bims-medebr 2023-02-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒02‒26
39 papers selected by
Regina F. Fernández
Johns Hopkins University

Astrocytes regulate inhibitory neurotransmission through GABA uptake, metabolism, and recycling.
Cross-talk between energy and redox metabolism in astrocyte-neuron functional cooperation.
A monocarboxylate transporter-dependent mechanism confers resistance to exercise-induced fatigue in a high-altitude hypoxic environment.
Monocarboxylate transporter-dependent mechanism is involved in the adaptability of the body to exercise-induced fatigue under high-altitude hypoxia environment.
Sex-specific effects of high-fat diet on rat brain glucose metabolism and early-onset dementia symptoms.
Neuroinflammation, Energy and Sphingolipid Metabolism Biomarkers Are Revealed by Metabolic Modeling of Autistic Brains.
Triheptanoin, an odd-medium-chain triglyceride, impacts brain cognitive function in young and aged mice.
Cholesterol metabolism: Towards a therapeutic approach for multiple sclerosis.
Effects of Ventromedial Hypothalamic Nucleus (VMN) Aromatase Gene Knockdown on VMN Glycogen Metabolism and Glucoregulatory Neurotransmission.
Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and glycerol-mediated gluconeogenesis in mice.
Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death.
Ether Lipid-Mediated Antioxidant Defense in Alzheimer's Disease.
2DG and glycolysis as therapeutic targets for status epilepticus.
Pearls & Oysters: Paroxysmal Exercise-Induced Dyskinesias Due to Pyruvate Dehydrogenase Deficiency.
HPRT1 Deficiency Induces Alteration of Mitochondrial Energy Metabolism in the Brain.
Lysosomal phospholipase A2 contributes to the biosynthesis of the atypical late endosome lipid bis(monoacylglycero)phosphate.
Lipid metabolism in dopaminergic neurons influences light entrainment.
Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism.
The Imbalance of Astrocytic Mitochondrial Dynamics Following Blast-Induced Traumatic Brain Injury.
Mitochondrial Lipid Peroxidation Is Responsible for Ferroptosis.
Liver's influence on the brain through the action of bile acids.
A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity.
Neuroglia Cells Transcriptomic in Brain Development, Aging and Neurodegenerative Diseases.
Age-Associated Upregulation of Glutamate Transporters and Glutamine Synthetase in Senescent Astrocytes In Vitro and in the Mouse and Human Hippocampus.
Involvement of Mitochondrial Dysfunction in FOXG1 Syndrome.
Mfsd2a attenuated hypoxic-ischemic brain damage via protection of the blood-brain barrier in mfat-1 transgenic mice.
The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats.
Stroke-like episodes in adult mitochondrial disease.
Neurotoxicity of ischemic astrocytes involves STAT3-mediated metabolic switching and depends on glycogen usage.
GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice.
Protective effect of quercetin against paraquat-induced brain mitochondrial disruption in mice.
Short- and long-term cognitive and metabolic effects of medium-chain triglyceride supplementation in rats.
Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.
Neuroimaging in mitochondrial disease.
Cholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols.
Transcriptomic profiling of the developing brain revealed cell-type and brain-region specificity in a mouse model of prenatal stress.
Metabolic Imaging and Molecular Biology Reveal the Interplay between Lipid Metabolism and DHA-Induced Modulation of Redox Homeostasis in RPE Cells.
An enzymatic fluorimetric assay for determination of N-acetylaspartate.
Ror1 promotes PPARα-mediated fatty acid metabolism in astrocytes.

Essays Biochem. 2023 Feb 21. pii: EBC20220208. [Epub ahead of print]

Astrocytes regulate inhibitory neurotransmission through GABA uptake, metabolism, and recycling.

Jens V Andersen, Arne Schousboe, Petrine Wellendorph.

  Synaptic regulation of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) is essential for brain function. Cerebral GABA homeostasis is tightly regulated through multiple mechanisms and is directly coupled to the metabolic collaboration between neurons and astrocytes. In this essay, we outline and discuss the fundamental roles of astrocytes in regulating synaptic GABA signaling. A major fraction of synaptic GABA is removed from the synapse by astrocytic uptake. Astrocytes utilize GABA as a metabolic substrate to support glutamine synthesis. The astrocyte-derived glutamine is subsequently transferred to neurons where it serves as the primary precursor of neuronal GABA synthesis. The flow of GABA and glutamine between neurons and astrocytes is collectively termed the GABA-glutamine cycle and is essential to sustain GABA synthesis and inhibitory signaling. In certain brain areas, astrocytes are even capable of synthesizing and releasing GABA to modulate inhibitory transmission. The majority of oxidative GABA metabolism in the brain takes place in astrocytes, which also leads to synthesis of the GABA-related metabolite γ-hydroxybutyric acid (GHB). The physiological roles of endogenous GHB remain unclear, but may be related to regulation of tonic inhibition and synaptic plasticity. Disrupted inhibitory signaling and dysfunctional astrocyte GABA handling are implicated in several diseases including epilepsy and Alzheimer's disease. Synaptic GABA homeostasis is under astrocytic control and astrocyte GABA uptake, metabolism, and recycling may therefore serve as relevant targets to ameliorate pathological inhibitory signaling.

Keywords:  GABA; amino acid metabolism; astrocytes; neurotransmitters; synaptic transmission

DOI:  https://doi.org/10.1042/EBC20220208
Essays Biochem. 2023 Feb 21. pii: EBC20220075. [Epub ahead of print]

Cross-talk between energy and redox metabolism in astrocyte-neuron functional cooperation.

Angeles Almeida, Daniel Jimenez-Blasco, Juan P Bolaños.

  Astrocytes show unique anatomical, morphological, and metabolic features to take up substrates from the blood and metabolize them for local delivery to active synapses to sustain neuron function. In the present review, we specifically focus on key molecular aspects of energy and redox metabolism that facilitate this astrocyte-neuronal coupling in a controlled manner. Basal glycolysis is co-ordinated by the anaphase-promoting complex/cyclosome (APC/C)-Cdh1, a ubiquitin ligase that targets the proglycolytic enzyme 6-phosphofructokinase-2,6-bisphosphastate-3 (PFKFB3) for degradation. APC/C-Cdh1 activity is more robust in neurons than in astrocytes, which determine that PFKFB3 abundance and glycolytic rate are weaker in neurons. The low PFKFB3 activity in neurons facilitates glucose-6-phosphate oxidation via the pentose-phosphate pathway, which promotes antioxidant protection. Conversely, the high PFKFB3 activity in astrocytes allows the production and release of glycolytic lactate, which is taken up by neurons that use it as an oxidizable substrate. Importantly, the mitochondrial respiratory chain is tighter assembled in neurons than in astrocytes, thus the bioenergetic efficiency of mitochondria is higher in neurons. Because of this, the production of reactive oxygen species (mROS) by mitochondrial complex I is very low in neurons and very high in astrocytes. Such a naturally occurring high abundance of mROS in astrocytes physiologically determines a specific transcriptional fingerprint that contributes to sustaining cognitive performance. We conclude that the energy and redox metabolism of astrocytes must complementarily match that of neurons to regulate brain function and animal welfare.

Keywords:  animal welfare; astrocytes; metabolic coupling; neurons; redox homeostasis

DOI:  https://doi.org/10.1042/EBC20220075
Sci Rep. 2023 Feb 20. 13(1): 2949

A monocarboxylate transporter-dependent mechanism confers resistance to exercise-induced fatigue in a high-altitude hypoxic environment.

Chen Gao, Binni Yang, Yurong Li, Wenjuan Pei.

The body is more prone to fatigue in a high-altitude hypoxic environment, in which fatigue occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance in brain energy metabolism. During strenuous exercise, lactate released from astrocytes is taken up by neurons via monocarboxylate transporters (MCTs) as a substrate for energy metabolism. The present study investigated the correlations among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury in a high-altitude hypoxic environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude, low-pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of MCT2 and MCT4 in the cerebral motor cortex, the average neuronal density in the hippocampus, and the brain lactate content. The results illustrate that the average exhaustive time, neuronal density, MCT expression and brain lactate content were positively correlated with the altitude acclimatization time. These findings demonstrate that an MCT-dependent mechanism is involved in the adaptability of the body to central fatigue and provide a potential basis for medical intervention for exercise-induced fatigue in a high-altitude hypoxic environment.

DOI: https://doi.org/10.1038/s41598-023-30093-1
Brain Res Bull. 2023 Feb 15. pii: S0361-9230(23)00041-2. [Epub ahead of print]195 78-85

Monocarboxylate transporter-dependent mechanism is involved in the adaptability of the body to exercise-induced fatigue under high-altitude hypoxia environment.

Chen Gao, Binni Yang, Yurong Li, Wenjuan Pei.

  Under high-altitude hypoxia environment, the body is more prone to fatigue, which occurs in both peripheral muscles and the central nervous system (CNS). The key factor determining the latter is the imbalance of brain energy metabolism, which makes it difficult to maintain the central nervous system to send peripheral nerve impulse continuously. During strenuous exercise, lactate released from astrocytes is taken up by neurons stored for energy to maintain synaptic transmission, a process mediated by monocarboxylate transporters (MCTs) in CNS. The present study investigated the correlation among the adaptability to exercise-induced fatigue, brain lactate metabolism and neuronal hypoxia injury under high-altitude hypoxia environment. Rats were subjected to exhaustive incremental load treadmill exercise under either normal pressure and normoxic conditions or simulated high-altitude low pressure and hypoxic conditions, with subsequent evaluation of the average exhaustive time as well as the expression of monocarboxylate transporters 2 (MCT2), MCT4, the average neuronal density in the cerebral motor cortex, and the lactate content in rat brain. At the early stage of simulated high-altitude environment, the average exhaustive time and neuronal density of rats decreased rapidly, then gradually recovered to some extent with the extension of altitude acclimatization time. The expression of MCT2, MCT4 and the lactate content in rat brain also increased gradually with the extension of altitude acclimatization time. After the application of lactate transport inhibitor, the recovery of exercise capacity of rats after altitude acclimatization was quickly blocked, and the neuronal injury in the cerebral motor cortex of rats was also significantly aggravated. These findings demonstrate that MCT-dependent mechanism is involved in the adaptability of the body to central fatigue, and provide a potential basis for medical intervention for exercise-induced fatigue under high-altitude hypoxia environment.

Keywords:  Altitude acclimatization; Fatigue; High altitude; Lactate; Monocarboxylate transporters; Rat

DOI:  https://doi.org/10.1016/j.brainresbull.2023.02.007
Mech Ageing Dev. 2023 Feb 22. pii: S0047-6374(23)00021-0. [Epub ahead of print] 111795

Sex-specific effects of high-fat diet on rat brain glucose metabolism and early-onset dementia symptoms.

Azam Abedi, Tahereh Foroutan, Leila Mohaghegh Shalmani, Leila Dargahi.

  Peripheral metabolic disturbances are associated with a variety of clinical health consequences and may contribute to the development of neurocognitive disorders. This study investigates whether long-term high-fat diet (HFD) consumption changes the brain glucose metabolism and impairs memory performance in a sex-dependent manner. Male and female rats, after weaning, were fed HFD or normal chow diet (NCD) for 16 weeks. Behavioral tests for spatial memory and an 18F-FDG-PET scan were performed. Also, the expression of brain insulin resistance markers and Alzheimer's pathology-related genes was assessed by qPCR. The Morris water maze and Y-maze results showed, respectively, that memory retrieval and spatial working memory were impaired only in HFD male rats compared to NCD controls. In addition, measuring whole brain 18F-FDG uptake indicated a significant reduction in glucose metabolism in male but not female HFD rats. Analysis of 15 genes related to glucose metabolism and Alzheimer's pathology, in the hippocampus, showed that expression of GLUT3, IRS2, and IDE is significantly reduced in HFD male rats. Our results suggest that sex affects the HFD-induced dysregulation of brain glucose metabolism and cognitive performance.

Keywords:  Brain glucose metabolism; Early-onset dementia; High fat diet; Insulin resistance

DOI:  https://doi.org/10.1016/j.mad.2023.111795
Biomedicines. 2023 Feb 16. pii: 583. [Epub ahead of print]11(2):

Neuroinflammation, Energy and Sphingolipid Metabolism Biomarkers Are Revealed by Metabolic Modeling of Autistic Brains.

Elif Esvap, Kutlu O Ulgen.

  Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders generally characterized by repetitive behaviors and difficulties in communication and social behavior. Despite its heterogeneous nature, several metabolic dysregulations are prevalent in individuals with ASD. This work aims to understand ASD brain metabolism by constructing an ASD-specific prefrontal cortex genome-scale metabolic model (GEM) using transcriptomics data to decipher novel neuroinflammatory biomarkers. The healthy and ASD-specific models are compared via uniform sampling to identify ASD-exclusive metabolic features. Noticeably, the results of our simulations and those found in the literature are comparable, supporting the accuracy of our reconstructed ASD model. We identified that several oxidative stress, mitochondrial dysfunction, and inflammatory markers are elevated in ASD. While oxidative phosphorylation fluxes were similar for healthy and ASD-specific models, and the fluxes through the pathway were nearly undisturbed, the tricarboxylic acid (TCA) fluxes indicated disruptions in the pathway. Similarly, the secretions of mitochondrial dysfunction markers such as pyruvate are found to be higher, as well as the activities of oxidative stress marker enzymes like alanine and aspartate aminotransferases (ALT and AST) and glutathione-disulfide reductase (GSR). We also detected abnormalities in the sphingolipid metabolism, which has been implicated in many inflammatory and immune processes, but its relationship with ASD has not been thoroughly explored in the existing literature. We suggest that important sphingolipid metabolites, such as sphingosine-1-phosphate (S1P), ceramide, and glucosylceramide, may be promising biomarkers for the diagnosis of ASD and provide an opportunity for the adoption of early intervention for young children.

Keywords:  autism spectrum disorder; genome-scale metabolic modeling; mitochondrial dysfunction; neuroinflammation; oxidative stress; sphingolipid

DOI:  https://doi.org/10.3390/biomedicines11020583
Nutr Neurosci. 2023 Feb 21. 1-11

Triheptanoin, an odd-medium-chain triglyceride, impacts brain cognitive function in young and aged mice.

L S da Rocha, C B Mendes, J S Silva, R L G F Alcides, I P Mendonça, B L S Andrade-da-Costa, S S Machado, A Ximenes-da-Silva.

  ABSTRACTThe brain aging process triggers cognitive function impairment, such as memory loss and compromised quality of life. Cognitive impairment is based on bioenergetic status, with reduced glucose uptake and metabolism in aged brains. Anaplerotic substrates are reported to promote mitochondrial ATP generation, having been tested in clinical trials for the treatment of neurological disorders and metabolic diseases.Objectives and Methods: To assess whether the improvement in oxidative capacity ameliorates cognitive function in adults (12 weeks), and aged (22-month-old) C57/6BJ mice, they received (1) a ketogenic diet, (2) a ketogenic diet supplemented with the anaplerotic substance, triheptanoin, or (3) a control diet for 12 weeks. Spontaneous alternation and time spent in a previously closed arm in the Y-maze test and time interacting with an unknown object in the novel object recognition test (NORT) were used to evaluate working memory. Acetylcholinesterase (AChE) activity in the prefrontal lobe, brain left hemisphere, and cerebellum was also evaluated. Glucose transporter 3 (GLUT3) expression in the prefrontal lobe was analyzed by western blotting.Results: The ketogenic diet (KD) reduced spontaneous alternation in aged mice, leading to lower AChE activity in the aged prefrontal lobe and cerebellum, and in the parieto-temporal-occipital lobe of adult mice. Furthermore, KD decreased GLUT3 protein expression in the frontal lobe of the adults.Discussion: Supplementation of KD with triheptanoin prevented memory impairment and showed similar values of AChE activity and GLUT3 expression compared to the controls. Our data suggest that triheptanoin has a potential role in the bioenergetic capacity of the brain, improving cognitive function.

Keywords:  Triheptanoin; aging; brain; ketogenic diet; memory

DOI:  https://doi.org/10.1080/1028415X.2023.2178096
Neurochem Int. 2023 Feb 15. pii: S0197-0186(23)00029-3. [Epub ahead of print]164 105501

Cholesterol metabolism: Towards a therapeutic approach for multiple sclerosis.

Yu-Han Gao, Xing Li.

  Growing evidence points to the importance of cholesterol in preserving brain homeostasis. Cholesterol makes up the main component of myelin in the brain, and myelin integrity is vital in demyelinating diseases such as multiple sclerosis. Because of the connection between myelin and cholesterol, the interest in cholesterol in the central nervous system increased during the last decade. In this review, we provide a detailed overview on brain cholesterol metabolism in multiple sclerosis and its role in promoting oligodendrocyte precursor cell differentiation and remyelination.

Keywords:  Central nervous system; Cholesterol metabolism; Multiple sclerosis; Myelin

DOI:  https://doi.org/10.1016/j.neuint.2023.105501
Biology (Basel). 2023 Feb 03. pii: 242. [Epub ahead of print]12(2):

Effects of Ventromedial Hypothalamic Nucleus (VMN) Aromatase Gene Knockdown on VMN Glycogen Metabolism and Glucoregulatory Neurotransmission.

Karen P Briski, A S M Hasan Mahmood, Md Main Uddin, Mostafa M H Ibrahim, Khaggeswar Bheemanapally.

  The enzyme aromatase is expressed at high levels in the ventromedial hypothalamic nucleus (VMN), a principal component of the brain gluco-regulatory network. Current research utilized selective gene knockdown tools to investigate the premise that VMN neuroestradiol controls glucostasis. Intra-VMN aromatase siRNA administration decreased baseline aromatase protein expression and tissue estradiol concentrations and either reversed or attenuated the hypoglycemic regulation of these profiles in a VMN segment-specific manner. Aromatase gene repression down-regulated protein biomarkers for gluco-stimulatory (nitric oxide; NO) and -inhibitory (gamma-aminobutyric acid; GABA) neurochemical transmitters. Insulin-induced hypoglycemia (IIH) up- or down-regulated neuronal nitric oxide synthase (nNOS) and glutamate decarboxylase65/67 (GAD), respectively, throughout the VMN. Interestingly, IIH caused divergent changes in tissue aromatase and estradiol levels in rostral (diminished) versus middle and caudal (elevated) VMN. Aromatase knockdown prevented hypoglycemic nNOS augmentation in VMN middle and caudal segments, but abolished the GAD inhibitory response to IIH throughout this nucleus. VMN nitrergic and GABAergic neurons monitor stimulus-specific glycogen breakdown. Here, glycogen synthase (GS) and phosphorylase brain- (GPbb; AMP-sensitive) and muscle- (GPmm; noradrenergic -responsive) type isoform responses to aromatase siRNA were evaluated. Aromatase repression reduced GPbb and GPmm content in euglycemic controls and prevented hypoglycemic regulation of GPmm but not GPbb expression while reversing glycogen accumulation. Aromatase siRNA elevated baseline glucagon and corticosterone secretion and abolished hypoglycemic hyperglucagonemia and hypercorticosteronemia. Outcomes document the involvement of VMN neuroestradiol signaling in brain control of glucose homeostasis. Aromatase regulation of VMN gluco-regulatory signaling of hypoglycemia-associated energy imbalance may entail, in part, control of GP variant-mediated glycogen disassembly.

Keywords:  aromatase; gene knockdown; glutamate decarboxylase; insulin-induced hypoglycemia; neuronal nitric oxide synthase; ventromedial hypothalamic nucleus

DOI:  https://doi.org/10.3390/biology12020242
bioRxiv. 2023 Feb 18. pii: 2023.02.17.528992. [Epub ahead of print]

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and glycerol-mediated gluconeogenesis in mice.

Nicole K H Yiew, Daniel Ferguson, Kevin Cho, Stanislaw Deja, Chaowapong Jarasvaraparn, Andrew J Lutkewitte, Sandip Mukherjee, Xiaorong Fu, Jason M Singer, Gary J Patti, Shawn C Burgess, Brian N Finck.

The liver coordinates the systemic response to nutrient deprivation and availability by producing glucose from gluconeogenesis during fasting and synthesizing lipids via de novo lipogenesis (DNL) when carbohydrates are abundant. Mitochondrial pyruvate metabolism is believed to play important roles in both gluconeogenesis and DNL. We examined the effects of hepatocyte-specific mitochondrial pyruvate carrier (MPC) deletion on the fasting-refeeding response. Rates of DNL during refeeding were impaired by liver MPC deletion, but this did not reduce intrahepatic lipid content. During fasting, glycerol is converted to glucose by two pathways; a cytosolic pathway essentially reversing glycolysis and a mitochondrial pathway requiring the MPC. MPC deletion reduced the incorporation of 13 C-glycerol into TCA cycle metabolites but not into newly synthesized glucose. However, suppression of glycerol metabolism did not affect glucose concentrations in fasted hepatocyte-specific MPC-deficient mice. Thus, glycerol-mediated gluconeogenesis and glucose production by kidney and intestine may compensate for MPC deficiency in hepatocytes.

DOI: https://doi.org/10.1101/2023.02.17.528992
Antioxidants (Basel). 2023 Feb 15. pii: 491. [Epub ahead of print]12(2):

Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death.

Beom-Seok Kang, Bo-Young Choi, A-Ra Kho, Song-Hee Lee, Dae-Ki Hong, Min-Kyu Park, Si-Hyun Lee, Chang-Juhn Lee, Hyeun-Wook Yang, Seo-Young Woo, Se-Wan Park, Dong-Yeon Kim, Jae-Bong Park, Won-Suk Chung, Sang-Won Suh.

  Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte-neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.

Keywords:  astrocyte–neuron lactate shuttle; global cerebral ischemia; neuronal death; pyruvate kinase M2; sodium l-lactate

DOI:  https://doi.org/10.3390/antiox12020491
Antioxidants (Basel). 2023 Jan 28. pii: 293. [Epub ahead of print]12(2):

Ether Lipid-Mediated Antioxidant Defense in Alzheimer's Disease.

Mariona Jové, Natàlia Mota-Martorell, Èlia Obis, Joaquim Sol, Meritxell Martín-Garí, Isidre Ferrer, Manuel Portero-Otin, Reinald Pamplona.

  One of the richest tissues in lipid content and diversity of the human body is the brain. The human brain is constitutively highly vulnerable to oxidative stress. This oxidative stress is a determinant in brain aging, as well as in the onset and progression of sporadic (late-onset) Alzheimer's disease (sAD). Glycerophospholipids are the main lipid category widely distributed in neural cell membranes, with a very significant presence for the ether lipid subclass. Ether lipids have played a key role in the evolution of the human brain compositional specificity and functionality. Ether lipids determine the neural membrane structural and functional properties, membrane trafficking, cell signaling and antioxidant defense mechanisms. Here, we explore the idea that ether lipids actively participate in the pathogenesis of sAD. Firstly, we evaluate the quantitative relevance of ether lipids in the human brain composition, as well as their role in the human brain evolution. Then, we analyze the implications of ether lipids in neural cell physiology, highlighting their inherent antioxidant properties. Finally, we discuss changes in ether lipid content associated with sAD and their physiopathological implications, and propose a mechanism that, as a vicious cycle, explains the potential significance of ether lipids in sAD.

Keywords:  antioxidants; human brain; lipid oxidation; lipidomics; neurodegeneration; plasmalogens

DOI:  https://doi.org/10.3390/antiox12020293
Epilepsy Behav. 2023 Feb 16. pii: S1525-5050(23)00026-4. [Epub ahead of print]140 109108

2DG and glycolysis as therapeutic targets for status epilepticus.

Thomas P Sutula, Nathan B Fountain.

  2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE.

Keywords:  2-deoxy-D-glucose; Epilepsy; Glycolytic inhibition; Metabolism; Seizures

DOI:  https://doi.org/10.1016/j.yebeh.2023.109108
Neurology. 2023 Feb 20. pii: 10.1212/WNL.0000000000207142. [Epub ahead of print]

Pearls & Oysters: Paroxysmal Exercise-Induced Dyskinesias Due to Pyruvate Dehydrogenase Deficiency.

Claudio M de Gusmao, Isabella Peixoto de Barcelos, Anna L R Pinto, Laura Silveira-Moriyama.

Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency or mitochondrial respiratory chain disorders. A 4-year-old boy with a history of febrile seizures presented with paroxysmal dystonia, triggered by exercise, or occurring at rest. Additional investigations demonstrated pallidal hyperintensities on brain MRI and low CSF glucose. Pyruvate and lactate were elevated. The clinical presentation, combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurological presentations.

DOI: https://doi.org/10.1212/WNL.0000000000207142
Mol Neurobiol. 2023 Feb 21.

HPRT1 Deficiency Induces Alteration of Mitochondrial Energy Metabolism in the Brain.

Andrey Y Vinokurov, Vladislav O Soldatov, Evgenia S Seregina, Angelina I Dolgikh, Pavel A Tagunov, Andrey V Dunaev, Marina Y Skorkina, Alexey V Deykin, Andrey Y Abramov.

  Alterations in function of hypoxanthine guanine phosphoribosyl transferase (HPRT), one of the major enzymes involved in purine nucleotide exchange, lead to overproduction of uric acid and produce various symptoms of Lesch-Nyhan syndrome (LNS). One of the hallmarks of LNS is maximal expression of HPRT in the central nervous system with the highest activity of this enzyme in the midbrain and basal ganglia. However, the nature of neurological symptoms has yet to be clarified in details. Here, we studied whether HPRT1 deficiency changes mitochondrial energy metabolism and redox balance in murine neurons from the cortex and midbrain. We found that HPRT1 deficiency inhibits complex I-dependent mitochondrial respiration resulting in increased levels of mitochondrial NADH, reduction of the mitochondrial membrane potential, and increased rate of reactive oxygen species (ROS) production in mitochondria and cytosol. However, increased ROS production did not induce oxidative stress and did not decrease the level of endogenous antioxidant glutathione (GSH). Thus, disruption of mitochondrial energy metabolism but not oxidative stress could play a role of potential trigger of brain pathology in LNS.

Keywords:  Complex I inhibition; HPRT deficiency; Mitochondrial dysfunction; Reactive oxygen species

DOI:  https://doi.org/10.1007/s12035-023-03266-2
Commun Biol. 2023 Feb 23. 6(1): 210

Lysosomal phospholipase A2 contributes to the biosynthesis of the atypical late endosome lipid bis(monoacylglycero)phosphate.

Jacinda Chen, Amaury Cazenave-Gassiot, Yimeng Xu, Paola Piroli, Robert Hwang, Laura DeFreitas, Robin Barry Chan, Gilbert Di Paolo, Renu Nandakumar, Markus R Wenk, Catherine Marquer.

The late endosome/lysosome (LE/Lys) lipid bis(monoacylglycero)phosphate (BMP) plays major roles in cargo sorting and degradation, regulation of cholesterol and intercellular communication and has been linked to viral infection and neurodegeneration. Although BMP was initially described over fifty years ago, the enzymes regulating its synthesis remain unknown. The first step in the BMP biosynthetic pathway is the conversion of phosphatidylglycerol (PG) into lysophosphatidylglycerol (LPG) by a phospholipase A2 (PLA2) enzyme. Here we report that this enzyme is lysosomal PLA2 (LPLA2). We show that LPLA2 is sufficient to convert PG into LPG in vitro. We show that modulating LPLA2 levels regulates BMP levels in HeLa cells, and affects downstream pathways such as LE/Lys morphology and cholesterol levels. Finally, we show that in a model of Niemann-Pick disease type C, overexpressing LPLA2 alleviates the LE/Lys cholesterol accumulation phenotype. Altogether, we shed new light on BMP biosynthesis and contribute tools to regulate BMP-dependent pathways.

DOI: https://doi.org/10.1038/s42003-023-04573-z
J Neurochem. 2023 Feb 23.

Lipid metabolism in dopaminergic neurons influences light entrainment.

Regina F Fernandez, Emily S Wilson, Victoria Diaz, Jonatan Martínez-Gardeazabal, Rachel Foguth, Jason R Cannon, Shelley N Jackson, Brian P Hermann, Jeffrey B Eells, Jessica M Ellis.

Dietary lipids, particularly omega-3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of circadian rhythms. However, the ability to draw a direct link between dopaminergic omega-3 fatty acid metabolism and behavioral outcomes has been limited to the use of diet-based approaches, which are confounded by systemic effects. Here, neuronal lipid metabolism was targeted in a diet-independent manner by manipulation of long-chain acyl-CoA synthetase 6 (ACSL6) expression. ACSL6 performs the initial reaction for cellular fatty acid metabolism and prefers the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). The loss of Acsl6 in mice (Acsl6-/- ) depletes neuronal membranes of DHA content and results in phenotypes linked to dopaminergic control, such as hyperlocomotion, impaired short-term spatial memory, and imbalances in dopamine neurochemistry. To investigate the role of dopaminergic ACSL6 on these outcomes, a dopaminergic neuron-specific ACSL6 knockout mouse was generated (Acsl6DA-/- ). Acsl6DA-/- mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6-/- and the Acsl6DA-/- mice were similar to control mice under basal conditions. However, upon light entrainment, a mimetic of jetlag, both the complete knockout of ACSL6 and the dopaminergic-neuron specific loss of ACSL6 resulted in a longer recovery to entrainment compared to control mice. In conclusion, these data demonstrate that ACSL6 in dopaminergic neurons alters dopamine metabolism and regulation of light entrainment suggesting that DHA-metabolism mediated by ACSL6 plays a role in dopamine neuron biology.

DOI: https://doi.org/10.1111/jnc.15793
J Neuroinflammation. 2023 Feb 20. 20(1): 43

Amyloid-β accumulation in human astrocytes induces mitochondrial disruption and changed energy metabolism.

Marlena Zyśk, Chiara Beretta, Luana Naia, Abdulkhalek Dakhel, Linnea Påvénius, Hjalmar Brismar, Maria Lindskog, Maria Ankarcrona, Anna Erlandsson.

  BACKGROUND: Astrocytes play a central role in maintaining brain energy metabolism, but are also tightly connected to the pathogenesis of Alzheimer's disease (AD). Our previous studies demonstrate that inflammatory astrocytes accumulate large amounts of aggregated amyloid-beta (Aβ). However, in which way these Aβ deposits influence their energy production remain unclear.METHODS: The aim of the present study was to investigate how Aβ pathology in astrocytes affects their mitochondria functionality and overall energy metabolism. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ42 fibrils for 7 days and analyzed over time using different experimental approaches.
RESULTS: Our results show that to maintain stable energy production, the astrocytes initially increased their mitochondrial fusion, but eventually the Aβ-mediated stress led to abnormal mitochondrial swelling and excessive fission. Moreover, we detected increased levels of phosphorylated DRP-1 in the Aβ-exposed astrocytes, which co-localized with lipid droplets. Analysis of ATP levels, when blocking certain stages of the energy pathways, indicated a metabolic shift to peroxisomal-based fatty acid β-oxidation and glycolysis.
CONCLUSIONS: Taken together, our data conclude that Aβ pathology profoundly affects human astrocytes and changes their entire energy metabolism, which could result in disturbed brain homeostasis and aggravated disease progression.

Keywords:  Alzheimer’s disease; DRP-1; Glia; Lipid droplets; Mitochondria dynamics

DOI:  https://doi.org/10.1186/s12974-023-02722-z
Biomedicines. 2023 Jan 24. pii: 329. [Epub ahead of print]11(2):

The Imbalance of Astrocytic Mitochondrial Dynamics Following Blast-Induced Traumatic Brain Injury.

Fernanda Guilhaume-Correa, Alicia M Pickrell, Pamela J VandeVord.

  Mild blast-induced traumatic brain injury (bTBI) is a modality of injury that has been of major concern considering a large number of military personnel exposed to explosive blast waves. bTBI results from the propagation of high-pressure static blast forces and their subsequent energy transmission within brain tissue. Exposure to this overpressure energy causes a diffuse injury that leads to acute cell damage and, if chronic, leads to detrimental long-term cognitive deficits. The literature presents a neuro-centric approach to the role of mitochondria dynamics dysfunction in bTBI, and changes in astrocyte-specific mitochondrial dynamics have not been characterized. The balance between fission and fusion events is known as mitochondrial dynamics. As a result of fission and fusion, the mitochondrial structure is constantly altering its shape to respond to physiological stimuli or stress, which in turn affects mitochondrial function. Astrocytic mitochondria are recognized to play an essential role in overall brain metabolism, synaptic transmission, and neuron protection. Mitochondria are vulnerable to injury insults, leading to the increase in mitochondrial fission, a mechanism controlled by the GTPase dynamin-related protein (Drp1) and the phosphorylation of Drp1 at serine 616 (p-Drp1s616). This site is critical to mediate the Drp1 translocation to mitochondria to promote fission events and consequently leads to fragmentation. An increase in mitochondrial fragmentation could have negative consequences, such as promoting an excessive generation of reactive oxygen species or triggering cytochrome c release. The aim of the present study was to characterize the unique pattern of astrocytic mitochondrial dynamics by exploring the role of DRP1 with a combination of in vitro and in vivo bTBI models. Differential remodeling of the astrocytic mitochondrial network was observed, corresponding with increases in p-Drp1S616 four hours and seven days post-injury. Further, results showed a time-dependent reactive astrocyte phenotype transition in the rat hippocampus. This discovery can lead to innovative therapeutics targets to help prevent the secondary injury cascade after blast injury that involves mitochondria dysfunction.

Keywords:  acute; astrocytes; blast-induced traumatic brain injury; fission and dynamin-related protein; mild; mitochondrial dynamics; sub-acute

DOI:  https://doi.org/10.3390/biomedicines11020329
Cells. 2023 Feb 13. pii: 611. [Epub ahead of print]12(4):

Mitochondrial Lipid Peroxidation Is Responsible for Ferroptosis.

Konstantin G Lyamzaev, Alisa A Panteleeva, Ruben A Simonyan, Armine V Avetisyan, Boris V Chernyak.

  Ferroptosis induced by erastin (an inhibitor of cystine transport) and butionine sulfoximine (an inhibitor of glutathione biosynthesis) was prevented by the mitochondria-targeted antioxidants SkQ1 and MitoTEMPO. These effects correlate with the prevention of mitochondrial lipid peroxidation, which precedes cell death. Methylene blue, a redox agent that inhibits the production of reactive oxygen species (ROS) in complex I of the mitochondrial electron transport chain, also inhibits ferroptosis and mitochondrial lipid peroxidation. Activation of ROS production in complex I with rotenone in the presence of ferrous iron stimulates lipid peroxidation in isolated mitochondria, while ROS produced by complex III are ineffective. SkQ1 and methylene blue inhibit lipid peroxidation. We suggest that ROS formed in complex I promote mitochondrial lipid peroxidation and ferroptosis.

Keywords:  complex I; ferroptosis; mitochondria; mitochondria targeted antioxidants; mtROS

DOI:  https://doi.org/10.3390/cells12040611
Front Neurosci. 2023 ;17 1123967

Liver's influence on the brain through the action of bile acids.

Xin Yi Yeo, Li Yang Tan, Woo Ri Chae, Dong-Yup Lee, Yong-An Lee, Torsten Wuestefeld, Sangyong Jung.

  The liver partakes as a sensor and effector of peripheral metabolic changes and a regulator of systemic blood and nutrient circulation. As such, abnormalities arising from liver dysfunction can influence the brain in multiple ways, owing to direct and indirect bilateral communication between the liver and the brain. Interestingly, altered bile acid composition resulting from perturbed liver cholesterol metabolism influences systemic inflammatory responses, blood-brain barrier permeability, and neuron synaptic functions. Furthermore, bile acids produced by specific bacterial species may provide a causal link between dysregulated gut flora and neurodegenerative disease pathology through the gut-brain axis. This review will cover the role of bile acids-an often-overlooked category of active metabolites-in the development of neurological disorders associated with neurodegeneration. Further studies into bile acid signaling in the brain may provide insights into novel treatments against neurological disorders.

Keywords:  bile acid; brain; gut microbiome; liver; neurodegeneration

DOI:  https://doi.org/10.3389/fnins.2023.1123967
bioRxiv. 2023 Feb 19. pii: 2023.02.18.529095. [Epub ahead of print]

A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity.

Abbi R Hernandez, Maya E Barrett, Katelyn N Lubke, Andrew P Maurer, Sara N Burke.

Age-related cognitive decline has been linked to distinct patterns of cellular dysfunction in the prelimbic cortex (PL) and the CA3 subregion of the hippocampus. Because higher cognitive functions require both structures, selectively targeting a neurobiological change in one region, at the expense of the other, is not likely to restore normal behavior in older animals. One change with age that both the PL and CA3 share, however, is a reduced ability to utilize glucose, which can produce aberrant neural activity patterns. The current study used a ketogenic diet (KD) intervention, which reduces the brainâ€™s reliance on glucose, and has been shown to improve cognition, as a metabolic treatment for restoring neural ensemble dynamics in aged rats. Expression of the immediate-early genes Arc and Homer 1a were used to quantify the neural ensembles that were active in the home cage prior to behavior, during a working memory/biconditional association task, and a continuous spatial alternation task. Aged rats on the control diet had increased activity in CA3 and less ensemble overlap in PL between different task conditions than did the young animals. In the PL, the KD was associated with increased activation of neurons in the superficial cortical layers. The KD did not lead to any significant changes in CA3 activity. These observations suggest that the KD does not restore neuron activation patterns in aged animals, but rather the availability of ketone bodies in the frontal cortices may permit the engagement of compensatory mechanisms that produce better cognitive outcomes.Significance Statement: This study extends understanding of how a ketogenic diet (KD) intervention may improve cognitive function in older adults. Young and aged rats were given 3 months of a KD or a calorie-match control diet and then expression of the immediate-early genes Arc and Homer 1a were measured to examine neural ensemble dynamics during cognitive testing. The KD diet was associated with increased activation of neurons in the superficial layers of the PL, but there were no changes in CA3. These observations are significant because they suggest that compensatory mechanisms for improving cognition are engaged in the presence of elevated ketone bodies. This metabolic shift away from glycolysis can meet the energetic needs of the frontal cortices when glucose utilization is compromised.

DOI: https://doi.org/10.1101/2023.02.18.529095
Aging Dis. 2023 Feb 01. 14(1): 63-83

Neuroglia Cells Transcriptomic in Brain Development, Aging and Neurodegenerative Diseases.

Leonard Radu Pinosanu, Bogdan Capitanescu, Daniela Glavan, Sanziana Godeanu, Israel Ferna Ndez Cadenas, Thorsten R Doeppner, Dirk M Hermann, Adrian-Tudor Balseanu, Catalin Bogdan, Aurel Popa-Wagner.

  Glia cells are essential for brain functioning during development, aging and disease. However, the role of astroglia plays during brain development is quite different from the role played in the adult lesioned brain. Therefore, a deeper understanding of pathomechanisms underlying astroglia activity in the aging brain and cerebrovascular diseases is essential to guide the development of new therapeutic strategies. To this end, this review provides a comparison between the transcriptomic activity of astroglia cells during development, aging and neurodegenerative diseases, including cerebral ischemia. During fetal brain development, astrocytes and microglia often affect the same developmental processes such as neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, and synaptic pruning. In the adult brain astrocytes are a critical player in the synapse remodeling by mediating synapse elimination while microglia activity has been associated with changes in synaptic plasticity and remove cell debris by constantly sensing the environment. However, in the lesioned brain astrocytes proliferate and play essential functions with regard to energy supply to the neurons, neurotransmission and buildup of a protective scar isolating the lesion site from the surroundings. Inflammation, neurodegeneration, or loss of brain homeostasis induce changes in microglia gene expression, morphology, and function, generally referred to as "primed" microglia. These changes in gene expression are characterized by an enrichment of phagosome, lysosome, and antigen presentation signaling pathways and is associated with an up-regulation of genes encoding cell surface receptors. In addition, primed microglia are characterized by upregulation of a network of genes in response to interferon gamma. Conclusion. A comparison of astroglia cells transcriptomic activity during brain development, aging and neurodegenerative disorders might provide us with new therapeutic strategies with which to protect the aging brain and improve clinical outcome.

Keywords:  astrocytes; brain; development; microglia; neurodegeneration; transcriptomics

DOI:  https://doi.org/10.14336/AD.2022.0621
ASN Neuro. 2023 Jan-Dec;15:15 17590914231157974

Age-Associated Upregulation of Glutamate Transporters and Glutamine Synthetase in Senescent Astrocytes In Vitro and in the Mouse and Human Hippocampus.

Isadora Matias, Luan Pereira Diniz, Ana Paula Bergamo Araujo, Isabella Vivarini Damico, Pâmella de Moura, Felipe Cabral-Miranda, Fabiola Diniz, Belisa Parmeggiani, Valeria de Mello Coelho, Renata E P Leite, Claudia K Suemoto, Gustavo Costa Ferreira, Regina Célia Cussa Kubrusly, Flávia Carvalho Alcantara Gomes.

  Aging is marked by complex and progressive physiological changes, including in the glutamatergic system, that lead to a decline of brain function. Increased content of senescent cells in the brain, such as glial cells, has been reported to impact cognition both in animal models and human tissue during normal aging and in the context of neurodegenerative disease. Changes in the glutamatergic synaptic activity rely on the glutamate-glutamine cycle, in which astrocytes handle glutamate taken up from synapses and provide glutamine for neurons, thus maintaining excitatory neurotransmission. However, the mechanisms of glutamate homeostasis in brain aging are still poorly understood. Herein, we showed that mouse senescent astrocytes in vitro undergo upregulation of GLT-1, GLAST, and glutamine synthetase (GS), along with the increased enzymatic activity of GS and [3H]-D-aspartate uptake. Furthermore, we observed higher levels of GS and increased [3H]-D-aspartate uptake in the hippocampus of aged mice, although the activity of GS was similar between young and old mice. Analysis of a previously available RNAseq dataset of mice at different ages revealed upregulation of GLAST and GS mRNA levels in hippocampal astrocytes during aging. Corroborating these rodent data, we showed an increased number of GS + cells, and GS and GLT-1 levels/intensity in the hippocampus of elderly humans. Our data suggest that aged astrocytes undergo molecular and functional changes that control glutamate-glutamine homeostasis upon brain aging.

Keywords:  GLT-1; aging; astrocyte; glutamate-glutamine cycle; hippocampus; senescence

DOI:  https://doi.org/10.1177/17590914231157974
Genes (Basel). 2023 Jan 17. pii: 246. [Epub ahead of print]14(2):

Involvement of Mitochondrial Dysfunction in FOXG1 Syndrome.

Victoria A Bjerregaard, Amanda M Levy, Mille S Batz, Ravina Salehi, Mathis Hildonen, Trine B Hammer, Rikke S Møller, Claus Desler, Zeynep Tümer.

  FOXG1 (Forkhead box g1) syndrome is a neurodevelopmental disorder caused by a defective transcription factor, FOXG1, important for normal brain development and function. As FOXG1 syndrome and mitochondrial disorders have shared symptoms and FOXG1 regulates mitochondrial function, we investigated whether defective FOXG1 leads to mitochondrial dysfunction in five individuals with FOXG1 variants compared to controls (n = 6). We observed a significant decrease in mitochondrial content and adenosine triphosphate (ATP) levels and morphological changes in mitochondrial network in the fibroblasts of affected individuals, indicating involvement of mitochondrial dysfunction in FOXG1 syndrome pathogenesis. Further investigations are warranted to elucidate how FOXG1 deficiency impairs mitochondrial homeostasis.

Keywords:  FOXG1 syndrome; mitochondrial dysfunction; mitochondrial homeostasis; mitochondrial morphology; mitochondrial respiratory capacity; neurodevelopmental disorders

DOI:  https://doi.org/10.3390/genes14020246
Cell Mol Life Sci. 2023 Feb 23. 80(3): 71

Mfsd2a attenuated hypoxic-ischemic brain damage via protection of the blood-brain barrier in mfat-1 transgenic mice.

Xiaoxue Li, Yumeng Zhang, Jianghao Chang, Chenglin Zhang, Lin Li, Yifan Dai, Haiyuan Yang, Ying Wang.

  Previous studies have shown that mfat-1 transgenic mice have protective effects against some central nervous system (CNS) disorders, owing to the high docosahexaenoic acid (DHA) content enriched in their brains. However, whether this protective effect is connected to the blood-brain barrier (BBB) remains unclear. This study aims to investigate the mechanisms of the protective effect against hypoxic-ischemic brain damage (HIBD) of mfat-1 transgenic mice. mfat-1 mice not only demonstrated a significant amelioration of neurological dysfunction and neuronal damage but also partly maintained the physiological permeability of the BBB after HIBD. We initially showed this was associated with elevated major facilitator superfamily domain-containing 2a (Mfsd2a) expression on the BBB, resulting from more lysophosphatidylcholine (LPC)-DHA entering the brain. Wild-type (WT) mice showed a similar Mfsd2a expression trend after long-term feeding with an LPC-DHA-rich diet. Knockdown of Mfsd2a by siRNA intra-cerebroventricular (ICV) injection neutralized the protective effect against HIBD-induced BBB disruption in mfat-1 mice, further validating the protective function of Mfsd2a on BBB. HIBD-induced BBB high permeability was attenuated by Mfsd2a, primarily through a transcellular pathway to decrease caveolae-like vesicle-mediated transcytosis. Taken together, these findings not only reveal that mfat-1 transgenic mice have higher expression of Mfsd2a on the BBB, which partly sustains BBB permeability via vesicular transcytosis to alleviate the severity of HIBD, but also suggest that dietary intake of LPC-DHA may upregulate Mfsd2a expression as a novel therapeutic strategy for BBB dysfunction and survival in HIBD patients.

Keywords:  Apoptosis; Hepatocytes; LC–MS/MS; NormFinder; PLA1; TEM

DOI:  https://doi.org/10.1007/s00018-023-04716-9
J Cereb Blood Flow Metab. 2023 Feb 21. 271678X231157958

The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats.

Nisha Singh, Eilidh MacNicol, Ottavia DiPasquale, Karen Randall, David Lythgoe, Ndabezinhle Mazibuko, Camilla Simmons, Pierluigi Selvaggi, Stephanie Stephenson, Federico E Turkheimer, Diana Cash, Fernando Zelaya, Alessandro Colasanti.

  Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p = 0.02) and rats (F(1,5)26.04, p = 0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p = 0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t = 2.6(16) p = 0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB's hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB's ability to enhance cerebral metabolism might be limited.

Keywords:  Cerebral blood flow; Methylene Blue; cerebral glucose metabolism; cerebral oxygen metabolism; imaging

DOI:  https://doi.org/10.1177/0271678X231157958
Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00005-1. [Epub ahead of print]194 65-78

Stroke-like episodes in adult mitochondrial disease.

Yi Shiau Ng, Gráinne S Gorman.

  Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients. In addition, several lines of evidence supporting neuronal hyper-excitability as the key mechanism of stroke-like episodes are discussed. The management of stroke-like episodes should focus on aggressive seizure management and treatment for concomitant complications such as intestinal pseudo-obstruction. There is no robust evidence to prove the efficacy of l-arginine for both acute and prophylactic settings. Progressive brain atrophy and dementia are the sequalae of recurrent stroke-like episode, and the underlying genotype in part predicts prognosis.

Keywords:  MELAS; Neuronal hyper-excitability; POLG; Seizures; Status epilepticus; m.3243A>G

DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00005-1
Glia. 2023 Feb 22.

Neurotoxicity of ischemic astrocytes involves STAT3-mediated metabolic switching and depends on glycogen usage.

Mina Borbor, Dongpei Yin, Ulf Brockmeier, Chen Wang, Marius Doeckel, Matthias Pillath-Eilers, Britta Kaltwasser, Dirk M Hermann, Egor Dzyubenko.

  Astrocytic responses are critical for the maintenance of neuronal networks in health and disease. In stroke, reactive astrocytes undergo functional changes potentially contributing to secondary neurodegeneration, but the mechanisms of astrocyte-mediated neurotoxicity remain elusive. Here, we investigated metabolic reprogramming in astrocytes following ischemia-reperfusion in vitro, explored their role in synaptic degeneration, and verified the key findings in a mouse model of stroke. Using indirect cocultures of primary mouse astrocytes and neurons, we demonstrate that transcription factor STAT3 controls metabolic switching in ischemic astrocytes promoting lactate-directed glycolysis and hindering mitochondrial function. Upregulation of astrocytic STAT3 signaling associated with nuclear translocation of pyruvate kinase isoform M2 and hypoxia response element activation. Reprogrammed thereby, the ischemic astrocytes induced mitochondrial respiration failure in neurons and triggered glutamatergic synapse loss, which was prevented by inhibiting astrocytic STAT3 signaling with Stattic. The rescuing effect of Stattic relied on the ability of astrocytes to utilize glycogen bodies as an alternative metabolic source supporting mitochondrial function. After focal cerebral ischemia in mice, astrocytic STAT3 activation was associated with secondary synaptic degeneration in the perilesional cortex. Inflammatory preconditioning with LPS increased astrocytic glycogen content, reduced synaptic degeneration, and promoted neuroprotection post stroke. Our data indicate the central role of STAT3 signaling and glycogen usage in reactive astrogliosis and suggest novel targets for restorative stroke therapy.

Keywords:  astrocyte-neuronal interaction; cerebral ischemia; glycolysis; metabolic reprogramming; neuroprotection; oxidative phosphorylation; synaptic degeneration

DOI:  https://doi.org/10.1002/glia.24357
Mol Psychiatry. 2023 Feb 21.

GWAS-identified bipolar disorder risk allele in the FADS1/2 gene region links mood episodes and unsaturated fatty acid metabolism in mutant mice.

Hirona Yamamoto, Hyeon-Cheol Lee-Okada, Masashi Ikeda, Takumi Nakamura, Takeo Saito, Atsushi Takata, Takehiko Yokomizo, Nakao Iwata, Tadafumi Kato, Takaoki Kasahara.

Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.

DOI: https://doi.org/10.1038/s41380-023-01988-2
Curr Drug Saf. 2023 Feb 22.

Protective effect of quercetin against paraquat-induced brain mitochondrial disruption in mice.

Parisa Saberi-Hasanabadi, Reza Sedaghatnejad, Hamidreza Mohammadi.

  BACKGROUND: Paraquat is a highly toxic quaternary ammonium herbicide widely used in agriculture. It is an agent that induces pulmonary toxicity via the redox cyclic reaction.OBJECTIVE: The present study investigated the protective effect of quercetin against paraquat-induced brain mitochondria disruption in mice.
METHODS: Paraquat (1.25 mg/kg, intraperitoneally) was administered to the mice, and then quercetin (50, 100, 200 mg/kg) was injected i.p. Oxidative damage biomarkers such as reactive oxygen species, protein carbonyl, lipid peroxidation, glutathione content, and mitochondrial function were assessed in the brain mitochondria.
RESULTS: The results showed that paraquat significantly (P < 0.001) increased the reactive oxygen species, protein carbonyl, and lipid peroxidation and significantly (P <0.0001) decreased the glutathione content and mitochondrial function in the brain cells. Administration of the quercetin at doses of 50, 100, and 200 mg/kg significantly reduced reactive oxygen species, lipid peroxidation, and protein carbonyl and improved mitochondrial function and glutathione content in the mice brain mitochondrial compared to the paraquat group. Quercetin at 200 mg/kg dose had better effectiveness than 50 and 100 mg/kg doses.
CONCLUSION: Our results suggest that quercetin in a dose-dependent manner has neuroprotective effects, probably by free radicals scavenging or enhancing the antioxidant mechanisms in the brain mitochondria. It seems that quercetin could modulate protein and lipid oxidation and improve oxidative damage induced by paraquat in the early stages.

Keywords:  Glutathione; Mitochondria; Neuroprotective; Oxidative stress; Paraquat; Quercetin

DOI:  https://doi.org/10.2174/1574886318666230222123346
Heliyon. 2023 Feb;9(2): e13446

Short- and long-term cognitive and metabolic effects of medium-chain triglyceride supplementation in rats.

Ksenia Shcherbakova, Alexander Schwarz, Irina Ivleva, Veronika Nikitina, Darya Krytskaya, Sergey Apryatin, Marina Karpenko, Alexander Trofimov.

  Medium-chain triglycerides (MCT) possess neuroprotective properties. However, the long-term metabolic consequences of supplementing a regular diet with cognition-enhancing doses of MCT are largely unknown. We studied the effects of chronic (28 days) supplementation of regular diet with different doses of MCT oil (1, 3, or 6 g/kg/day) or water (control) on working memory (Y-maze), behavior in the Open Field, spatial learning (Morris water maze), and weight of internal organs in male Wistar 2.5-m.o. Rats. In a separate experiment, we evaluated acute (single gavage) and chronic (28 days) effects of MCT or lard supplementation (3 g/kg) on blood biochemical parameters. MCT-1 and MCT-3 doses improved working memory in YM. In MWM, MCT-6 treatment improved spatial memory. Chronic MCT-1 or MCT-3 treatment did not affect internal organ weight, while MCT-6 dose increased liver weight and the brown/white adipose tissue ratio. Acutely, MCT administration elevated blood β-hydroxybutyrate and malondialdehyde levels. Chronic MCT administration (3 g/kg) did not affect the blood levels of glucose, lactate, pyruvate, acetoacetate, β-hydroxybutyrate, total and HDL cholesterol, triglycerides, malondialdehyde, and aspartate transaminase and alanine transaminase activities. Therefore, daily supplementation of standard feed with MCT resulted in mild intermittent ketosis. It improved working memory at lower concentrations without significant adverse side effects. At higher concentrations, it improved long-term spatial memory but also resulted in organ weight changes and is likely unsafe. These results highlight the importance of monitoring the metabolic effects of MCT supplementation alongside cognitive assessment in future studies of MCT's neuroprotective properties.

Keywords:  Cholesterol; Ketosis; Malondialdehyde; Medium-chain triglycerides; Metabolic health; Neuroprotection; Spatial memory; Working memory

DOI:  https://doi.org/10.1016/j.heliyon.2023.e13446
ASN Neuro. 2023 Jan-Dec;15:15 17590914231159226

Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.

Jinjing Jia, Jiayi Yin, Yu Zhang, Guangtao Xu, Min Wang, Haiying Jiang, Li Li, Xiansi Zeng, Dongsheng Zhu.

  Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Keywords:  AMPK/Sirt1/PGC1α; Alzheimer's disease; mitochondrial biogenesis; neuroprotection; thioredoxin-1

DOI:  https://doi.org/10.1177/17590914231159226
Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00016-6. [Epub ahead of print]194 173-185

Neuroimaging in mitochondrial disease.

Felix Distelmaier, Thomas Klopstock.

  The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage. A classic example is Leigh syndrome, which causes symmetric alterations of basal ganglia and brain stem. Leigh syndrome can be caused by different genetic defects (>75 known disease genes) with variable disease onset ranging from infancy to adulthood. Other mitochondrial diseases are characterized by focal brain lesions, which is a core feature of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Apart from gray matter, also white matter can be affected by mitochondrial dysfunction. White matter lesions vary depending on the underlying genetic defect and may progress into cystic cavities. In view of the recognizable patterns of brain damage in mitochondrial diseases, neuroimaging techniques play a key role in diagnostic work-up. In the clinical setting, magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are the mainstay of diagnostic work-up. Apart from visualization of brain anatomy, MRS allows the detection of metabolites such as lactate, which is of specific interest in the context of mitochondrial dysfunction. However, it is important to note that findings like symmetric basal ganglia lesions on MRI or a lactate peak on MRS are not specific, and that there is a broad range of disorders that can mimic mitochondrial diseases on neuroimaging. In this chapter, we will review the spectrum of neuroimaging findings in mitochondrial diseases and discuss important differential diagnoses. Moreover, we will give an outlook on novel biomedical imaging tools that may provide interesting insights into mitochondrial disease pathophysiology.

Keywords:  Brain; Central nervous system; Leigh disease; Magnetic resonance imaging; Neurodegeneration; OXPHOS

DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00016-6
Nat Commun. 2023 Feb 17. 14(1): 915

Cholesterol esters form supercooled lipid droplets whose nucleation is facilitated by triacylglycerols.

Calvin Dumesnil, Lauri Vanharanta, Xavier Prasanna, Mohyeddine Omrane, Maxime Carpentier, Apoorva Bhapkar, Giray Enkavi, Veijo T Salo, Ilpo Vattulainen, Elina Ikonen, Abdou Rachid Thiam.

Cellular cholesterol can be metabolized to its fatty acid esters, cholesteryl esters (CEs), to be stored in lipid droplets (LDs). With triacylglycerols (TGs), CEs represent the main neutral lipids in LDs. However, while TG melts at ~4 °C, CE melts at ~44 °C, raising the question of how CE-rich LDs form in cells. Here, we show that CE forms supercooled droplets when the CE concentration in LDs is above 20% to TG and, in particular, liquid-crystalline phases when the fraction of CEs is above 90% at 37 °C. In model bilayers, CEs condense and nucleate droplets when the CE/phospholipid ratio reaches over 10-15%. This concentration is reduced by TG pre-clusters in the membrane that thereby facilitate CE nucleation. Accordingly, blocking TG synthesis in cells is sufficient to strongly dampen CE LD nucleation. Finally, CE LDs emerged at seipins, which cluster and nucleate TG LDs in the ER. However, when TG synthesis is inhibited, similar numbers of LDs are generated in the presence and absence of seipin, suggesting that seipin controls CE LD formation via its TG clustering capacity. Our data point to a unique model whereby TG pre-clusters, favorable at seipins, catalyze the nucleation of CE LDs.

DOI: https://doi.org/10.1038/s41467-023-36375-6
BMC Genomics. 2023 Feb 24. 24(1): 86

Transcriptomic profiling of the developing brain revealed cell-type and brain-region specificity in a mouse model of prenatal stress.

Yuhao Dong, Jie Weng, Yueyan Zhu, Daijing Sun, Wei He, Qi Chen, Jin Cheng, Ying Zhu, Yan Jiang.

  BACKGROUND: Prenatal stress (PS) is considered as a risk factor for many mental disorders. PS-induced transcriptomic alterations may contribute to the functional dysregulation during brain development. Here, we used RNA-seq to explore changes of gene expression in the mouse fetal brain after prenatal exposure to chronic unpredictable mild stress (CUMS).RESULTS: We compared the stressed brains to the controls and identified groups of significantly differentially expressed genes (DEGs). GO analysis on up-regulated DEGs revealed enrichment for the cell cycle pathways, while down-regulated DEGs were mostly enriched in the neuronal pathways related to synaptic transmission. We further performed cell-type enrichment analysis using published scRNA-seq data from the fetal mouse brain and revealed cell-type-specificity for up- and down-regulated DEGs, respectively. The up-regulated DEGs were highly enriched in the radial glia, while down-regulated DEGs were enriched in different types of neurons. Cell deconvolution analysis further showed altered cell fractions in the stressed brain, indicating accumulation of neuroblast and impaired neurogenesis. Moreover, we also observed distinct brain-region expression pattern when mapping DEGs onto the developing Allen brain atlas. The up-regulated DEGs were primarily enriched in the dorsal forebrain regions including the cortical plate and hippocampal formation. Surprisingly, down-regulated DEGs were found excluded from the cortical region, but highly expressed on various regions in the ventral forebrain, midbrain and hindbrain.
CONCLUSION: Taken together, we provided an unbiased data source for transcriptomic alterations of the whole fetal brain after chronic PS, and reported differential cell-type and brain-region vulnerability of the developing brain in response to environmental insults during the pregnancy.

Keywords:  Brain-region-specificity; Cell-type-specificity; Embryonic brain; Gene transcription; Maternal stress

DOI:  https://doi.org/10.1186/s12864-023-09186-8
Antioxidants (Basel). 2023 Jan 31. pii: 339. [Epub ahead of print]12(2):

Metabolic Imaging and Molecular Biology Reveal the Interplay between Lipid Metabolism and DHA-Induced Modulation of Redox Homeostasis in RPE Cells.

Giada Bianchetti, Maria Elisabetta Clementi, Beatrice Sampaolese, Cassandra Serantoni, Alessio Abeltino, Marco De Spirito, Shlomo Sasson, Giuseppe Maulucci.

  Diabetes-induced oxidative stress induces the development of vascular complications, which are significant causes of morbidity and mortality in diabetic patients. Among these, diabetic retinopathy (DR) is often caused by functional changes in the blood-retinal barrier (BRB) due to harmful oxidative stress events in lipids, proteins, and DNA. Docosahexaenoic acid (DHA) has a potential therapeutic effect against hyperglycemia-induced oxidative damage and apoptotic pathways in the main constituents of BRB, retinal pigment epithelium cells (ARPE-19). Effective antioxidant response elicited by DHA is driven by the activation of the Nrf2/Nqo1 signaling cascade, which leads to the formation of NADH, a reductive agent found in the cytoplasm. Nrf2 also induces the expression of genes encoding enzymes involved in lipid metabolism. This study, therefore, aims at investigating the modulation of lipid metabolism induced by high-glucose (HG) on ARPE-19 cells through the integration of metabolic imaging and molecular biology to provide a comprehensive functional and molecular characterization of the mechanisms activated in the disease, as well the therapeutic role of DHA. This study shows that HG augments RPE metabolic processes by enhancing lipid metabolism, from fatty acid uptake and turnover to lipid biosynthesis and β-oxidation. DHA exerts its beneficial effect by ameliorating lipid metabolism and reducing the increased ROS production under HG conditions. This investigation may provide novel insight for formulating novel treatments for DR by targeting lipid metabolism pathways.

Keywords:  blood-retinal barrier; diabetic retinopathy; docosahexaenoic acid (DHA); human retinal pigment epithelium cells (ARPE-19); lipid metabolism; metabolic imaging; oxidative stress; retinal diseases; β-oxidation

DOI:  https://doi.org/10.3390/antiox12020339
Anal Biochem. 2023 Feb 15. pii: S0003-2697(23)00048-9. [Epub ahead of print]667 115083

An enzymatic fluorimetric assay for determination of N-acetylaspartate.

Ivonne Becker, Matthias Eckhardt.

  N-acetylaspartate (NAA) is an abundant metabolite in the mammalian brain and a precursor of the neuropeptide N-acetylaspartylglutamate (NAAG). The physiological role of NAA is not fully understood and requires further studies. We here describe the development of a coupled enzymatic fluorimetric assay for the determination of NAA in biological samples. Deproteinized tissue extracts are first passed through a strong cation exchange column to remove aspartate. NAA in the sample is hydrolysed by aspartoacylase and released aspartate oxidized using l-aspartate oxidase. Generated H2O2 is measured with peroxidase in a fluorimetric assay using Ampliflu Red. The limit of detection and the lower limit of quantification are 1.0 μM (10 pmol/well) and 3.3 μM (33 pmol/well), respectively, with a linear range to 100 μM. Specificity of the assay was confirmed using samples from mice deficient in NAA synthase Nat8l that were spiked with NAA. Analysis of samples from aspartoacylase-deficient mice showed a 2 to 3-fold increase in brain NAA concentration, in line with previous reports. Mice lacking NAAG synthetases had a slightly reduced (-10%) brain NAA level. Thus, the new fluorimetric enzymatic assay is useful to perform sensitive and large scale quantification of NAA in biological samples without the need for expensive equipment.

Keywords:  Aspartoacylase; Coupled enzymatic assay; N-acetylaspartate; l-aspartate oxidase

DOI:  https://doi.org/10.1016/j.ab.2023.115083
Genes Cells. 2023 Feb 22.

Ror1 promotes PPARα-mediated fatty acid metabolism in astrocytes.

Yuki Tanaka, Yasuhiro Minami, Mitsuharu Endo.

  Ror1 signaling regulates cell polarity, migration, proliferation, and differentiation during developmental morphogenesis, and plays an important role in regulating neurogenesis in the embryonic neocortices. However, the role of Ror1 signaling in the brains after birth remains largely unknown. Here, we found that expression levels of Ror1 in the mouse neocortices increase during the postnatal period, when astrocytes mature and start expressing GFAP. Indeed, Ror1 is highly expressed in cultured post-mitotic mature astrocytes. RNA-Seq analysis revealed that Ror1 expressed in cultured astrocytes mediates upregulated expression of genes related to fatty acid (FA) metabolism, including the gene encoding carnitine palmitoyl-transferase 1a (Cpt1a), the rate-limiting enzyme of mitochondrial fatty acid β-oxidation (FAO). We also found that Ror1 promotes the degradation of lipid droplets (LDs) accumulated in the cytoplasm of cultured astrocytes after oleic acid loading, and that suppressed expression of Ror1 decreases the amount of FAs localized at mitochondria, intracellular ATP levels, and expression levels of peroxisome proliferator-activated receptor α (PPARα) target genes, including Cpt1a. Collectively, these findings indicate that Ror1 signaling promotes PPARα-mediated transcription of FA metabolism-related genes, thereby facilitating the availability of FAs derived from LDs for mitochondrial FAO in the mature astrocytes. This article is protected by copyright. All rights reserved.

Keywords:  Cpt1a; PPARα; astrocyte; fatty acid; gene expression; lipid droplet; lipid metabolism; β-oxidation

DOI:  https://doi.org/10.1111/gtc.13013