bims-medebr 2024-07-28 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒07‒28
24 papers selected by
Regina F. Fernández, Johns Hopkins University

Neurodevelopment Is Dependent on Maternal Diet: Placenta and Brain Glucose Transporters GLUT1 and GLUT3.
APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons.
β-Hydroxybutyrate Improves the Redox Status, Cytokine Production and Phagocytic Potency of Glucose-Deprived HMC3 Human Microglia-like Cells.
Prenatal molecular diagnosis of pyruvate dehydrogenase complex deficiency enables rapid initiation of ketogenic diet.
Hypoxic-Ischemic Insult Alters Polyamine and Neurotransmitter Abundance in the Specific Neonatal Rat Brain Subregions.
Altered neuronal lactate dehydrogenase A expression affects cognition in a sex- and age-dependent manner.
Dietary LPC-Bound n-3 LCPUFA Protects against Neonatal Brain Injury in Mice but Does Not Enhance Stem Cell Therapy.
Lipid accumulation drives cellular senescence in dopaminergic neurons.
Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.
Role of palmitoylation on the neuronal glycine transporter GlyT2.
Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition.
Pyruvate dehydrogenase complex E1 subunit α crotonylation modulates cocaine-associated memory through hippocampal neuron activation.
New findings about neuropathological outcomes in the PKU mouse throughout lifespan.
Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1).
Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.
Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer's disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics.
Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment.
3-Hydroxy-3-Methylglutaric Acid Disrupts Brain Bioenergetics, Redox Homeostasis, and Mitochondrial Dynamics and Affects Neurodevelopment in Neonatal Wistar Rats.
Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.
High-resolution diffusion magnetic resonance imaging and spatial-transcriptomic in developing mouse brain.
Sex-Specific Changes to Brain Fatty Acids, Plasmalogen, and Plasma Endocannabinoids in Offspring Exposed to Maternal and Postnatal High-Linoleic-Acid Diets.
Application of synthetic biology strategies to promote biosynthesis of fatty acids and their derivatives.
Neuroprotective Mechanism of MOTS-c in TBI Mice: Insights from Integrated Transcriptomic and Metabolomic Analyses.
The metabolic role of vitamin D in children's neurodevelopment: a network study.

Nutrients. 2024 Jul 21. pii: 2363. [Epub ahead of print]16(14):

Neurodevelopment Is Dependent on Maternal Diet: Placenta and Brain Glucose Transporters GLUT1 and GLUT3.

Tomoko Daida, Bo-Chul Shin, Carlos Cepeda, Sherin U Devaskar.

  Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

Keywords:  Huntington’s disease; brain; glucose transporter; glucose transporter 3; maternal diet; neurodegenerative disorders; neurodevelopment; neurodevelopmental disorders; placenta; postnatal diet

DOI:  https://doi.org/10.3390/nu16142363
Cells. 2024 Jul 17. pii: 1207. [Epub ahead of print]13(14):

APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons.

Vanessa Budny, Yannic Knöpfli, Debora Meier, Kathrin Zürcher, Chantal Bodenmann, Siri L Peter, Terry Müller, Marie Tardy, Cedric Cortijo, Christian Tackenberg.

  The apolipoprotein E4 (APOE4) allele represents the major genetic risk factor for Alzheimer's disease (AD). In contrast, APOE2 is known to lower the AD risk, while APOE3 is defined as risk neutral. APOE plays a prominent role in the bioenergetic homeostasis of the brain, and early-stage metabolic changes have been detected in the brains of AD patients. Although APOE is primarily expressed by astrocytes in the brain, neurons have also been shown as source for APOE. However, the distinct roles of the three APOE isoforms in neuronal energy homeostasis remain poorly understood. In this study, we generated pure human neurons (iN cells) from APOE-isogenic induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4, or carrying an APOE knockout (KO) to investigate APOE isoform-specific effects on neuronal energy metabolism. We showed that endogenously produced APOE4 enhanced mitochondrial ATP production in APOE-isogenic iN cells but not in the corresponding iPS cell line. This effect neither correlated with the expression levels of mitochondrial fission or fusion proteins nor with the intracellular or secreted levels of APOE, which were similar for APOE2, APOE3, and APOE4 iN cells. ATP production and basal respiration in APOE-KO iN cells strongly differed from APOE4 and more closely resembled APOE2 and APOE3 iN cells, indicating a gain-of-function mechanism of APOE4 rather than a loss-of-function. Taken together, our findings in APOE isogenic iN cells reveal an APOE genotype-dependent and neuron-specific regulation of oxidative energy metabolism.

Keywords:  Alzheimer’s disease; apolipoprotein E (APOE); energy metabolism; glycolysis; human neurons; induced pluripotent stem cells (iPSCs); mitochondria; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.3390/cells13141207
J Neuroimmune Pharmacol. 2024 Jul 23. 19(1): 35

β-Hydroxybutyrate Improves the Redox Status, Cytokine Production and Phagocytic Potency of Glucose-Deprived HMC3 Human Microglia-like Cells.

Anil Kumar Rana, Babita Bhatt, Mohit Kumar.

  Brain glucose deprivation is a component of the pathophysiology of ischemia, glucose transporter1 (GLUT1) deficiency, neurological disorders and occurs transiently in diabetes. Microglia, the neuroimmune cells must function effectively to offer immune defence and debris removal in low-energy settings. Brain glucose deprivation may compromise microglial functions further escalating the disease pathology and deteriorating the overall mental health. In the current study, HMC3 human microglia-like cells were cultured in vitro and exposed to glucose deprivation to investigate the effects of glucose deprivation on phenotypic state, redox status, secretion of cytokines and phagocytic capabilities of HMC3 cells. However, HMC3 cells were able to proliferate in the absence of glucose but showed signs of redox imbalance and mitochondrial dysfunction, as demonstrated by decreased MTT reduction and Mito Tracker™ staining of cells, along with a concomitant reduction in NOX2 protein, superoxide, and nitrite levels. Reduced levels of secreted TNF and IL-1β were the signs of compromised cytokine secretion by glucose-deprived HMC3 microglia-like cells. Moreover, glucose-deprived HMC3 cells also showed reduced phagocytic activity as assessed by fluorescently labelled latex beads-based functional phagocytosis assay. β-hydroxybutyrate (BHB) supplementation restored the redox status, mitochondrial health, cytokine secretion, and phagocytic activity of glucose-deprived HMC3 microglia-like cells. Overall, impaired brain glucose metabolism may hinder microglia's capacity to release diffusible immune factors and perform phagocytosis. This could escalate the mental health issues in neurological diseases where brain glucose metabolism is compromised. Moreover, nutritional ketosis or exogenous ketone supplementation such as BHB may be utilized as a potential metabolic therapies for these conditions.

Keywords:  Cytokines; Glucose deprivation; HMC3; Human microglia; Phagocytosis; β-Hydroxybutyrate

DOI:  https://doi.org/10.1007/s11481-024-10139-5
Am J Med Genet A. 2024 Jul 26. e63825

Prenatal molecular diagnosis of pyruvate dehydrogenase complex deficiency enables rapid initiation of ketogenic diet.

Aaron B Bowen, Otto Rapalino, Camilo Jaimes, Eva-Maria Ratai, Yingyi Zhong, Elizabeth A Thiele, Amy Kritzer, Rebecca D Ganetzky, Nina B Gold, Melissa A Walker.

  Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder of carbohydrate oxidation characterized by lactic acidosis and central nervous system involvement. Knowledge of the affected metabolic pathways and clinical observations suggest that early initiation of the ketogenic diet may ameliorate the metabolic and neurologic course of the disease. We present a case in which first trimester ultrasound identified structural brain abnormalities prompting a prenatal molecular diagnosis of PDCD. Ketogenic diet, thiamine, and N-acetylcysteine were initiated in the perinatal period with good response, including sustained developmental progress. This case highlights the importance of a robust neurometabolic differential diagnosis for prenatally diagnosed structural anomalies and the use of prenatal molecular testing to facilitate rapid, genetically tailored intervention.

Keywords:  MR spectroscopy; ketogenic diet; mitochondrial disease; prenatal genetic testing; prenatal neuroimaging; pyruvate dehydrogenase complex deficiency

DOI:  https://doi.org/10.1002/ajmg.a.63825
ACS Chem Neurosci. 2024 Jul 26.

Hypoxic-Ischemic Insult Alters Polyamine and Neurotransmitter Abundance in the Specific Neonatal Rat Brain Subregions.

Hynek Mácha, Dominika Luptáková, Ivo Juránek, Per E Andrén, Vladimír Havlíček.

  Neonatal hypoxic-ischemic (HI) brain insult is a major cause of neonatal mortality and morbidity. To assess the underlying pathological mechanisms, we mapped the spatiotemporal changes in polyamine, amino acid, and neurotransmitter levels, following HI insult (by the Rice-Vannucci method) in the brains of seven-day-old rat pups. Matrix-assisted laser desorption/ionization mass spectrometry imaging of chemically modified small-molecule metabolites by 4-(anthracen-9-yl)-2-fluoro-1-methylpyridin-1-ium iodide revealed critical HI-related metabolomic changes of 22 metabolites in 14 rat brain subregions, much earlier than light microscopy detected signs of neuronal damage. For the first time, we demonstrated excessive polyamine oxidation and accumulation of 3-aminopropanal in HI neonatal brains, which was later accompanied by neuronal apoptosis enhanced by increases in glycine and norepinephrine in critically affected brain regions. Specifically, putrescine, cadaverine, and 3-aminopropanal increased significantly as early as 12 h postinsult, mainly in motor and somatosensory cortex, hippocampus, and midbrain, followed by an increase in norepinephrine 24 h postinsult, which was predominant in the caudate putamen, the region most vulnerable to HI. The decrease of γ-aminobutyric acid (GABA) and the continuous dysregulation of the GABAergic system together with low taurine levels up to 36 h sustained progressive neurodegenerative cellular processes. The molecular alterations presented here at the subregional rat brain level provided unprecedented insight into early metabolomic changes in HI-insulted neonatal brains, which may further aid in the identification of novel therapeutic targets for the treatment of neonatal HI encephalopathy.

Keywords:  MALDI mass spectrometry imaging; cerebrospinal fluid; histology; metabolome dynamics; neonatal hypoxic-ischemic encephalopathy; neurotransmitters; polyamines

DOI:  https://doi.org/10.1021/acschemneuro.4c00190
iScience. 2024 Jul 19. 27(7): 110342

Altered neuronal lactate dehydrogenase A expression affects cognition in a sex- and age-dependent manner.

Ariel K Frame, Jessica L Sinka, Marc Courchesne, Rashad A Muhammad, Sandra Grahovac-Nemeth, Mark A Bernards, Robert Bartha, Robert C Cumming.

  The astrocyte-neuron lactate shuttle (ANLS) model posits that astrocyte-generated lactate is transported to neurons to fuel memory processes. However, neurons express high levels of lactate dehydrogenase A (LDHA), the rate-limiting enzyme of lactate production, suggesting a cognitive role for neuronally generated lactate. It was hypothesized that lactate metabolism in neurons is critical for learning and memory. Here transgenic mice were generated to conditionally induce or knockout (KO) the Ldha gene in CNS neurons of adult mice. High pattern separation memory was enhanced by neuronal Ldha induction in young females, and by neuronal Ldha KO in aged females. In older mice, Ldha induction caused cognitive deficits whereas Ldha KO caused cognitive improvements. Genotype-associated cognitive changes were often only observed in one sex or oppositely in males and females. Thus, neuronal-generated lactate has sex-specific cognitive effects, is largely indispensable at young age, and may be detrimental to learning and memory with aging.

Keywords:  Behavioral neuroscience; Cellular neuroscience; Molecular neuroscience; Neuroscience; Sensory neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.110342
Nutrients. 2024 Jul 12. pii: 2252. [Epub ahead of print]16(14):

Dietary LPC-Bound n-3 LCPUFA Protects against Neonatal Brain Injury in Mice but Does Not Enhance Stem Cell Therapy.

Eva C Hermans, Carlon C E van Gerven, Line Johnsen, Jørn E Tungen, Cora H Nijboer, Caroline G M de Theije.

  Neonatal hypoxic-ischemic (HI) brain injury is a prominent cause of neurological morbidity, urging the development of novel therapies. Interventions with n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) and mesenchymal stem cells (MSCs) provide neuroprotection and neuroregeneration in neonatal HI animal models. While lysophosphatidylcholine (LPC)-bound n-3 LCPUFAs enhance brain incorporation, their effect on HI brain injury remains unstudied. This study investigates the efficacy of oral LPC-n-3 LCPUFAs from Lysoveta following neonatal HI in mice and explores potential additive effects in combination with MSC therapy. HI was induced in 9-day-old C57BL/6 mice and Lysoveta was orally supplemented for 7 subsequent days, with or without intranasal MSCs at 3 days post-HI. At 21-28 days post-HI, functional outcome was determined using cylinder rearing, novel object recognition, and open field tasks, followed by the assessment of gray (MAP2) and white (MBP) matter injury. Oral Lysoveta diminished gray and white matter injury but did not ameliorate functional deficits following HI. Lysoveta did not further enhance the therapeutic potential of MSC therapy. In vitro, Lysoveta protected SH-SY5Y neurons against oxidative stress. In conclusion, short-term oral administration of Lysoveta LPC-n-3 LCPUFAs provides neuroprotection against neonatal HI by mitigating oxidative stress injury but does not augment the efficacy of MSC therapy.

Keywords:  LPC-DHA; LPC-EPA; Lysoveta; intranasal; krill oil; mesenchymal stem cell therapy; neonatal hypoxic-ischemic brain injury; neuroprotection; oral supplementation; oxidative stress

DOI:  https://doi.org/10.3390/nu16142252
Aging (Albany NY). 2024 Jul 19. undefined

Lipid accumulation drives cellular senescence in dopaminergic neurons.

Taylor Russo, Markus Riessland.

  Parkinson's disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying cause(s) of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients. Interestingly, the most common genetic risk factor for PD is Glucosylceramidase Beta 1 (GBA), which encodes a lysosomal glucocerebrosidase (GCase) that cleaves the beta-glucosidic linkage of lipids known as glucocerebrosides (GluCer). We have recently discovered that artificial induction of GluCer accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. Here, we discuss the relevance of the age-related aggregation of lipids as well as the direct functional link between general lipid aggregation, cellular senescence, and inflammaging of DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells. These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.

Keywords:  Parkinson’s disease; cellular senescence; glucosylceramides; lipids; lysosomes; neuroinflammation

DOI:  https://doi.org/10.18632/aging.206030
J Lipid Res. 2024 Jul 20. pii: S0022-2275(24)00106-8. [Epub ahead of print] 100601

Cardiolipin remodeling maintains the inner mitochondrial membrane in cells with saturated lipidomes.

Kailash Venkatraman, Itay Budin.

  Cardiolipin (CL) is a unique, four-chain phospholipid synthesized in the inner mitochondrial membrane (IMM). The acyl chain composition of CL is regulated through a remodeling pathway, whose loss causes mitochondrial dysfunction in Barth syndrome (BTHS). Yeast has been used extensively as a model system to characterize CL metabolism, but mutants lacking its two remodeling enzymes, Cld1p and Taz1p, exhibit mild structural and respiratory phenotypes compared to mammalian cells. Here we show the essential role of CL remodeling in the structure and function of the IMM in yeast grown under reduced oxygenation. Microaerobic fermentation, which mimics natural yeast environments, caused the accumulation of saturated fatty acids and, under these conditions, remodeling mutants showed a loss of IMM ultrastructure. We extended this observation to HEK293 cells, where iPLA2 inhibition by Bromoenol lactone resulted in respiratory dysfunction and cristae loss upon mild treatment with exogenous saturated fatty acids. In microaerobic yeast, remodeling mutants accumulated unremodeled, saturated CL, but also displayed reduced total CL levels, highlighting the interplay between saturation and CL biosynthesis and breakdown. We identified the mitochondrial phospholipase A1 Ddl1p as a regulator of CL levels, and those of its precursors phosphatidylglycerol and phosphatidic acid, under these conditions. Loss of DDL1 partially rescued IMM structure in cells unable to initiate CL remodeling and had differing lipidomic effects depending on oxygenation. These results introduce a revised yeast model for investigating CL remodeling and suggest that its structural functions are dependent on the overall lipid environment in the mitochondrion.

Keywords:  Barth Syndrome; Cardiolipin; Lipid saturation; Mitochondria; Phospholipids

DOI:  https://doi.org/10.1016/j.jlr.2024.100601
J Neurochem. 2024 Jul 20.

Role of palmitoylation on the neuronal glycine transporter GlyT2.

R Felipe, J Sarmiento-Jiménez, E Camafeita, J Vázquez, B López-Corcuera.

  The neuronal glycine transporter GlyT2 removes glycine from the synaptic cleft through active Na+, Cl-, and glycine cotransport contributing to the termination of the glycinergic signal as well as supplying substrate to the presynaptic terminal for the maintenance of the neurotransmitter content in synaptic vesicles. Patients with mutations in the human GlyT2 gene (SLC6A5), develop hyperekplexia or startle disease (OMIM 149400), characterized by hypertonia and exaggerated startle responses to trivial stimuli that may have lethal consequences in the neonates as a result of apnea episodes. Post-translational modifications in cysteine residues of GlyT2 are an aspect of structural interest we analyzed. Our study is compatible with a reversible and short-lived S-acylation in spinal cord membranes, detectable by biochemical and proteomics methods (acyl-Rac binding and IP-ABE) confirmed with positive and negative controls (palmitoylated and non-palmitoylated proteins). According to a short-lived modification, direct labeling using click chemistry was faint but mostly consistent. We have analyzed the physiological properties of a GlyT2 mutant lacking the cysteines with high prediction of palmitoylation and the mutant is less prone to be included in lipid rafts, an effect also observed upon treatment with the palmitoylation inhibitor 2-bromopalmitate. This work demonstrates there are determinants of lipid raft inclusion associated with the GlyT2 mutated cysteines, which are presumably modified by palmitoylation.

Keywords:  GlyT2; cysteine; glycine; lipid rafts; palmitoylation; transporter

DOI:  https://doi.org/10.1111/jnc.16181
Nat Commun. 2024 Jul 23. 15(1): 6209

Membrane remodeling by FAM92A1 during brain development regulates neuronal morphology, synaptic function, and cognition.

Liang Wang, Ziyun Yang, Fudo Satoshi, Xavier Prasanna, Ziyi Yan, Helena Vihinen, Yaxing Chen, Yue Zhao, Xiumei He, Qian Bu, Hongchun Li, Ying Zhao, Linhong Jiang, Feng Qin, Yanping Dai, Ni Zhang, Meng Qin, Weihong Kuang, Yinglan Zhao, Eija Jokitalo, Ilpo Vattulainen, Tommi Kajander, Hongxia Zhao, Xiaobo Cen.

The Bin/Amphiphysin/Rvs (BAR) domain protein FAM92A1 is a multifunctional protein engaged in regulating mitochondrial ultrastructure and ciliogenesis, but its physiological role in the brain remains unclear. Here, we show that FAM92A1 is expressed in neurons starting from embryonic development. FAM92A1 knockout in mice results in altered brain morphology and age-associated cognitive deficits, potentially due to neuronal degeneration and disrupted synaptic plasticity. Specifically, FAM92A1 deficiency impairs diverse neuronal membrane morphology, including the mitochondrial inner membrane, myelin sheath, and synapses, indicating its roles in membrane remodeling and maintenance. By determining the crystal structure of the FAM92A1 BAR domain, combined with atomistic molecular dynamics simulations, we uncover that FAM92A1 interacts with phosphoinositide- and cardiolipin-containing membranes to induce lipid-clustering and membrane curvature. Altogether, these findings reveal the physiological role of FAM92A1 in the brain, highlighting its impact on synaptic plasticity and neural function through the regulation of membrane remodeling and endocytic processes.

DOI: https://doi.org/10.1038/s41467-024-50565-w
Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00858-1. [Epub ahead of print]43(8): 114529

Pyruvate dehydrogenase complex E1 subunit α crotonylation modulates cocaine-associated memory through hippocampal neuron activation.

Hongchun Li, Xiaoyu Liuha, Rong Chen, Yuzhou Xiao, Wei Xu, Yuanyi Zhou, Lin Bai, Jie Zhang, Yue Zhao, Ying Zhao, Liang Wang, Feng Qin, Yaxing Chen, Shuang Han, Qingfan Wei, Shu Li, Dingwen Zhang, Qian Bu, Xiaojie Wang, Linhong Jiang, Yanping Dai, Ni Zhang, Weihong Kuang, Meng Qin, Hongbo Wang, Jingwei Tian, Yinglan Zhao, Xiaobo Cen.

  Neuronal activation is required for the formation of drug-associated memory, which is critical for the development, persistence, and relapse of drug addiction. Nevertheless, the metabolic mechanisms underlying energy production for neuronal activation remain poorly understood. In the study, a large-scale proteomics analysis of lysine crotonylation (Kcr), a type of protein posttranslational modification (PTM), reveals that cocaine promoted protein Kcr in the hippocampal dorsal dentate gyrus (dDG). We find that Kcr is predominantly discovered in a few enzymes critical for mitochondrial energy metabolism; in particular, pyruvate dehydrogenase (PDH) complex E1 subunit α (PDHA1) is crotonylated at the lysine 39 (K39) residue through P300 catalysis. Crotonylated PDHA1 promotes pyruvate metabolism by activating PDH to increase ATP production, thus providing energy for hippocampal neuronal activation and promoting cocaine-associated memory recall. Our findings identify Kcr of PDHA1 as a PTM that promotes pyruvate metabolism to enhance neuronal activity for cocaine-associated memory.

Keywords:  CP: Neuroscience; PDHA1; cocaine-associated memory; dorsal dentate gyrus; hippocampal neuronal activation; lysine crotonylation

DOI:  https://doi.org/10.1016/j.celrep.2024.114529
Mol Genet Metab. 2024 Jul 19. pii: S1096-7192(24)00427-X. [Epub ahead of print]143(1-2): 108543

New findings about neuropathological outcomes in the PKU mouse throughout lifespan.

Alessandro Bregalda, Claudia Carducci, Tiziana Pascucci, Patrizia Ambrogini, Stefano Sartini, Francesca Pierigè, Emanuele di Carlo, Elena Fiori, Donald Ielpo, Marica Pagliarini, Vincenzo Leuzzi, Mauro Magnani, Luigia Rossi.

  Phenylketonuria (PKU, OMIM 261600) is a genetic disorder caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, PKU leads to systemic phenylalanine (Phe) accumulation, which can result in irreversible brain damage and intellectual disabilities. In the last 60 years, early and strict dietary restriction of phenylalanine (Phe) intake proved to prevent the severe clinical phenotype of untreated PKU. While the specific mechanisms through which phenylalanine causes brain damage are still poorly understood, preclinical models have been deeply explored to characterize the neurotoxic effect of Phe on neurodevelopmental processes. At the same time, that on the aging brain still needs to be explored. In the brain of untreated PAHEnu2(-/-) mouse, we previously reported a reduction of myelin basic protein (MBP) during postnatal development up to 60 PND. Later in the diseased mouse's life, a spontaneous and persistent restoration of MBP was detected. In this present longitudinal study, ranging from 14 to 540 post-natal days (PND) of untreated PAHEnu2(-/-) mice, we further investigated: a) the long-life consistency of two Phe-related brain metabolic alterations, such as large neutral amino acids (LNAA) and biogenic amine neurotransmitters' depletion; b) the outcome of locomotor functions during the same life span; c) the integrity of myelin as assessed ex vivo by central (hippocampus) and peripheral (extensor digitorum longus-sciatic nerve) action potential conduction velocities. In contrast with the results of other studies, brain Leu, Ile, and Val concentrations were not significantly altered in the brain PAHEnu2(-/-) mouse. On the other hand, 3-O-Methyldopa (3-OMD, a biomarker of L-DOPA), serotonin, and its associated metabolites were reduced throughout most of the considered time points, with consistent reductions observed prevalently from 14 to 60 PND. Normal saltatory conduction was restored after 60 PND and remained normal at the last examination at 360 PND, resulting nonetheless in a persistent locomotor impairment throughout a lifetime. These new findings contribute to laying the foundations for the preclinical characterization of aging in PKU, confirming neurotransmitter defects as consistent metabolic traits. LNAAs have a minor role, if any, in brain damage pathogenesis. Transient myelin synthesis failure may impact brain connectivity during postnatal development but not nervous signal conduction.

Keywords:  LNAA; Motor Skills; Myelin Integrity; Neurotransmitters; Phenylketonuria

DOI:  https://doi.org/10.1016/j.ymgme.2024.108543
Pharm Res. 2024 Jul 24.

Iron Reduces the Trafficking of Fatty Acids from Human Immortalised Brain Microvascular Endothelial Cells Through Modulation of Fatty Acid Transport Protein 1 (FATP1/SLC27A1).

Showmika T Supti, Liam M Koehn, Stephanie A Newman, Yijun Pan, Joseph A Nicolazzo.

  PURPOSE: Alzheimer's disease (AD) is associated with brain accumulation of amyloid-beta (Aβ) and neurofibrillary tangle formation, in addition to reduced brain docosahexaenoic acid (DHA) and increased brain iron levels. DHA requires access across the blood-brain barrier (BBB) to enter the brain, and iron has been shown to affect the expression and function of a number of BBB transporters. Therefore, this study aimed to assess the effect of iron on the expression and function of fatty acid binding protein 5 (FABP5) and fatty acid transport protein 1 (FATP1), both which mediate brain endothelial cell trafficking of DHA.METHODS: The mRNA and protein levels of FABP5 and FATP1 in human cerebral microvascular endothelial (hCMEC/D3) cells was assessed by RT-qPCR and Western blot, respectively following ferric ammonium citrate (FAC) treatment (up to 750 µM, 72 h). The function of FABP5 and FATP1 was assessed via uptake and efflux of radiolabelled 3H-oleic acid and 14C-DHA.
RESULTS: FAC (500 µM, 72 h) had no impact on the expression of FABP5 at the protein and mRNA level in hCMEC/D3 cells, which was associated with a lack of effect on the uptake of 14C-DHA. FAC led to a 19.7% reduction in FATP1 protein abundance in hCMEC/D3 cells with no impact on mRNA levels, and this was associated with up to a 32.6% reduction in efflux of 14C-DHA.
CONCLUSIONS: These studies demonstrate a role of iron in down-regulating FATP1 protein abundance and function at the BBB, which may have implications on fatty acid access to the brain.

Keywords:  blood-brain barrier; docosahexaenoic acid; fatty acid binding protein 5; fatty acid transport protein 1; iron

DOI:  https://doi.org/10.1007/s11095-024-03743-w
J Inherit Metab Dis. 2024 Jul 25.

Pathological variants in nuclear genes causing mitochondrial complex III deficiency: An update.

Kristýna Čunátová, Erika Fernández-Vizarra.

  Mitochondrial disorders are a group of clinically and biochemically heterogeneous genetic diseases within the group of inborn errors of metabolism. Primary mitochondrial diseases are mainly caused by defects in one or several components of the oxidative phosphorylation system (complexes I-V). Within these disorders, those associated with complex III deficiencies are the least common. However, thanks to a deeper knowledge about complex III biogenesis, improved clinical diagnosis and the implementation of next-generation sequencing techniques, the number of pathological variants identified in nuclear genes causing complex III deficiency has expanded significantly. This updated review summarizes the current knowledge concerning the genetic basis of complex III deficiency, and the main clinical features associated with these conditions.

Keywords:  complex III assembly; complex III deficiency; mitochondrial disease; nuclear gene pathogenic variants; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.1002/jimd.12751
Nat Commun. 2024 Jul 24. 15(1): 6252

Spatially and temporally probing distinctive glycerophospholipid alterations in Alzheimer's disease mouse brain via high-resolution ion mobility-enabled sn-position resolved lipidomics.

Shuling Xu, Zhijun Zhu, Daniel G Delafield, Michael J Rigby, Gaoyuan Lu, Megan Braun, Luigi Puglielli, Lingjun Li.

Dysregulated glycerophospholipid (GP) metabolism in the brain is associated with the progression of neurodegenerative diseases including Alzheimer's disease (AD). Routine liquid chromatography-mass spectrometry (LC-MS)-based large-scale lipidomic methods often fail to elucidate subtle yet important structural features such as sn-position, hindering the precise interrogation of GP molecules. Leveraging high-resolution demultiplexing (HRdm) ion mobility spectrometry (IMS), we develop a four-dimensional (4D) lipidomic strategy to resolve GP sn-position isomers. We further construct a comprehensive experimental 4D GP database of 498 GPs identified from the mouse brain and an in-depth extended 4D library of 2500 GPs predicted by machine learning, enabling automated profiling of GPs with detailed acyl chain sn-position assignment. Analyzing three mouse brain regions (hippocampus, cerebellum, and cortex), we successfully identify a total of 592 GPs including 130 pairs of sn-position isomers. Further temporal GPs analysis in the three functional brain regions illustrates their metabolic alterations in AD progression.

DOI: https://doi.org/10.1038/s41467-024-50299-9
Int J Mol Sci. 2024 Jul 21. pii: 7952. [Epub ahead of print]25(14):

Targeting Mitochondrial Dysfunction and Reactive Oxygen Species for Neurodegenerative Disease Treatment.

Eui-Hwan Choi, Mi-Hye Kim, Sun-Ji Park.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases, and they affect millions of people worldwide, particularly older individuals. Therefore, there is a clear need to develop novel drug targets for the treatment of age-related neurodegenerative diseases. Emerging evidence suggests that mitochondrial dysfunction and reactive oxygen species (ROS) generation play central roles in the onset and progression of neurodegenerative diseases. Mitochondria are key regulators of respiratory function, cellular energy adenosine triphosphate production, and the maintenance of cellular redox homeostasis, which are essential for cell survival. Mitochondrial morphology and function are tightly regulated by maintaining a balance among mitochondrial fission, fusion, biogenesis, and mitophagy. In this review, we provide an overview of the main functions of mitochondria, with a focus on recent progress highlighting the critical role of ROS-induced oxidative stress, dysregulated mitochondrial dynamics, mitochondrial apoptosis, mitochondria-associated inflammation, and impaired mitochondrial function in the pathogenesis of age-related neurodegenerative diseases, such as AD and PD. We also discuss the potential of mitochondrial fusion and biogenesis enhancers, mitochondrial fission inhibitors, and mitochondria-targeted antioxidants as novel drugs for the treatment of these diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms25147952
Biomedicines. 2024 Jul 15. pii: 1563. [Epub ahead of print]12(7):

3-Hydroxy-3-Methylglutaric Acid Disrupts Brain Bioenergetics, Redox Homeostasis, and Mitochondrial Dynamics and Affects Neurodevelopment in Neonatal Wistar Rats.

Josyane de Andrade Silveira, Manuela Bianchin Marcuzzo, Jaqueline Santana da Rosa, Nathalia Simon Kist, Chrístofer Ian Hernandez Hoffmann, Andrey Soares Carvalho, Rafael Teixeira Ribeiro, André Quincozes-Santos, Carlos Alexandre Netto, Moacir Wajner, Guilhian Leipnitz.

  3-Hydroxy-3-methylglutaric acidemia (HMGA) is a neurometabolic inherited disorder characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in the brain and biological fluids of patients. Symptoms often appear in the first year of life and include mainly neurological manifestations. The neuropathophysiology is not fully elucidated, so we investigated the effects of intracerebroventricular administration of HMG on redox and bioenergetic homeostasis in the cerebral cortex and striatum of neonatal rats. Neurodevelopment parameters were also evaluated. HMG decreased the activity of glutathione reductase (GR) and increased catalase (CAT) in the cerebral cortex. In the striatum, HMG reduced the activities of superoxide dismutase, glutathione peroxidase, CAT, GR, glutathione S-transferase, and glucose-6-phosphate dehydrogenase. Regarding bioenergetics, HMG decreased the activities of succinate dehydrogenase and respiratory chain complexes II-III and IV in the cortex. HMG also decreased the activities of citrate synthase and succinate dehydrogenase, as well as complex IV in the striatum. HMG further increased DRP1 levels in the cortex, indicating mitochondrial fission. Finally, we found that the HMG-injected animals showed impaired performance in all sensorimotor tests examined. Our findings provide evidence that HMG causes oxidative stress, bioenergetic dysfunction, and neurodevelopmental changes in neonatal rats, which may explain the neuropathophysiology of HMGA.

Keywords:  3-hydroxy-3-methylglutaric acidemia; bioenergetics; brain; neurodevelopment; oxidative stress

DOI:  https://doi.org/10.3390/biomedicines12071563
Nat Metab. 2024 Jul 24.

Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality.

Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J Pérez-Moreno, María I Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E Rosales-Nieves, Alberto Pascual.

Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs.

DOI: https://doi.org/10.1038/s42255-024-01081-0
Neuroimage. 2024 Jul 20. pii: S1053-8119(24)00227-1. [Epub ahead of print]297 120734

High-resolution diffusion magnetic resonance imaging and spatial-transcriptomic in developing mouse brain.

Xinyue Han, Surendra Maharjan, Jie Chen, Yi Zhao, Yi Qi, Leonard E White, G Allan Johnson, Nian Wang.

  Brain development is a highly complex process regulated by numerous genes at the molecular and cellular levels. Brain tissue exhibits serial microstructural changes during the development process. High-resolution diffusion magnetic resonance imaging (dMRI) affords a unique opportunity to probe these changes in the developing brain non-destructively. In this study, we acquired multi-shell dMRI datasets at 32 µm isotropic resolution to investigate the tissue microstructure alterations, which we believe to be the highest spatial resolution dMRI datasets obtained for postnatal mouse brains. We adapted the Allen Developing Mouse Brain Atlas (ADMBA) to integrate quantitative MRI metrics and spatial transcriptomics. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI) metrics were used to quantify brain development at different postnatal days. We demonstrated that the differential evolutions of fiber orientation distributions contribute to the distinct development patterns in white matter (WM) and gray matter (GM). Furthermore, the genes enriched in the nervous system that regulate brain structure and function were expressed in spatial correlation with age-matched dMRI. This study is the first one providing high-resolution dMRI, including DTI, DKI, and NODDI models, to trace mouse brain microstructural changes in WM and GM during postnatal development. This study also highlighted the genotype-phenotype correlation of spatial transcriptomics and dMRI, which may improve our understanding of brain microstructure changes at the molecular level.

Keywords:  Brain development; DKI; DTI; Diffusion magnetic resonance imaging; NODDI; Spatial transcriptomics

DOI:  https://doi.org/10.1016/j.neuroimage.2024.120734
Int J Mol Sci. 2024 Jul 19. pii: 7911. [Epub ahead of print]25(14):

Sex-Specific Changes to Brain Fatty Acids, Plasmalogen, and Plasma Endocannabinoids in Offspring Exposed to Maternal and Postnatal High-Linoleic-Acid Diets.

Henry C Ezechukwu, Luke J Ney, Madeline A Jarvis, Nirajan Shrestha, Olivia J Holland, James S M Cuffe, Anthony V Perkins, Suk-Yu Yau, Andrew J McAinch, Deanne H Hryciw.

  Linoleic acid (LA) is required for neuronal development. We have previously demonstrated sex-specific changes in cardiovascular and hepatic function in rat offspring from mothers consuming a high-LA diet, with some effects associated with reduced LA concentration in the postnatal diet. At this time, the impact of a high-maternal-LA diet on offspring brain development and the potential for the postnatal diet to alter any adverse changes are unknown. Rat offspring from mothers fed low- (LLA) or high-LA (HLA) diets during pregnancy and lactation were weaned at postnatal day 25 (PN25) and fed LLA or HLA diets until sacrifice in adulthood (PN180). In the offspring's brains, the postnatal HLA diet increased docosapentaenoate in males. The maternal HLA diet increased LA, arachidonate, docosapentaenoate, C18:0 dimethylacetal (DMA), C16:0 DMA, C16:0 DMA/C16:0, and C18:0 DMA/C18:0, but decreased eoicosenoate, nervoniate, lignocerate, and oleate in males. Maternal and postnatal HLA diets reduced oleate and vaccenate and had an interaction effect on myristate, palmitoleate, and eicosapentaenoate in males. In females, maternal HLA diet increased eicosadienoate. Postnatal HLA diet increased stearate and docosapentaenoate. Maternal and postnatal HLA diets had an interaction effect on oleate, arachidate, and docosahexaenoic acid (DHA)/omega (n)-6 docosapentaenoic acid (DPA) in females. Postnatal HLA diet decreased DHA/n-6 DPA in males and females. Postnatal HLA diet increased plasma endocannabinoids (arachidonoyl ethanolamide and 2-arachidonoyl glycerol), as well as other N-acyl ethanolamides and testosterone. HLA diet alters brain fatty acids, plasma endocannabinoids, and plasmalogen concentrations in a development-specific and sex-specific manner.

Keywords:  brain; endocannabinoids; fatty acids; linoleic acid; maternal diet; plasmalogen

DOI:  https://doi.org/10.3390/ijms25147911
Adv Appl Microbiol. 2024 ;pii: S0065-2164(24)00032-7. [Epub ahead of print]128 83-104

Application of synthetic biology strategies to promote biosynthesis of fatty acids and their derivatives.

Haiqian Yang, Jie Gao, Xiaowei Peng, Yejun Han.

  Fatty acids and their derivatives are indispensable biomolecules in all organisms, and can be used as intermediates in the synthesis of pharmaceuticals, biofuels and pesticides, and thus their demand has increased dramatically in recent years. In addition to serving as structural components of cell membranes and metabolic energy, fatty acids and their derivatives can also be used as signal transduction and regulatory bioactive molecules to regulate cell functions. Biosynthesis of fatty acids and their derivatives through microbial catalysis provides green and alternative options to meet the goal. However, the low biosynthetic titer of fatty acids and their derivatives limits their industrial production and application. In this review, we first summarize the metabolic pathways and related enzymes of fatty acids and their derivatives biosynthesis. Then, the strategies and research progress of biosynthesis of fatty acids and derivatives through metabolic and enzyme engineering were reviewed. The biosynthesis of saturated fatty acids (medium chain fatty acids and long chain fatty acids), bioactive fatty acids (PUFAs, oxylipins, ether lipids), and their derivatives with microbial and enzymatic catalysis were respectively summarized. Finally, synthetic biology strategies to improve fatty acids and their derivatives production through enzyme rational design, carbon metabolism flux, cofactors balance, and metabolic pathways design were discussed. The review provides references and prospects for fatty acids and their derivatives biosynthesis and industrial production.

Keywords:  Bioactivity; Fatty acids and derivatives; Metabolic and enzyme engineering; Synthetic biology

DOI:  https://doi.org/10.1016/bs.aambs.2024.05.002
Drug Des Devel Ther. 2024 ;18 2971-2987

Neuroprotective Mechanism of MOTS-c in TBI Mice: Insights from Integrated Transcriptomic and Metabolomic Analyses.

Fengfeng Li, Yang Jia, Jun Fang, Linqiang Gong, Yazhou Zhang, Shanshan Wei, Linlin Wu, Pei Jiang.

  Background: Traumatic brain injury (TBI) is a condition characterized by structural and physiological disruptions in brain function caused by external forces. However, as the highly complex and heterogenous nature of TBI, effective treatments are currently lacking. Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) has shown notable antinociceptive and anti-inflammatory effects, yet its detailed neuroprotective effects and mode of action remain incompletely understood. This study investigated the neuroprotective effects and the underlying mechanisms of MOTS-c.Methods: Adult male C57BL/6 mice were randomly divided into three groups: control (CON) group, MOTS-c group and TBI group. Enzyme-linked immunosorbent assay (ELISA) kit method was used to measure the expression levels of MOTS-c in different groups. Behavioral tests were conducted to assess the effects of MOTS-c. Then, transcriptomics and metabolomics were performed to search Differentially Expressed Genes (DEGs) and Differentially Expressed Metabolites (DEMs), respectively. Moreover, the integrated transcriptomics and metabolomics analysis were employed using R packages and online Kyoto Encyclopedia of Genes and Genomes (KEGG) database.
Results: ELISA kit method showed that TBI resulted in a decrease in the expression of MOTS-c. and peripheral administration of MOTS-c could enter the brain tissue after TBI. Behavioral tests revealed that MOTS-c improved memory, learning, and motor function impairments in TBI mice. Additionally, transcriptomic analysis screened 159 differentially expressed genes. Metabolomic analysis identified 491 metabolites with significant differences. Integrated analysis found 14 KEGG pathways, primarily related to metabolic pathways. Besides, several signaling pathways were enriched, including neuroactive ligand-receptor interaction and retrograde endocannabinoid signaling.
Conclusion: TBI reduced the expression of MOTS-c. MOTS-c reduced inflammatory responses, molecular damage, and cell death by down-regulating macrophage migration inhibitory factor (MIF) expression and activating the retrograde endocannabinoid signaling pathway. In addition, MOTS-c alleviated the response to hypoxic stress and enhanced lipid β-oxidation to provide energy for the body following TBI. Overall, our study offered new insights into the neuroprotective mechanisms of MOTS-c in TBI mice.

Keywords:  MOTS-c; TBI; metabolomics; neuroprotective; transcriptomics

DOI:  https://doi.org/10.2147/DDDT.S460265
Sci Rep. 2024 Jul 23. 14(1): 16929

The metabolic role of vitamin D in children's neurodevelopment: a network study.

Margherita De Marzio, Jessica Lasky-Su, Su H Chu, Nicole Prince, Augusto A Litonjua, Scott T Weiss, Rachel S Kelly, Kimberly R Glass.

Neurodevelopmental disorders are rapidly increasing in prevalence and have been linked to various environmental risk factors. Mounting evidence suggests a potential role of vitamin D in child neurodevelopment, though the causal mechanisms remain largely unknown. Here, we investigate how vitamin D deficiency affects children's communication development, particularly in relation to Autism Spectrum Disorder (ASD). We do so by developing an integrative network approach that combines metabolomic profiles, clinical traits, and neurodevelopmental data from a pediatric cohort. Our results show that low levels of vitamin D are associated with changes in the metabolic networks of tryptophan, linoleic, and fatty acid metabolism. These changes correlate with distinct ASD-related phenotypes, including delayed communication skills and respiratory dysfunctions. Additionally, our analysis suggests the kynurenine and serotonin sub-pathways may mediate the effect of vitamin D on early life communication development. Altogether, our findings provide metabolome-wide insights into the potential of vitamin D as a therapeutic option for ASD and other communication disorders.

DOI: https://doi.org/10.1038/s41598-024-67835-8