bims-medebr 2022-11-27 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–11–27
twenty-one papers selected by
Regina F. Fernández, Johns Hopkins University

G-Protein-Coupled Lactate Receptor GPR81 Control of VMNvl Glucoregulatory Neurotransmitter and 5'-AMP-Activated Protein Kinase Expression.
Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology.
Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination.
Targeting Oncogenic Rewiring of Lipid Metabolism for Glioblastoma Treatment.
Mitochondria Transfer in Brain Injury and Disease.
Pathophysiological Abnormalities in Migraine Ameliorated by Ketosis: A Proof-of-Concept Review.
Brain sex-dependent alterations after prolonged high fat diet exposure in mice.
Serum Metabolomic Characterization in Pigs in Relation to Birth Weight Category and Neonatal Nutrition.
MPC2 variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy.
Carnitine Intake and Serum Levels Associate Positively with Postnatal Growth and Brain Size at Term in Very Preterm Infants.
Choline Improves Neonatal Hypoxia-Ischemia Induced Changes in Male but Not Female Rats.
Novel localization of folate transport systems in the murine central nervous system.
Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.
Simultaneous dynamic glucose-enhanced (DGE) MRI and fiber photometry measurements of glucose in the healthy mouse brain.
4-Hydroxynonenal Modulates Blood-Brain Barrier Permeability In Vitro through Changes in Lipid Composition and Oxidative Status of Endothelial Cells and Astrocytes.
The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.
Progress in research on the role of clinical nutrition in treating traumatic brain injury affecting the neurovascular unit.
Flavin Mononucleotide-Dependent l-Lactate Dehydrogenases: Expanding the Toolbox of Enzymes for l-Lactate Biosensors.
Impact prediction of translocation of the mitochondrial outer membrane 70 as biomarker in Alzheimer's disease.
ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma.
Mechanistic insights on impact of Adenosine monophosphate-activated protein kinase (AMPK) mediated signalling pathways on cerebral ischemic injury.

Am J Physiol Regul Integr Comp Physiol. 2022 Nov 21.

G-Protein-Coupled Lactate Receptor GPR81 Control of VMNvl Glucoregulatory Neurotransmitter and 5'-AMP-Activated Protein Kinase Expression.

Sagor Chandra Roy, Prabhat R Napit, Madhu Babu Pasula, Khaggeswar Bheemanapally, Karen P Briski.

  Astrocytes store glycogen as energy and promote neuro-metabolic stability through supply of oxidizable L-lactate. Whether lactate regulates ventromedial hypothalamic nucleus (VMN) glucostatic function as a metabolic volume transmitter is unknown. Current research investigated whether G-protein-coupled lactate receptor GPR81 controls astrocyte glycogen metabolism and glucose-regulatory neurotransmission in the ventrolateral VMN (VMNvl), where glucose-regulatory neurons reside. Female rats were pretreated by intra-VMN GPR81 or scramble siRNA infusion before insulin or vehicle injection. VMNvl cell or tissue samples were acquired by laser-catapult- or micropunch microdissection for Western blot protein or uHPLC-electrospray ionization-mass spectrometric glycogen analyses. Data show that GPR81 regulates eu- and/or hypoglycemic patterns of VMNvl astrocyte glycogen metabolic enzyme and 5'-AMP-activated protein kinase (AMPK) protein expression according to VMNvl segment. GPR81 inhibits baseline rostral and caudal VMNvl glycogen accumulation, but mediates glycogen breakdown in the former site during hypoglycemia. During euglycemia, GPR81 suppresses the transmitter marker neuronal nitric oxide synthase (nNOS) in rostral and caudal VMNvl nitrergic neurons, but stimulates (rostral VMNvl) or inhibits (caudal VMNvl) GABAergic neuron glutamate decarboxylase65/67 (GAD)protein. During hypoglycemia, GPR81 regulates AMPK activation in nitrergic and GABAergic neurons located in the rostral, but not caudal. VMNvl. VMN GPR81 knockdown amplified hypoglycemic hypercorticosteronemia, but not hyperglucagonemia. Results provide novel proof that VMNvl astrocyte and glucose-regulatory neurons express GPR81 protein. Data identify neuroanatomical subpopulations of VMNvl astrocytes and glucose-regulatory neurons that exhibit differential reactivity to GPR81 input. Heterogeneous GPR81 effects during eu- versus hypoglycemia infer that energy state may affect cellular sensitivity to or post-receptor processing of lactate transmitter signaling.

Keywords:  AMPK; GPR81; glycogen; neuronal nitric oxide synthase; ventrolateral ventromedial hypothalamic nucleus

DOI:  https://doi.org/10.1152/ajpregu.00100.2022
Cells. 2022 Nov 15. pii: 3616. [Epub ahead of print]11(22):

Lipid Dys-Homeostasis Contributes to APOE4-Associated AD Pathology.

Adina-Nicoleta Lazar, Linda Hanbouch, Lydie Boussicaut, Baptiste Fourmaux, Patricia Daira, Mark J Millan, Nathalie Bernoud-Hubac, Marie-Claude Potier.

  The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer's disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention.

Keywords:  APOE4; Alzheimer’s disease; Aβ peptide; lipid homeostasis; tau

DOI:  https://doi.org/10.3390/cells11223616
Mol Neurodegener. 2022 Nov 23. 17(1): 75

Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination.

Na Wang, Minghui Wang, Suren Jeevaratnam, Cassandra Rosenberg, Tadafumi C Ikezu, Francis Shue, Sydney V Doss, Alla Alnobani, Yuka A Martens, Melissa Wren, Yan W Asmann, Bin Zhang, Guojun Bu, Chia-Chen Liu.

   BACKGROUND: Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear.
METHODS: To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination.
RESULTS: We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice.
CONCLUSIONS: Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.

Keywords:  Demyelination; Lipid droplets; Microglia; Remyelination; apoE isoforms

DOI:  https://doi.org/10.1186/s13024-022-00577-1
Int J Mol Sci. 2022 Nov 10. pii: 13818. [Epub ahead of print]23(22):

Targeting Oncogenic Rewiring of Lipid Metabolism for Glioblastoma Treatment.

Haksoo Lee, Dahye Kim, BuHyun Youn.

  Glioblastoma (GBM) is the most malignant primary brain tumor. Despite increasing research on GBM treatment, the overall survival rate has not significantly improved over the last two decades. Although recent studies have focused on aberrant metabolism in GBM, there have been few advances in clinical application. Thus, it is important to understand the systemic metabolism to eradicate GBM. Together with the Warburg effect, lipid metabolism has emerged as necessary for GBM progression. GBM cells utilize lipid metabolism to acquire energy, membrane components, and signaling molecules for proliferation, survival, and response to the tumor microenvironment. In this review, we discuss fundamental cholesterol, fatty acid, and sphingolipid metabolism in the brain and the distinct metabolic alterations in GBM. In addition, we summarize various studies on the regulation of factors involved in lipid metabolism in GBM therapy. Focusing on the rewiring of lipid metabolism will be an alternative and effective therapeutic strategy for GBM treatment.

Keywords:  cholesterol; fatty acid; glioblastoma; lipid metabolism; metabolic reprogramming; sphingolipid

DOI:  https://doi.org/10.3390/ijms232213818
Cells. 2022 Nov 14. pii: 3603. [Epub ahead of print]11(22):

Mitochondria Transfer in Brain Injury and Disease.

Lauren H Fairley, Amandine Grimm, Anne Eckert.

  Intercellular mitochondria transfer is a novel form of cell signalling in which whole mitochondria are transferred between cells in order to enhance cellular functions or aid in the degradation of dysfunctional mitochondria. Recent studies have observed intercellular mitochondria transfer between glia and neurons in the brain, and mitochondrial transfer has emerged as a key neuroprotective mechanism in a range of neurological conditions. In particular, artificial mitochondria transfer has sparked widespread interest as a potential therapeutic strategy for brain disorders. In this review, we discuss the mechanisms and effects of intercellular mitochondria transfer in the brain. The role of mitochondrial transfer in neurological conditions, including neurodegenerative disease, brain injury, and neurodevelopmental disorders, is discussed as well as therapeutic strategies targeting mitochondria transfer in the brain.

Keywords:  brain; glia; mitochondria; neuron

DOI:  https://doi.org/10.3390/cells11223603
J Integr Neurosci. 2022 Oct 11. 21(6): 167

Pathophysiological Abnormalities in Migraine Ameliorated by Ketosis: A Proof-of-Concept Review.

Panitda Huynh, Pasquale Calabrese.

  Migraine is a prevalent heterogeneous neurological disorder, enumerated as the eighth most disabling neurological disorder by the World Health Organization. The growing advancement in technology and investigation of various facets of cerebral metabolism in migraine has shed light to metabolic mechanisms in migraine pathophysiology. A growing number of clinical research postulates migraine as a reaction to oxidative stress levels that go beyond antioxidant capacity or cerebral energy deficiency. This has become an extremely attractive subject area and over the past years there has also been a sustained research activity in using ketone bodies (KB) as a novel potential migraine prophylaxis. Not much epidemiological research has been conducted to exhibit the efficacy of ketone bodies in abnormal metabolism in migraine pathophysiology. Therefore, a better understanding of ketone bodies in metabolic migraine may provide novel therapeutic opportunities. The goal of this review is to assess present understanding on potential migraine triggers, as well as how ketogenic interventions support metabolic disability in migraines and address the therapeutic importance of ketones in migraine treatment, accenting clinical studies (including neuroimaging and therapeutic studies). This review is intended to demonstrate existing literature on the effects of ketone bodies on metabolic migraine traits to guide the readership through current concepts and foster a perspective for future research.

Keywords:  attacks frequency; cerebral energy metabolism; headache; ketone bodies; ketosis; metabolism; migraine

DOI:  https://doi.org/10.31083/j.jin2106167
Commun Biol. 2022 Nov 21. 5(1): 1276

Brain sex-dependent alterations after prolonged high fat diet exposure in mice.

Valentina Murtaj, Silvia Penati, Sara Belloli, Maria Foti, Angela Coliva, Angela Papagna, Cecilia Gotti, Elisa Toninelli, Remy Chiaffarelli, Stefano Mantero, Susanna Pucci, Michela Matteoli, Maria Luisa Malosio, Rosa Maria Moresco.

We examined effects of exposing female and male mice for 33 weeks to 45% or 60% high fat diet (HFD). Males fed with either diet were more vulnerable than females, displaying higher and faster increase in body weight and more elevated cholesterol and liver enzymes levels. Higher glucose metabolism was revealed by PET in the olfactory bulbs of both sexes. However, males also displayed altered anterior cortex and cerebellum metabolism, accompanied by a more prominent brain inflammation relative to females. Although both sexes displayed reduced transcripts of neuronal and synaptic genes in anterior cortex, only males had decreased protein levels of AMPA and NMDA receptors. Oppositely, to anterior cortex, cerebellum of HFD-exposed mice displayed hypometabolism and transcriptional up-regulation of neuronal and synaptic genes. These results indicate that male brain is more susceptible to metabolic changes induced by HFD and that the anterior cortex versus cerebellum display inverse susceptibility to HFD.

DOI: https://doi.org/10.1038/s42003-022-04214-x
J Anim Sci. 2022 Nov 19. pii: skac386. [Epub ahead of print]

Serum Metabolomic Characterization in Pigs in Relation to Birth Weight Category and Neonatal Nutrition.

Michael O Wellington, Lucas A Rodrigues, Melissa A Quinn, Josiane C Panisson, David P Ferguson, Daniel A Columbus.

  The objective of this study was to characterize developmental differences in low birth weight (LBW) and normal birth weight (NBW) piglets with or without pre-weaning nutrient restriction using serum metabolomic profile analysis. At farrowing, 112 piglets were identified as LBW (1.22 ± 0.28 kg) or NBW (1.70 ± 0.27 kg) and were randomly assigned to receive normal nutrition (NN) or restricted nutrition (RN) (6 h/day no suckling) from d 2 to 28 post-farrow (n=8pigs/group). On d 28, piglets were weaned onto a common diet. Fasted blood samples were obtained on d 28 and 56 (n=8pigs/group) and were analyzed using quantitative metabolomics via a combination of direct injection mass spectrometry with a reverse-phase LC-MS/MS custom assay. Data were normalized using logarithmic transformation and auto-scaling. Partial least squares discriminant analysis (PLS-DA) was carried out to further explore the differential metabolites among the groups (metaboanalyst.ca) with an integrated enrichment and pathway topography analysis. On d 28, LBW piglets had lower levels of essential amino acids as well as reduced metabolites associated with fatty acid oxidation, glycolysis, and the TCA cycle compared to the NBW group. The overall reduction of metabolites associated with energy production and regulation suggests that LBW vs. NBW are in an energy-survival state. On d 56, LBW pigs had increased utilization of fatty acids and resultant ketone production, evident by increased carnitines, acetoacetate, β-hydroxybutyrate, and glycerol compared to NBW pigs. Additionally, compared to the NBW pigs LBW pigs had a consistent decrease in serum glucose and lactate as well as reduced TCA cycle metabolites: pyruvate, succinate, citrate, and α-ketoglutaric acid similar to d 28. Low reliance on glycolysis and the TCA cycle and higher glycerol production in the LBW pigs may indicate impairments in glucose tolerance at 56 d. In summary, LBW piglets appear to have more metabolic alterations in early life, which is not resolved with adequate nutrition or refeeding and may elucidate physiological and metabolic mechanisms of poor growth and life performance compared to NBW pigs later in life.

Keywords:  low birth weight; metabolomics; nutrition; piglets

DOI:  https://doi.org/10.1093/jas/skac386
Brain. 2022 Nov 23. pii: awac444. [Epub ahead of print]

MPC2 variants disrupt mitochondrial pyruvate metabolism and cause an early-onset mitochondriopathy.

Claire Pujol, Elise Lebigot, Pauline Gaignard, Said Galai, Ichraf Kraoua, Jean-Philippe Bault, Rodolphe Dard, Ilhem Ben Youssef-Turki, Souheil Omar, Audrey Boutron, Timothy Wai, Abdelhamid Slama.

  Pyruvate is an essential metabolite produced by glycolysis in the cytosol and must be transported across the inner mitochondrial membrane (IMM) into the mitochondrial matrix, where it is oxidized to fuel mitochondrial respiration. Pyruvate import is performed by Mitochondrial Pyruvate Carrier (MPC), a hetero-oligomeric complex composed by interdependent subunits MPC1 and MPC2. Pathogenic variants in MPC1 gene disrupt mitochondrial pyruvate uptake and oxidation and cause autosomal-recessive early-onset neurological dysfunction in humans. The present work describes the first pathogenic variants in MPC2 associated with human disease in four patients from two unrelated families. In the first family, patients presented with antenatal developmental abnormalities, harbored a homozygous c.148T > C (p.Trp50Arg) variant. In the second family, patients that presented with infantile encephalopathy carried missense c.2T > G (p.Met1? ) variant disrupting the initiation codon. Patient-derived skin fibroblasts exhibit decreased pyruvate-driven oxygen consumption rates with normal activities of the pyruvate dehydrogenase complex and mitochondrial respiratory chain and no defects in mitochondrial content nor morphology. Re-expression of wild type MPC2 restored pyruvate-dependent respiration rates in patient-derived fibroblasts. The discovery of pathogenic variants in MPC2 therefore broadens the clinical and genetic landscape associated with inborn errors in pyruvate metabolism.

Keywords:  metabolism; mitochondria; pyruvate carrier

DOI:  https://doi.org/10.1093/brain/awac444
Nutrients. 2022 Nov 09. pii: 4725. [Epub ahead of print]14(22):

Carnitine Intake and Serum Levels Associate Positively with Postnatal Growth and Brain Size at Term in Very Preterm Infants.

Suvi Manninen, Sanna Silvennoinen, Paula Bendel, Maria Lankinen, Ursula S Schwab, Ulla Sankilampi.

  Carnitine has an essential role in energy metabolism with possible neuroprotective effects. Very preterm (VPT, <32 gestation weeks) infants may be predisposed to carnitine deficiency during hospitalization. We studied the associations of carnitine intake and serum carnitine levels with growth and brain size at term equivalent age (TEA) in VPT infants. This prospective cohort study included 35 VTP infants admitted to Kuopio University Hospital, Finland. Daily nutrient intakes were registered at postnatal weeks (W) 1 and 5, and serum carnitine levels were determined at W1, W5, and TEA. The primary outcomes were weight, length, and head circumference Z-score change from birth to TEA, as well as brain size at TEA in magnetic resonance imaging. Carnitine intake at W1 and W5, obtained from enteral milk, correlated positively with serum carnitine levels. Both carnitine intake and serum levels at W1, W5, and TEA showed a positive correlation with weight, length, and head circumference Z-score change and with brain size at TEA. In linear models, independent positive associations of carnitine intake and serum carnitine levels with length and head circumference Z-score change and brain size at TEA were seen. In VPT infants, sufficient carnitine intake during hospitalization is necessary since it is associated with better postnatal growth and larger brain size at term age.

Keywords:  acylcarnitine; brain size; carnitine; pediatric nutrition; postnatal growth; preterm

DOI:  https://doi.org/10.3390/nu14224725
Int J Mol Sci. 2022 Nov 12. pii: 13983. [Epub ahead of print]23(22):

Choline Improves Neonatal Hypoxia-Ischemia Induced Changes in Male but Not Female Rats.

Tayo Adeyemo, Ayodele Jaiyesimi, Jill G Bumgardner, Charity Lohr, Aditi Banerjee, Mary C McKenna, Jaylyn Waddell.

  Choline is an essential nutrient with many roles in brain development and function. Supplementation of choline in early development can have long-lasting benefits. Our experiments aimed to determine the efficacy of choline supplementation in a postnatal day (PND) 10 rat model of neonatal hypoxia ischemia (HI) at term using both male and female rat pups. Choline (100 mg/kg) or saline administration was initiated the day after birth and given daily for 10 or 14 consecutive days. We determined choline's effects on neurite outgrowth of sex-specific cultured cerebellar granule cells after HI with and without choline. The magnitude of tissue loss in the cerebrum was determined at 72 h after HI and in adult rats. The efficacy of choline supplementation in improving motor ability and learning, tested using eyeblink conditioning, were assessed in young adult male and female rats. Overall, we find that choline improves neurite outgrowth, short-term histological measures and learning ability in males. Surprisingly, choline did not benefit females, and appears to exacerbate HI-induced changes.

Keywords:  choline; eyeblink conditioning; hypoxia ischemia; neonate; neurite outgrowth; sex differences

DOI:  https://doi.org/10.3390/ijms232213983
Fluids Barriers CNS. 2022 Nov 23. 19(1): 92

Novel localization of folate transport systems in the murine central nervous system.

Vishal Sangha, Md Tozammel Hoque, Jeffrey T Henderson, Reina Bendayan.

   BACKGROUND: Folates are a family of B9 vitamins that serve as one-carbon donors critical to biosynthetic processes required for the development and function of the central nervous system (CNS) in mammals. Folate transport is mediated by three highly specific systems: (1) folate receptor alpha (FRα; FOLR1/Folr1), (2) the reduced folate-carrier (RFC; SLC19A1/Slc19a1) and (3) the proton-coupled folate transporter (PCFT; SLC46A1/Slc46a1). Folate transport into and out of the CNS occurs at the blood-cerebrospinal fluid barrier (BCSFB), mediated by FRα and PCFT. Impairment of folate transport at the BCSFB results in cerebral folate deficiency in infants characterized by severe neurological deficiencies and seizures. In contrast to the BCSFB, CNS folate transport at other brain barriers and brain parenchymal cells has not been extensively investigated. The aim of this study is to characterize folate transport systems in the murine CNS at several known barriers encompassing the BCSFB, arachnoid barrier (AB), blood-brain barrier (BBB) and parenchymal cells (astrocytes, microglia, neurons).
METHODS: Applying immunohistochemistry, localization of folate transport systems (RFC, PCFT, FRα) was examined at CNS barriers and parenchymal sites in wildtype (C57BL6/N) mice. Subcellular localization of the folate transport systems was further assessed in an in vitro model of the mouse AB. Gene and protein expression was analyzed in several in vitro models of brain barriers and parenchyma by qPCR and western blot analysis.
RESULTS: RFC, PCFT, and FRα expression was localized within the BCSFB and BBB consistent with previous reports. Only RFC and PCFT expression was detected at the AB. Varied levels of RFC and PCFT expression were detected in neuronal and glial cells.
CONCLUSIONS: Localization of RFC and PCFT within the AB, described here for the first time, suggest that AB may contribute to folate transport between the peripheral circulation and the CSF. RFC and PCFT expression observed in astrocytes and microglia is consistent with the role that one or both of these transporters may play in delivering folates into cells within brain parenchyma. These studies provide insights into mechanisms of folate transport in the CNS and may enhance our understanding of the critical role folates play in neurodevelopment and in the development of novel treatment strategies for disorders of brain folate deficiency due to impaired transporter function.

Keywords:  Arachnoid barrier; Blood–brain barrier; Blood–cerebrospinal fluid barrier; Cerebral folate deficiency; Folate receptor; Folates; Proton-coupled folate transporter; Reduced folate carrier

DOI:  https://doi.org/10.1186/s12987-022-00391-3
Int J Mol Sci. 2022 Nov 11. pii: 13933. [Epub ahead of print]23(22):

Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.

Inês M S Guerra, Helena B Ferreira, Tânia Melo, Hugo Rocha, Sónia Moreira, Luísa Diogo, Maria Rosário Domingues, Ana S P Moreira.

  Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism (IEMs) caused by defects in the fatty acid (FA) mitochondrial β-oxidation. The most common FAODs are characterized by the accumulation of medium-chain FAs and long-chain (3-hydroxy) FAs (and their carnitine derivatives), respectively. These deregulations are associated with lipotoxicity which affects several organs and potentially leads to life-threatening complications and comorbidities. Changes in the lipidome have been associated with several diseases, including some IEMs. In FAODs, the alteration of acylcarnitines (CARs) and FA profiles have been reported in patients and animal models, but changes in polar and neutral lipid profile are still scarcely studied. In this review, we present the main findings on FA and CAR profile changes associated with FAOD pathogenesis, their correlation with oxidative damage, and the consequent disturbance of mitochondrial homeostasis. Moreover, alterations in polar and neutral lipid classes and lipid species identified so far and their possible role in FAODs are discussed. We highlight the need of mass-spectrometry-based lipidomic studies to understand (epi)lipidome remodelling in FAODs, thus allowing to elucidate the pathophysiology and the identification of possible biomarkers for disease prognosis and an evaluation of therapeutic efficacy.

Keywords:  CPT2D; FAOD; LCHADD; MCADD; VLCADD; inborn errors of metabolism; lipid changes; lipidomics; mass spectrometry; oxidative stress

DOI:  https://doi.org/10.3390/ijms232213933
Neuroimage. 2022 Nov 22. pii: S1053-8119(22)00883-7. [Epub ahead of print] 119762

Simultaneous dynamic glucose-enhanced (DGE) MRI and fiber photometry measurements of glucose in the healthy mouse brain.

Afroditi Eleftheriou, Luca Ravotto, Matthias T Wyss, Geoffrey Warnock, Anita Siebert, Moritz Zaiss, Bruno Weber.

  Glucose is the main energy source in the brain and its regulated uptake and utilization are important biomarkers of pathological brain function. Glucose Chemical Exchange Saturation Transfer (GlucoCEST) and its time-resolved version Dynamic Glucose-Enhanced MRI (DGE) are promising approaches to monitor glucose and detect tumors, since it is radioactivity-free, does not require 13C labelling and it is easily translatable to the clinics. The main principle of DGE is clear. However, what remains to be established is to which extent the signal reflects vascular, extracellular or intracellular glucose. To elucidate the compartmental contributions to the DGE signal, we coupled it with FRET-based fiber photometry of genetically encoded sensors, a technique that combines quantitative glucose readout with cellular specificity. The glucose sensor FLIIP was used with fiber photometry to measure astrocytic and neuronal glucose changes upon injection of D-glucose, 3OMG and L-glucose, in the anaesthetized murine brain. By correlating the kinetic profiles of the techniques, we demonstrate the presence of a vascular contribution to the signal, especially at early time points after injection. Furthermore, we show that, in the case of the commonly used contrast agent 3OMG, the DGE signal actually anticorrelates with the glucose concentration in neurons and astrocytes.

Keywords:  fiber photometry; genetically encoded sensors; glucoCEST; kinetic modelling; two-photon microscopy

DOI:  https://doi.org/10.1016/j.neuroimage.2022.119762
Int J Mol Sci. 2022 Nov 19. pii: 14373. [Epub ahead of print]23(22):

4-Hydroxynonenal Modulates Blood-Brain Barrier Permeability In Vitro through Changes in Lipid Composition and Oxidative Status of Endothelial Cells and Astrocytes.

Marina Cindrić, Ana Čipak Gašparović, Lidija Milković, Ivana Tartaro Bujak, Branka Mihaljević, Neven Žarković, Kamelija Žarković.

  Blood brain barrier (BBB) is a dynamic interface responsible for proper functioning of brain, but also a major obstacle for effective treatment of neurological diseases. Increased levels of free radicals, in high ferrous and high lipid content surrounding, induce lipid peroxidation, leading to production of 4-hydroxynonenal (HNE). HNE modifies all key proteins responsible for proper brain functioning thus playing a major role in the onset of neurological diseases. To investigate HNE effects on BBB permeability, we developed two in vitro BBB models-'physiological' and 'pathological'. The latter mimicked HNE modified extracellular matrix under oxidative stress conditions in brain pathologies. We showed that exogenous HNE induce activation of antioxidative defense systems by increasing catalase activity and glutathione content as well as reducing lipid peroxide levels in endothelial cells and astrocytes of 'physiological' model. While in 'pathological' model, exogenous HNE further increased lipid peroxidation levels of endothelial cells and astrocytes, followed by increase in Nrf2 and glutathione levels in endothelial cells. At lipid composition level, HNE caused increase in ω3 polyunsaturated fatty acid (PUFA) level in endothelial cells, followed by decrease in ω3 PUFA level and increase in monounsaturated fatty acid level in astrocytes. Using these models, we showed for the first time that HNE in 'pathological' model can reduce BBB permeability.

Keywords:  4-hydroxynonenal; astrocytes; blood–brain barrier; lipid composition

DOI:  https://doi.org/10.3390/ijms232214373
Proc Natl Acad Sci U S A. 2022 Nov 29. 119(48): e2119824119

The phosphorylation of AMPKβ1 is critical for increasing autophagy and maintaining mitochondrial homeostasis in response to fatty acids.

Eric M Desjardins, Brennan K Smith, Emily A Day, Serge Ducommun, Matthew J Sanders, Joshua P Nederveen, Rebecca J Ford, Stephen L Pinkosky, Logan K Townsend, Robert M Gutgesell, Rachel Lu, Kei Sakamoto, Gregory R Steinberg.

  Fatty acids are vital for the survival of eukaryotes, but when present in excess can have deleterious consequences. The AMP-activated protein kinase (AMPK) is an important regulator of multiple branches of metabolism. Studies in purified enzyme preparations and cultured cells have shown that AMPK is allosterically activated by small molecules as well as fatty acyl-CoAs through a mechanism involving Ser108 within the regulatory AMPK β1 isoform. However, the in vivo physiological significance of this residue has not been evaluated. In the current study, we generated mice with a targeted germline knock-in (KI) mutation of AMPKβ1 Ser108 to Ala (S108A-KI), which renders the site phospho-deficient. S108A-KI mice had reduced AMPK activity (50 to 75%) in the liver but not in the skeletal muscle. On a chow diet, S108A-KI mice had impairments in exogenous lipid-induced fatty acid oxidation. Studies in mice fed a high-fat diet found that S108A-KI mice had a tendency for greater glucose intolerance and elevated liver triglycerides. Consistent with increased liver triglycerides, livers of S108A-KI mice had reductions in mitochondrial content and respiration that were accompanied by enlarged mitochondria, suggestive of impairments in mitophagy. Subsequent studies in primary hepatocytes found that S108A-KI mice had reductions in palmitate- stimulated Cpt1a and Ppargc1a mRNA, ULK1 phosphorylation and autophagic/mitophagic flux. These data demonstrate an important physiological role of AMPKβ1 Ser108 phosphorylation in promoting fatty acid oxidation, mitochondrial biogenesis and autophagy under conditions of high lipid availability. As both ketogenic diets and intermittent fasting increase circulating free fatty acid levels, AMPK activity, mitochondrial biogenesis, and mitophagy, these data suggest a potential unifying mechanism which may be important in mediating these effects.

Keywords:  AMPK; NAFLD; autophagy; fat oxidation; mitochondria

DOI:  https://doi.org/10.1073/pnas.2119824119
Nutr Rev. 2022 Nov 21. pii: nuac099. [Epub ahead of print]

Progress in research on the role of clinical nutrition in treating traumatic brain injury affecting the neurovascular unit.

Jin-Qing Lai, Xiang-Rong Chen, Shu Lin, Chun-Nuan Chen, Xuan-Xuan Zheng.

  The neurovascular unit (NVU) is composed of neurons, glial cells, and blood vessels. NVU dysfunction involves the processes of neuroinflammation, and microcirculatory disturbances, as well as neuronal injury after traumatic brain injury (TBI). Traditional anti-inflammatory drugs have limited efficacy in improving the prognosis of TBI. Thus, treatments that target NVU dysfunction may provide a breakthrough. A large number of clinical studies have shown that the nutritional status of patients with TBI was closely related to their conditions and prognoses. Nutrient complexes and complementary therapies for the treatment of TBI are therefore being implemented in many preclinical studies. Importantly, the mechanism of action for this treatment may be related to repair of NVU dysfunction by ensuring adequate omega-3 fatty acids, curcumin, resveratrol, apigenin, vitamins, and minerals. These nutritional supplements hold promise for translation to clinical therapy. In addition, dietary habits also play an important role in the rehabilitation of TBI. Poor dietary habits may worsen the pathology and prognosis of TBI. Adjusting dietary habits, especially with a ketogenic diet, may improve outcomes in patients with TBI. This article discusses the impact of clinical nutrition on NVU dysfunction after TBI, focusing on nutritional complexes and dietary habits.

Keywords:  clinical nutrition; dietary habits; neurovascular unit; traumatic brain injury

DOI:  https://doi.org/10.1093/nutrit/nuac099
ACS Omega. 2022 Nov 15. 7(45): 41480-41492

Flavin Mononucleotide-Dependent l-Lactate Dehydrogenases: Expanding the Toolbox of Enzymes for l-Lactate Biosensors.

Lidiia Tsvik, Beate Steiner, Peter Herzog, Dietmar Haltrich, Leander Sützl.

The development of L-lactate biosensors has been hampered in recent years by the lack of availability and knowledge about a wider range and diversity of L-lactate-oxidizing enzymes that can be used as bioelements in these sensors. For decades, L-lactate oxidase of Aerococcus viridans (AvLOx) has been used almost exclusively in the field of L-lactate biosensor development and has achieved somewhat like a monopoly status as a biocatalyst for these applications. Studies on other L-lactate-oxidizing enzymes are sparse and are often missing biochemical data. In this work, we made use of the vast amount of sequence information that is currently available on protein databases to investigate the naturally occurring diversity of L-lactate-utilizing enzymes of the flavin mononucleotide (FMN)-dependent α-hydroxy acid oxidoreductase (HAOx) family. We identified the HAOx sequence space specific for L-lactate oxidation and additionally discovered a not-yet described class of soluble and FMN-dependent L-lactate dehydrogenases, which are promising for the construction of second-generation biosensors or other biotechnological applications. Our work paves the way for new studies on α-hydroxy acid biosensors and proves that there is more to the HAOx family than AvLOx.

DOI: https://doi.org/10.1021/acsomega.2c05257
Front Aging Neurosci. 2022 ;14 1013943

Impact prediction of translocation of the mitochondrial outer membrane 70 as biomarker in Alzheimer's disease.

Xi Cao, Yanting Chen, Xiaoyu Sang, Shunliang Xu, Zhaohong Xie, Zhengyu Zhu, Ping Wang, Jianzhong Bi, Linlin Xu.

  Mitochondrial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). The translocase of the outer membrane (TOM) complex controls the input of mitochondrial precursor proteins to maintain mitochondrial function under pathophysiological conditions. However, its role in AD development remains unclear. TOM70 is an important translocase present in the TOM complex. In the current study, we found that TOM70 levels were reduced in the peripheral blood and hippocampus of the APP/PS1 mice. In addition, we examined the whole-blood mRNA levels of TOM70 in patients with AD, dementia with Lewy bodies (DLB), and post-stroke dementia (PSD). Our study revealed that the mRNA level of TOM70 was decreased in the blood samples of patients with AD, which was also correlated with the progression of clinical stages. Therefore, we proposed that the expression of TOM70 could be a promising biomarker for AD diagnosis and monitoring of disease progression.

Keywords:  Alzheimer's disease; TOM70; biomarker; gene expression; progression

DOI:  https://doi.org/10.3389/fnagi.2022.1013943
Life Sci Alliance. 2023 Jan;pii: e202201400. [Epub ahead of print]6(1):

ZBTB18 inhibits SREBP-dependent lipid synthesis by halting CTBPs and LSD1 activity in glioblastoma.

Roberto Ferrarese, Annalisa Izzo, Geoffroy Andrieux, Simon Lagies, Johanna Paulina Bartmuss, Anie Priscilla Masilamani, Alix Wasilenko, Daniela Osti, Stefania Faletti, Rana Schulzki, Shuai Yuan, Eva Kling, Valentino Ribecco, Dieter Henrik Heiland, Stefan Tholen, Marco Prinz, Giuliana Pelicci, Bernd Kammerer, Melanie Boerries, Maria Stella Carro.

Enhanced fatty acid synthesis is a hallmark of tumors, including glioblastoma. SREBF1/2 regulate the expression of enzymes involved in fatty acid and cholesterol synthesis. Yet, little is known about the precise mechanism regulating SREBP gene expression in glioblastoma. Here, we show that a novel interaction between the co-activator/co-repressor CTBP and the tumor suppressor ZBTB18 regulates the expression of SREBP genes. In line with our findings, metabolic assays and glucose tracing analysis confirm the reduction in several phospholipid species upon ZBTB18 expression. Our study identifies CTBP1/2 and LSD1 as co-activators of SREBP genes and indicates that the functional activity of the CTBP-LSD1 complex is altered by ZBTB18. ZBTB18 binding to the SREBP gene promoters is associated with reduced LSD1 demethylase activity of H3K4me2 and H3K9me2 marks. Concomitantly, the interaction between LSD1, CTBP, and ZNF217 is increased, suggesting that ZBTB18 promotes LSD1 scaffolding function. Our results outline a new epigenetic mechanism enrolled by ZBTB18 and its co-factors to regulate fatty acid synthesis that could be targeted to treat glioblastoma patients.

DOI: https://doi.org/10.26508/lsa.202201400
Neurosci Res. 2022 Nov 17. pii: S0168-0102(22)00286-3. [Epub ahead of print]

Mechanistic insights on impact of Adenosine monophosphate-activated protein kinase (AMPK) mediated signalling pathways on cerebral ischemic injury.

Palak Kalra, Heena Khan, Thakur Gurjeet Singh, Amarjot Kaur Grewal.

  Cerebral ischemia is the primary cause of morbidity and mortality worldwide due to the perturbations in the blood supply to the brain. The brain triggers a cascade of complex metabolic and cellular defects in response to ischemic stress. However, due to the disease heterogeneity and complexity, ischemic injury's metabolic and cellular pathologies remain elusive, and the link between various pathological mechanisms is difficult to determine. Efforts to develop effective treatments for these disorders have yielded limited efficacy, with no proper cure available to date. Recent clinical and experimental research indicates that several neuronal diseases commonly coexist with metabolic dysfunction, which may aggravate neurological symptoms. As a result, it stands to a reason that metabolic hormones could be a potential therapeutic target for major NDDs. Moreover, fasting signals also influence the circadian clock, as AMPK phosphorylates and promotes the degradation of the photo-sensing receptor (cryptochrome). Here, the interplay of AMPK signaling between metabolic regulation and neuronal death and its role for pathogenesis and therapeutics has been studied. We have also highlighted a significant signaling pathway, i.e., the adenosine monophosphate-activated protein kinase (AMPK) involved in the relationship between the metabolism and ischemia, which could be used as a target for future studies therapeutics, and review some of the clinical progress in this area.

Keywords:  Adenosine monophosphate-activated protein kinase; Adiponectin; Ghrelin; Insulin; Ischemia; Leptin; Neuroprotection; metabolic

DOI:  https://doi.org/10.1016/j.neures.2022.11.006