bims-medebr 2022-09-04 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–09–04
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Bedside interpretation of cerebral energy metabolism utilizing microdialysis in neurosurgical and general intensive care.
Brain laterality evaluated by F-18 fluorodeoxyglucose positron emission computed tomography in autism spectrum disorders.
Hypothalamic Hnscr regulates glucose balance by mediating central inflammation and insulin signal.
Shift in phospholipid and fatty acid contents accompanies brain myelination.
Labelfree mapping and profiling of altered lipid homeostasis in the rat hippocampus after traumatic stress: Role of oxidative homeostasis.
Docosahexaenoic Acid Increases Vesicular Glutamate Transporter 2 Protein Levels in Differentiated NG108-15 Cells.
GPHR-mediated acidification of the Golgi lumen is essential for cholesterol biosynthesis in the brain.
Brain spectroscopic measures of glutamatergic and neuronal metabolism and glial activation influence white matter integrity in bipolar depression.
Intranasal Insulin Attenuates the Long-term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats.
TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity and normal lactate levels.
Hyperoxia by short-term promotes oxidative damage and mitochondrial dysfunction in rat brain.
Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder.
Identification and characterization of LPLAT7 as an sn-1-specific lysophospholipid acyltransferase.
Current knowledge of protein palmitoylation in gliomas.
Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease.
Emerging Role of Neuron-Glia in Neurological Disorders: At a Glance.
Functional brain activity is highly associated with cortical myelination in neonates.
SIRT3 regulates mitochondrial biogenesis in aging-related diseases.
Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.
Ketogenic diet: an effective treatment approach for neurodegenerative diseases.
HDL, cholesterol efflux, and ABCA1: Free from good and evil dualism.
Myo-inositol moderates maternal BMI and glycemia related variations in in-vitro placental 13C-DHA-metabolism, altering their relationships with birthweight.

Front Neurol. 2022 ;13 968288

Bedside interpretation of cerebral energy metabolism utilizing microdialysis in neurosurgical and general intensive care.

Carl-Henrik Nordström, Axel Forsse, Rasmus Peter Jakobsen, Simon Mölström, Troels Halfeldt Nielsen, Palle Toft, Urban Ungerstedt.

  The microdialysis technique was initially developed for monitoring neurotransmitters in animals. In 1995 the technique was adopted to clinical use and bedside enzymatic analysis of glucose, pyruvate, lactate, glutamate and glycerol. Under clinical conditions microdialysis has also been used for studying cytokines, protein biomarkers, multiplex proteomic and metabolomic analyses as well as for pharmacokinetic studies and evaluation of blood-brain barrier function. This review focuses on the variables directly related to cerebral energy metabolism and the possibilities and limitations of microdialysis during routine neurosurgical and general intensive care. Our knowledge of cerebral energy metabolism is to a large extent based on animal experiments performed more than 40 years ago. However, the different biochemical information obtained from various techniques should be recognized. The basic animal studies analyzed brain tissue homogenates while the microdialysis technique reflects the variables in a narrow zone of interstitial fluid surrounding the probe. Besides the difference of the volume investigated, the levels of the biochemical variables differ in different compartments. During bedside microdialysis cerebral energy metabolism is primarily reflected in measured levels of glucose, lactate and pyruvate and the lactate to pyruvate (LP) ratio. The LP ratio reflects cytoplasmatic redox-state which increases instantaneously during insufficient aerobic energy metabolism. Cerebral ischemia is characterized by a marked increase in intracerebral LP ratio at simultaneous decreases in intracerebral levels of pyruvate and glucose. Mitochondrial dysfunction is characterized by a moderate increase in LP ratio at a very marked increase in cerebral lactate and normal or elevated levels of pyruvate and glucose. The patterns are of importance in particular for interpretations in transient cerebral ischemia. A new technique for evaluating global cerebral energy metabolism by microdialysis of the draining cerebral venous blood is discussed. In experimental studies it has been shown that pronounced global cerebral ischemia is reflected in venous cerebral blood. Jugular bulb microdialysis has been investigated in patients suffering from subarachnoid hemorrhage, during cardiopulmonary bypass and resuscitation after out of hospital cardiac arrest. Preliminary results indicate that the new technique may give valuable information of cerebral energy metabolism in clinical conditions when insertion of an intracerebral catheter is contraindicated.

Keywords:  cardiac arrest; cerebral energy metabolism; ischemia; lactate; microdialysis; mitochondrial dysfunction; pyruvate; resuscitation

DOI:  https://doi.org/10.3389/fneur.2022.968288
Front Mol Neurosci. 2022 ;15 901016

Brain laterality evaluated by F-18 fluorodeoxyglucose positron emission computed tomography in autism spectrum disorders.

Keattichai Keeratitanont, Daris Theerakulpisut, Narong Auvichayapat, Chanyut Suphakunpinyo, Niramol Patjanasoontorn, Somsak Tiamkao, Supatporn Tepmongkol, Benjapa Khiewvan, Yutapong Raruenrom, Piyawan Srisuruk, Suchat Paholpak, Paradee Auvichayapat.

   Background and rationale: Autism spectrum disorder (ASD) is a neuropsychiatric disorder that has no curative treatment. Little is known about the brain laterality in patients with ASD. F-18 fluorodeoxyglucose positron emission computed tomography (F-18 FDG PET/CT) is a neuroimaging technique that is suitable for ASD owing to its ability to detect whole brain functional abnormalities in a short time and is feasible in ASD patients. The purpose of this study was to evaluate brain laterality using F-18 FDG PET/CT in patients with high-functioning ASD.
Materials and methods: This case-control study recruited eight ASD patients who met the DSM-5 criteria, the recorded data of eight controls matched for age, sex, and handedness were also enrolled. The resting state of brain glucose metabolism in the regions of interest (ROIs) was analyzed using the Q.Brain software. Brain glucose metabolism and laterality index in each ROI of ASD patients were compared with those of the controls. The pattern of brain metabolism was analyzed using visual analysis and is reported in the data description.
Results: The ASD group's overall brain glucose metabolism was lower than that of the control group in both the left and right hemispheres, with mean differences of 1.54 and 1.21, respectively. We found statistically lower mean glucose metabolism for ASD patients than controls in the left prefrontal lateral (Z = 1.96, p = 0.049). The left laterality index was found in nine ROIs for ASD and 11 ROIs for the control. The left laterality index in the ASD group was significantly lower than that in the control group in the prefrontal lateral (Z = 2.52, p = 0.012), precuneus (Z = 2.10, p = 0.036), and parietal inferior (Z = 1.96, p = 0.049) regions.
Conclusion: Individuals with ASD have lower brain glucose metabolism than control. In addition, the number of ROIs for left laterality index in the ASD group was lower than control. Left laterality defects may be one of the causes of ASD. This knowledge can be useful in the treatment of ASD by increasing the left-brain metabolism. This trial was registered in the Thai Clinical Trials Registry (TCTR20210705005).

Keywords:  F-18 FDG PET/CT; autism spectrum disorders; brain glucose metabolism; laterality; positron emission tomography; treatment by non-invasive brain stimulation

DOI:  https://doi.org/10.3389/fnmol.2022.901016
Cell Prolif. 2022 Aug 30. e13332

Hypothalamic Hnscr regulates glucose balance by mediating central inflammation and insulin signal.

Ya Liu, Yi-Fan Guo, Hui Peng, Hai-Yan Zhou, Tian Su, Mi Yang, Qi Guo, Xiao Ye, Yan Huang, Tie-Jian Jiang.

OBJECTIVES: Hypothalamic dysfunction leads to glucose metabolic imbalance; however, the mechanisms still need clarification. Our current study was to explore the role of hypothalamic Hnscr in glucose metabolism.
MATERIALS AND METHODS: Using Hnscr knockout or htNSC-specific Hnscr overexpression mice, we evaluated the effects of Hnscr on glucose metabolism through GTTs, ITTs, serum indicator measurements, etc. Immunofluorescence staining and Western blotting were performed to test inflammation levels and insulin signalling in hypothalamus. Conditioned medium intervene were used to investigate the effects of htNSCs on neuronal cell line. We also detected the glucose metabolism of mice with htNSCs implantation.
RESULTS: Hnscr expression decreased in the hypothalamus after high-fat diet feed. Hnscr-null mice displayed aggravated systematic insulin resistance, while mice with htNSC-specific Hnscr overexpression had the opposite phenotype. Notably, Hnscr-null mice had increased NF-κB signal in htNSCs, along with enhanced inflammation and damaged insulin signal in neurons located in arcuate nucleus of hypothalamus. The secretions, including sEVs, of Hnscr-deficient htNSCs mediated the detrimental effects on the CNS cell line. Locally implantation with Hnscr-depleted htNSCs disrupted glucose homeostasis.
CONCLUSIONS: This study demonstrated that decreased Hnscr in htNSCs led to systematic glucose imbalance through activating NF-κB signal and dampening insulin signal in hypothalamic neurons.

DOI: https://doi.org/10.1111/cpr.13332
Biochimie. 2022 Aug 30. pii: S0300-9084(22)00214-0. [Epub ahead of print]

Shift in phospholipid and fatty acid contents accompanies brain myelination.

Vanessa Naffaa, Romain Magny, Anne Regazzetti, Juliette Van Steenwinckel, Pierre Gressens, Olivier Laprévote, Nicolas Auzeil, Anne-Laure Schang.

  In the central nervous system, lipids represent approximately 70% of myelin dry weight and play a key role in axon insulation and action potential conduction velocity. Lipids may thus represent sensitive markers of myelin status in physiological and pathological contexts. In this study, a comprehensive lipidomic analysis by ultra-high-performance liquid chromatography and high-resolution mass spectrometry was performed on myelin-enriched fractions prepared from mouse brains. Two developmental stages were compared: an early rapid myelination stage (postnatal day 15, P15), and a late basal myelination stage (P40). Besides an expected enrichment in characteristic myelin lipids, our study revealed a profound remodeling in phospholipid subclasses during myelination. It included a dramatic decrease in phosphatidylcholine (PC) content and an increase in phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) contents, concomitant to an increased proportion of monounsaturated fatty acids (MUFA) in these subclasses. Lipidomic results were supported by upregulated expression of genes involved in PE, PI, PS and MUFA synthesis in maturing O4+ oligodendrocytes. Highlighted lipid changes may represent key features of brain myelination that could be explored in the context of myelin pathologies.

Keywords:  Brain development; Lipid; Lipidomics; Myelin; Oligodendrocyte

DOI:  https://doi.org/10.1016/j.biochi.2022.08.010
Neurobiol Stress. 2022 Sep;20 100476

Labelfree mapping and profiling of altered lipid homeostasis in the rat hippocampus after traumatic stress: Role of oxidative homeostasis.

D Parker Kelley, Ardalan Chaichi, Alexander Duplooy, Dhirendra Singh, Manas Ranjan Gartia, Joseph Francis.

  Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid oxidative and homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.

Keywords:  Cholesterol; Lipids; PTSD; ROS; Raman; Stress

DOI:  https://doi.org/10.1016/j.ynstr.2022.100476
Biol Pharm Bull. 2022 ;45(9): 1385-1388

Docosahexaenoic Acid Increases Vesicular Glutamate Transporter 2 Protein Levels in Differentiated NG108-15 Cells.

Daisuke Miyazawa, Yeonjoo Lee, Mao Tsuchiya, Tomoko Tahira, Hideki Mizutani, Naoki Ohara.

  Docosahexaenoic acid (DHA; 22:6n-3), which is enriched in the neuronal membrane, plays a variety of roles in the brain. Vesicular glutamate transporters (VGLUTs) are responsible for incorporating glutamine into synaptic vesicles. We investigated the influence of DHA on the fatty acid profile and the levels of VGLUT1 and VGLUT2 proteins in differentiated NG108-15 cells, a neuroblastoma-glioma hybrid cell line. NG108-15 cells were plated and 24 h later the medium was replaced with Dulbecco's modified Eagle's medium supplemented with 1% fetal bovine serum, 0.2 mM dibutyryl cAMP, and 100 nM dexamethasone, which was added to induce differentiation. After 6 d, the amount of DHA in the cells was increased by addition of DHA to the medium. VGLUT2 levels were increased by the addition of DHA. These data indicate that DHA affected the levels of VGLUT2 in NG108-15 cells under differentiation-promoting conditions, suggesting that DHA affects brain functions involving VGLUT2.

Keywords:  NG108-15 cell; docosahexaenoic acid (DHA); vesicular glutamate transporter 2 (VGLUT2)

DOI:  https://doi.org/10.1248/bpb.b22-00132
FEBS Lett. 2022 Sep 03.

GPHR-mediated acidification of the Golgi lumen is essential for cholesterol biosynthesis in the brain.

Yu-Shin Sou, Junji Yamaguchi, Hiroshi Kameda, Keisuke Masuda, Yusuke Maeda, Yasuo Uchiyama, Masato Koike.

  The Golgi pH regulator (GPHR) is essential for maintaining the function and morphology of the Golgi apparatus through the regulation of luminal acidic pH. Abnormal morphology of the Golgi apparatus is associated with neurodegenerative diseases. Here, we found that knockout of GPHR in the mouse brain led to morphological changes in the Golgi apparatus and neurodegeneration, which included brain atrophy, neuronal cell death, and gliosis. Furthermore, in the GPHR knockout mouse brain, transcriptional activity of sterol regulatory element-binding protein 2 (SREBP2) decreased, resulting in a reduction in cholesterol levels. GPHR-deficient cells exhibited suppressed neurite outgrowth, which was recovered by exogenous expression of the active form of SREBP2. Our results show that GPHR-mediated luminal acidification of the Golgi apparatus maintains proper cholesterol levels and, thereby, neuronal morphology.

Keywords:  GPHR; Golgi apparatus; Golgi fragmentation; Golgi pH; SREBP2; cholesterol

DOI:  https://doi.org/10.1002/1873-3468.14491
Psychiatry Res Neuroimaging. 2022 Aug 27. pii: S0925-4927(22)00095-6. [Epub ahead of print]326 111534

Brain spectroscopic measures of glutamatergic and neuronal metabolism and glial activation influence white matter integrity in bipolar depression.

Beatrice Bravi, Irene Bollettini, Camilla Di Pasquasio, Andrea Falini, Cristina Colombo, Raffaella Zanardi, Sara Poletti, Francesco Benedetti.

  Bipolar disorder (BD) is associated with alterations in white matter (WM) microstructure, glutamatergic neurotransmission, and glia activity. Previous studies showed higher concentrations of glutamate (Glu), glutamate+glutamine (Glx), and reduced N-acetyl-aspartate (NAA) in BD. We investigated brain concentrations of Glu, Glx, NAA, mI as indirect marker of microglia activation, and Glx/NAA ratio as index of neuronal damage through 1H-MR, and WM integrity with Tract-Based Spatial Statistics in 93 depressed BD patients and 58 healthy controls (HC). We tested for linear effects of cited spectroscopic metabolites on DTI measures of WM integrity with general linear models for each group, then performing a conjunction analysis of Glx/NAA and mI concentration on the same measures. Statistical analyses (whole sample) revealed higher concentration of Glx/NAA, Glx and mI in BD patients compared to HC, and a positive association between mI and the ratio. DTI analyses (87 BD and 35 HC) showed a significant association of Glx/NAA ratio, and mI with WM microstructure. Conjunction analysis revealed a joint negative association between Glx/NAA and mI with fractional anisotropy. This is the first study showing an association between brain metabolites involved in neuronal damage, and glial activation and the alterations in WM consistently reported in BD.

Keywords:  Bipolar disorder; Glutamate; Inflammation; TBSS

DOI:  https://doi.org/10.1016/j.pscychresns.2022.111534
Dev Neurosci. 2022 Aug 30.

Intranasal Insulin Attenuates the Long-term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats.

Lauren McClure Yauch, Kathleen Ennis-Czerniak, William H Frey Ii, Ivan Tkac, Raghavendra B Rao.

Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer's Disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group) or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut 4 and Glut8) and poly(ADP-ribose)polymerase-1(Parp1, a marker of oxidative stress) were determined on P7 using in vivo 1H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis and synaptogenesis were determined at adulthood using 1H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ+INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus.

DOI: https://doi.org/10.1159/000526627
J Inherit Metab Dis. 2022 Sep 01.

TRIT1 defect leads to a recognizable phenotype of myoclonic epilepsy, speech delay, strabismus, progressive spasticity and normal lactate levels.

Ewout Muylle, Huafang Jiang, Christin Johnsen, Seul Kee Byeon, Wasantha Ranatunga, Kishore Garapati, Roman M Zenka, Graeme Preston, Akhilesh Pandey, Tamas Kozicz, Fang Fang, Eva Morava.

  TRIT1 defect is a rare, autosomal-recessive disorder of transcription, initially described as a condition with developmental delay, myoclonic seizures and abnormal mitochondrial function. Currently, only thirteen patients have been reported. We reviewed the genetic, clinical and metabolic aspects of the disease in all known patients, including two novel, unrelated TRIT1 cases with abnormalities in oxidative phosphorylation complexes I and IV in fibroblasts. Taken together the features of all fifteen patients, TRIT1 defect could be identified as a potentially recognizable syndrome including myoclonic epilepsy, speech delay, strabismus, progressive spasticity and variable microcephaly, with normal lactate levels. Half of the patients had oxidative phosphorylation complex measurements and had multiple complex abnormalities.

Keywords:  OXPHOS; lipidomics; mitochondrial tRNA; myoclonic seizures; spasticity

DOI:  https://doi.org/10.1002/jimd.12550
Respir Physiol Neurobiol. 2022 Aug 27. pii: S1569-9048(22)00122-7. [Epub ahead of print]306 103963

Hyperoxia by short-term promotes oxidative damage and mitochondrial dysfunction in rat brain.

Richard Simon Machado, Leonardo Tenfen, Larissa Joaquim, Everton Venicius Rosa Lanzzarin, Gabriela Costa Bernardes, Sandra Regina Bonfante, Khiany Mathias, Erica Biehl, Érick Bagio, Solange de Souza Stork, Tais Denicol, Mariana Pacheco de Oliveira, Mariella Reinol da Silva, Lucinéia Gainski Danielski, Rafaella Willig de Quadros, Gislaine Tezza Rezin, Silvia Resende Terra, Jairo Nunes Balsini, Fernanda Frederico Gava, Fabricia Petronilho.

  Oxygen (O2) therapy is used as a therapeutic protocol to prevent or treat hypoxia. However, a high inspired fraction of O2 (FIO2) promotes hyperoxia, a harmful condition for the central nervous system (CNS). The present study evaluated parameters of oxidative stress and mitochondrial dysfunction in the brain of rats exposed to different FIO2. Male Wistar rats were exposed to hyperoxia (FIO2 40 % and 60 %) compared to the control group (FIO2 21 %) for 2 h. Oxidative stress, neutrophilic infiltration, and mitochondrial respiratory chain enzymes were determined in the hippocampus, striatum, cerebellum, cortex, and prefrontal cortex after O2 exposure. The animals exposed to hyperoxia showed increased lipid peroxidation, formation of carbonyl proteins, N/N concentration, and neutrophilic infiltration in some brain regions, like hippocampus, striatum, and cerebellum being the most affected. Furthermore, CAT activity and activity of mitochondrial enzyme complexes were also altered after exposure to hyperoxia. Rats exposed to hyperoxia showed increase in oxidative stress parameters and mitochondrial dysfunction in brain structures.

Keywords:  Brain; Hyperoxia; Oxidative stress; Oxygen

DOI:  https://doi.org/10.1016/j.resp.2022.103963
Transl Psychiatry. 2022 Aug 30. 12(1): 353

Mitochondria DNA copy number, mitochondria DNA total somatic deletions, Complex I activity, synapse number, and synaptic mitochondria number are altered in schizophrenia and bipolar disorder.

Sujan C Das, Brooke E Hjelm, Brandi L Rollins, Adolfo Sequeira, Ling Morgan, Audrey A Omidsalar, Alan F Schatzberg, Jack D Barchas, Francis S Lee, Richard M Myers, Stanley J Watson, Huda Akil, William E Bunney, Marquis P Vawter.

Mitochondrial dysfunction is a neurobiological phenomenon implicated in the pathophysiology of schizophrenia and bipolar disorder that can synergistically affect synaptic neurotransmission. We hypothesized that schizophrenia and bipolar disorder share molecular alterations at the mitochondrial and synaptic levels. Mitochondria DNA (mtDNA) copy number (CN), mtDNA common deletion (CD), mtDNA total deletion, complex I activity, synapse number, and synaptic mitochondria number were studied in the postmortem human dorsolateral prefrontal cortex (DLPFC), superior temporal gyrus (STG), primary visual cortex (V1), and nucleus accumbens (NAc) of controls (CON), and subjects with schizophrenia (SZ), and bipolar disorder (BD). The results showed (i) the mtDNA CN is significantly higher in DLPFC of both SZ and BD, decreased in the STG of BD, and unaltered in V1 and NAc of both SZ and BD; (ii) the mtDNA CD is significantly higher in DLPFC of BD while unaltered in STG, V1, and NAc of both SZ and BD; (iii) The total deletion burden is significantly higher in DLPFC in both SZ and BD while unaltered in STG, V1, and NAc of SZ and BD; (iv) Complex I activity is significantly lower in DLPFC of both SZ and BD, which is driven by the presence of medications, with no alteration in STG, V1, and NAc. In addition, complex I protein concentration, by ELISA, was decreased across three cortical regions of SZ and BD subjects; (v) The number of synapses is decreased in DLPFC of both SZ and BD, while the synaptic mitochondria number was significantly lower in female SZ and female BD compared to female controls. Overall, these findings will pave the way to understand better the pathophysiology of schizophrenia and bipolar disorder for therapeutic interventions.

DOI: https://doi.org/10.1038/s41398-022-02127-1
J Lipid Res. 2022 Aug 29. pii: S0022-2275(22)00104-3. [Epub ahead of print] 100271

Identification and characterization of LPLAT7 as an sn-1-specific lysophospholipid acyltransferase.

Hiroki Kawana, Masaya Ozawa, Takeaki Shibata, Hirofumi Ohnishi, Yukitaka Sato, Kuniyuki Kano, Hideo Shindou, Takao Shimizu, Nozomu Kono, Junken Aoki.

  The main fatty acids at the sn-1 position of phospholipids (PLs) are saturated or monounsaturated fatty acids such as palmitic acid (C16:0), stearic acid (C18:0), and oleic acid (C18:1), and are constantly replaced, like unsaturated fatty acids at the sn-2 position. However, little is known about the molecular mechanism underlying the replacement of fatty acids at the sn-1 position, i.e., the sn-1 remodeling. Previously, we established a method to evaluate the incorporation of fatty acids into the sn-1 position of lysophospholipids (lyso-PLs). Here, we used this method to identify the enzymes capable of incorporating fatty acids into the sn-1 position of lyso-PLs (sn-1 lysophospholipid acyltransferase (LPLAT)). Screenings using siRNA knockdown and recombinant proteins for 14 LPLATs identified LPLAT7/ lysophosphatidylglycerol acyltransferase 1 (LPGAT1) as a candidate. In vitro, we found LPLAT7 mainly incorporated several fatty acids into the sn-1 position of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), with weak activities toward other lyso-PLs. Interestingly, however, only C18:0-containing phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were specifically reduced in the LPLAT7 mutant cells and tissues from knockout mice, with a concomitant increase in the level of C16:0- and C18:1-containing PC and PE. Consistent with this, the incorporation of deuterium-labeled C18:0 into PLs dramatically decreased in the mutant cells, while deuterium-labeled C16:0 and C18:1 showed the opposite dynamic. Identifying LPLAT7 as an sn-1 LPLAT facilitates understanding the biological significance of sn-1 fatty acid remodeling of PLs. We also propose to use the new nomenclature, LPLAT7, for LPGAT1 since the newly assigned enzymatic activities are quite different from the LPGAT1s previously reported.

Keywords:  LPGAT1; LPLAT7; Phospholipid; fatty-acid remodeling; lysophospholipid acyltransferase; oleic acid; palmitic acid; sn-1; sn-2; stearic acid

DOI:  https://doi.org/10.1016/j.jlr.2022.100271
Mol Biol Rep. 2022 Aug 31.

Current knowledge of protein palmitoylation in gliomas.

Feng Tang, Zhenyuan Liu, Xi Chen, Jinzhou Yang, Zefen Wang, Zhiqiang Li.

  Malignant tumor cells can obtain proliferative benefits from deviant metabolic networks. Emerging evidence suggests that lipid metabolism are dramatically altered in gliomas and excessive fatty acd accumulation is detrimentally correlated with the prognosis of glioma patients. Glioma cells possess remarkably high levels of free fatty acids, which, in turn, enhance post-translational modifications (e.g. palmitoylation). Our and other groups found that palmitoylational modification is essential for remaining intracellular homeostasis and cell survival. Disrupting the balance between palmitoylation and depalmitoylation affects glioma cell viability, apoptosis, invasion, self-renew and pyroptosis. In this review, we focused on summarizing roles and relevant mechanisms of protein palmitoylational modification in gliomas.

Keywords:  Glioma; Lipid metabolism; Palmitoylation; Post-translational modification; Protein therapeutics

DOI:  https://doi.org/10.1007/s11033-022-07809-z
Front Pediatr. 2022 ;10 969741

Intravenous branched-chain amino-acid-free solution for the treatment of metabolic decompensation episodes in Spanish pediatric patients with maple syrup urine disease.

Paula Sánchez-Pintos, Silvia Meavilla, María Goretti López-Ramos, Ángeles García-Cazorla, Maria L Couce.

   Background: Metabolic decompensation episodes (DEs) in Maple Syrup urine disease (MSUD) result in brain accumulation of toxic branched-chain amino acids (BCAAs) and their respective branched-chain α-keto acids that could induce neuroinflammation, disturb brain bioenergetics, and alter glutamate and glutamine synthesis. These episodes require immediate intervention to prevent irreversible neurological damage. Intravenous (IV) administration of BCAA-free solution could represent a powerful alternative for emergency treatment of decompensations.
Methods: This pediatric series discusses the management of DEs in MSUD patients with IV BCAA-free solution, as an emergency treatment for DEs or as a prophylactic in cases requiring surgery. Clinical evolution, amino acid profile and adverse effects were evaluated.
Results: We evaluated the use of BCAA-free solution in 5 DEs in 5 MSUD pediatric patients, all with significantly elevated plasma leucine levels at admission (699-3296 μmol/L) and in 1 episode of risk of DE due to surgery. Leucine normalization was achieved in all cases with resolution or improvement of clinical symptoms following IV BCAA-free solution. The duration of administration ranged from 3-20 days. Administration of IV BCAA-free solution at the beginning of a DE could reverse depletion of the amino acids that compete with BCAAs for the LAT1 transporter, and the observed depletion of alanine, despite IV alanine supplementation. No related adverse events were observed.
Conclusions: Administration of standardized IV BCAA-free solution in emergency settings constitutes an important and safe alternative for the treatment of DEs in MSUD, especially in pediatric patients for whom oral or enteral treatment is not viable.

Keywords:  MSUD; dietary treatment; intravenous branched-chain amino acid-free formula; metabolic decompensation; metabolic emergency treatment

DOI:  https://doi.org/10.3389/fped.2022.969741
Oxid Med Cell Longev. 2022 ;2022 3201644

Emerging Role of Neuron-Glia in Neurological Disorders: At a Glance.

Md Mominur Rahman, Md Rezaul Islam, Md Yamin, Md Mohaimenul Islam, Md Taslim Sarker, Atkia Farzana Khan Meem, Aklima Akter, Talha Bin Emran, Simona Cavalu, Rohit Sharma.

Based on the diverse physiological influence, the impact of glial cells has become much more evident on neurological illnesses, resulting in the origins of many diseases appearing to be more convoluted than previously happened. Since neurological disorders are often random and unknown, hence the construction of animal models is difficult to build, representing a small fraction of people with a gene mutation. As a result, an immediate necessity is grown to work within in vitro techniques for examining these illnesses. As the scientific community recognizes cell-autonomous contributions to a variety of central nervous system illnesses, therapeutic techniques involving stem cells for treating neurological diseases are gaining traction. The use of stem cells derived from a variety of sources is increasingly being used to replace both neuronal and glial tissue. The brain's energy demands necessitate the reliance of neurons on glial cells in order for it to function properly. Furthermore, glial cells have diverse functions in terms of regulating their own metabolic activities, as well as collaborating with neurons via secreted signaling or guidance molecules, forming a complex network of neuron-glial connections in health and sickness. Emerging data reveals that metabolic changes in glial cells can cause morphological and functional changes in conjunction with neuronal dysfunction under disease situations, highlighting the importance of neuron-glia interactions in the pathophysiology of neurological illnesses. In this context, it is required to improve our understanding of disease mechanisms and create potential novel therapeutics. According to research, synaptic malfunction is one of the features of various mental diseases, and glial cells are acting as key ingredients not only in synapse formation, growth, and plasticity but also in neuroinflammation and synaptic homeostasis which creates critical physiological capacity in the focused sensory system. The goal of this review article is to elaborate state-of-the-art information on a few glial cell types situated in the central nervous system (CNS) and highlight their role in the onset and progression of neurological disorders.

DOI: https://doi.org/10.1155/2022/3201644
Cereb Cortex. 2022 Aug 27. pii: bhac321. [Epub ahead of print]

Functional brain activity is highly associated with cortical myelination in neonates.

Ziyi Huang, Wenjian Gao, Zhengwang Wu, Gang Li, Jingxin Nie.

  Functional organization of the human cerebral cortex is highly constrained by underlying brain structures, but how functional activity is associated with different brain structures during development is not clear, especially at the neonatal stage. Since long-range functional connectivity is far from mature in the dynamically developing neonatal brain, it is of great scientific significance to investigate the relationship between different structural and functional features at the local level. To this end, for the first time, correlation and regression analyses were performed to examine the relationship between cortical morphology, cortical myelination, age, and local brain functional activity, as well as functional connectivity strength using high-resolution structural and resting-state functional MRI data of 177 neonates (29-44 postmenopausal weeks, 98 male and 79 female) from both static and dynamic perspectives. We found that cortical myelination was most strongly associated with local brain functional activity across the cerebral cortex than other cortical structural features while controlling the age effect. These findings suggest the crucial role of cortical myelination in local brain functional development at birth, providing valuable insights into the fundamental biological basis of functional activity at this early developmental stage.

Keywords:  Brain structure and function; MRI; cortical myelination; local brain activity; neonate

DOI:  https://doi.org/10.1093/cercor/bhac321
J Biomed Res. 2022 Jun 28. 1-12

SIRT3 regulates mitochondrial biogenesis in aging-related diseases.

Hong-Yan Li, Zhi-You Cai.

  Sirtuin 3 (SIRT3), the main family member of mitochondrial deacetylase, targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism, reactive oxygen species production and clearance, oxidative stress, and aging. Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis, thus leading to the defect in mitochondrial function and insufficient ATP production. Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis, dampening mitochondrial function. Mitochondrial dysfunction plays an important role in several diseases related to aging, such as cardiovascular disease, cancer and neurodegenerative diseases. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) launches mitochondrial biogenesis through activating nuclear respiratory factors. These factors act on genes, transcribing and translating mitochondrial DNA to generate new mitochondria. PGC1α builds a bridge between SIRT3 and mitochondrial biogenesis. This review described the involvement of SIRT3 and mitochondrial dynamics, particularly mitochondrial biogenesis in aging-related diseases, and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.

Keywords:  PGC1α; SIRT3; aging-related diseases; mitochondrial biogenesis

DOI:  https://doi.org/10.7555/JBR.36.20220078
Hum Mutat. 2022 Aug 28.

Biallelic pathogenic variants in COX11 are associated with an infantile-onset mitochondrial encephalopathy.

Rocio Rius, Neal K Bennett, Kaustuv Bhattacharya, Lisa G Riley, Zafer Yüksel, Luke E Formosa, Alison G Compton, Russell C Dale, Mark J Cowley, Velimir Gayevskiy, Saeed Al Tala, Abdulrahman A Almehery, Michael T Ryan, David R Thorburn, Ken Nakamura, John Christodoulou.

  Primary mitochondrial diseases are a group of genetically and clinically heterogeneous disorders resulting from oxidative phosphorylation (OXPHOS) defects. COX11 encodes a copper chaperone that participates in the assembly of complex IV (CIV) and has not been previously linked to human disease. In a previous study, we identified that COX11 knockdown decreased cellular ATP derived from respiration, and that ATP levels could be restored with CoQ10 supplementation. This finding is surprising since COX11 has no known role in CoQ10 biosynthesis. Here, we report a novel gene-disease association by identifying biallelic pathogenic variants in COX11 associated with infantile-onset mitochondrial encephalopathies in two unrelated families using trio genome and exome sequencing. Functional studies showed that mutant COX11 fibroblasts had decreased ATP levels which could be rescued by CoQ10 . These results not only suggest that COX11 variants cause defects in energy production but reveal a potential metabolic therapeutic strategy for patients with COX11 variants. This article is protected by copyright. All rights reserved.

Keywords:  COX11; Coenzyme Q; OXPHOS; mitochondrial disorders

DOI:  https://doi.org/10.1002/humu.24453
Curr Neuropharmacol. 2022 Aug 30.

Ketogenic diet: an effective treatment approach for neurodegenerative diseases.

Ye Tao, Sean X Leng, Haiyan Zhang.

  This review discusses the effects and mechanisms of ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, medium-protein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.

Keywords:  Alzheimer's disease ; Amyotrophic lateral sclerosis ; Ketogenic diet ; Parkinson's disease ; microbiota–gut–brain axis; neurodegenerative diseases

DOI:  https://doi.org/10.2174/1570159X20666220830102628
J Pharmacol Sci. 2022 Oct;pii: S1347-8613(22)00054-8. [Epub ahead of print]150(2): 81-89

HDL, cholesterol efflux, and ABCA1: Free from good and evil dualism.

Masatsune Ogura.

  Homozygotes for loss-of-function mutations in ABCA1 cause Tangier disease. The phenotype of their markedly reduced or loss of blood high-density lipoprotein (HDL) cholesterol, as well as examination of ATP-binding cassette transporter A1 (ABCA1)-deficient mice, proved that ABCA1 is a key player in HDL production. The ABCA1-mediated cholesterol efflux is the first step in the reverse cholesterol transport system and understanding the regulation of its expression was expected to lead to the development of anti-atherosclerotic drugs. However, from the viewpoint of intracellular cholesterol homeostasis, it is difficult to say that simple activation of ABCA1 or promotion of cholesterol efflux is a good strategy. To date, there is no evidence that HDL-increasing drugs by enhancing ABCA1 expression prevent atherosclerotic disease in humans. On the other hand, in situations where intracellular cholesterol homeostasis is disrupted by inflammation, aging, or metabolic abnormalities, a strategy that restores reduced ABCA1 expression and cholesterol efflux in a timely and localized manner may be useful.

Keywords:  ABCA1; Cholesterol efflux; Drug discovery; HDL; Intracellular cholesterol homeostasis

DOI:  https://doi.org/10.1016/j.jphs.2022.07.004
Sci Rep. 2022 Sep 01. 12(1): 14895

Myo-inositol moderates maternal BMI and glycemia related variations in in-vitro placental 13C-DHA-metabolism, altering their relationships with birthweight.

Oliver C Watkins, Preben Selvam, Reshma Appukuttan Pillai, Victoria K B Cracknell-Hazra, Hannah E J Yong, Neha Sharma, Amaury Cazenave-Gassiot, Anne K Bendt, Keith M Godfrey, Rohan M Lewis, Markus R Wenk, Shiao-Yng Chan.

Transplacental docosahexaenoic-acid (DHA) supply for fetal development is regulated by placental DHA-lipid metabolism. Both maternal diabetes and obesity are linked to possible decreased fetal circulating DHA and increased placental DHA-lipids. Since myo-inositol is a promising intervention for gestational diabetes (GDM), we aimed to determine whether myo-inositol could rectify perturbations in placental DHA metabolism associated with maternal increasing glycemia and obesity and examine links with birthweight. Term placental villous explants from 17 women representing a range of BMIs and mid-gestational glycemia, were incubated with 13C-labeled-DHA for 48 h, in 0.3 µmol/L (control) or 60 µmol/L myo-inositol. Individual newly synthesized 13C-DHA-labeled lipid species were quantified by liquid-chromatography-mass-spectrometry. Compared with controls, incubation with myo-inositol decreased most 13C-DHA-lipids in placental explants from women with higher BMI or higher glycemia, but increased 13C-DHA-lipids with normal BMI or lower glycemia. Myo-inositol also increased 13C-DHA-labeled lipids in cases of lower birthweight centile, but induced decreases at higher centiles. Myo-inositol therefore lowered DHA-lipids in placenta with high basal placental DHA-lipid production (higher BMI and glycemia) but increased DHA-lipids where basal processing capacity is low. Myo-inositol thus moderates placental DHA metabolism towards a physiological mean which may in turn moderate birthweight.

DOI: https://doi.org/10.1038/s41598-022-18309-2