2-AG metabolism in astrocytes, but not in neurons, protects the brain from TBI-induced neuropathology might shed some light on this unsolved issue. This review provides an overview of MAGL as a potential therapeutic target for neurodegenerative diseases and discusses possible mechanisms underlying the neuroprotective effects of restraining degradation of 2-AG in the brain.
    Keywords:  2-Arachidonoylglycerol; Alzheimer’s disease; Endocannabinoid; Monoacylglycerol lipase; Neurodegenerative disease; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.pharmthera.2023.108394
  5. Metabolites. 2023 Mar 01. pii: 369. [Epub ahead of print]13(3):
    Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy.
    Patrycja Maszka, Magdalena Kwasniak-Butowska, Dominik Cysewski, Jaroslaw Slawek, Ryszard T Smolenski, Marta Tomczyk.
      The prevalence of neurodegenerative diseases (NDs) is increasing due to the aging population and improved longevity. They are characterized by a range of pathological hallmarks, including protein aggregation, mitochondrial dysfunction, and oxidative stress. The aim of this review is to summarize the alterations in brain energy and amino acid metabolism in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Based on our findings, we proposed a group of selected metabolites related to disturbed energy or mitochondrial metabolism as potential indicators or predictors of disease. We also discussed the hidden challenges of metabolomics studies in NDs and proposed future directions in this field. We concluded that biochemical parameters of brain energy metabolism disruption (obtained with metabolomics) may have potential application as a diagnostic tool for the diagnosis, prediction, and monitoring of the effectiveness of therapies for NDs. However, more studies are needed to determine the sensitivity of the proposed candidates. We suggested that the most valuable biomarkers for NDs studies could be groups of metabolites combined with other neuroimaging or molecular techniques. To attain clinically applicable results, the integration of metabolomics with other "omic" techniques might be required.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; biomarker; energy metabolism; neurodegeneration
    DOI:  https://doi.org/10.3390/metabo13030369
  6. eNeuro. 2023 Mar 27. pii: ENEURO.0430-22.2023. [Epub ahead of print]
    Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs.
    Line I Christiansen, Bo Holmqvist, Xiaoyu Pan, Kristine Holgersen, Sandy E H Lindholm, Nicole L Henriksen, Douglas G Burrin, David Ley, Thomas Thymann, Per Torp Sangild, Stanislava Pankratova.
      Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction and poor neurological outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and regional and cellular brain development. Pigs were treated with 2.25 mg/kg/day of recombinant human IGF-1/IGF binding protein 3 complex from birth until Day 5 or 9 before collection of brain samples for quantitative immunohistochemistry (IHC), RNA-seq and qPCR analyses. Brain protein synthesis was measured using in vivo labeling with [2H5] phenylalanine. We showed that the IGF-1 receptor was widely distributed in the brain and largely coexisted with immature neurons. Region-specific quantification of IHC labeling showed that IGF-1 treatment promoted neuronal differentiation, increased subcortical myelination, and attenuated synaptogenesis in a region- and time-dependent manner. The expression levels of genes involved in neuronal and oligodendrocyte maturation, angiogenic and transport functions were altered, reflecting enhanced brain maturation in response to IGF-1 treatment. Cerebellar protein synthesis was increased by 19% at Day 5 and 14% at Day 9 after IGF-1 treatment. Treatment had no effect on Iba1-positive microglia or regional brain weights and did not affect motor development or the expression of genes related to IGF-1 signaling. In conclusion, the data show that supplemental IGF-1 promotes brain maturation in newborn preterm pigs. The results provide further support for IGF-1 supplementation therapy in the early postnatal period in preterm infants.SIGNIFICANCE STATEMENTDeficiency of systemic insulin-like growth factor-1 (IGF-1) is associated with delayed neurological development in preterm infants. Here, we show that the IGF-1 receptor is primarily expressed in immature neurons in the developing brain of the translational preterm pig model. Supplementation with IGF-1 accelerates neuron differentiation in the hippocampus and promotes myelination in subcortical white matter regions in a time-dependent way. Furthermore, systemic IGF-1 supplementation stimulates cerebral protein synthesis. Our study suggests that IGF-1 therapy in the early postnatal period might be supportive for neurodevelopment in preterm infants.
    Keywords:  IGF-1; IGF1R; cortex; developing brain; hippocampus
    DOI:  https://doi.org/10.1523/ENEURO.0430-22.2023
  7. Biology (Basel). 2023 Mar 08. pii: 414. [Epub ahead of print]12(3):
    A Perspective on the Link between Mitochondria-Associated Membranes (MAMs) and Lipid Droplets Metabolism in Neurodegenerative Diseases.
    Tânia Fernandes, M Rosário Domingues, Paula I Moreira, Cláudia F Pereira.
      Mitochondria interact with the endoplasmic reticulum (ER) through contacts called mitochondria-associated membranes (MAMs), which control several processes, such as the ER stress response, mitochondrial and ER dynamics, inflammation, apoptosis, and autophagy. MAMs represent an important platform for transport of non-vesicular phospholipids and cholesterol. Therefore, this region is highly enriched in proteins involved in lipid metabolism, including the enzymes that catalyze esterification of cholesterol into cholesteryl esters (CE) and synthesis of triacylglycerols (TAG) from fatty acids (FAs), which are then stored in lipid droplets (LDs). LDs, through contact with other organelles, prevent the toxic consequences of accumulation of unesterified (free) lipids, including lipotoxicity and oxidative stress, and serve as lipid reservoirs that can be used under multiple metabolic and physiological conditions. The LDs break down by autophagy releases of stored lipids for energy production and synthesis of membrane components and other macromolecules. Pathological lipid deposition and autophagy disruption have both been reported to occur in several neurodegenerative diseases, supporting that lipid metabolism alterations are major players in neurodegeneration. In this review, we discuss the current understanding of MAMs structure and function, focusing on their roles in lipid metabolism and the importance of autophagy in LDs metabolism, as well as the changes that occur in neurogenerative diseases.
    Keywords:  ER–mitochondria contacts; energy production; lipid storage; lipophagy; neurodegenerative disorders
    DOI:  https://doi.org/10.3390/biology12030414
  8. Metabolites. 2023 Mar 16. pii: 433. [Epub ahead of print]13(3):
    A Comprehensive NMR Analysis of Serum and Fecal Metabolites in Familial Dysautonomia Patients Reveals Significant Metabolic Perturbations.
    Stephanann M Costello, Alexandra M Cheney, Annie Waldum, Brian Tripet, Maria Cotrina-Vidal, Horacio Kaufmann, Lucy Norcliffe-Kaufmann, Frances Lefcort, Valérie Copié.
      Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer's (AD) and Parkinson's (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut-brain axis of FD. Here, 1H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut-brain-metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.
    Keywords:  ELP1; NMR metabolomics; elongator protein subunit 1; familial dysautonomia; gut–brain–metabolism axis; human stool and serum polar metabolite profiles; metabolism; multivariate statistical analysis; neurodegenerative diseases; neurological disorders
    DOI:  https://doi.org/10.3390/metabo13030433
  9. Int J Mol Sci. 2023 Mar 08. pii: 5187. [Epub ahead of print]24(6):
    Young Astrocytic Mitochondria Attenuate the Elevated Level of CCL11 in the Aged Mice, Contributing to Cognitive Function Improvement.
    Ryosuke Tashiro, Dan Ozaki, Jesus Bautista-Garrido, Guanghua Sun, Lidiya Obertas, Alexis S Mobley, Gab Seok Kim, Jaroslaw Aronowski, Joo Eun Jung.
      Aging drives cognitive decline, and mitochondrial dysfunction is a hallmark of age-induced neurodegeneration. Recently, we demonstrated that astrocytes secrete functional mitochondria (Mt), which help adjacent cells to resist damage and promote repair after neurological injuries. However, the relationship between age-dependent changes in astrocytic Mt function and cognitive decline remains poorly understood. Here, we established that aged astrocytes secret less functional Mt compared to young astrocytes. We found the aging factor C-C motif chemokine 11 (CCL11) is elevated in the hippocampus of aged mice, and that its level is reduced upon systemic administration of young Mt, in vivo. Aged mice receiving young Mt, but not aged Mt improved cognitive function and hippocampal integrity. Using a CCL11-induced aging-like model in vitro, we found that astrocytic Mt protect hippocampal neurons and enhance a regenerative environment through upregulating synaptogenesis-related gene expression and anti-oxidants that were suppressed by CCL11. Moreover, the inhibition of CCL11-specific receptor C-C chemokine receptor 3 (CCR3) boosted the expression of synaptogenesis-related genes in the cultured hippocampal neurons and restored the neurite outgrowth. This study suggests that young astrocytic Mt can preserve cognitive function in the CCL11-mediated aging brain by promoting neuronal survival and neuroplasticity in the hippocampus.
    Keywords:  CCL11; aging; astrocytes; cognition; hippocampus; mitochondria; neuroplasticity
    DOI:  https://doi.org/10.3390/ijms24065187
  10. J Exp Biol. 2023 Mar 27. pii: jeb.245355. [Epub ahead of print]
    The roles of brain lipids and polar metabolites in the hypoxia tolerance of deep-diving pinnipeds.
    Gerrit A Martens, Cornelia Geßner, Lars P Folkow, Marina Creydt, Markus Fischer, Thorsten Burmester.
      Lipids make up more than half of the human brain's dry weight, yet the composition and function of the brain lipidome is not well characterized. They not only provide the structural basis of cell membranes, but also take part in a wide variety of biochemical processes. In neurodegenerative diseases, lipids can facilitate neuroprotection and serve as diagnostic biomarkers. The study of organisms adapted to extreme environments may prove particularly valuable in understanding mechanisms that protect against stressful conditions and prevent neurodegeneration. The brain of the hooded seal (Cystophora cristata) exhibits a remarkable tolerance to low tissue oxygen levels (hypoxia). While neurons of most terrestrial mammals suffer irreversible damage after only short periods of hypoxia, in vitro experiments revealed that neurons of the hooded seal show prolonged functional integrity even in severe hypoxia. How the brain lipidome may contribute to the hypoxia tolerance of marine mammals has been poorly studied. We performed an untargeted lipidomics analysis, which revealed that lipid species are significantly modulated in marine mammals compared with non-diving mammals. Increased levels of sphingomyelin species may have important implications in efficient signal transduction in the seal brain. Substrate assays revealed elevated normoxic tissue levels of glucose and lactate, which may suggest an enhanced glycolytic capacity. Additionally, the neurotransmitters glutamate and glutamine were decreased, which may indicate decreased excitatory synaptic signaling in marine mammals. Analysis of hypoxia-exposed brain tissue suggests that these represent constitutive mechanisms rather than an induced response towards hypoxic conditions.
    Keywords:  Brain; Hypoxia; Lipidome; Marine mammals; Oxidative stress; Pinniped
    DOI:  https://doi.org/10.1242/jeb.245355
  11. Mol Genet Metab Rep. 2023 Jun;35 100968
    Ketogenic diet in action: Metabolic profiling of pyruvate dehydrogenase deficiency.
    Eri Ogawa, Takako Hishiki, Noriyo Hayakawa, Hisato Suzuki, Kenjiro Kosaki, Makoto Suematsu, Toshiki Takenouchi.
      The pyruvate dehydrogenase complex serves as the main connection between cytosolic glycolysis and the tricarboxylic acid cycle within mitochondria. An infant with pyruvate dehydrogenase complex deficiency was treated with vitamin B1 supplementation and a ketogenic diet. These dietary modifications resolved the renal tubular reabsorption, central apnea, and transfusion-dependent anemia. A concurrent metabolome analysis demonstrated the resolution of the amino aciduria and an increased total amount of substrates in the tricarboxylic acid cycle, reflecting the improved mitochondrial energetics. Glutamate was first detected in the cerebrospinal fluid, accompanied by a clinical improvement, after the ketogenic ratio was increased to 3:1; thus, glutamate levels in cerebrospinal fluid may represent a biomarker for neuronal recovery. Metabolomic analyses of body fluids are useful for monitoring therapeutic effects in infants with inborn errors of carbohydrate metabolism.
    Keywords:  Ketogenic diet; Metabolome; Pyruvate dehydrogenase deficiency; Whole genome sequencing
    DOI:  https://doi.org/10.1016/j.ymgmr.2023.100968
  12. Metabolites. 2023 Mar 09. pii: 407. [Epub ahead of print]13(3):
    Metabolic and Transcriptomic Changes in the Mouse Brain in Response to Short-Term High-Fat Metabolic Stress.
    Ji-Kwang Kim, Sehoon Hong, Jina Park, Seyun Kim.
      The chronic consumption of diets rich in saturated fats leads to obesity and associated metabolic disorders including diabetes and atherosclerosis. Intake of a high-fat diet (HFD) is also recognized to dysregulate neural functions such as cognition, mood, and behavior. However, the effects of short-term high-fat diets on the brain are elusive. Here, we investigated molecular changes in the mouse brain following an acute HFD for 10 days by employing RNA sequencing and metabolomics profiling. Aberrant expressions of 92 genes were detected in the brain tissues of acute HFD-exposed mice. The differentially expressed genes were enriched for various pathways and processes such as superoxide metabolism. In our global metabolomic profiling, a total of 59 metabolites were significantly altered by the acute HFD. Metabolic pathways upregulated from HFD-exposed brain tissues relative to control samples included oxidative stress, oxidized polyunsaturated fatty acids, amino acid metabolism (e.g., branched-chain amino acid catabolism, and lysine metabolism), and the gut microbiome. Acute HFD also elevated levels of N-acetylated amino acids, urea cycle metabolites, and uracil metabolites, further suggesting complex changes in nitrogen metabolism. The observed molecular events in the present study provide a valuable resource that can help us better understand how acute HFD stress impacts brain homeostasis.
    Keywords:  brain; metabolism pathway; metabolomics; obesity; transcriptomics
    DOI:  https://doi.org/10.3390/metabo13030407
  13. Int J Mol Sci. 2023 Mar 13. pii: 5476. [Epub ahead of print]24(6):
    Mitochondrial Bioenergetics, Redox Balance, and Calcium Homeostasis Dysfunction with Defective Ultrastructure and Quality Control in the Hippocampus of Aged Female C57BL/6J Mice.
    Angie K Torres, Claudia Jara, Jesús Llanquinao, Matías Lira, Daniela Cortés-Díaz, Cheril Tapia-Rojas.
      Aging is a physiological process that generates progressive decline in many cellular functions. There are many theories of aging, and one of great importance in recent years is the mitochondrial theory of aging, in which mitochondrial dysfunction that occurs at advanced age could be responsible for the aged phenotype. In this context, there is diverse information about mitochondrial dysfunction in aging, in different models and different organs. Specifically, in the brain, different studies have shown mitochondrial dysfunction mainly in the cortex; however, until now, no study has shown all the defects in hippocampal mitochondria in aged female C57BL/6J mice. We performed a complete analysis of mitochondrial function in 3-month-old and 20-month-old (mo) female C57BL/6J mice, specifically in the hippocampus of these animals. We observed an impairment in bioenergetic function, indicated by a decrease in mitochondrial membrane potential, O2 consumption, and mitochondrial ATP production. Additionally, there was an increase in ROS production in the aged hippocampus, leading to the activation of antioxidant signaling, specifically the Nrf2 pathway. It was also observed that aged animals had deregulation of calcium homeostasis, with more sensitive mitochondria to calcium overload and deregulation of proteins related to mitochondrial dynamics and quality control processes. Finally, we observed a decrease in mitochondrial biogenesis with a decrease in mitochondrial mass and deregulation of mitophagy. These results show that during the aging process, damaged mitochondria accumulate, which could contribute to or be responsible for the aging phenotype and age-related disabilities.
    Keywords:  aging; bioenergetic; hippocampus; mitochondria; mitochondrial function
    DOI:  https://doi.org/10.3390/ijms24065476
  14. Int J Mol Sci. 2023 Mar 22. pii: 5986. [Epub ahead of print]24(6):
    Neuronal Prosurvival Role of Ceramide Synthase 2 by Olidogendrocyte-to-Neuron Extracellular Vesicle Transfer.
    Álvaro Casadomé-Perales, Sara Naya, Elisa Fernández-Martínez, Bea G Mille, Marta Guerrero-Valero, Héctor Peinado, Francesc X Guix, Carlos G Dotti, Ernest Palomer.
      Ageing is associated with notorious alterations in neurons, i.e., in gene expression, mitochondrial function, membrane degradation or intercellular communication. However, neurons live for the entire lifespan of the individual. One of the reasons why neurons remain functional in elderly people is survival mechanisms prevail over death mechanisms. While many signals are either pro-survival or pro-death, others can play both roles. Extracellular vesicles (EVs) can signal both pro-toxicity and survival. We used young and old animals, primary neuronal and oligodendrocyte cultures and neuroblastoma and oligodendrocytic lines. We analysed our samples using a combination of proteomics and artificial neural networks, biochemistry and immunofluorescence approaches. We found an age-dependent increase in ceramide synthase 2 (CerS2) in cortical EVs, expressed by oligodendrocytes. In addition, we show that CerS2 is present in neurons via the uptake of oligodendrocyte-derived EVs. Finally, we show that age-associated inflammation and metabolic stress favour CerS2 expression and that oligodendrocyte-derived EVs loaded with CerS2 lead to the expression of the antiapoptotic factor Bcl2 in inflammatory conditions. Our study shows that intercellular communication is altered in the ageing brain, which favours neuronal survival through the transfer of oligodendrocyte-derived EVs containing CerS2.
    Keywords:  CerS2; EVs; brain ageing; exosomes; intercellular communication; oligodendrocyte-to-neuron
    DOI:  https://doi.org/10.3390/ijms24065986
  15. Acta Neuropathol Commun. 2023 Mar 27. 11(1): 52
    Disrupted myelin lipid metabolism differentiates frontotemporal dementia caused by GRN and C9orf72 gene mutations.
    Oana C Marian, Jonathan D Teo, Jun Yup Lee, Huitong Song, John B Kwok, Ramon Landin-Romero, Glenda Halliday, Anthony S Don.
      Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.
    Keywords:  Cholesterol; FTD; Lipidomics; Lysosome; Progranulin; TDP-43
    DOI:  https://doi.org/10.1186/s40478-023-01544-7
  16. Curr Opin Neurobiol. 2023 Mar 23. pii: S0959-4388(23)00027-2. [Epub ahead of print]80 102702
    From seconds to days: Neural plasticity viewed through a lipid lens.
    John P Vaughen, Emma Theisen, Thomas R Clandinin.
      Many adult neurons are dynamically remodeled across timescales ranging from the rapid addition and removal of specific synaptic connections, to largescale structural plasticity events that reconfigure circuits over hours, days, and months. Membrane lipids, including brain-enriched sphingolipids, play crucial roles in these processes. In this review, we summarize progress at the intersection of neuronal activity, lipids, and structural remodeling. We highlight how brain activity modulates lipid metabolism to enable adaptive structural plasticity, and showcase glia as key players in membrane remodeling. These studies reveal that lipids act as critical signaling molecules that instruct the dynamic architecture of the brain.
    DOI:  https://doi.org/10.1016/j.conb.2023.102702
  17. Brain Pathol. 2023 Mar 28. e13157
    Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy.
    Tingting Dong, Zai-Qiang Zhang, Li-Hong Sun, Weilong Zhang, Zhaohui Zhu, Lin Lin, Lin Yang, An Lv, Chunying Liu, Qing Li, Rui-Feng Yang, Xiuru Zhang, Yamei Niu, Hou-Zao Chen, De-Pei Liu, Wei-Min Tong.
      Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age-dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N-acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo-insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.
    Keywords:  Mic60; antioxidant; mitochondria; mitochondrial encephalomyopathies; neurodegeneration; reactive oxygen species
    DOI:  https://doi.org/10.1111/bpa.13157
  18. Metabolites. 2023 Mar 04. pii: 384. [Epub ahead of print]13(3):
    Neurotransmitters in Type 2 Diabetes and the Control of Systemic and Central Energy Balance.
    Amnah Al-Sayyar, Maha M Hammad, Michayla R Williams, Mohammed Al-Onaizi, Jehad Abubaker, Fawaz Alzaid.
      Efficient signal transduction is important in maintaining the function of the nervous system across tissues. An intact neurotransmission process can regulate energy balance through proper communication between neurons and peripheral organs. This ensures that the right neural circuits are activated in the brain to modulate cellular energy homeostasis and systemic metabolic function. Alterations in neurotransmitters secretion can lead to imbalances in appetite, glucose metabolism, sleep, and thermogenesis. Dysregulation in dietary intake is also associated with disruption in neurotransmission and can trigger the onset of type 2 diabetes (T2D) and obesity. In this review, we highlight the various roles of neurotransmitters in regulating energy balance at the systemic level and in the central nervous system. We also address the link between neurotransmission imbalance and the development of T2D as well as perspectives across the fields of neuroscience and metabolism research.
    Keywords:  diabetes; energy balance; metabolism; neurotransmitters; obesity
    DOI:  https://doi.org/10.3390/metabo13030384
  19. J Lipid Res. 2023 Mar 27. pii: S0022-2275(23)00037-8. [Epub ahead of print] 100364
    The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis.
    Serhii Chornyi, Rob Ofman, Janet Koster, Hans R Waterham.
      Peroxisomes are single-membrane bounded organelles, that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the synthesis of ether lipids/plasmalogens. The first step in de novo ether lipid synthesis is mediated by the peroxisomal enzyme glyceronephosphate O-acyltransferase, which has a strict substrate specificity reacting only with the long-chain acyl-CoAs. The aim of this study was to determine the origin of these long-chain acyl-CoAs. To this end, we developed a sensitive method for the measurement of de novo ether phospholipid synthesis in cells and, by CRISPR/Cas9 genome editing, generated a series of HeLa cell lines with deficiencies of proteins involved in peroxisomal biogenesis, beta-oxidation, ether lipid synthesis, or metabolite transport. Our results show that the long-chain acyl-CoAs required for the first step of ether lipid synthesis can be imported from the cytosol by the peroxisomal ABCD proteins, in particular ABCD3. Furthermore, we show that these acyl-CoAs can be produced intraperoxisomally by chain shortening of CoA esters of very long-chain fatty acids via beta-oxidation. Our results demonstrate that peroxisomal beta-oxidation and ether lipid synthesis are intimately connected and that the peroxisomal ABC transporters play a crucial role in de novo ether lipid synthesis.
    Keywords:  Biosynthesis; Fatty acid; Metabolism; Phospholipids; Transport; Zellweger syndrome
    DOI:  https://doi.org/10.1016/j.jlr.2023.100364
  20. Exp Neurol. 2023 Mar 27. pii: S0014-4886(23)00076-6. [Epub ahead of print] 114392
    Activation of TRPV4 induces intraneuronal tau hyperphosphorylation via cholesterol accumulation.
    Kangshuai Du, Yunxiao Dou, Kui Chen, Yanxin Zhao.
      Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel, whose aberrant function in neurons has been reported to participate in the progression of brain disorders, including Alzheimer's disease (AD). However, the influence of TRPV4 activation on tau hyperphosphorylation in AD has not yet been elucidated. Since disturbed brain cholesterol homeostasis is considered to be related to excessive tau phosphorylation, this study aimed to explore whether dysregulation of TRPV4 affects tau phosphorylation and whether it involves cholesterol unbalance. Our data indicated that TRPV4 activation increased tau phosphorylation in the cortex and hippocampus of P301S tauopathy mouse model and aggravated its cognitive decline. In addition, we detected that TRPV4 activation upregulated cholesterol levels in primary neurons, and the elevation of cholesterol promoted hyperphosphorylation of tau. TRPV4 knockdown improved tau hyperphosphorylation by reducing intracellular cholesterol accumulation. Our results suggest that activation of TRPV4 may take part in the pathological mechanism of AD by promoting intraneuronal tau hyperphosphorylation in a cholesterol-dependent manner.
    Keywords:  Alzheimer's disease (AD); Cholesterol; Tau; Transient receptor potential vanilloid 4 (TRPV4)
    DOI:  https://doi.org/10.1016/j.expneurol.2023.114392
  21. CNS Neurol Disord Drug Targets. 2023 Mar 30.
    Acetyl-L-carnitine and Amyotrophic Lateral Sclerosis: current evidence and potential use.
    Fabiola De Marchi, Sakthipriyan Venkatesan, Massimo Saraceno, Letizia Mazzini, Elena Grossini.
       BACKGROUND: The management of neurodegenerative diseases can be frustrating for clinicians, given the limited progress of conventional medicine in this context.
    AIM: For this reason, a more comprehensive, integrative approach is urgently needed. Among various emerging focuses for intervention, the modulation of central nervous system energetics, oxidative stress, and inflammation is becoming more and more promising.
    METHOD: In particular, electrons leakage involved in the mitochondrial energetics can generate reactive oxygen-free radical-related mitochondrial dysfunction that would contribute to the etiopathology of many disorders, such as Alzheimer's and other dementias, Parkinson's disease, multiple sclerosis, stroke, and amyotrophic lateral sclerosis (ALS).
    RESULTS: In this context, using agents, like acetyl L-carnitine (ALCAR), provides mitochondrial support, reduces oxidative stress, and improves synaptic transmission.
    CONCLUSION: This narrative review aims to update the existing literature on ALCAR molecular profile, tolerability, and translational clinical potential use in neurodegeneration, focusing on ALS.
    Keywords:  ALS; mitochondria; neurologic disease; oxidative stress; physiopathology; treatment
    DOI:  https://doi.org/10.2174/1871527322666230330083757
  22. CNS Neurosci Ther. 2023 Mar 27.
    Brain metabolic signatures in patients with genetic and nongenetic amyotrophic lateral sclerosis.
    Pan Liu, Yongxiang Tang, Wanzhen Li, Zhen Liu, Ming Zhou, Jian Li, Yanchun Yuan, Liangjuan Fang, Jifeng Guo, Lu Shen, Hong Jiang, Beisha Tang, Shuo Hu, Junling Wang.
       AIMS: To study the brain metabolic signature in Chinese amyotrophic lateral sclerosis (ALS) patients and compare the difference in brain metabolic patterns between ALS with and without genetic variants.
    METHODS: We included 146 patients with ALS and 128 healthy controls (HCs). All patients with ALS underwent genetic testing to screen for ALS related genetic variants and were then divided into genetic (n = 22) and nongenetic ALS (n = 93) subgroups. All participants underwent brain 18 F-FDG-PET scans. Group comparisons were performed using the two-sample t-test model of SPM12.
    RESULTS: We identified a large of hypometabolic clusters in ALS patients as compared with HCs, especially in the bilateral basal ganglia, midbrain, and cerebellum. Moreover, hypometabolism in the bilateral temporal lobe, precentral gyrus and hypermetabolism in the left anterior cingulate, occipital lobe, and bilateral frontal lobe were also found in ALS patients as compared with HCs. Compared with nongenetic ALS patients, genetic ALS patients showed hypometabolism in the right postcentral gyrus, precuneus, and middle occipital gyrus. The incidence of sensory disturbance in patients with genetic ALS was higher than that in patients with nongenetic ALS (5 of 22 [22.72%] vs. 7 of 93 [7.52%], p = 0.036).
    CONCLUSIONS: Our investigation provided unprecedented evidence of relative hypometabolism in the midbrain and cerebellum in ALS patients. Genetic ALS patients showed a specific signature of brain metabolism and a higher incidence of sensory disturbance, indicating that genetic factors may be an underlying cause affecting the brain metabolism and increasing the risk of sensory disturbance in ALS.
    Keywords:  18F-FDG-PET; amyotrophic lateral sclerosis; brain metabolism; genetic; whole exome sequencing
    DOI:  https://doi.org/10.1111/cns.14193
  23. Metabolites. 2023 Feb 23. pii: 331. [Epub ahead of print]13(3):
    Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5.
    Fangfang Chen, Hanna Friederike Willenbockel, Thekla Cordes.
      The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the "multiple-hit theory" and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.
    Keywords:  NaCT; SLC13A5; TCA cycle; citrate metabolism; citrate transport; compartmentalization; mass spectrometry; metabolic niche; mitochondria; tracing
    DOI:  https://doi.org/10.3390/metabo13030331
  24. Int J Mol Sci. 2023 Mar 13. pii: 5470. [Epub ahead of print]24(6):
    Microarrays, Enzymatic Assays, and MALDI-MS for Determining Specific Alterations to Mitochondrial Electron Transport Chain Activity, ROS Formation, and Lipid Composition in a Monkey Model of Parkinson's Disease.
    María Dolores García-Fernández, Ane Larrea, Roberto Fernández, Rafael Rodríguez-Puertas, Egoitz Astigarraga, Iván Manuel, Gabriel Barreda-Gómez.
      Multiple evidences suggest that mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease via the selective cell death of dopaminergic neurons, such as that which occurs after prolonged exposure to the mitochondrial electron transport chain (ETC) complex I inhibitor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP). However, the effects of chronic MPTP on the ETC complexes and on enzymes of lipid metabolism have not yet been thoroughly determined. To face these questions, the enzymatic activities of ETC complexes and the lipidomic profile of MPTP-treated non-human primate samples were determined using cell membrane microarrays from different brain areas and tissues. MPTP treatment induced an increase in complex II activity in the olfactory bulb, putamen, caudate, and substantia nigra, where a decrease in complex IV activity was observed. The lipidomic profile was also altered in these areas, with a reduction in the phosphatidylserine (38:1) content being especially relevant. Thus, MPTP treatment not only modulates ETC enzymes, but also seems to alter other mitochondrial enzymes that regulate the lipid metabolism. Moreover, these results show that a combination of cell membrane microarrays, enzymatic assays, and MALDI-MS provides a powerful tool for identifying and validating new therapeutic targets that might accelerate the drug discovery process.
    Keywords:  MALDI imaging mass spectrometry; Parkinson’s disease; microarray; mitochondria
    DOI:  https://doi.org/10.3390/ijms24065470
  25. Adv Exp Med Biol. 2023 ;1422 143-165
    Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.
    Stephanie M Cologna, Koralege C Pathmasiri, Melissa R Pergande, Avia Rosenhouse-Dantsker.
      Lipid mistrafficking is a biochemical hallmark of Niemann-Pick Type C (NPC) disease and is classically characterized with endo/lysosomal accumulation of unesterified cholesterol due to genetic mutations in the cholesterol transporter proteins NPC1 and NPC2. Storage of this essential signaling lipid leads to a sequence of downstream events, including oxidative stress, calcium imbalance, neuroinflammation, and progressive neurodegeneration, another hallmark of NPC disease. These observations have been validated in a growing number of studies ranging from NPC cell cultures and animal models to patient specimens. In recent reports, alterations in the levels of another class of critical signaling lipids, namely phosphoinositides, have been described in NPC disease. Focusing on cholesterol and phosphoinositides, the chapter begins by reviewing the interactions of NPC proteins with cholesterol and their role in cholesterol transport. It then continues to describe the modulation of cholesterol efflux in NPC disease. The chapter concludes with a summary of findings related to the functional consequences of perturbations in phosphoinositides in this fatal disease.
    Keywords:  Binding; Lysosome; Niemann-Pick disease type C; Signaling; Structure; Transport
    DOI:  https://doi.org/10.1007/978-3-031-21547-6_5
  26. Neurobiol Dis. 2023 Mar 29. pii: S0969-9961(23)00124-9. [Epub ahead of print] 106110
    Integrative analysis of metabolomics and proteomics unravels purine metabolism disorder in the SOD1G93A mouse model of amyotrophic lateral sclerosis.
    Xiaojiao Xu, Qiu Yang, Zheyi Liu, Rong Zhang, Hang Yu, Manli Wang, Sheng Chen, Guowang Xu, Yaping Shao, Weidong Le.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. In this study, we aimed to investigate the molecular changes at both metabolic and proteomic levels during disease progression to identify the most critical metabolic pathways and underlying mechanisms involved in ALS pathophysiological changes. Utilizing liquid chromatography-mass spectrometry-based metabolomics, we analyzed the metabolites levels of plasma, lumbar spinal cord, and motor cortex from SOD1G93A mice and wildtype (WT) littermates at different stages. To elucidate the regulatory network underlying metabolic changes, we further analyzed the proteomics profile in the spinal cords of SOD1G93A and WT mice. A group of metabolites implicated in purine metabolism, methionine cycle, and glycolysis were found differentially expressed in ALS mice, and abnormal expressions of enzymes involved in these metabolic pathways were also confirmed. Notably, we first demonstrated that dysregulation of purine metabolism might contribute to the pathogenesis and disease progression of ALS. Furthermore, dysregulated fatty acid metabolism, TCA cycle, arginine and proline metabolism, and folate-mediated one‑carbon metabolism are also important events in ALS pathophysiology. The identified differential metabolites and proteins in our study could complement existing data on metabolic reprogramming in ALS, which might provide new insight into the pathological mechanisms and novel therapeutic targets of ALS.
    Keywords:  Amyotrophic lateral sclerosis; Folate and methionine cycle; Liquid chromatography-mass spectrometry; Metabolomics; Proteomics; Purine metabolism
    DOI:  https://doi.org/10.1016/j.nbd.2023.106110
  27. Biomedicines. 2023 Mar 11. pii: 861. [Epub ahead of print]11(3):
    Alzheimer's Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity.
    Michele Cerasuolo, Michele Papa, Anna Maria Colangelo, Maria Rosaria Rizzo.
      Alzheimer's disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid β (Aβ) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood-brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid β (Aβ) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.
    Keywords:  Alzheimer’s disease; blood–brain barrier; glia; neurovascular unit; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/biomedicines11030861
  28. Magn Reson Med. 2023 Mar 27.
    In vivo assessment of β-hydroxybutyrate metabolism in mouse brain using deuterium (2 H) MRS.
    Narayan Datt Soni, Anshuman Swain, Paul Jacobs, Halvor Juul, Ryan Armbruster, Ravi Prakash Reddy Nanga, Kavindra Nath, Corinde Wiers, John Detre, Ravinder Reddy.
       PURPOSE: To monitor the metabolic turnover of β-hydroxybutyrate (BHB) oxidation using 2 H-MRS in conjunction with intravenous administration of 2 H labeled BHB.
    METHODS: Nine-month-old mice were infused with [3,4,4,4]-2 H4 -BHB (d4 -BHB; 3.11 g/kg) through the tail vein using a bolus variable infusion rate for a period of 90 min. The labeling of downstream cerebral metabolites from the oxidative metabolism of d4 -BHB was monitored using 2 H-MRS spectra acquired with a home-built 2 H surface coil on a 9.4T preclinical MR scanner with a temporal resolution of 6.25 min. An exponential model was fit to the BHB and glutamate/glutamine (Glx) turnover curves to determine rate constants of metabolite turnover and to aid in the visualization of metabolite time courses.
    RESULTS: Deuterium label was incorporated into Glx from BHB metabolism through the tricarboxylic acid (TCA) cycle, with an increase in the level of [4,4]-2 H2 -Glx (d2 -Glx) over time and reaching a quasi-steady state concentration of ∼0.6 ± 0.1 mM following 30 min of infusion. Complete oxidative metabolic breakdown of d4 -BHB also resulted in the formation of semi-heavy water (HDO), with a four-fold (10.1 to ∼42.1 ± 7.3 mM) linear (R2  = 0.998) increase in its concentration by the end of infusion. The rate constant of Glx turnover from d4 -BHB metabolism was determined to be 0.034 ± 0.004 min-1 .
    CONCLUSION: 2 H-MRS can be used to monitor the cerebral metabolism of BHB with its deuterated form by measuring the downstream labeling of Glx. The integration of 2 H-MRS with deuterated BHB substrate provides an alternative and clinically promising MRS tool to detect neurometabolic fluxes in healthy and disease conditions.
    Keywords:  2H-MRS; TCA; brain; d4-BHB; ketone bodies; metabolism
    DOI:  https://doi.org/10.1002/mrm.29648
  29. Int J Mol Sci. 2023 Mar 22. pii: 5992. [Epub ahead of print]24(6):
    TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1.
    Shiraz Dib, Rodrigo Azevedo Loiola, Emmanuel Sevin, Julien Saint-Pol, Fumitaka Shimizu, Takashi Kanda, Jens Pahnke, Fabien Gosselet.
      Neuroinflammation and brain lipid imbalances are observed in Alzheimer's disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, cholesterol and HBP function in neurodegenerative disorders.
    Keywords:  ABCA1; ABCB1; LXR; TNFα; brain pericytes; cholesterol metabolism
    DOI:  https://doi.org/10.3390/ijms24065992
  30. Eur J Neurol. 2023 Mar 31.
    Lipids and Amyotrophic Lateral Sclerosis: A two-sample Mendelian Randomization Study.
    Kailin Xia, Veronika Klose, Josef Högel, Tao Huang, Linjing Zhang, Johannes Dorst, Dongsheng Fan, Albert C Ludolph.
       OBJECTIVE: Previous observational studies revealed a potential but partially controversial relation between lipid metabolism and risk of amyotrophic lateral sclerosis (ALS), potentially prone to bias. Therefore, we aimed to study whether lipid metabolism involves genetically determined risk factors for ALS through Mendelian randomization (MR) analysis.
    METHODS: Using GWASs summary-level data for total cholesterol (TC) (n=188,578), high-density lipoprotein cholesterol (HDL-C) (n=403,943), low-density lipoprotein cholesterol (LDL-C) (n=440,546), apolipoprotein A1(ApoA1) (n=391,193), apolipoprotein B (ApoB) (n=439,214), and ALS (12,577 cases and 23,475 controls), we implemented a bidirectional MR study to evaluate a genetic relation between lipids and ALS risk. We performed a mediation analysis to assess whether LDL-C is a potential mediator on the pathway from traits of LDL-C-related polyunsaturated fatty acids (PUFAs) to ALS risk.
    RESULTS: We identified genetically predicted increased lipid levels to be associated with the risk of ALS, whereby elevated LDL-C had the most potent effect (OR, 1.028; 95% CI, 1.008-1.049, p=0.006). The effect of increased levels of apolipoproteins on ALS was similar to their corresponding lipoproteins. ALS did not cause any changes in lipid levels. We found no relation between LDL-C-modifying lifestyles and ALS. The mediation analysis revealed that LDL-C could act as an active mediator for linoleic acid, with the mediation effect estimated to be 0.009.
    CONCLUSION: We provided high-level genetic evidence verifying the positive link between preclinically elevated lipid and ALS risk that had been described in previous genetic and observational studies. We also demonstrated the mediating role of LDL-C in the pathway from PUFAs to ALS.
    Keywords:  Mendelian randomization; amyotrophic lateral sclerosis; genetics; instrumental variables; lipids
    DOI:  https://doi.org/10.1111/ene.15810
  31. Molecules. 2023 Mar 14. pii: 2622. [Epub ahead of print]28(6):
    Deciphering Complex Interactions in Bioactive Lipid Signaling.
    Mauro Maccarrone.
      Lipids are usually viewed as metabolic fuel and structural membrane components. Yet, in recent years, different families of lipids able to act as authentic messengers between cells and/or intracellularly have been discovered. Such lipid signals have been shown to exert their biological activity via specific receptors that, by triggering distinct signal transduction pathways, regulate manifold pathophysiological processes in our body. Here, endogenous bioactive lipids produced from arachidonic acid (AA) and other poly-unsaturated fatty acids will be presented, in order to put into better perspective the relevance of their mutual interactions for health and disease conditions. To this end, metabolism and signal transduction pathways of classical eicosanoids, endocannabinoids and specialized pro-resolving mediators will be described, and the intersections and commonalities of their metabolic enzymes and binding receptors will be discussed. Moreover, the interactions of AA-derived signals with other bioactive lipids such as shingosine-1-phosphate and steroid hormones will be addressed.
    Keywords:  biased signaling; eicosanoid; endocannabinoid; metabolism; signal transduction; specialized pro-resolving mediator; sphingosine-1-phosphate; steroid
    DOI:  https://doi.org/10.3390/molecules28062622
  32. Sci China Life Sci. 2023 Mar 23.
    Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin.
    Lewei Dong, Jian Xiao, Shuai Liu, Gang Deng, Yacheng Liao, Beibei Chu, Xiaolu Zhao, Bao-Liang Song, Jie Luo.
      Peroxisomal disorders (PDs) are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions. X-linked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene, which encodes a transporter mediating the uptake of very long-chain fatty acids (VLCFAs). The curative approaches for PDs are very limited. Here, we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs. We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome. 2-Hydroxypropyl-β-cyclodextrin (HPCD) effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes. In ABCD1 knockdown cells, HPCD treatment lowered reactive oxygen species and VLCFA to normal levels. In Abcd1 knockout mice, HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex. The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration. Together, our results suggest that defective cholesterol transport underlies most, if not all, PDs, and that HPCD can serve as a novel and effective strategy for the treatment of PDs.
    Keywords:  ABCD1; VLCFA; X-ALD; cholesterol; cyclodextrin; lysosome; peroxisomal disorders; peroxisome
    DOI:  https://doi.org/10.1007/s11427-022-2260-4
  33. Prostaglandins Leukot Essent Fatty Acids. 2023 Mar 22. pii: S0952-3278(23)00038-8. [Epub ahead of print]192 102569
    Sex differences in hippocampal-dependent memory and the hippocampal lipidome in adolescent rats raised on diets with or without DHA.
    Daniel M Lamontagne-Kam, Saeideh Davari, Juan J Aristizabal-Henao, Seungjae Cho, Dan Chalil, John G Mielke, Ken D Stark.
      Recent studies suggest the effects of DHA supplementation on human memory may differ between females and males during infancy, adolescence, and early adulthood, but the underlying mechanisms are not clear. As a result, this study sought to examine the spatial memory and brain lipidomic profiles in female and male adolescent rats with or without a DHA-enriched diet that began perinatally with the supplementation of dams. Spatial learning and memory were examined in adolescent rats using the Morris Water Maze beginning at 6 weeks of age and animals were sacrificed at 7 weeks of age to permit isolation of brain tissue and blood samples. Behavioral testing showed that there was a significant diet x sex interaction for two key measures of spatial memory (distance to zone and time spent in the correct quadrant during the probe test), with female rats benefiting the most from DHA supplementation. Lipidomic analyses suggest levels of arachidonic acid (ARA) and n-6 docosapentaenoic acid (DPA) containing phospholipid species were lower in the hippocampus of DHA supplemented compared with control animals, and principal component analyses revealed a potential dietary treatment effect for hippocampal PUFA. Females fed DHA had slightly more PE P-18:0_22:6 and maintained levels of PE 18:0_20:4 in the hippocampus in contrast with males fed DHA. Understanding how DHA supplementation during the perinatal and adolescent periods changes cognitive function in a sex-specific manner has important implications for determining the dietary requirements of DHA. This study adds to previous work highlighting the importance of DHA for spatial memory and provides evidence that further research needs to consider how DHA supplementation can cause sex-specific changes.
    DOI:  https://doi.org/10.1016/j.plefa.2023.102569
  34. J Clin Invest. 2023 Mar 28. pii: e165019. [Epub ahead of print]
    CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.
    Charlotte Gehin, Museer A Lone, Winston Lee, Laura Capolupo, Sylvia Ho, Adekemi M Adeyemi, Erica H Gerkes, Alexander Pa Stegmann, Estrella López-Martín, Eva Bermejo-Sánchez, Beatriz Martínez-Delgado, Christiane Zweier, Cornelia Kraus, Bernt Popp, Vincent Strehlow, Daniel Gräfe, Ina Knerr, Eppie R Jones, Stefano Zamuner, Luciano A Abriata, Vidya Kunnathully, Brandon E Moeller, Anthony Vocat, Samuel Rommelaere, Jean-Philippe Bocquete, Evelyne Ruchti, Greta Limoni, Marine Van Campenhoudt, Samuel Bourgeat, Petra Henklein, Christian Gilissen, Bregje W van Bon, Rolph Pfundt, Marjolein H Willemsen, Jolanda H Schieving, Emanuela Leonardi, Fiorenza Soli, Alessandra Murgia, Hui Guo, Qiumeng Zhang, Kun Xia, Christina R Fagerberg, Christoph P Beier, Martin J Larsen, Irene Valenzuela, Paula Fernández-Álvarez, Shiyi Xiong, Robert Śmigiel, Vanesa López-González, Lluís Armengol, Manuela Morleo, Angelo Selicorni, Annalaura Torella, Moira Blyth, Nicola S Cooper, Valerie Wilson, Renske Oegema, Yvan Herenger, Aurore Garde, Ange-Line Bruel, Frederic Tran Mau-Them, Alexis Br Maddocks, Jennifer M Bain, Musadiq A Bhat, Gregory Costain, Peter Kannu, Ashish Marwaha, Neena L Champaigne, Michael J Friez, Ellen B Richardson, Vykuntaraju K Gowda, Varunvenkat M Srinivasan, Yask Gupta, Tze Y Lim, Simone Sanna-Cherchi, Bruno Lemaitre, Toshiyuki Yamaji, Kentaro Hanada, John E Burke, Ana Marija Jakšić, Brian D McCabe, Paolo De Los Rios, Thorsten Hornemann, Giovanni D'Angelo, Vincenzo A Gennarino.
      Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call CerTra syndrome. These findings uncover a central role for CERT autoregulation in the control of the sphingolipid biosynthetic flux, provide unexpected insight into the structural organisation of CERT, and suggest a possible therapeutic approach for CerTra syndrome patients.
    Keywords:  Cell Biology; Genetics; Lipid rafts; Neurodevelopment
    DOI:  https://doi.org/10.1172/JCI165019
  35. bioRxiv. 2023 Mar 14. pii: 2023.03.14.532547. [Epub ahead of print]
    Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis.
    Takahiro Fuchigami, Yutaka Itokazu, Robert K Yu.
      The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia-like NSCs contributing to neurogenesis throughout adulthood. However, the underlying regulatory mechanism during the transition from quiescent NSCs to activated NSCs in the postnatal NSC niche is not fully understood. Lipid metabolism and lipid composition play important roles in regulating NSC fate determination. Biological lipid membranes define the individual cellular shape and help maintain cellular organization and are highly heterogenous in structure and there exist diverse microdomains (also known as lipid rafts), which are enriched with sugar molecules, such as glycosphingolipids. An often overlooked but key aspect is that the functional activities of proteins and genes are highly dependent upon their molecular environments. We previously reported that ganglioside GD3 is the predominant species in NSCs and that the reduced postnatal NSC pools are observed in global GD3-synthase knockout (GD3S-KO) mouse brains. The specific roles of GD3 in determining the stage and cell-lineage determination of NSCs remain unclear, since global GD3S-KO mice cannot distinguish if GD3 regulates postnatal neurogenesis or developmental impacts. Here we show that inducible GD3 deletion in postnatal radial glia-like NSCs promotes the NSC activation, resulting in the loss of the long-term maintenance of the adult NSC pools. The reduced neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of GD3S-conditional-knockout mice led to impaired olfactory and memory functions. Thus, our results provide convincing evidence that postnatal GD3 maintains the quiescent state of radial glia-like NSCs in the adult NSC niche.
    DOI:  https://doi.org/10.1101/2023.03.14.532547
  36. Sci Rep. 2023 Mar 31. 13(1): 5275
    Modulation of cytotoxic amyloid fibrillation and mitochondrial damage of α-synuclein by catechols mediated conformational changes.
    Toktam Zohoorian-Abootorabi, Ali Akbar Meratan, Saeed Jafarkhani, Vladimir Muronetz, Thomas Haertlé, Ali Akbar Saboury.
      The interplay between α-synuclein (α-syn) and catechols plays a central role in Parkinson's disease. This may be related to the modulating effects of catechols on the various aspects of α-syn fibrillization. Some of these effects may be attributed to the membrane-binding properties of the protein. In this work, we compare the effect of some catechols, including dopamine, epinephrine, DOPAL, and levodopa in micromolar concentrations, on the in vitro cytotoxicity of α-syn fibrils on human neuroblastoma SH-SY5Y cells. The study was followed by comparing the interactions of resulting structures with rat brain mitochondria used as an in vitro biological model. The obtained results demonstrate that catechols-induced structures have lost their cytotoxicity mimicking apoptotic cell death mediated by α-syn aggregates in different proportions. Moreover, α-syn fibrils-induced mitochondrial dysfunction, evaluated by a range of biochemical assays, was modulated by catechols-modified α-syn oligomers in different manners, as levodopa and DOPAL demonstrated the maximal and minimal effects, respectively. The plausible mechanism causing the inhibition of α-syn cytotoxic fibrillization and mitochondrial dysfunction by catechols is discussed. Taken together, we propose that catechols can prevent the cytotoxic assembly of α-syn and its destructive effects on mitochondria at various stages, suggesting that decreased levels of catechols in dopaminergic neurons might accelerate the α-syn cytotoxicity and mitochondrial dysfunction implicating Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41598-023-32075-9
  37. Nat Chem Biol. 2023 Mar 27.
    Cytosolic and mitochondrial NADPH fluxes are independently regulated.
    Xiangfeng Niu, Ethan Stancliffe, Susan J Gelman, Lingjue Wang, Michaela Schwaiger-Haber, Joe L Rowles, Leah P Shriver, Gary J Patti.
      Although nicotinamide adenine dinucleotide phosphate (NADPH) is produced and consumed in both the cytosol and mitochondria, the relationship between NADPH fluxes in each compartment has been difficult to assess due to technological limitations. Here we introduce an approach to resolve cytosolic and mitochondrial NADPH fluxes that relies on tracing deuterium from glucose to metabolites of proline biosynthesis localized to either the cytosol or mitochondria. We introduced NADPH challenges in either the cytosol or mitochondria of cells by using isocitrate dehydrogenase mutations, administering chemotherapeutics or with genetically encoded NADPH oxidase. We found that cytosolic challenges influenced NADPH fluxes in the cytosol but not NADPH fluxes in mitochondria, and vice versa. This work highlights the value of using proline labeling as a reporter system to study compartmentalized metabolism and reveals that NADPH homeostasis in the cytosolic and mitochondrial locations of a cell are independently regulated, with no evidence for NADPH shuttle activity.
    DOI:  https://doi.org/10.1038/s41589-023-01283-9
  38. Front Pediatr. 2023 ;11 1071206
    New approaches to screening and management of neonatal hypoglycemia based on improved understanding of the molecular mechanism of hypoglycemia.
    Charles A Stanley, Paul S Thornton, Diva D De Leon.
      For the past 70 years, controversy about hypoglycemia in newborn infants has focused on a numerical "definition of neonatal hypoglycemia", without regard to its mechanism. This ignores the purpose of screening newborns for hypoglycemia, which is to identify those with pathological forms of hypoglycemia and to prevent hypoglycemic brain injury. Recent clinical and basic research indicates that the three major forms of neonatal hypoglycemia are caused by hyperinsulinism (recognizing also that other rare hormonal or metabolic conditions may also present during this time frame). These include transitional hypoglycemia, which affects all normal newborns in the first few days after birth; perinatal stress-induced hypoglycemia in high-risk newborns, which afflicts ∼1 in 1,200 newborns; and genetic forms of congenital hyperinsulinism which afflict ∼1 in 10,000-40,000 newborns. (1) Transitional hyperinsulinism in normal newborns reflects persistence of the low glucose threshold for insulin secretion during fetal life into the first few postnatal days. Recent data indicate that the underlying mechanism is decreased trafficking of ATP-sensitive potassium channels to the beta-cell plasma membrane, likely a result of the hypoxemic state of fetal life. (2) Perinatal stress-induced hyperinsulinism in high-risk infants appears to reflect an exaggeration of this normal low fetal glucose threshold for insulin release due to more severe and prolonged exposure to perinatal hypoxemia. (3) Genetic hyperinsulinism, in contrast, reflects permanent genetic defects in various steps controlling beta-cell insulin release, such as inactivating mutations of the K ATP-channel genes. The purpose of this report is to review our current knowledge of these three major forms of neonatal hyperinsulinism as a foundation for the diagnosis and management of hypoglycemia in newborn infants. This includes selection of appropriate interventions based on underlying disease mechanism; combined monitoring of both plasma glucose and ketone levels to improve screening for infants with persistent forms of hypoglycemia; and ultimately to ensure that infants at risk of persistent hyperinsulinemic hypoglycemia are recognized prior to discharge from the nursery.
    Keywords:  brain damage; glucose; insulin; ketones; newborns
    DOI:  https://doi.org/10.3389/fped.2023.1071206
  39. Int J Mol Sci. 2023 Mar 14. pii: 5525. [Epub ahead of print]24(6):
    Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity.
    Taylor C Harned, Radu V Stan, Ze Cao, Rajarshi Chakrabarti, Henry N Higgs, Catherine C Y Chang, Ta Yuan Chang.
      Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain unknown. Here, using biochemical fractionation techniques, we observe cholesterol accumulation at the MAM which leads to ACAT1/SOAT1 enrichment in this domain. MAM proteomics data suggests that ACAT1/SOAT1 inhibition strengthens the ER-mitochondria connection. Confocal and electron microscopy confirms that ACAT1/SOAT1 inhibition increases the number of ER-mitochondria contact sites and strengthens this connection by shortening the distance between these two organelles. This work demonstrates how directly manipulating local cholesterol levels at the MAM can alter inter-organellar contact sites and suggests that cholesterol buildup at the MAM is the impetus behind the therapeutic benefits of ACAT1/SOAT1 inhibition.
    Keywords:  ACAT inhibitors; ACAT1; Alzheimer’s disease; F12511; K-604; SOAT1; cholesterol; endoplasmic reticulum; lipid metabolism; mitochondria-associated membrane (MAM)
    DOI:  https://doi.org/10.3390/ijms24065525
  40. Int J Mol Sci. 2023 Mar 22. pii: 5956. [Epub ahead of print]24(6):
    Treatment with the Glycosphingolipid Modulator THI Rescues Myelin Integrity in the Striatum of R6/2 HD Mice.
    Giuseppe Pepe, Paola Lenzi, Luca Capocci, Federico Marracino, Ludovica Pizzati, Pamela Scarselli, Alba Di Pardo, Francesco Fornai, Vittorio Maglione.
      Huntington's disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2', 3' Cyclic Nucleotide 3'-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease.
    Keywords:  HD; glycosphingolipids; myelin; neurodegeneration
    DOI:  https://doi.org/10.3390/ijms24065956
  41. Antioxidants (Basel). 2023 Mar 03. pii: 631. [Epub ahead of print]12(3):
    24-Hydroxycholesterol Induces Tau Proteasome-Dependent Degradation via the SIRT1/PGC1α/Nrf2 Pathway: A Potential Mechanism to Counteract Alzheimer's Disease.
    Gabriella Testa, Serena Giannelli, Barbara Sottero, Erica Staurenghi, Giorgio Giaccone, Paola Caroppo, Paola Gamba, Gabriella Leonarduzzi.
      Considerable evidence indicates that cholesterol oxidation products, named oxysterols, play a key role in several events involved in Alzheimer's disease (AD) pathogenesis. Although the majority of oxysterols causes neuron dysfunction and degeneration, 24-hydroxycholesterol (24-OHC) has recently been thought to be neuroprotective also. The present study aimed at supporting this concept by exploring, in SK-N-BE neuroblastoma cells, whether 24-OHC affected the neuroprotective SIRT1/PGC1α/Nrf2 axis. We demonstrated that 24-OHC, through the up-regulation of the deacetylase SIRT1, was able to increase both PGC1α and Nrf2 expression and protein levels, as well as Nrf2 nuclear translocation. By acting on this neuroprotective pathway, 24-OHC favors tau protein clearance by triggering tau ubiquitination and subsequently its degradation through the ubiquitin-proteasome system. We also observed a modulation of SIRT1, PGC1α, and Nrf2 expression and synthesis in the brain of AD patients with the progression of the disease, suggesting their potential role in neuroprotection. These findings suggest that 24-OHC contributes to tau degradation through the up-regulation of the SIRT1/PGC1α/Nrf2 axis. Overall, the evidence points out the importance of avoiding 24-OHC loss, which can occur in the AD brain, and of limiting SIRT1, PGC1α, and Nrf2 deregulation in order to prevent the neurotoxic accumulation of hyperphosphorylated tau and counteract neurodegeneration.
    Keywords:  24-hydroxycholesterol; Alzheimer’s disease; Nrf2; proteasome; sirtuin 1; tau
    DOI:  https://doi.org/10.3390/antiox12030631
  42. J Cell Physiol. 2023 Mar 26.
    Human neurons lacking amyloid precursor protein exhibit cholesterol-associated developmental and presynaptic deficits.
    Haylee Mesa, Elaine Y Zhang, Yingcai Wang, Qi Zhang.
      Amyloid precursor protein (APP) produces aggregable β-amyloid peptides and its mutations are associated with familial Alzheimer's disease (AD), which makes it one of the most studied proteins. However, APP's role in the human brain remains unclear despite years of investigation. One problem is that most studies on APP have been carried out in cell lines or model organisms, which are physiologically different from human neurons in the brain. Recently, human-induced neurons (hiNs) derived from induced pluripotent stem cells (iPSCs) provide a practical platform for studying the human brain in vitro. Here, we generated APP-null iPSCs using CRISPR/Cas9 genome editing technology and differentiate them into matured human neurons with functional synapses using a two-step procedure. During hiN differentiation and maturation, APP-null cells exhibited less neurite growth and reduced synaptogenesis in serum-free but not serum-containing media. We have found that cholesterol (Chol) remedies those developmental defects in APP-null cells, consistent with Chol's role in neurodevelopment and synaptogenesis. The phenotypic rescue was also achieved by coculturing those cells with wild-type mouse astrocytes, suggesting that APP's developmental role is likely astrocytic. Next, we examined matured hiNs using patch-clamp recording and detected reduced synaptic transmission in APP-null cells. This change was largely due to decreased synaptic vesicle (SV) release and retrieval, which was confirmed by live-cell imaging using two SV-specific fluorescent reporters. Adding Chol shortly before stimulation mitigated the SV deficits in APP-null iNs, indicating that APP facilitates presynaptic membrane Chol turnover during the SV exo-/endocytosis cycle. Taken together, our study in hiNs supports the notion that APP contributes to neurodevelopment, synaptogenesis, and neurotransmission via maintaining brain Chol homeostasis. Given the vital role of Chol in the central nervous system, the functional connection between APP and Chol bears important implications in the pathogenesis of AD.
    Keywords:  amyloid precursor protein; cholesterol; iPSC; neuron; presynaptic
    DOI:  https://doi.org/10.1002/jcp.30999
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