bims-medebr 2022-08-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒08‒21
fifteen papers selected by
Regina F. Fernández
Johns Hopkins University

Early Life to Adult Brain Lipidome Dynamic: A Temporospatial Study Investigating Dietary Polar Lipid Supplementation Efficacy.
The synaptic lipidome in health and disease.
Energy crisis links to autophagy and ferroptosis in Alzheimer's disease: current evidence and future avenues.
Plasmalogen in the brain: Effects on cognitive functions and behaviors attributable to its properties.
Ether lipid transfer across the blood-brain and placental barriers does not improve by inactivation of the most abundant ABC transporters.
Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer's Disease Decreases Amyloid Beta Plaque Formation.
Chronic Cerebral Hypoperfusion Aggravates Parkinson's Disease Dementia-Like Symptoms and Pathology in 6-OHDA-Lesioned Rat through Interfering with Sphingolipid Metabolism.
Upper cerebellar glucose hypermetabolism in patients with temporal lobe epilepsy and interictal psychosis.
Transplantation of astrocytic mitochondria modulates neuronal antioxidant defense and neuroplasticity and promotes functional recovery after intracerebral hemorrhage.
Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia.
Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure.
Lesion-Induced Dystonia: Lessons Learned From Brain Networks Studies.
Oleate restores altered autophagic flux to rescue palmitate lipotoxicity in hypothalamic neurons.
Structure of a cholinergic cell membrane.
Profiling of fatty acid metabolism in the dorsal root ganglion after peripheral nerve injury.

Front Nutr. 2022 ;9 898655

Early Life to Adult Brain Lipidome Dynamic: A Temporospatial Study Investigating Dietary Polar Lipid Supplementation Efficacy.

Manuel Oliveira, Kyoko Koshibu, Andreas Rytz, Francesca Giuffrida, Sebastien Sultan, Amaury Patin, Mathieu Gaudin, Aurore Tomezyk, Pascal Steiner, Nora Schneider.

  The lipid composition of the brain is well regulated during development, and the specific temporospatial distribution of various lipid species is essential for the development of optimal neural functions. Dietary lipids are the main source of brain lipids and thus contribute to the brain lipidome. Human milk is the only source of a dietary lipids for exclusively breastfed infant. Notably, it contains milk fat globule membrane (MFGM) enriched in polar lipids (PL). While early life is a key for early brain development, the interplay between dietary intake of polar lipids and spatial dynamics of lipid distribution during brain development is poorly understood. Here, we carried out an exploratory study to assess the early postnatal temporal profiling of brain lipidome between postnatal day (PND) 7 and PND 50 using matrix-assisted laser desorption ionization as a mass spectrometry imaging (MALDI-MSI) in an in vivo preclinical model. We also assessed the effect of chronic supplementation with PL extracted from alpha-lactalbumin-enriched whey protein concentrate (WPC) containing 10% lipids, including major lipid classes found in the brain (37% phospholipids and 15% sphingomyelin). MALDI-MSI of the spatial and temporal accretion of lipid species during brain development showed that the brain lipidome is changing heterogeneously along time during brain development. In addition, increases in 400+ PL supplement-dependent lipids were observed. PL supplementation had significant spatial and temporal effect on specific fatty esters, glycerophosphocholines, glycerophosphoethanolamines, and phosphosphingolipids. Interestingly, the average levels of these lipids per brain area tended to be constant in various brain structures across the age groups, paralleling the general brain growth. In contrast, other lipids, such as cytidine diphosphate diacylglycerol, diacylglycerophosphates, phosphocholines, specific ether-phosphoethanolamines, phosphosphingolipids, glycerophosphoinositols, and glycerophosphoserines showed clear age-dependent changes uncoupled from the general brain growth. These results suggest that the dietary PL supplementation may preferentially provide the building blocks for the general brain growth during development. Our findings add to the understanding of brain-nutrient relations, their temporospatial dynamics, and potential impact on neurodevelopment.

Keywords:  MALDI-MSI; brain development; phospholipids; polar lipids; sphingolipids

DOI:  https://doi.org/10.3389/fnut.2022.898655
Biochim Biophys Acta Biomembr. 2022 Aug 11. pii: S0005-2736(22)00171-7. [Epub ahead of print]1864(11): 184033

The synaptic lipidome in health and disease.

Ana Sofia Vallés, Francisco J Barrantes.

  Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its uniquely high energetic requirements, posesses singular characteristics. Some of these are related to its extraordinary dotation of synapses, the specialized subcelluar structures where signal transmission between neurons occurs in the central nervous system. The post-synaptic compartment of excitatory synapses, the dendritic spine, harbors key molecules involved in neurotransmission tightly packed within a minute volume of a few femtoliters. The spine is further compartmentalized into nanodomains that facilitate the execution of temporo-spatially separate functions in the synapse. Lipids play important roles in this structural and functional compartmentalization and in mechanisms that impact on synaptic transmission. This review analyzes the structural and dynamic processes involving lipids at the synapse, highlighting the importance of their homeostatic balance for the physiology of this complex and highly specialized structure, and underscoring the pathologies associated with disbalances of lipid metabolism, particularly in the perinatal and late adulthood periods of life. Although small variations of the lipid profile in the brain take place throughout the adult lifespan, the pathophysiological consequences are clinically manifested mostly during late adulthood. Disturbances in lipid homeostasis in the perinatal period leads to alterations during nervous system development, while in late adulthood they favor the occurrence of neurodegenerative diseases.

Keywords:  Brain homeostasis; Brain metabolism; Dendritic spine; Lipid metabolism; Plasma membrane; Synapse; Synaptopathies

DOI:  https://doi.org/10.1016/j.bbamem.2022.184033
Curr Neuropharmacol. 2022 Aug 17.

Energy crisis links to autophagy and ferroptosis in Alzheimer's disease: current evidence and future avenues.

Da-Long He, Yong-Gang Fan, Zhan-You Wang.

  Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, and autophagy plays important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD, and discussed the interplays existing between energy crisis, autophagy and ferroptosis. In addition, we highlighted the potential network that autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new strategies for treating AD, meanwhile, the energy crisis in the progression of AD should gain more attention.

Keywords:  Alzheimer's disease; autophagy; beta-amyloid; energy crisis; ferroptosis; iron metabolism; tau protein

DOI:  https://doi.org/10.2174/1570159X20666220817140737
Brain Res Bull. 2022 Aug 12. pii: S0361-9230(22)00200-3. [Epub ahead of print]188 197-202

Plasmalogen in the brain: Effects on cognitive functions and behaviors attributable to its properties.

Jun Udagawa, Kodai Hino.

  Ether phospholipid compositions are altered in the plasma or brain of patients with brain disorders, such as Alzheimer and Parkinson's disease, including those with psychiatric disorders like schizophrenia and bipolar disorders. Notably, plasmenyl ethanolamine has a unique chemical structure, i.e., a vinyl-ether bond at the sn-1 position, which mainly links with polyunsaturated fatty acids (PUFAs) at the sn-2 position. Those characteristic moieties give plasmalogen molecules unique biophysical and chemical properties that modulate membrane trafficking, lipid rafts, intramolecular PUFA moieties, and oxidative states. Previous reports suggested that a deficiency in plasmenyl ethanolamine leads to disturbances of the myelin structure, synaptic neurotransmission and intracellular signaling, apoptosis of neurons, and neuroinflammation, accompanied by cognitive disturbances and aberrant behaviors like hyperactivity in mice. Therefore, this review summarizes the relationship between the biological functions of plasmalogen. We also proposed biophysical properties that alter brain phospholipid compositions related to aberrant behaviors and cognitive dysfunction. Finally, a brief review of possible remedial plasmalogen replacement therapies for neurological, psychiatric, and developmental disorders attributable to disturbed plasmalogen compositions in the organs and cells was conducted.

Keywords:  Behavior; Delivery; Neurological disorders; Plasmalogen

DOI:  https://doi.org/10.1016/j.brainresbull.2022.08.008
Brain Res Bull. 2022 Aug 15. pii: S0361-9230(22)00199-X. [Epub ahead of print]

Ether lipid transfer across the blood-brain and placental barriers does not improve by inactivation of the most abundant ABC transporters.

Fabian Dorninger, Frédéric M Vaz, Hans R Waterham, Jan B van Klinken, Gerhard Zeitler, Sonja Forss-Petter, Johannes Berger, Christoph Wiesinger.

  Phospholipid transport from the periphery to the brain is an understudied topic. When certain lipid species are deficient due to impaired synthesis, though, transfer across the blood-brain barrier is essential for replenishing lipids in the brain. For example, the deficiency in plasmalogens, the most abundant ether lipids in mammals, has detrimental effects on the brain, which is a major issue in inherited peroxisomal disorders but also contributes to more common disorders like Alzheimer's disease. Oral administration of alkylglycerols like batyl alcohol, which carry a pre-formed ether bond, enables replenishment of ether lipids in various peripheral tissues. However, plasmalogen deficiency in the brain cannot be overcome by this approach. Here, we tried to increase cerebral plasmalogen uptake by modulating the efflux transport across the blood-brain barrier. We hypothesized, based on previous literature, that at least some ether lipid species readily enter endothelial cells of the barrier through the transporter MFSD2A but are re-exported by ATP-binding cassette (ABC) transporters. By crossbreeding Mdr1a-/-/Mdr1b-/-/Bcrp-/- and ether lipid-deficient Gnpat-/- mice as well as pharmacological inhibition with MK-571 to inactivate the major ABC transporters at the blood-brain barrier, we evaluated the potential of combined ABC transporter inhibition and oral batyl alcohol administration for the treatment of plasmalogen deficiency. We found that even in the absence of the most abundant ABC transporters, batyl alcohol supplementation did not restore plasmalogen levels in the brain, despite the presence of a wide spectrum of ether lipid subspecies in the plasma as demonstrated by lipidomic analysis. Surprisingly, batyl alcohol treatment of pregnant Gnpat+/- dams had beneficial effects on the plasmalogen levels of Gnpat-/- offspring with defective ether lipid biosynthesis, independently of ABC transporter status at the placental barrier. Our results underline the autonomy of brain lipid homeostasis and indicate that peripheral supplementation of ether lipids is not sufficient to supply the brain with larger amounts of plasmalogens. Yet, the findings suggest that alkylglycerol treatment during pregnancy may pose a viable option to ameliorate some of the severe developmental defects of inborn ether lipid deficiency.

Keywords:  ATP-binding cassette transporter; Alzheimer’s disease; blood-brain barrier; peroxisome; plasmalogen; precursor supplementation

DOI:  https://doi.org/10.1016/j.brainresbull.2022.08.006
Mol Neurobiol. 2022 Aug 15.

Adult-Onset Deficiency of Mitochondrial Complex III in a Mouse Model of Alzheimer's Disease Decreases Amyloid Beta Plaque Formation.

Milena Pinto, Francisca Diaz, Nadee Nissanka, Chelsey S Guastucci, Placido Illiano, Roberta Brambilla, Carlos T Moraes.

  For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer's disease, but this association is still debated. It is unclear whether different mitochondrial dysfunctions, such as oxidative phosphorylation deficiency and oxidative stress, are triggers or rather consequences of the formation of amyloid aggregates. Likewise, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer's patients' brain remains poorly understood. Previous studies showed that genetic ablation of oxidative phosphorylation enzymes from early age decreased amyloid pathology, which were unexpected results. To better model oxidative phosphorylation defects in aging, we induced the ablation of mitochondrial Complex III (CIIIKO) in forebrain neurons of adult mice with amyloid pathology. We found that mitochondrial Complex III dysfunction in adult neurons induced mild oxidative stress but did not increase amyloid beta accumulation. On the contrary, CIIIKO-AD mice showed decreased plaque number, decreased Aβ42 toxic fragment, and altered amyloid precursor protein clearance pathway. Our results support the hypothesis that mitochondrial dysfunctions alone, caused by oxidative phosphorylation deficiency, is not the cause of amyloid accumulation.

Keywords:  Alzheimer’s disease; Mitochondria dysfunctions; Mouse model; Oxidative phosphorylation deficiency; Oxidative stress

DOI:  https://doi.org/10.1007/s12035-022-02992-3
Oxid Med Cell Longev. 2022 ;2022 5392966

Chronic Cerebral Hypoperfusion Aggravates Parkinson's Disease Dementia-Like Symptoms and Pathology in 6-OHDA-Lesioned Rat through Interfering with Sphingolipid Metabolism.

Yaohua Fan, Mengzhu Li, Chunxiao Wu, Yubiao Wu, Jiajun Han, Peipei Wu, Zifeng Huang, Qizhang Wang, Lijun Zhao, Dongfeng Chen, Meiling Zhu.

Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson's disease dementia (PDD), but this potential causality lacks mechanistic evidence. We selected bilateral common carotid artery occlusion (BCCAO) to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA). Four weeks after unilateral injection of 6-OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague-Dawley rats were divided into five groups of ten, including sham, PD+BCCAO 2 weeks, PD+BCCAO 1 week, PD, and BCCAO 2 weeks. Then, open field test (OFT) and Morris water maze test (MWM) were used to assess the PDD-like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin-eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real-time polymerase chain reaction. In this study, we found that CCH could aggravate PDD-like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD-like pathology (higher expression of α-Syn and Aβ in prefrontal cortex and striatum). Moreover, a potential relationship between differentially expressed mRNAs and lipid metabolism was revealed by RNA sequencing analysis. Lipidomics showed that CCH could affect the intensity of 5 lipids, including sphingomyelin (SM 9:0;2O/26:2; SM 8:1;2O/25:0; and SM 8:0;2O/28:4), cardiolipin, lysophosphatidylcholine, cholesteryl ester, and triacylglycerol. Interestingly, the KEGG pathway analysis of both RNA sequencing analysis and lipidomics suggested that CCH leaded to learning impairment by affecting sphingolipid metabolism. Finally, we found that CCH disrupts the sphingolipid metabolism by affecting the mRNA expression of SMPD1 and SMS2, leading to the accumulation of sphingomyelin in the prefrontal cortex. In summary, CCH, an independent exacerbating reason for impairment in learning and memory within the pathopoiesis of PD, aggravates Parkinson's disease dementia-like symptoms and pathology in 6-OHDA-lesioned rat through interfering with sphingolipid metabolism.

DOI: https://doi.org/10.1155/2022/5392966
Epilepsia Open. 2022 Aug 17.

Upper cerebellar glucose hypermetabolism in patients with temporal lobe epilepsy and interictal psychosis.

Daichi Sone, Noriko Sato, Yoko Shigemoto, Yukio Kimura, Hiroshi Matsuda.

  OBJECTIVE: Psychosis is an important comorbidity in epilepsy, but its pathophysiology is still unknown. The imaging modality 18 F-fluorodeoxyglucose-positron emission tomography (18 F-FDG PET) is widely used to measure brain glucose metabolism, and we speculated that 18 F-FDG PET may detect characteristic alteration patterns in individuals with temporal lobe epilepsy (TLE) and psychosis.METHODS: We enrolled 13 patients with TLE and interictal psychosis (TLE-P) and 21 patients with TLE without psychosis (TLE-N). All underwent interictal 18 F-FDG-PET scanning. Statistical Parametric Mapping (SPM)12 software was used for the normalization process, and we performed a voxel-wise comparison of the TLE-P and TLE-N groups.
RESULTS: Cerebral hypometabolic areas were observed in the ipsilateral temporal pole to hippocampus in both patient groups. In the TLE-P group, the voxel-wise comparison revealed significantly increased 18 F-FDG signals in the upper cerebellum, superior cerebellar peduncle, and midbrain. There were no significant between-group metabolic differences around the focus or other cerebral areas.
SIGNIFICANCE: Our results demonstrated significant hypermetabolism around the upper cerebellum in patients with TLE and interictal psychosis compared to patients with TLE without psychosis. These findings may reflect the involvement of the cerebellum in the underlying neurobiology of interictal psychosis and could contribute to a better understanding of this disorder.

Keywords:  18F-FDG PET; brain metabolism; interictal psychosis; temporal lobe epilepsy

DOI:  https://doi.org/10.1002/epi4.12645
J Neurosci. 2022 Aug 15. pii: JN-RM-2222-21. [Epub ahead of print]

Transplantation of astrocytic mitochondria modulates neuronal antioxidant defense and neuroplasticity and promotes functional recovery after intracerebral hemorrhage.

Ryosuke Tashiro, Jesus Bautista-Garrido, Dan Ozaki, Guanghua Sun, Lidiya Obertas, Alexis S Mobley, Gab Seok Kim, Jaroslaw Aronowski, Joo Eun Jung.

Astrocytes release functional mitochondria (Mt) that play regulatory and pro-survival functions upon entering adjacent cells. We recently demonstrated that these released Mt could enter microglia to promote their reparative/pro-phagocytic phenotype that assists in hematoma cleanup and neurological recovery after intracerebral hemorrhage (ICH). However, a relevance of astrocytic Mt transfer into neurons in protecting brain after ICH is unclear. Here, we found that ICH causes a robust increase in superoxide generation and elevated oxidative damage that coincides with loss of the mitochondrial enzyme manganese superoxide dismutase (Mn-SOD). The damaging effect of ICH was reversed by intravenous transplantation of astrocytic Mt that upon entering the brain (and neurons), restored Mn-SOD levels and reduced neurological deficits in male mice subjected to ICH. Using an in vitro ICH-like injury model in cultured neurons, we established that astrocytic Mt upon entering neurons prevented reactive oxygen species-induced oxidative stress and neuronal death by restoring neuronal Mn-SOD levels, while at the same time promoted neurite extension and upregulation of synaptogenesis-related gene expression. Furthermore, we found that Mt genome-encoded small peptide humanin (HN) that is normally abundant in Mt, could simulate Mt-transfer effect on neuronal Mn-SOD expression, oxidative stress, and neuroplasticity under ICH-like injury. This study demonstrates that adoptive astrocytic Mt transfer enhances neuronal Mn-SOD-mediated anti-oxidative defense and neuroplasticity in the brain, which potentiate functional recovery following ICH.SIGNIFICANCE STATEMENTMitochondrial dysfunction and antioxidant defense play essential role in brain damage after intracerebral hemorrhage (ICH). Astrocytes release functional mitochondria (Mt) that enter adjacent cells to help brain homeostatic function. Here, we show that systemic transplantation of astrocytic Mt restores ICH-impaired neuronal anti-oxidative defense, enhances neurite outgrowth, and improves stroke recovery after ICH. Our study suggests that systemic transplantation of astrocytic Mt could be considered as a novel and potentially promising strategy for ICH treatment.

DOI: https://doi.org/10.1523/JNEUROSCI.2222-21.2022
Nat Commun. 2022 Aug 15. 13(1): 4771

Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia.

Beata Jablonska, Katrina L Adams, Panagiotis Kratimenos, Zhen Li, Emma Strickland, Tarik F Haydar, Katharina Kusch, Klaus-Armin Nave, Vittorio Gallo.

Delayed oligodendrocyte (OL) maturation caused by hypoxia (Hx)-induced neonatal brain injury results in hypomyelination and leads to neurological disabilities. Previously, we characterized Sirt1 as a crucial regulator of OL progenitor cell (OPC) proliferation in response to Hx. We now identify Sirt2 as a critical promoter of OL differentiation during both normal white matter development and in a mouse model of Hx. Importantly, we find that Hx reduces Sirt2 expression in mature OLs and that Sirt2 overexpression in OPCs restores mature OL populations. Reduced numbers of Sirt2+ OLs were also observed in the white matter of preterm human infants. We show that Sirt2 interacts with p27Kip1/FoxO1, p21Cip1/Cdk4, and Cdk5 pathways, and that these interactions are altered by Hx. Furthermore, Hx induces nuclear translocation of Sirt2 in OPCs where it binds several genomic targets. Overall, these results indicate that a balance of Sirt1 and Sirt2 activity is required for developmental oligodendrogenesis, and that these proteins represent potential targets for promoting repair following white matter injury.

DOI: https://doi.org/10.1038/s41467-022-32462-2
Front Aging Neurosci. 2022 ;14 925728

Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure.

Keyu Chen, Dihan Lu, Xiaoyu Yang, Rui Zhou, Liangtian Lan, Yan Wu, Chen Wang, Xuanxian Xu, Mei Hua Jiang, Ming Wei, Xia Feng.

  Background: Developing brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains.Methods: The behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism.
Results: Behavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both in vivo and in vitro. Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.
Conclusions: Taken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.

Keywords:  OXPHOS; PGC-1α; Propofol; hippocampal neurogenesis; neural stem cell

DOI:  https://doi.org/10.3389/fnagi.2022.925728
Neurology. 2022 Aug 17. pii: 10.1212/WNL.0000000000201266. [Epub ahead of print]

Lesion-Induced Dystonia: Lessons Learned From Brain Networks Studies.

Chiung Chu Chen.

DOI: https://doi.org/10.1212/WNL.0000000000201266
Mol Cell Endocrinol. 2022 Aug 15. pii: S0303-7207(22)00201-5. [Epub ahead of print] 111753

Oleate restores altered autophagic flux to rescue palmitate lipotoxicity in hypothalamic neurons.

Wenyuan He, Andy Tran, Chuck T Chen, Neruja Loganthan, Richard P Bazinet, Denise D Belsham.

  Accumulation of excess lipids in non-adipose tissues, such as the hypothalamus, is termed lipotoxicity and causative of free fatty acid-mediated pathology in metabolic disease. This study aimed to elucidate the molecular mechanisms behind oleate (OA)- and palmitate (PA)-mediated changes in hypothalamic neurons. Using the well-characterized hypothalamic neuronal cell model, mHypoE-46, we assessed gene changes through qRT-PCR, cell death with quantitative imaging, PA metabolism using stable isotope labeling, and cellular mechanisms using pharmacological modulation of lipid metabolism and autophagic flux. Palmitate (PA) disrupts gene expression, including Npy, Grp78, and Il-6 mRNA in mHypoE-46 hypothalamic neurons. Blocking PA metabolism using triacsin-C prevented the increase of these genes, implying that these changes depend on PA intracellular metabolism. Co-incubation with oleate (OA) is also potently protective and prevents cell death induced by increasing concentrations of PA. However, OA does not decrease 13C-PA incorporation into diacylglycerol and phospholipids. Remarkably, OA can reverse PA toxicity even after significant PA metabolism and cellular impairment. OA can restore PA-mediated impairment of autophagy to prevent or reverse the accumulation of PA metabolites through lysosomal degradation, and not through other reported mechanisms. The autophagic flux inhibitor chloroquine mimics PA toxicity by upregulating autophagy-related genes, Npy, Grp78, and Il-6, an effect partially reversed by OA. Chloroquine also prevented the OA defense against PA toxicity, whereas the autophagy inducer rapamycin provided some protection. Thus, PA impairment of autophagic flux significantly contributes to its lipotoxicity, and OA-mediated protection requires functional autophagy. Overall, our results suggest that impairment of autophagy contributes to hypothalamic lipotoxicity.

Keywords:  Autophagy; Hypothalamus; Lipid metabolism; Lipotoxicity; Oleate; Palmitate

DOI:  https://doi.org/10.1016/j.mce.2022.111753
Proc Natl Acad Sci U S A. 2022 Aug 23. 119(34): e2207641119

Structure of a cholinergic cell membrane.

Nigel Unwin.

  Cell membranes are complex assemblies of proteins and lipids making transient or long-term associations that have yet to be characterized at a molecular level. Here, cryo-electron microscopy is applied to determine how phospholipids and cholesterol arrange between neighboring proteins (nicotinic acetylcholine receptors) of Torpedo cholinergic membrane. The lipids exhibit distinct properties in the two leaflets of the bilayer, influenced by the protein surfaces and by differences in cholesterol concentration. In the outer leaflet, the lipids show no consistent motif away from the protein surfaces, in keeping with their assumed fluidity. In the inner leaflet, where the cholesterol concentration is higher, the lipids organize into extensive close-packed linear arrays. These arrays are built from the sterol groups of cholesterol and the initial saturated portions of the phospholipid hydrocarbon chains. Together, they create an ordered ∼7 Å-thick "skin" within the hydrophobic core of the bilayer. The packing of lipids in the arrays appears to bear a close relationship to the linear cholesterol arrays that form crystalline monolayers at the air-water interface.

Keywords:  acetylcholine receptor; cholesterol; cryo-EM; lipid bilayer; phospholipid

DOI:  https://doi.org/10.1073/pnas.2207641119
Front Pain Res (Lausanne). 2022 ;3 948689

Profiling of fatty acid metabolism in the dorsal root ganglion after peripheral nerve injury.

Shota Yamamoto, Tomomi Hashidate-Yoshida, Takao Shimizu, Hideo Shindou.

  Peripheral nerve injury (PNI) induces neuronal hyperexcitability, which underlies neuropathic pain. The emergence of RNA sequencing technologies has enabled profiling of transcriptional changes in pathological conditions. However, these approaches do not provide information regarding metabolites such as lipids that are not directly encoded by genes. Fatty acids (FAs) are some of the essential lipids in mammalian organisms and are mainly stored as membrane phospholipids. In response to various biological stimuli, FAs are rapidly released and converted into several mediators, such as eicosanoids and docosanoids. FAs themselves or their metabolites play important roles in physiology and pathology. In this study, using a comprehensive lipidomic analysis of FA metabolites, 152 species were measured in the dorsal root ganglia of mice at multiple time points after PNI. We found that PNI increased the ω-6 FA metabolites produced by cyclooxygenases but not those produced by lipoxygenases or cytochrome P450 enzymes in the dorsal root ganglia. In contrast, ω-3 FA metabolites biosynthesized by any enzyme transiently increased after nerve injury. Overall, these findings provide a new resource and valuable insights into PNI pathologies, including pain and nerve regeneration.

Keywords:  dorsal root ganglion; fatty acid; leukotrien; lipid mediator; pain; peripheral nerve injury; prostaglandin

DOI:  https://doi.org/10.3389/fpain.2022.948689