bims-medebr 2024-12-01 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–12–01
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.
Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer's Disease.
Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.
Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer's disease models.
Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.
A therapeutic approach to pantothenate kinase associated neurodegeneration: a pilot study.
Loss of peroxiredoxin 6 (PRDX6) alters lipid composition and distribution resulting in increased sensitivity to ferroptosis.
Cerebral magnetic resonance spectroscopy - insights into preterm brain injury.
Lactate metabolism and histone lactylation in the central nervous system disorders: impacts and molecular mechanisms.
Modulation of OPC Mitochondrial Function by Inhibiting USP30 Promotes Their Differentiation.
Accumulation of Bioactive Lipid Species in LPS-Induced Neuroinflammation Models Analysed with Multi-Modal Mass Spectrometry Imaging.
N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.
Rotenone adaptation promotes migration and invasion of p53-wild-type colon cancer through lipid metabolism.
APOE4 and age affect the brain entorhinal cortex structure and blood arachidonic acid and docosahexaenoic acid levels after mild TBI.
The Role of Alpha-Linolenic Acid and Other Polyunsaturated Fatty Acids in Mental Health: A Narrative Review.
Elovanoids, a Novel Class of Lipid Mediators, Are Neuroprotective in a Traumatic Brain Injury Model in Rats.
Diacylglycerol metabolism and homeostasis in fungal physiology.
Neuronal viability/astrocyte activity ratio in the dorsolateral prefrontal cortex as a biomarker of Alzheimer's dementia: a proton magnetic resonance spectroscopy study.
Targeted Chiral Metabolomics of D-Amino Acids: Their Emerging Role as Potential Biomarkers in Neurological Diseases with a Focus on Their Liquid Chromatography-Mass Spectrometry Analysis upon Chiral Derivatization.

Mol Brain. 2024 Nov 27. 17(1): 87

Loss of mitochondrial enzyme GPT2 leads to reprogramming of synaptic glutamate metabolism.

Ozan Baytas, Shawn M Davidson, Julie A Kauer, Eric M Morrow.

  Recessive loss-of-function mutations in the mitochondrial enzyme Glutamate Pyruvate Transaminase 2 (GPT2) cause intellectual disability in children. Given this cognitive disorder, and because glutamate metabolism is tightly regulated to sustain excitatory neurotransmission, here we investigate the role of GPT2 in synaptic function. GPT2 catalyzes a reversible reaction interconverting glutamate and pyruvate with alanine and alpha-ketoglutarate, a TCA cycle intermediate; thereby, GPT2 may play an important role in linking mitochondrial tricarboxylic acid (TCA) cycle with synaptic transmission. In mouse brain, we find that GPT2 is enriched in mitochondria of synaptosomes (isolated synaptic terminals). Loss of Gpt2 in mouse appears to lead to reprogramming of glutamate and glutamine metabolism, and to decreased glutamatergic synaptic transmission. Whole-cell patch-clamp recordings in pyramidal neurons of CA1 hippocampal slices from Gpt2-null mice reveal decreased excitatory post-synaptic currents (mEPSCs) without changes in mEPSC frequency, or importantly, changes in inhibitory post-synaptic currents (mIPSCs). Additional evidence of defective glutamate release included reduced levels of glutamate released from Gpt2-null synaptosomes measured biochemically. Glutamate release from synaptosomes was rescued to wild-type levels by alpha-ketoglutarate supplementation. Additionally, we observed evidence of altered metabolism in isolated Gpt2-null synaptosomes: decreased TCA cycle intermediates, and increased glutamate dehydrogenase activity. Notably, alterations in the TCA cycle and the glutamine pool were alleviated by alpha-ketoglutarate supplementation. In conclusion, our data support a model whereby GPT2 mitochondrial activity may contribute to glutamate availability in pre-synaptic terminals, thereby highlighting potential interactions between pre-synaptic mitochondrial metabolism and synaptic transmission.

Keywords:  Cognitive development; Disease; GPT2; Glutamate; Intellectual disability; Neurometabolic; Neurometabolism; Synapse; TCA cycle

DOI:  https://doi.org/10.1186/s13041-024-01154-x
Biomolecules. 2024 Oct 26. pii: 1362. [Epub ahead of print]14(11):

Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer's Disease.

Michele Cerasuolo, Irene Di Meo, Maria Chiara Auriemma, Giuseppe Paolisso, Michele Papa, Maria Rosaria Rizzo.

  Aging induces complex changes in the lipid profiles across different areas of the brain. These changes can affect the function of brain cells and may contribute to neurodegenerative diseases such as Alzheimer's disease. Research shows that while the overall lipid profile in the human brain remains quite steady throughout adulthood, specific changes occur with age, especially after the age of 50. These changes include a slow decline in total lipid content and shifts in the composition of fatty acids, particularly in glycerophospholipids and cholesterol levels, which can vary depending on the brain region. Lipid rafts play a crucial role in maintaining membrane integrity and facilitating cellular signaling. In the context of Alzheimer's disease, changes in the composition of lipid rafts have been associated with the development of the disease. For example, alterations in lipid raft composition can lead to increased accumulation of amyloid β (Aβ) peptides, contributing to neurotoxic effects. Lipid droplets store neutral lipids and are key for cellular energy metabolism. As organisms age, the dynamics of lipid droplets in the brain change, with evidence suggesting a decline in metabolic activity over time. This reduced activity may lead to an imbalance in lipid synthesis and mobilization, contributing to neurodegenerative processes. In model organisms like Drosophila, studies have shown that lipid metabolism in the brain can be influenced by diet and insulin signaling pathways, crucial for maintaining metabolic balance. The interplay between lipid metabolism, oxidative stress, and inflammation is critical in the context of aging and Alzheimer's disease. Lipid peroxidation, a consequence of oxidative stress, can lead to the formation of reactive aldehydes that further damage neurons. Inflammatory processes can also disrupt lipid metabolism, contributing to the pathology of AD. Consequently, the accumulation of oxidized lipids can affect lipid raft integrity, influencing signaling pathways involved in neuronal survival and function.

Keywords:  Alzheimer’s disease; aging; brain lipids; lipid droplets; lipid rafts

DOI:  https://doi.org/10.3390/biom14111362
J Lipid Res. 2024 Nov 26. pii: S0022-2275(24)00221-9. [Epub ahead of print] 100716

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment.

Katherine M Ranard, Bruce Appel.

  Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR-Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with an abnormal eye phenotype and demonstrate that even morphologically normal siblings exhibit dysregulated vision and stress response gene pathways. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities, and provide insight into maternal nutritional strategies that optimize infant brain health.

Keywords:  Nutrition; docosahexaenoic acid; elongation of very long-chain fatty acid 2; maternal diet; neurodevelopment; omega-3 fatty acids; vision; zebrafish

DOI:  https://doi.org/10.1016/j.jlr.2024.100716
Cell Death Dis. 2024 Nov 24. 15(11): 856

Enhancing mitochondrial one-carbon metabolism is neuroprotective in Alzheimer's disease models.

Yizhou Yu, Civia Z Chen, Ivana Celardo, Bryan Wei Zhi Tan, James D Hurcomb, Nuno Santos Leal, Rebeka Popovic, Samantha H Y Loh, L Miguel Martins.

Alzheimer's disease (AD) is the most common form of age-related dementia. In AD, the death of neurons in the central nervous system is associated with the accumulation of toxic amyloid β peptide (Aβ) and mitochondrial dysfunction. Mitochondria are signal transducers of metabolic and biochemical information, and their impairment can compromise cellular function. Mitochondria compartmentalise several pathways, including folate-dependent one-carbon (1C) metabolism and electron transport by respiratory complexes. Mitochondrial 1C metabolism is linked to electron transport through complex I of the respiratory chain. Here, we analysed the proteomic changes in a fly model of AD by overexpressing a toxic form of Aβ (Aβ-Arc). We found that expressing Aβ-Arc caused alterations in components of both complex I and mitochondrial 1C metabolism. Genetically enhancing mitochondrial 1C metabolism through Nmdmc improved mitochondrial function and was neuroprotective in fly models of AD. We also found that exogenous supplementation with the 1C donor folinic acid improved mitochondrial health in both mammalian cells and fly models of AD. We found that genetic variations in MTHFD2L, the human orthologue of Nmdmc, were linked to AD risk. Additionally, Mendelian randomisation showed that increased folate intake decreased the risk of developing AD. Overall, our data suggest enhancement of folate-dependent 1C metabolism as a viable strategy to delay the progression and attenuate the severity of AD.

DOI: https://doi.org/10.1038/s41419-024-07179-3
bioRxiv. 2024 Nov 18. pii: 2024.11.18.624141. [Epub ahead of print]

Microglia States are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.

Boyang Li, Shaowei Wang, Bilal Kerman, Cristelle Hugo, E Keats Shwab, Chang Shu, Ornit Chiba-Falek, Zoe Arvanitakis, Hussein Yassine.

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD) but much less is known on the key cell types and pathways driving mechanisms of senescence in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed whole transcriptomic data and utilized single-cell RNA seq integration techniques to unveil the convoluted cell-type-specific and sub-cell-type-state-specific senescence pathologies in AD using both ROSMAP and Sea-AD datasets. We identified that microglia are central components to AD associated senescence phenotypes in ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex of 239 AD and 188 non-AD) among non-neuron cell types. We identified that homeostatic, inflammatory, phagocytic, lipid processing and neuronal surveillance microglia states were associated with AD associated senescence in ROSMAP (152,459 microglia nuclei from six regions of brain tissue of 138 early AD, 79 late AD and 226 control subject) and in Sea-AD (82,486 microglia nuclei of 42 dementia, 42 no dementia and 5 reference subjects) via integrative analysis, which preserves the meaningful biological information of microglia cell states across the datasets. We assessed top senescence associated bioprocesses including mitochondrial, apoptosis, oxidative stress, ER stress, endosomes, and lysosomes systems. Specifically, we found that senescent microglia have altered cholesterol related bioprocesses and dysregulated cholesterol. We discovered three gene co-expression modules, which represent the specific cholesterol related senescence transcriptomic signatures in postmortem brains. To validate these findings, the activation of specific cholesterol associated senescence transcriptomic signatures was assessed using integrative analysis of snRNA-seq data from iMGs (microglia induced from iPSCs) exposed to myelin, Abeta, and synaptosomes (56,454 microglia across two replicates of untreated and four treated groups). In vivo cholesterol associated senescence transcriptomic signatures were preserved and altered after treatment with AD pathological substrates in iMGs. This study provides the first evidence that dysregulation of cholesterol metabolism in microglia is a major driver of senescence pathologies in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to slow down AD progression.

DOI: https://doi.org/10.1101/2024.11.18.624141
Orphanet J Rare Dis. 2024 Nov 28. 19(1): 442

A therapeutic approach to pantothenate kinase associated neurodegeneration: a pilot study.

Alessandra Pereira, Carolina Fischinger Moura de Souza, Mónica Álvarez-Córdoba, Diana Reche-López, José Antonio Sánchez-Alcázar.

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic neurological disorders frequently associated with iron accumulation in the basal nuclei of the brain characterized by progressive spasticity, dystonia, muscle rigidity, neuropsychiatric symptoms, and retinal degeneration or optic nerve atrophy. Pantothenate kinase-associated neurodegeneration (PKAN) is one of the most widespread NBIA disorders. The diagnosis of PKAN is established with clinical features and the "eye of the tiger" sign identified on brain MRI and the identification of biallelic pantothenate kinase 2 (PANK2) pathogenic variants on molecular genetic testing. PANK2 catalyzes the first reaction of coenzyme A (CoA) biosynthesis, thus, altered PANK2 activity is expected to induce CoA deficiency as well as low levels of essential metabolic intermediates such as 4'-phosphopantetheine which is a necessary cofactor for critical proteins involved in cytosolic and mitochondrial pathways such as fatty acid biosynthesis, mitochondrial respiratory complex I assembly and lysine and tetrahydrofolate metabolism, among other metabolic processes.
METHODS: In this manuscript, we examined the effect of a multitarget complex supplements (pantothenate, pantethine, omega-3 and vitamin E) on in vitro patient-derived cellular models and the clinical outcome of the adjuvant supplements in combination with the baseline neurological medication in three PKAN patients.
RESULTS: Multitarget complex supplements significantly reduced iron accumulation and increased PANK2 and ACP expression levels in the cellular models derived from all three PKAN patients. In addition, the adjunct treatment to the standard neurological medication improved or stabilized the clinical symptoms of patients.
CONCLUSIONS: Our results suggest that multitarget complex supplements can be clinically useful as augmentation therapy for PKAN patients harboring pathogenic variants with residual enzyme levels.
TRIAL REGISTRATION: CAAE: 58219522.6.0000.5330. Registered 25 May 2022-Retrospectively registered, https://plataformabrasil.saude.gov.br/visao/pesquisador/gerirPesquisa/gerirPesquisaAgrupador.jsf .

DOI: https://doi.org/10.1186/s13023-024-03453-x
Biochem J. 2024 Nov 27. pii: BCJ20240445. [Epub ahead of print]

Loss of peroxiredoxin 6 (PRDX6) alters lipid composition and distribution resulting in increased sensitivity to ferroptosis.

Daniel J Lagal, Ángel Ortiz-Alcántara, José R Pedrajas, Brian McDonagh, J Antonio Bárcena, Raquel Requejo-Aguilar, C Alicia Padilla.

  Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme involved in phospholipid peroxide repair and metabolism. In this study we investigated the global lipid composition of a human hepatocarcinoma cell line SNU475 lacking PRDX6 and lipid related cellular processes. There was a general decrease in multiple lipids species upon loss of PRDX6, in particular sphingomyelins and acylcarnitines, consistent with previously observed alterations in cell signaling pathways and mitochondrial dysfunction. Deprivation of docosahexaenoic acid and related species was also evident. However, a few striking exceptions are worth highlighting: 1) Three specific arachidonic acid (AA) containing phophatidylcholines (PC) increased significantly. The increase of sn1-stearic/sn2-PUFA containing PC and sn2-AA containing plasmenyls are indicative of a preference of PRDX6 iPLA2 activity for these AA storage glycerophospholipids. 2) Several polyunsaturated fatty acids (PUFA) and PUFA containing triacylglycerols accumulated together with increased formation of lipid droplets, an indication of altered FA flux and PUFA sequestration in PRDX6 knockout cells. Loss of PRDX6 resulted in increased sensitivity to erastin-induced ferroptosis, independent of selenium and GPX4, as a consequence of increased levels of lipid hydroperoxides, that reverted to normal levels upon rescue with PRDX6. <SPAN style="font-weight: 400;">The results presented demonstrate that all three enzymatic activities of PRDX6 contribute to the role of this multifunctional enzyme in diverse cellular processes, including membrane phospholipid remodeling and glycerophospholipid functional diversity, resulting in altered lipid peroxides and modulation of AA disposition and traffic. These contributions highlight the complexity of the changes that loss of PRDX6 exerts on cell functionality.</SPAN>.

Keywords:  Lipid peroxidation; ferroptosis; lipid droplet; lipid raft; lysophospholipids; phospholipase A2

DOI:  https://doi.org/10.1042/BCJ20240445
J Perinatol. 2024 Nov 28.

Cerebral magnetic resonance spectroscopy - insights into preterm brain injury.

Magdalena Zasada, Paulina Karcz, Marta Olszewska, Aleksandra Kowalik, Wojciech Zasada, Izabela Herman-Sucharska, Przemko Kwinta.

OBJECTIVE: Magnetic resonance spectroscopy (1H-MRS) may provide clinically relevant data regarding metabolic processes that govern the course of preterm brain injury.
STUDY DESIGN: 46 very preterm infants (VP) were evaluated by magnetic resonance imaging and 1H-MRS at term-equivalent age. Brain injury was assessed according to the Kidokoro scale. Moreover, 17 term-born infants with hypoxic-ischemic encephalopathy (HIE) were scanned. The metabolic profile of the central nervous system was obtained from the bilateral thalamus.
RESULT: The Lipids/Creatine, Choline/Creatine, N-acetyl aspartate/Choline, Lactate/N-acetyl aspartate, and Lactate/Creatine ratios differed between VP infants with moderate+severe brain damage and those without brain injury. Moreover, VP infants with moderate+severe brain damage had higher Lactate/ N-acetyl aspartate and Lactate/Creatine ratios than HIE group.
CONCLUSION: There were significant differences in the cerebral metabolite profile at TEA between VP infants with and without brain injury. The 1H-MRS profile of VP infants with moderate+severe brain damage may reflect profound chronic metabolic alterations.

DOI: https://doi.org/10.1038/s41372-024-02172-2
J Neuroinflammation. 2024 Nov 28. 21(1): 308

Lactate metabolism and histone lactylation in the central nervous system disorders: impacts and molecular mechanisms.

Yao Wang, Ping Li, Yuan Xu, Linyu Feng, Yongkang Fang, Guini Song, Li Xu, Zhou Zhu, Wei Wang, Qi Mei, Minjie Xie.

  Brain takes up approximately 20% of the total body oxygen and glucose consumption due to its relatively high energy demand. Glucose is one of the major sources to generate ATP, the process of which can be realized via glycolysis, oxidative phosphorylation, pentose phosphate pathways and others. Lactate serves as a hub molecule amid these metabolic pathways, as it may function as product of glycolysis, substrate of a variety of enzymes and signal molecule. Thus, the roles of lactate in central nervous system (CNS) diseases need to be comprehensively elucidated. Histone lactylation is a novel lactate-dependent epigenetic modification that plays an important role in immune regulation and maintaining homeostasis. However, there's still a lack of studies unveiling the functions of histone lactylation in the CNS. In this review, we first comprehensively reviewed the roles lactate plays in the CNS under both physiological and pathological conditions. Subsequently, we've further discussed the functions of histone lactylation in various neurological diseases. Furthermore, future perspectives regarding histone lactylation and its therapeutic potentials in stroke are also elucidated, which may possess potential clinical applications.

Keywords:  CNS diseases; Histone lactylation; Inflammation; Lactate

DOI:  https://doi.org/10.1186/s12974-024-03303-4
Glia. 2024 Nov 27.

Modulation of OPC Mitochondrial Function by Inhibiting USP30 Promotes Their Differentiation.

Allison L Soung, Roxanne V Kyauk, Shristi Pandey, Yun-An A Shen, Mike Reichelt, Han Lin, Zhiyu Jiang, Praveen Kirshnamoorthy, Oded Foreman, Benjamin E Lauffer, Tracy J Yuen.

  Multiple lines of evidence indicate that mitochondrial dysfunction occurs in demyelinating diseases, such as multiple sclerosis (MS). Failure of remyelination is thought to be caused in part by a block of oligodendrocyte progenitor cell (OPC) differentiation into oligodendrocytes, which generate myelin sheaths around axons. The process of OPC differentiation requires a substantial amount of energy and high demand for ATP which is supplied through the mitochondria. In this study, we highlight mitochondrial gene expression changes during OPC differentiation in two murine models of remyelination and in human postmortem MS brains. Given these transcriptional alterations, we then investigate whether genetic alteration of USP30, a mitochondrial deubiquitinase, enhances OPC differentiation and myelination. By genetic knockout of USP30, we observe increased OPC differentiation and myelination without affecting OPC proliferation and survival in in vitro and ex vivo assays. We also find that OPC differentiation is accelerated in vivo following focal demyelination in USP30 knockout mice. The promotion of OPC differentiation and myelination observed is associated with increased oxygen consumption rates in USP30 knockout OPCs. Together, these data indicate a role for mitochondrial function and USP30 in OPC differentiation and myelination.

Keywords:  USP30; demyelination; mitochondria; myelination; oligodendrocytes; remyelination

DOI:  https://doi.org/10.1002/glia.24648
Int J Mol Sci. 2024 Nov 08. pii: 12032. [Epub ahead of print]25(22):

Accumulation of Bioactive Lipid Species in LPS-Induced Neuroinflammation Models Analysed with Multi-Modal Mass Spectrometry Imaging.

Irma Berrueta Razo, Kerry Shea, Tiffany-Jayne Allen, Hervé Boutin, Adam McMahon, Nicholas Lockyer, Philippa J Hart.

  Neuroinflammation is a complex biological process related to a variety of pathologies, often requiring better understanding in order to develop new, targeted therapeutic interventions. Within this context, multimodal Mass Spectrometry Imaging (MSI) has been used to characterise molecular changes in neuroinflammation for biomarker discovery not possible to other techniques. In this study, molecules including bioactive lipids were detected across inflamed regions of the brain in rats treated with lipopolysaccharide (LPS). The detected lipids may be acting as inflammatory mediators of the immune response. We identified that N-acyl-phosphatidylethanolamine (NAPE) species accumulated in the inflamed area. The presence of these lipids could be related to the endocannabinoid (eCB) signalling system, mediating an anti-inflammatory response from microglial cells at the site of injury to balance pro-inflammation and support neuronal protection. In addition, polyunsaturated fatty acids (PUFAs), specifically n-3 and n-6 species, were observed to accumulate in the area where LPS was injected. PUFAs are directly linked to anti-inflammatory mediators resolving inflammation. Finally, acylcarnitine species accumulated around the inflammation region. Accumulation of these molecules could be due to a deficient β-oxidation cycle.

Keywords:  DESI; MALDI; TOF-SIMS; mass spectrometry imaging; neuroinflammation

DOI:  https://doi.org/10.3390/ijms252212032
Cell Commun Signal. 2024 Nov 25. 22(1): 564

N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.

Federica Felice, Pamela De Falco, Martina Milani, Serena Castelli, Antonella Ragnini-Wilson, Giacomo Lazzarino, Nadia D'Ambrosi, Fabio Ciccarone, Maria Rosa Ciriolo.

   BACKGROUND: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases. N-acetylaspartate (NAA) is a brain metabolite predominantly produced by neurons and is crucial for central nervous system health. Alterations in NAA metabolism are observed in disorders such as Multiple Sclerosis and Canavan disease. While NAA's role in oligodendrocytes and astrocytes has been investigated, its impact on microglial function remains less understood.
METHODS: The murine BV2 microglial cell line and primary microglia were used as experimental models. Cells were treated with exogenous NAA and stimulated with LPS/IFN-γ to reproduce the pro-inflammatory phenomenon. HPLC and immunofluorescence analysis were used to study lipid metabolism following NAA treatment. Automated fluorescence microscopy was used to analyze phagocytic activity. The effects on the pro-inflammatory response were evaluated by analysis of protein/mRNA expression and ChIP assay of typical inflammatory markers.
RESULTS: NAA treatment promotes an increase in both lipid synthesis and degradation, and enhances the phagocytic activity of BV2 cells, thus fostering surveillant microglia characteristics. Importantly, NAA decreases the pro-inflammatory state induced by LPS/IFN-γ via the activation of histone deacetylases (HDACs). These findings were validated in primary microglial cells, highlighting the impact on cellular metabolism and inflammatory responses.
CONCLUSIONS: The study highlighted the role of NAA in reinforcing the oxidative metabolism of surveillant microglial cells and, most importantly, in buffering the inflammatory processes characterizing reactive microglia. These results suggest that the decreased levels of NAA observed in neurodegenerative disorders can contribute to chronic neuroinflammation.

Keywords:  Anti-inflammatory response; Histone deacetylases; Lipid turnover; Microglial polarization; NAA; Oxidative metabolism

DOI:  https://doi.org/10.1186/s12964-024-01947-6
Clin Transl Oncol. 2024 Nov 29.

Rotenone adaptation promotes migration and invasion of p53-wild-type colon cancer through lipid metabolism.

Yingying Shi, Zhen Cao, Ling Ge, Lin Lei, Dan Tao, Juan Zhong, Dan Xu, Tao Geng, Xuetao Li, Ziwei Li, Shuaishuai Xing, Xinyu Wu, Zhongxu Wang, Linjun Li.

   BACKGROUND: The association between mitochondrial dysfunction and multiple metabolic adaptations is increasingly being proven. We previously elucidated that mitochondrial complex I deficiency can promote glycolysis in mut-p53 SW480 cells. However, studies have revealed a phenotype with attenuated glycolysis but enhanced fatty acid oxidation (FAO) in invasive tumors. The interplay between complex I and FAO in carcinogenesis remains obscure.
METHODS: The p53 wild-type RKO cells were exposed to rotenone over at least 2 months to acquire rotenone adaptation cells. Then the transwell invasion assays and expression of metabolic enzymes were first detected in rotenone adaptation cells to illustrate whether rotenone adaptation is correlated with the invasion and FAO. The levels of epithelial-to-mesenchymal transition (EMT)-related proteins and acetyl-CoA in rotenone adaptation cells treated with etomoxir (ETO) and acetate were evaluated to verify the role of CPT1A in regulating invasion. Finally, the levels of reactive oxygen species (ROS) were detected. Meanwhile, the invasiveness and histone acetylation levels of rotenone adaptation cells were observed after adding an ROS inhibitor (N-acetyl-L-cysteine NAC) to demonstrate the molecular connection between FAO and invasion during rotenone adaptation.
RESULTS: We found long-term exposure to rotenone (a mitochondrial complex I inhibitor) led to EMT and high CPT1A expression in wt-p53 colon cancer. The inhibition of CPT1A suppressed the invasion and reduced histone acetylation, which was rescued by supplementing with acetate. Mechanistically, ROS is crucial for lipid metabolism remodeling.
CONCLUSION: Our study provides a novel understanding of the role of complex I in lipid reprogramming facilitating colon cancer invasion and metastasis.

Keywords:  CPT1A; Histone acetylation; Migration and invasion; Mitochondrial complex I; Rotenone

DOI:  https://doi.org/10.1007/s12094-024-03785-x
Sci Rep. 2024 11 25. 14(1): 29150

APOE4 and age affect the brain entorhinal cortex structure and blood arachidonic acid and docosahexaenoic acid levels after mild TBI.

Gregory Aldrich, James E Evans, Roderick Davis, Lucia Jurin, Sarah Oberlin, Daniel Niedospial, Aurore Nkiliza, Michael Mullan, Kimbra Kenney, J Kent Werner, Katie Edwards, Jessica M Gill, Hannah M Lindsey, Emily L Dennis, William C Walker, Elisabeth Wilde, Fiona Crawford, Laila Abdullah.

  A reduction in the thickness and volume of the brain entorhinal cortex (EC), together with changes in blood arachidonic acid (AA) and docosahexaenoic acid (DHA), are associated with Alzheimer's disease (AD) among apolipoprotein E ε4 carriers. Magnetic Resonance Imaging (n = 631) and plasma lipidomics (n = 181) were performed using the LIMBIC/CENC cohort to examine the influence of ε4 on AA- and DHA-lipids and EC thickness and volume in relation to mild traumatic brain injury (mTBI). Results showed that left EC thickness was higher among ε4 carriers with mTBI. Repeated mTBI (r-mTBI) was associated with reduced right EC thickness after controlling for ε4, age and sex. Age, plus mTBI chronicity were linked to increased EC White Matter Volume (WMV). After controlling for age and sex, the advancing age of ε4 carriers with blast mTBI was associated with reduced right EC Grey Matter Volume (GMV) and thickness. Among ε4 carriers, plasma tau and Aβ40 were associated with mTBI and blast mTBI, respectively. Chronic mTBI, ε4 and AA to DHA ratios in phosphatidylcholine, ethanolamides, and phosphatidylethanolamine were associated with decreased left EC GMV and WMV. Further research is needed to explore these as biomarkers for detecting AD pathology following mTBI.

Keywords:  Apolipoprotein E; Arachidonic acid; Blast injury; Docosahexaenoic acid; Entorhinal cortex; Repetitive mild traumatic brain injury; Traumatic brain injury

DOI:  https://doi.org/10.1038/s41598-024-80153-3
Int J Mol Sci. 2024 Nov 20. pii: 12479. [Epub ahead of print]25(22):

The Role of Alpha-Linolenic Acid and Other Polyunsaturated Fatty Acids in Mental Health: A Narrative Review.

Camilla Bertoni, Cecilia Pini, Alessandra Mazzocchi, Carlo Agostoni, Paolo Brambilla.

  The present review investigates the relationship between polyunsaturated fatty acids (PUFAs) and mental health disorders, such as dementia, psychosis, schizophrenia, Alzheimer's disease, anorexia nervosa, and impairment problems in animals and human models. Data were collected from a variety of studies: randomized intervention trials, observational and interventional studies, case reports, and epidemiological studies. The evidence suggests that PUFAs are beneficial for mental health, brain function, and behavior. ALA, EPA, and DHA have very significant neuroprotective properties, particularly in inducing changes to the synaptic membrane and modulating brain cell signaling. In the case of neurodegenerative disorders, PUFAs incorporated into cellular membranes have been shown to protect against cell atrophy and death. The formal analyses of the included studies pointed to a decrease in ALA, EPA, and DHA levels in various populations (e.g., children, adolescents, adults, and seniors) presenting with different types of mental disorders. These results indicate that PUFA supplementation may be considered as an innovative therapeutic strategy to reduce the risk of neuronal degeneration.

Keywords:  ADHD; Alzheimer’s disease; PUFA; alpha-linolenic acid; bipolar disorder; dementia; depression; mental health; neurodevelopment; psychosis; schizophrenia

DOI:  https://doi.org/10.3390/ijms252212479
Biomedicines. 2024 Nov 08. pii: 2555. [Epub ahead of print]12(11):

Elovanoids, a Novel Class of Lipid Mediators, Are Neuroprotective in a Traumatic Brain Injury Model in Rats.

Nicolas G Bazan, Andre Obenaus, Larissa Khoutorova, Pranab K Mukherjee, Bokkyoo Jun, Rostyslav Semikov, Ludmila Belayev.

   BACKGROUND: In the United States, traumatic brain injury (TBI) contributes significantly to mortality and morbidity. Elovanoids (ELVs), a novel class of homeostatic lipid mediators we recently discovered and characterized, have demonstrated neuroprotection in experimental stroke models but have never been tested after TBI.
METHODS: A moderate fluid-percussion injury (FPI) model was used on male rats that were treated with ELVs by intravenous (IV) or intranasal (IN) delivery. In addition, using liquid chromatography-mass spectrometry (LC-MS/MS), we examined whether ELVs could be detected in brain tissue after IN delivery.
RESULTS: ELVs administered intravenously 1 h after FPI improved behavior on days 2, 3, 7, and 14 by 20, 23, 31, and 34%, respectively, and preserved hippocampal CA3 and dentate gyrus (DG) volume loss compared to the vehicle. Whole-brain tractography revealed that ELV-IV treatment increased corpus callosum white matter fibers at the injury site. In comparison to treatment with saline on days 2, 3, 7, and 14, ELVs administered intranasally at 1 h and 24 h after FPI showed improved neurological scores by 37, 45, 41, and 41%. T2-weighted imaging (T2WI) abnormalities, such as enlarged ventricles and cortical thinning, were reduced in rats treated by ELV-IN delivery compared to the vehicle. On day 3, ELVs were detected in the striatum and ipsilateral cortex of ELV-IN-treated rats.
CONCLUSION: We have demonstrated that both ELV-IN and ELV-IV administration offer high-grade neuroprotection that can be selectively supplied to the brain. This discovery may lead to innovative therapeutic targets for secondary injury cascade prevention following TBI.

Keywords:  T2 mapping; diffusion tensor imaging; fluid-percussion injury; omega-3 fatty acids; white matter

DOI:  https://doi.org/10.3390/biomedicines12112555
FEMS Yeast Res. 2024 Nov 28. pii: foae036. [Epub ahead of print]

Diacylglycerol metabolism and homeostasis in fungal physiology.

Sudipta Mondal, Biswajit Pal, Rajan Sankaranarayanan.

  Diacylglycerol (DAG) is a relatively simple and primitive form of lipid, which does not possess a phospholipid headgroup. Being a central metabolite of the lipid metabolism network, DAGs are omnipresent in all life forms. While the role of DAG has been established in membrane and storage lipid biogenesis, it can impart crucial physiological functions including membrane shapeshifting, regulation of membrane protein activity and transduction of cellular signalling as a lipid-based secondary messenger. Besides, the chemical diversity of DAGs, due to fatty acyl chain composition, has been proposed to be the basis of its functional diversity. Therefore, cells must regulate DAG level at a spatio-temporal scale for homeostasis and adaptation. The vast network of eukaryotic lipid metabolism has been unravelled majorly by studying yeast models. Here, we review the current understanding and the emerging concepts in metabolic and functional aspects of DAG regulation in yeast. The implications can be extended to understand pathogenic fungi and mammalian counterparts as well as disease aetiology.

Keywords:  Acyl-chain diversity; Diacylglycerol; Disco-interacting protein 2; Lipid metabolism; Lipid second messenger; Membrane contact site; Organelle membranes

DOI:  https://doi.org/10.1093/femsyr/foae036
Cereb Cortex. 2024 Nov 05. pii: bhae465. [Epub ahead of print]34(11):

Neuronal viability/astrocyte activity ratio in the dorsolateral prefrontal cortex as a biomarker of Alzheimer's dementia: a proton magnetic resonance spectroscopy study.

Shreya Jha, Edgardo Torres-Carmona, Yusuke Iwata, Clement Ma, Ariel Graff-Guerrero, Corinne E Fischer, Benoit Mulsant, Bruce G Pollock, Tarek K Rajji, Sanjeev Kumar.

  N-acetyl-aspartate (NAA) and myo-inositol (mI) are neurometabolites reflecting neuronal viability and astrocyte activity, respectively. These are quantified using proton magnetic resonance spectroscopy (1H-MRS) and may be biomarkers for Alzheimer's disease dementia (AD). Our objectives were: 1) Compare dorsolateral prefrontal cortex (DLPFC) NAA and mI levels between AD and cognitively healthy control participants (HC) 2) assess if NAA/mI ratio can distinguish groups, and 3) explore the relationship between metabolites and cognition. The study included 64 participants over 55, 41 with AD. Bilateral DLPFC NAA and mI levels were quantified using 3 T 1H-MRS and normalized to H2O. NAA and NAA/mI ratio were lower in AD vs. HC. mI was unchanged. The NAA/mI ratio at a cut-off value of 1.69 showed 59% sensitivity and 87% specificity at distinguishing AD from HC. NAA was associated positively with cognition. In conclusion, DLPFC metabolite changes suggest altered mitochondrial function in AD. NAA/mI ratio shows good specificity in distinguishing AD from HC, suggesting its role in complementing other biomarkers. Future studies should evaluate NAA/mI ratio with other disease specific biomarkers.

Keywords:  Myo-inositol; N-acetyl aspartate; cognition; diagnostic tests; metabolites

DOI:  https://doi.org/10.1093/cercor/bhae465
Int J Mol Sci. 2024 Nov 19. pii: 12410. [Epub ahead of print]25(22):

Targeted Chiral Metabolomics of D-Amino Acids: Their Emerging Role as Potential Biomarkers in Neurological Diseases with a Focus on Their Liquid Chromatography-Mass Spectrometry Analysis upon Chiral Derivatization.

Cinzia Lella, Liam Nestor, Dimitri De Bundel, Yvan Vander Heyden, Ann Van Eeckhaut.

  In neuroscience research, chiral metabolomics is an emerging field, in which D-amino acids play an important role as potential biomarkers for neurological diseases. The targeted chiral analysis of the brain metabolome, employing liquid chromatography (LC) coupled to mass spectrometry (MS), is a pivotal approach for the identification of biomarkers for neurological diseases. This review provides an overview of D-amino acids in neurological diseases and of the state-of-the-art strategies for the enantioselective analysis of chiral amino acids (AAs) in biological samples to investigate their putative role as biomarkers for neurological diseases. Fluctuations in D-amino acids (D-AAs) levels can be related to the pathology of neurological diseases, for example, through their role in the modulation of N-methyl-D-aspartate receptors and neurotransmission. Because of the trace presence of these biomolecules in mammals and the complex nature of biological matrices, highly sensitive and selective analytical methods are essential. Derivatization strategies with chiral reagents are highlighted as critical tools for enhancing detection capabilities. The latest advances in chiral derivatization reactions, coupled to LC-MS/MS analysis, have improved the enantioselective quantification of these AAs and allow the separation of several chiral metabolites in a single analytical run. The enhanced performances of these methods can provide an accurate correlation between specific D-AA profiles and disease states, allowing for a better understanding of neurological diseases and drug effects on the brain.

Keywords:  D-amino acids; LC-MS/MS; biomarkers; chemical derivatization; chirality; enantioselective analysis; neurological diseases

DOI:  https://doi.org/10.3390/ijms252212410