bims-medebr 2024-02-11 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–02–11
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

Astrocyte-derived lactate in stress disorders.
Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.
The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus.
Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.
The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.
Ultrahigh Resolution Mass Spectrometry Imaging Maps Brain Lipidome Alterations Associated with Mild Traumatic Brain Injury.
The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.
Mapping the lipidome in mitochondria-associated membranes (MAMs) in an in vitro model of Alzheimer's disease.
Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems.
Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.
URB447 Is Neuroprotective in Both Male and Female Rats after Neonatal Hypoxia-Ischemia and Enhances Neurogenesis in Females.
Maternal environmental enrichment protects neonatal brains from hypoxic-ischemic challenge by mitigating brain energetic dysfunction and modulating glial cell responses.
Role of mitochondria in neonatal hypoxic-ischemic encephalopathy.
Longitudinal changes in brain metabolites following pediatric concussion.
Genetic deletion of hormone-sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet-induced obesity on memory.
LipidSIM: Inferring mechanistic lipid biosynthesis perturbations from lipidomics with a flexible, low-parameter, markov modeling framework.
Structural basis for lysophosphatidylserine recognition by GPR34.
Hyperpolarized 13 C magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: First investigations in a large animal model.
The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring.

Neurobiol Dis. 2024 Jan 29. pii: S0969-9961(24)00016-0. [Epub ahead of print]192 106417

Astrocyte-derived lactate in stress disorders.

Farah Chamaa, Pierre J Magistretti, Hubert Fiumelli.

  Stress disorders are psychiatric disorders arising following stressful or traumatic events. They could deleteriously affect an individual's health because they often co-occur with mental illnesses. Considerable attention has been focused on neurons when considering the neurobiology of stress disorders. However, like other mental health conditions, recent studies have highlighted the importance of astrocytes in the pathophysiology of stress-related disorders. In addition to their structural and homeostatic support role, astrocytes actively serve several functions in regulating synaptic transmission and plasticity, protecting neurons from toxic compounds, and providing metabolic support for neurons. The astrocyte-neuron lactate shuttle model sets forth the importance of astrocytes in providing lactate for the metabolic supply of neurons under intense activity. Lactate also plays a role as a signaling molecule and has been recently studied regarding its antidepressant activity. This review discusses the involvement of astrocytes and brain energy metabolism in stress and further reflects on the importance of lactate as an energy supply in the brain and its emerging antidepressant role in stress-related disorders.

Keywords:  Antidepressants; Astrocyte-neuron lactate shuttle; Astrocytes; Lactate; Stress disorders

DOI:  https://doi.org/10.1016/j.nbd.2024.106417
Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2305035121

Brain energy metabolism is optimized to minimize the cost of enzyme synthesis and transport.

Johan Gustafsson, Jonathan L Robinson, Henrik Zetterberg, Jens Nielsen.

  The energy metabolism of the brain is poorly understood partly due to the complex morphology of neurons and fluctuations in ATP demand over time. To investigate this, we used metabolic models that estimate enzyme usage per pathway, enzyme utilization over time, and enzyme transportation to evaluate how these parameters and processes affect ATP costs for enzyme synthesis and transportation. Our models show that the total enzyme maintenance energy expenditure of the human body depends on how glycolysis and mitochondrial respiration are distributed both across and within cell types in the brain. We suggest that brain metabolism is optimized to minimize the ATP maintenance cost by distributing the different ATP generation pathways in an advantageous way across cell types and potentially also across synapses within the same cell. Our models support this hypothesis by predicting export of lactate from both neurons and astrocytes during peak ATP demand, reproducing results from experimental measurements reported in the literature. Furthermore, our models provide potential explanation for parts of the astrocyte-neuron lactate shuttle theory, which is recapitulated under some conditions in the brain, while contradicting other aspects of the theory. We conclude that enzyme usage per pathway, enzyme utilization over time, and enzyme transportation are important factors for defining the optimal distribution of ATP production pathways, opening a broad avenue to explore in brain metabolism.

Keywords:  ANLS; brain metabolism; genome-scale models; mathematical modeling; metabolism

DOI:  https://doi.org/10.1073/pnas.2305035121
J Neurochem. 2024 Feb 09.

The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus.

Daniela M Magalhães, Nicolas A Stewart, Myrthe Mampay, Sara O Rolle, Chloe M Hall, Emad Moeendarbary, Melanie S Flint, Ana M Sebastião, Cláudia A Valente, Marcus K Dymond, Graham K Sheridan.

  The small-molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1-phosphate (S1P) analogue currently used to treat relapsing-remitting multiple sclerosis in both adults and children. FTY720 can cross the blood-brain barrier (BBB) and, over time, accumulate in lipid-rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor-mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry-based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy-phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up-regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down-regulated. FTY720 also modulated anxiety-like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system.

Keywords:  FTY720; forced swim test; hippocampus; lipidomics; sphingomyelin lipids

DOI:  https://doi.org/10.1111/jnc.16073
Int J Mol Sci. 2024 Jan 23. pii: 1386. [Epub ahead of print]25(3):

Dysfunctional Postnatal Mitochondrial Energy Metabolism in a Patient with Neurodevelopmental Defects Caused by Intrauterine Growth Restriction Due to Idiopathic Placental Insufficiency.

Martine Uittenbogaard, Andrea L Gropman, Matthew T Whitehead, Christine A Brantner, Eliana Gropman, Anne Chiaramello.

  We report the case of a four-year-old male patient with a complex medical history born prematurely as the result of intrauterine growth restriction due to placental insufficiency. His clinical manifestations included severe neurodevelopmental deficits, global developmental delay, Pierre-Robin sequence, and intractable epilepsy with both generalized and focal features. The proband's low levels of citrulline and lactic acidosis provoked by administration of Depakoke were evocative of a mitochondrial etiology. The proband's genotype-phenotype correlation remained undefined in the absence of nuclear and mitochondrial pathogenic variants detected by deep sequencing of both genomes. However, live-cell mitochondrial metabolic investigations provided evidence of a deficient oxidative-phosphorylation pathway responsible for adenosine triphosphate (ATP) synthesis, leading to chronic energy crisis in the proband. In addition, our metabolic analysis revealed metabolic plasticity in favor of glycolysis for ATP synthesis. Our mitochondrial morphometric analysis by transmission electron microscopy confirmed the suspected mitochondrial etiology, as the proband's mitochondria exhibited an immature morphology with poorly developed and rare cristae. Thus, our results support the concept that suboptimal levels of intrauterine oxygen and nutrients alter fetal mitochondrial metabolic reprogramming toward oxidative phosphorylation (OXPHOS) leading to a deficient postnatal mitochondrial energy metabolism. In conclusion, our collective studies shed light on the long-term postnatal mitochondrial pathophysiology caused by intrauterine growth restriction due to idiopathic placental insufficiency and its negative impact on the energy-demanding development of the fetal and postnatal brain.

Keywords:  OXPHOS deficit; fetal growth restriction; metabolic reprogramming; mitochondrial dysfunction; neurodevelopmental deficits; placental insufficiency

DOI:  https://doi.org/10.3390/ijms25031386
Neurochem Int. 2024 Feb 02. pii: S0197-0186(24)00007-X. [Epub ahead of print] 105680

The role of mitochondrial uncoupling in the regulation of mitostasis after traumatic brain injury.

W Brad Hubbard, Gopal V Velmurugan, Patrick G Sullivan.

  Mitostasis, the maintenance of healthy mitochondria, plays a critical role in brain health. The brain's high energy demands and reliance on mitochondria for energy production make mitostasis vital for neuronal function. Traumatic brain injury (TBI) disrupts mitochondrial homeostasis, leading to secondary cellular damage, neuronal degeneration, and cognitive deficits. Mild mitochondrial uncoupling, which dissociates ATP production from oxygen consumption, offers a promising avenue for TBI treatment. Accumulating evidence, from endogenous and exogenous mitochondrial uncoupling, suggests that mitostasis is closely regulating by mitochondrial uncoupling and cellular injury environments may be more sensitive to uncoupling. Mitochondrial uncoupling can mitigate calcium overload, reduce oxidative stress, and induce mitochondrial proteostasis and mitophagy, a process that eliminates damaged mitochondria. The interplay between mitochondrial uncoupling and mitostasis is ripe for further investigation in the context of TBI. These multi-faceted mechanisms of action for mitochondrial uncoupling hold promise for TBI therapy, with the potential to restore mitochondrial health, improve neurological outcomes, and prevent long-term TBI-related pathology.

Keywords:  Calcium; Dinitrophenol; Mitochondria; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.neuint.2024.105680
bioRxiv. 2024 Jan 25. pii: 2024.01.25.577203. [Epub ahead of print]

Ultrahigh Resolution Mass Spectrometry Imaging Maps Brain Lipidome Alterations Associated with Mild Traumatic Brain Injury.

Dmitry Leontyev, Alexis N Pulliam, Xin Ma, David A Gaul, Michelle C LaPlaca, Facundo M Fernández.

Background: Traumatic brain injury (TBI) is a global public health problem, with 50-60 million incidents per year, most of which are considered mild (mTBI). Despite its massive impact, the pathology of TBI is not fully understood, and there is a paucity of information on brain lipid dysregulation following mTBI. To gain more insight on mTBI pathology, a non-targeted spatial metabolomics workflow utilizing ultrahigh resolution mass spectrometry imaging was developed to measure brain region-specific lipid alterations in rats.
Results: Multivariate models were created for regions of interest including the hippocampus, cortex, corpus callosum, white matter and gray matter to identify lipids that discriminated between control and injured brains. The hippocampus model differentiated control and injured brains with an area under the curve of 0.994, using only four lipid markers. Lipid classes that were consistently selected for discrimination included polyunsaturated fatty acid-containing phosphatidylcholines (PC), lysophosphatidylcholines (LPC), LPC-plasmalogens (LPC-P), PC potassium adducts and ceramide phosphoinositols (PI-Cer). Many of the polyunsaturated fatty acid-containing PC, LPC-P, and PI-Cer selected have never been previously reported as altered in TBI.
Significance: The lipid alterations observed indicate that neuroinflammation, oxidative stress and disrupted sodium-potassium pumps are important pathologies that can explain cognitive deficits associated with mTBI. Therapeutics which target and attenuate these pathologies may be beneficial to limit persistent damage following a mild brain injury.

DOI: https://doi.org/10.1101/2024.01.25.577203
EMBO J. 2024 Feb 05.

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.

Isaac O Akefe, Saber H Saber, Benjamin Matthews, Bharat G Venkatesh, Rachel S Gormal, Daniel G Blackmore, Suzy Alexander, Emma Sieriecki, Yann Gambin, Jesus Bertran-Gonzalez, Nicolas Vitale, Yann Humeau, Arnaud Gaudin, Sevannah A Ellis, Alysee A Michaels, Mingshan Xue, Benjamin Cravatt, Merja Joensuu, Tristan P Wallis, Frédéric A Meunier.

  The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1+/- mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory.

Keywords:  Free Fatty Acids; Learning and Memory; Lipids; Myristic Acid; Phospholipase A1

DOI:  https://doi.org/10.1038/s44318-024-00030-7
J Neurochem. 2024 Feb 07.

Mapping the lipidome in mitochondria-associated membranes (MAMs) in an in vitro model of Alzheimer's disease.

Tânia Fernandes, Tânia Melo, Tiago Conde, Bruna Neves, Pedro Domingues, Rosa Resende, Cláudia F Pereira, Paula I Moreira, Maria Rosário Domingues.

  The disruption of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) plays a relevant role in Alzheimer's disease (AD). MAMs have been implicated in neuronal dysfunction and death since it is associated with impairment of functions regulated in this subcellular domain, including lipid synthesis and trafficking, mitochondria dysfunction, ER stress-induced unfolded protein response (UPR), apoptosis, and inflammation. Since MAMs play an important role in lipid metabolism, in this study we characterized and investigated the lipidome alterations at MAMs in comparison with other subcellular fractions, namely microsomes and mitochondria, using an in vitro model of AD, namely the mouse neuroblastoma cell line (N2A) over-expressing the APP familial Swedish mutation (APPswe) and the respective control (WT) cells. Phospholipids (PLs) and fatty acids (FAs) were isolated from the different subcellular fractions and analyzed by HILIC-LC-MS/MS and GC-MS, respectively. In this in vitro AD model, we observed a down-regulation in relative abundance of some phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE) species with PUFA and few PC with saturated and long-chain FA. We also found an up-regulation of CL, and antioxidant alkyl acyl PL. Moreover, multivariate analysis indicated that each organelle has a specific lipid profile adaptation in N2A APPswe cells. In the FAs profile, we found an up-regulation of C16:0 in all subcellular fractions, a decrease of C18:0 levels in total fraction (TF) and microsomes fraction, and a down-regulation of 9-C18:1 was also found in mitochondria fraction in the AD model. Together, these results suggest that the over-expression of the familial APP Swedish mutation affects lipid homeostasis in MAMs and other subcellular fractions and supports the important role of lipids in AD physiopathology.

Keywords:  Alzheimer's disease; ER-mitochondria contacts; lipid dyshomeostasis; lipidomics; subcellular fractions

DOI:  https://doi.org/10.1111/jnc.16072
CNS Neurosci Ther. 2024 Feb;30(2): e14576

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems.

Mengruo Jiang, Liyuan Wang, Hui Sheng.

   BACKGROUND: Depression is the most disabling neuropsychiatric disorder, causing difficulties in daily life activities and social interactions. The exact mechanisms of depression remain largely unclear. However, some studies have shown that mitochondrial dysfunction would play a crucial role in the occurrence and development of depression.
AIMS: To summarize the known knowledge about the role of mitochondrial dysfunction in the pathogenesis of depression.
METHODS: We review the recent literature， including 105 articles, to summarize the mitochondrial energy metabolism and quality control systems in the occurrence and development of depression. Some antidepressants which may exert their effects by improving mitochondrial function are also discussed.
RESULTS: Impaired brain energy metabolism and (or) damaged mitochondrial quality control systems have been reported not only in depression patients but in animal models of depression. Although the classical antidepressants have not been specially designed to target mitochondria, the evidence suggests that many antidepressants may exert their effects by improving mitochondrial function.
CONCLUSIONS: This brief review focuses on the findings that implicate mitochondrial dysfunction and the quality control systems as important etiological factors in the context of depressive disorders. It will help us to understand the various concepts of mitochondrial dysfunction in the pathogenesis of depression, and to explore novel and more targeted therapeutic approaches for depression.

Keywords:  depression; energy metabolism; mitochondria; mitochondrial quality control system

DOI:  https://doi.org/10.1111/cns.14576
Hum Mol Genet. 2024 Feb 07. pii: ddae018. [Epub ahead of print]

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency.

Vanitha Nithianandam, Souvarish Sarkar, Mel B Feany.

  Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

Keywords:  Drosophila; complex I deficiency; mitochondria; neurotoxicity; proteostasis

DOI:  https://doi.org/10.1093/hmg/ddae018
Int J Mol Sci. 2024 Jan 28. pii: 1607. [Epub ahead of print]25(3):

URB447 Is Neuroprotective in Both Male and Female Rats after Neonatal Hypoxia-Ischemia and Enhances Neurogenesis in Females.

Gorane Beldarrain, Marc Chillida, Enrique Hilario, Borja Herrero de la Parte, Antonia Álvarez, Daniel Alonso-Alconada.

  The need for new and effective treatments for neonates suffering from hypoxia-ischemia is urgent, as the only implemented therapy in clinics is therapeutic hypothermia, only effective in 50% of cases. Cannabinoids may modulate neuronal development and brain plasticity, but further investigation is needed to better describe their implication as a neurorestorative therapy after neonatal HI. The cannabinoid URB447, a CB1 antagonist/CB2 agonist, has previously been shown to reduce brain injury after HI, but it is not clear whether sex may affect its neuroprotective and/or neurorestorative effect. Here, URB447 strongly reduced brain infarct, improved neuropathological score, and augmented proliferative capacity and neurogenic response in the damaged hemisphere. When analyzing these effects by sex, URB447 ameliorated brain damage in both males and females, and enhanced cell proliferation and the number of neuroblasts only in females, thus suggesting a neuroprotective effect in males and a double neuroprotective/neurorestorative effect in females.

Keywords:  endocannabinoid system; neonatal hypoxia–ischemia; neurogenesis; neuroprotection

DOI:  https://doi.org/10.3390/ijms25031607
Exp Neurol. 2024 Feb 05. pii: S0014-4886(24)00039-6. [Epub ahead of print]374 114713

Maternal environmental enrichment protects neonatal brains from hypoxic-ischemic challenge by mitigating brain energetic dysfunction and modulating glial cell responses.

L E Durán-Carabali, F K Odorcky, L K Grun, F Schmitz, O V Ramires Junior, M R de Oliveria, K F Campos, E Hoeper, A V S Carvalho, S Greggio, G T Venturine, E R Zimmer, F Barbé-Tuana, A T S Wyse, C A Netto.

  There is evidence that maternal milieu and changes in environmental factors during the prenatal period may exert a lasting impact on the brain health of the newborn, even in case of neonatal brain hypoxia-ischemia (HI). The present study aimed to investigate the effects of maternal environmental enrichment (EE) on HI-induced energetic and metabolic failure, along with subsequent neural cell responses in the early postnatal period. Male Wistar pups born to dams exposed to maternal EE or standard conditions (SC) were randomly divided into Sham-SC, HI-SC, Sham-EE, and HI-EE groups. Neonatal HI was induced on postnatal day (PND) 3. The Na+,K+-ATPase activity, mitochondrial function and neuroinflammatory related-proteins were assessed at 24 h and 48 h after HI. MicroPET-FDG scans were used to measure glucose uptake at three time points: 24 h post-HI, PND18, and PND24. Moreover, neuronal preservation and glial cell responses were evaluated at PND18. After HI, animals exposed to maternal EE showed an increase in Na+,K+-ATPase activity, preservation of mitochondrial potential/mass ratio, and a reduction in mitochondrial swelling. Glucose uptake was preserved in HI-EE animals from PND18 onwards. Maternal EE attenuated HI-induced cell degeneration, white matter injury, and reduced astrocyte immunofluorescence. Moreover, the HI-EE group exhibited elevated levels of IL-10 and a reduction in Iba-1 positive cells. Data suggested that the regulation of AKT/ERK1/2 signaling pathways could be involved in the effects of maternal EE. This study evidenced that antenatal environmental stimuli could promote bioenergetic and neural resilience in the offspring against early HI damage, supporting the translational value of pregnancy-focused environmental treatments.

Keywords:  Enrichment; Glial cells; Metabolism; Mitochondrial; Neurodevelopment; Pregnancy

DOI:  https://doi.org/10.1016/j.expneurol.2024.114713
Histol Histopathol. 2024 Jan 15. 18710

Role of mitochondria in neonatal hypoxic-ischemic encephalopathy.

Weijing Kong, Cheng Lu.

Neonatal hypoxic-ischemic encephalopathy, an important cause of death as well as long-term disability in survivors, is caused by oxygen and glucose deprivation, and limited blood flow. Following hypoxic-ischemic injury in the neonatal brain, three main biochemical damages (excitotoxicity, oxidative stress, and exacerbated inflammation) are triggered. Mitochondria are involved in all three cascades. Mitochondria are the nexus of metabolic pathways to offer most of the energy that our body needs. Hypoxic-ischemic injury affects the characteristics of mitochondria, including dynamics, permeability, and ATP production, which also feed back into the process of neonatal hypoxic-ischemic encephalopathy. Mitochondria can be a cellular hub in inflammation, which is another main response of the injured neonatal brain. Some treatments for neonatal hypoxic-ischemic encephalopathy affect the function of mitochondria or target mitochondria, including therapeutic hypothermia and erythropoietin. This review presents the main roles of mitochondria in neonatal hypoxic-ischemic encephalopathy and discusses some potential treatments directed at mitochondria, which may foster the development of new therapeutic strategies for this encephalopathy.

DOI: https://doi.org/10.14670/HH-18-710
Sci Rep. 2024 Feb 08. 14(1): 3242

Longitudinal changes in brain metabolites following pediatric concussion.

Pediatric Emergency Research Canada A-CAP study team

Concussion is commonly characterized by a cascade of neurometabolic changes following injury. Magnetic Resonance Spectroscopy (MRS) can be used to quantify neurometabolites non-invasively. Longitudinal changes in neurometabolites have rarely been studied in pediatric concussion, and fewer studies consider symptoms. This study examines longitudinal changes of neurometabolites in pediatric concussion and associations between neurometabolites and symptom burden. Participants who presented with concussion or orthopedic injury (OI, comparison group) were recruited. The first timepoint for MRS data collection was at a mean of 12 days post-injury (n = 545). Participants were then randomized to 3 (n = 243) or 6 (n = 215) months for MRS follow-up. Parents completed symptom questionnaires to quantify somatic and cognitive symptoms at multiple timepoints following injury. There were no significant changes in neurometabolites over time in the concussion group and neurometabolite trajectories did not differ between asymptomatic concussion, symptomatic concussion, and OI groups. Cross-sectionally, Choline was significantly lower in those with persistent somatic symptoms compared to OI controls at 3 months post-injury. Lower Choline was also significantly associated with higher somatic symptoms. Although overall neurometabolites do not change over time, choline differences that appear at 3 months and is related to somatic symptoms.

DOI: https://doi.org/10.1038/s41598-024-52744-7
J Neurochem. 2024 Feb 05.

Genetic deletion of hormone-sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet-induced obesity on memory.

Cecilia Skoug, Oksana Rogova, Peter Spégel, Cecilia Holm, João M N Duarte.

  Hormone-sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet-induced obesity. HSL-/-, HSL+/-, and HSL+/+ mice of either sex were fed high-fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild-type mice. CBF was positively correlated with lectin-stained vessel density. HSL deletion did not exacerbate HFD-induced microgliosis in the hippocampus and hypothalamus. HSL-/- mice showed preserved memory performance when compared to wild-type mice, and HSL deletion did not significantly aggravate HFD-induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD-induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet-induced obesity. While HSL-/- mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD-induced neuroinflammation and memory dysfunction.

Keywords:  eicosanoids; endocannabinoids; lipids; memory; vasoconstriction; vasodilation

DOI:  https://doi.org/10.1111/jnc.16064
Metab Eng. 2024 Feb 02. pii: S1096-7176(24)00010-7. [Epub ahead of print]

LipidSIM: Inferring mechanistic lipid biosynthesis perturbations from lipidomics with a flexible, low-parameter, markov modeling framework.

Chenguang Liang, Sue Murray, Yang Li, Richard Lee, Audrey Low, Shruti Sasaki, Austin W T Chiang, Wen-Jen Lin, Joel Mathews, Will Barnes, Nathan E Lewis.

Lipid metabolism is a complex and dynamic system involving numerous enzymes at the junction of multiple metabolic pathways. Disruption of these pathways leads to systematic dyslipidemia, a hallmark of many pathological developments, such as nonalcoholic steatohepatitis and diabetes. Recent advances in computational tools can provide insights into the dysregulation of lipid biosynthesis, but limitations remain due to the complexity of lipidomic data, limited knowledge of interactions among involved enzymes, and technical challenges in standardizing across different lipid types. Here, we present a low-parameter, biologically interpretable framework named Lipid Synthesis Investigative Markov model (LipidSIM), which models and predicts the source of perturbations in lipid biosynthesis from lipidomic data. LipidSIM achieves this by accounting for the interdependency between the lipid species via the lipid biosynthesis network and generates testable hypotheses regarding changes in lipid biosynthetic reactions. This feature allows the integration of lipidomics with other omics types, such as transcriptomics, to elucidate the direct driving mechanisms of altered lipidomes due to treatments or disease progression. To demonstrate the value of LipidSIM, we first applied it to hepatic lipidomics following Keap1 knockdown and found that changes in mRNA expression of the lipid pathways were consistent with the LipidSIM-predicted fluxes. Second, we used it to study lipidomic changes following intraperitoneal injection of CCl4 to induce fast NAFLD/NASH development and the progression of fibrosis and hepatic cancer. Finally, to show the power of LipidSIM for classifying samples with dyslipidemia, we used a Dgat2-knockdown study dataset. Thus, we show that as it demands no a priori knowledge of enzyme kinetics, LipidSIM is a valuable and intuitive framework for extracting biological insights from complex lipidomic data.

DOI: https://doi.org/10.1016/j.ymben.2024.01.004
Nat Commun. 2024 Feb 07. 15(1): 902

Structural basis for lysophosphatidylserine recognition by GPR34.

Tamaki Izume, Ryo Kawahara, Akiharu Uwamizu, Luying Chen, Shun Yaginuma, Jumpei Omi, Hiroki Kawana, Fengjue Hou, Fumiya K Sano, Tatsuki Tanaka, Kazuhiro Kobayashi, Hiroyuki H Okamoto, Yoshiaki Kise, Tomohiko Ohwada, Junken Aoki, Wataru Shihoya, Osamu Nureki.

GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-Gi complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.

DOI: https://doi.org/10.1038/s41467-024-45046-z
NMR Biomed. 2024 Feb 05. e5110

Hyperpolarized 13 C magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: First investigations in a large animal model.

Ted C K Andelius, Esben S S Hansen, Nikolaj Bøgh, Mette V Pedersen, Kasper J Kyng, Tine B Henriksen, Christoffer Laustsen.

  Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13 C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13 C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13 C studies, [1-13 C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13 C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult.

Keywords:  animal model; hyperpolarized MRI; hypoxic ischemic encephalopathy; neonatology

DOI:  https://doi.org/10.1002/nbm.5110
Front Nutr. 2023 ;10 1330414

The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring.

Irena Jovanovic Macura, Ivana Djuricic, Tamara Major, Desanka Milanovic, Sladjana Sobajic, Selma Kanazir, Sanja Ivkovic.

   Introduction: During fetal development, the proper development of neural and visual systems relies on the maternal supplementation of omega-3 fatty acids through placental transfer. Pregnant women are strongly advised to augment their diet with additional sources of omega-3, such as fish oil (FO). This supplementation has been linked to a reduced risk of preterm birth, pre-eclampsia, and perinatal depression. Recently, higher doses of omega-3 supplementation have been recommended for pregnant women. Considering that omega-3 fatty acids, particularly docosahexaenoic acid (DHA), play a crucial role in maintaining the delicate homeostasis required for the proper functioning of the retina and photoreceptors the effects of high-dose fish oil (FO) supplementation during pregnancy and lactation on the retina and retinal pigmented epithelium (RPE) in healthy offspring warrant better understanding.
Methods: The fatty acid content and the changes in the expression of the genes regulating cholesterol homeostasis and DHA transport in the retina and RPE were evaluated following the high-dose FO supplementation.
Results: Our study demonstrated that despite the high-dose FO treatment during pregnancy and lactation, the rigorous DHA homeostasis in the retina and RPE of the two-month-old offspring remained balanced. Another significant finding of this study is the increase in the expression levels of major facilitator superfamily domain-containing protein (Mfsd2a), a primary DHA transporter. Mfsd2a also serves as a major regulator of transcytosis during development, and a reduction in Mfsd2a levels poses a major risk for the development of leaky blood vessels.
Conclusion: Impairment of the blood-retinal barrier (BRB) is associated with the development of numerous ocular diseases, and a better understanding of how to manipulate transcytosis in the BRB during development can enhance drug delivery through the BRB or contribute to the repair of central nervous system (CNS) barriers.

Keywords:  DHA; EPA; Mfsd2a; RPE; fish oil; lactation; pregnancy; retina

DOI:  https://doi.org/10.3389/fnut.2023.1330414