bims-medebr 2023-02-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒02‒12
39 papers selected by
Regina F. Fernández
Johns Hopkins University

Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β.
Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway.
Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer's Disease.
Oxidized linoleic acid metabolites regulate neuronal morphogenesis in vitro.
L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.
The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.
The role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury.
Neuronal SIRT3 deletion predisposes to female-specific alterations in cellular metabolism, memory, and network excitability.
FDG-PET shows weak correlation between focal motor weakness and brain metabolic alterations in ALS.
Role of ceramides and sphingolipidsin Parkinson's disease.
Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice.
Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.
A combined computational-biophysical approach to understanding fatty acid binding to FABP7.
DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.
The Protective Role of Glutathione on Zinc-Induced Neuron Death after Brain Injuries.
Tanycyte, the neuron whisperer.
Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke.
Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.
Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1.
Creatine Transporter Deficiency Presenting as Failure to Thrive: A Case Report of a Novel SLC6A8 Variant Causing a Treatable but Likely Underdiagnosed Genetic Disorder.
Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential.
Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-traumatic brain injury anxiety and social impairment.
The effects of ketogenic diet on beta-hydroxybutyrate, arachidonic acid, and oxidative stress in pediatric epilepsy.
Hemispheric analysis of mitochondrial Complex I and II activity in the mouse model of ischemia-reperfusion-induced injury.
The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.
Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.
Lipidomic changes of cerebral cortex in aldehyde dehydrogenase-2 knock-in heterozygote mice after chronic alcohol exposure.
UBA52 Attunes VDAC1-Mediated Mitochondrial Dysfunction and Dopaminergic Neuronal Death.
Layer-specific mitochondrial diversity across hippocampal CA2 dendrites.
Ketogenic diet for epilepsy control and enhancement in adaptive behavior.
Association of Fatty Acid Desaturase 1 rs174547 Polymorphism with the Composition of Long-Chain Polyunsaturated Fatty Acids in Serum Glycerophospholipids during Pregnancy.
The Role of Ketogenic Diet in the Treatment of Neuroblastoma.
Alternations of Lipoprotein Profiles in the Plasma as Biomarkers of Huntington's Disease.
Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice.
How astrocytic ATP shapes neuronal activity and brain circuits.
Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production.
Decreased β-hydroxybutyrate and ketogenic amino acid levels in depressed human adults.
Cholesterol metabolism in the regulation of inflammatory responses.

J Neurochem. 2023 Feb 10.

Apolipoprotein E ε4 modulates astrocyte neuronal support functions in the presence of amyloid-β.

Rebecca M Fleeman, Madison K Kuhn, Dennis C Chan, Elizabeth A Proctor.

  Apolipoprotein E (APOE) is a lipid transporter produced predominantly by astrocytes in the brain. The ε4 variant of APOE (APOE4) is the strongest and most common genetic risk factor for Alzheimer's disease (AD). Although the molecular mechanisms of this increased risk are unclear, APOE4 is known to alter immune signaling and lipid and glucose metabolism. Astrocytes provide various forms of support to neurons, including regulating neuronal metabolism and immune responses through cytokine signaling. Changes in astrocyte function due to APOE4 may therefore decrease neuronal support, leaving neurons more vulnerable to stress and disease insults. To determine whether APOE4 alters astrocyte neuronal support functions, we measured glycolytic and oxidative metabolism of neurons treated with conditioned media from APOE4 or APOE3 (the common, risk-neutral variant) primary astrocyte cultures. We found that APOE4 neurons treated with conditioned media from resting APOE4 astrocytes had similar metabolism to APOE3 neurons treated with media from resting APOE3 astrocytes, but treatment with astrocytic conditioned media from astrocytes challenged with amyloid-β (Aβ), a key pathological protein in AD, caused APOE4 neurons to increase their basal mitochondrial and glycolytic metabolic rates more than APOE3 neurons. These changes were not due to differences in astrocytic lactate production or glucose utilization, but instead correlated with increased glycolytic ATP production and a lack of cytokine secretion in response to Aβ. Additionally, we identified that astrocytic cytokine signatures could predict basal metabolism on neurons treated with the astrocytic conditioned media. Together, these findings suggest that in the presence of Aβ, APOE4 astrocytes alter immune and metabolic functions that result in a compensatory increase in neuronal metabolic stress.

Keywords:  ATP; Astrocytes; amyloid-β; cytokines; glucose; glycolysis; immunometabolism

DOI:  https://doi.org/10.1111/jnc.15781
Cells. 2023 Feb 02. pii: 486. [Epub ahead of print]12(3):

Effect of the Ketone Body, D-β-Hydroxybutyrate, on Sirtuin2-Mediated Regulation of Mitochondrial Quality Control and the Autophagy-Lysosomal Pathway.

Juan Carlos Gómora-García, Teresa Montiel, Melanie Hüttenrauch, Ashley Salcido-Gómez, Lizbeth García-Velázquez, Yazmin Ramiro-Cortés, Juan Carlos Gomora, Susana Castro-Obregón, Lourdes Massieu.

  Mitochondrial activity and quality control are essential for neuronal homeostasis as neurons rely on glucose oxidative metabolism. The ketone body, D-β-hydroxybutyrate (D-BHB), is metabolized to acetyl-CoA in brain mitochondria and used as an energy fuel alternative to glucose. We have previously reported that D-BHB sustains ATP production and stimulates the autophagic flux under glucose deprivation in neurons; however, the effects of D-BHB on mitochondrial turnover under physiological conditions are still unknown. Sirtuins (SIRTs) are NAD+-activated protein deacetylases involved in the regulation of mitochondrial biogenesis and mitophagy through the activation of transcription factors FOXO1, FOXO3a, TFEB and PGC1α coactivator. Here, we aimed to investigate the effect of D-BHB on mitochondrial turnover in cultured neurons and the mechanisms involved. Results show that D-BHB increased mitochondrial membrane potential and regulated the NAD+/NADH ratio. D-BHB enhanced FOXO1, FOXO3a and PGC1α nuclear levels in an SIRT2-dependent manner and stimulated autophagy, mitophagy and mitochondrial biogenesis. These effects increased neuronal resistance to energy stress. D-BHB also stimulated the autophagic-lysosomal pathway through AMPK activation and TFEB-mediated lysosomal biogenesis. Upregulation of SIRT2, FOXOs, PGC1α and TFEB was confirmed in the brain of ketogenic diet (KD)-treated mice. Altogether, the results identify SIRT2, for the first time, as a target of D-BHB in neurons, which is involved in the regulation of autophagy/mitophagy and mitochondrial quality control.

Keywords:  autophagy; ketone bodies; lysosomal biogenesis; mitophagy; sirtuin2

DOI:  https://doi.org/10.3390/cells12030486
Cells. 2023 Jan 25. pii: 410. [Epub ahead of print]12(3):

Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer's Disease.

Xin Zhang, Long Wu, Russell H Swerdlow, Liqin Zhao.

  Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer's disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.

Keywords:  ApoE2; ApoE4; Warburg effect; apolipoprotein E; brain resilience; glycolysis; hexokinase; late-onset Alzheimer’s disease (LOAD)

DOI:  https://doi.org/10.3390/cells12030410
Neurochem Int. 2023 Feb 07. pii: S0197-0186(23)00034-7. [Epub ahead of print] 105506

Oxidized linoleic acid metabolites regulate neuronal morphogenesis in vitro.

Felipe da Costa Souza, Ana Cristina G Grodzki, Rhianna K Morgan, Zhichao Zhang, Ameer Y Taha, Pamela J Lein.

  Linoleic acid (LA, 18:2n-6) is an essential nutrient for optimal infant growth and brain development. The effects of LA in the brain are thought to be mediated by oxygenated metabolites of LA known as oxidized LA metabolites (OXLAMs), but evidence is lacking to directly support this hypothesis. This study investigated whether OXLAMs modulate key neurodevelopmental processes including axon outgrowth, dendritic arborization, cell viability and synaptic connectivity. Primary cortical neuron-glia co-cultures from postnatal day 0-1 male and female rats were exposed for 48h to the following OXLAMs: 1) 13-hydroxyoctadecadienoic acid (13-HODE); 2) 9-hydroxyoctadecadienoic acid (9-HODE); 3) 9,10-dihydroxy-12Z-octadecenoic acid (9,10-DiHOME); 4) 12(13)epoxy-9Z-octadecenoic acid (12(13)-EpOME); 5) 9,10,13-trihydroxy-11-octadecenoic acid (9,10,13-TriHOME); 6) 9-oxo-10E,12Z-octadecadienoic acid (9-OxoODE); and 7) 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME). Axonal outgrowth, evaluated by Tau-1 immunostaining, was increased by 9-HODE, but decreased by 12,13-DiHOME in male but not female neurons. Dendrite arborization, evaluated by MAP2B-eGFP expression, was affected by 9-HODE, 9-OxoODE, and 12(13)-EpOME in male neurons and, by 12(13)-EpOME in female neurons. Neither cell viability nor synaptic connectivity were significantly altered by OXLAMs. Overall, this study shows select OXLAMs modulate neuron morphology in a sex-dependent manner, with males neurons being more susceptible.

Keywords:  Dendritic arborization; Linoleic acid; Neuronal morphogenesis; OXLAMs; Oxylipins; Primary neuronal cultures

DOI:  https://doi.org/10.1016/j.neuint.2023.105506
EMBO J. 2023 Feb 06. e112647

L-arginine homeostasis governs adult neural stem cell activation by modulating energy metabolism in vivo.

Mingyue Xu, Ye Guo, Min Wang, Xing Luo, Xuning Shen, Zhimin Li, Lei Wang, Weixiang Guo.

  Neurogenesis in the developing and adult brain is intimately linked to remodeling of cellular metabolism. However, it is still unclear how distinct metabolic programs and energy sources govern neural stem cell (NSC) behavior and subsequent neuronal differentiation. Here, we found that adult mice lacking the mitochondrial urea metabolism enzyme, Arginase-II (Arg-II), exhibited NSC overactivation, thereby leading to accelerated NSC pool depletion and decreased hippocampal neurogenesis over time. Mechanistically, Arg-II deficiency resulted in elevated L-arginine levels and induction of a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) caused by impaired attachment of hexokinase-I to mitochondria. Notably, selective inhibition of OXPHOS ameliorated NSC overactivation and restored abnormal neurogenesis in Arg-II deficient mice. Therefore, Arg-II-mediated intracellular L-arginine homeostasis directly influences the metabolic fitness of neural stem cells that is essential to maintain neurogenesis with age.

Keywords:  Adult neurogenesis; Arginase-II; Hexokinase; L-arginine; NSC pool

DOI:  https://doi.org/10.15252/embj.2022112647
Cells. 2023 Jan 28. pii: 429. [Epub ahead of print]12(3):

The Crosstalk between Microbiome and Mitochondrial Homeostasis in Neurodegeneration.

Fivos Borbolis, Eirini Mytilinaiou, Konstantinos Palikaras.

  Mitochondria are highly dynamic organelles that serve as the primary cellular energy-generating system. Apart from ATP production, they are essential for many biological processes, including calcium homeostasis, lipid biogenesis, ROS regulation and programmed cell death, which collectively render them invaluable for neuronal integrity and function. Emerging evidence indicates that mitochondrial dysfunction and altered mitochondrial dynamics are crucial hallmarks of a wide variety of neurodevelopmental and neurodegenerative conditions. At the same time, the gut microbiome has been implicated in the pathogenesis of several neurodegenerative disorders due to the bidirectional communication between the gut and the central nervous system, known as the gut-brain axis. Here we summarize new insights into the complex interplay between mitochondria, gut microbiota and neurodegeneration, and we refer to animal models that could elucidate the underlying mechanisms, as well as novel interventions to tackle age-related neurodegenerative conditions, based on this intricate network.

Keywords:  Alzheimer’s disease; Amyotrophic Lateral Sclerosis; Huntington’s disease; ageing; gut–brain axis; microbiome; mitochondria; neurodegeneration

DOI:  https://doi.org/10.3390/cells12030429
Mitochondrion. 2023 Feb 04. pii: S1567-7249(23)00009-0. [Epub ahead of print]69 57-63

The role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury.

Li Cheng, Bin Cai, Dezhi Lu, Hong Zeng.

  Mitochondrial dysfunction occurs in the early stage of axonal degeneration after spinal cord injury and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, etc., which play a key role in axonal degeneration and regeneration under physiological and pathological conditions. Failure of axonal regeneration can lead to long-term structural and functional damage. Several recent studies have shown that improved mitochondrial energy metabolism provides conditions for axonal regeneration and central nervous system repair. Here, we describe the role of mitochondrial energy metabolism in neuroprotection and axonal regeneration after spinal cord injury and review recent advances in targeted mitochondrial therapy.

Keywords:  Axon regeneration; Energy metabolism; Mitochondria; Mitochondrial dysfunction; Spinal cord injury

DOI:  https://doi.org/10.1016/j.mito.2023.01.009
J Neurosci. 2023 Feb 08. pii: JN-RM-1259-22. [Epub ahead of print]

Neuronal SIRT3 deletion predisposes to female-specific alterations in cellular metabolism, memory, and network excitability.

Jennifer N Pearson-Smith, Ruth Fulton, Christopher Q Huynh, Anna G Figueroa, Gia B Huynh, Li-Ping Liang, Lindsey B Gano, Cole R Michel, Nichole Reisdorph, Richard Reisdorph, Kristofer S Fritz, Eric Verdin, Manisha Patel.

Mitochondrial dysfunction is an early event in the pathogenesis of neurological disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass-spectrometry based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons in the cortex and hippocampus produces altered neuronal excitability and metabolic dysfunction in female mice. Targeted deletion of SIRT3 from neuronal helix-loop-helix 1 (NEX)-expressing neurons resulted in mitochondrial hyperacetylation, female-specific superoxide dismutase-2 (SOD2) modification, increased steady-state superoxide levels, metabolic reprogramming, altered neuronal excitability and working spatial memory deficits. Inducible neuronal deletion of SIRT3 likewise produced female-specific deficits in spatial working memory. Together, the data demonstrate that deletion of SIRT3 from forebrain neurons selectively predisposes female mice to deficits in mitochondrial and cognitive function.SIGNIFICANCE STATEMENT:Mitochondrial SIRT3 is an enzyme shown to regulate energy metabolism and antioxidant function, by direct deacetylation of proteins. In this study, we show that neuronal SIRT3 deficiency renders female mice selectively vulnerable to impairment in redox and metabolic function, spatial memory, and neuronal excitability. The observed sex-specific effects on cognition and neuronal excitability in female SIRT3 deficient mice suggest that mitochondrial dysfunction may be one factor underlying comorbid neuronal diseases such as Alzheimer's disease and epilepsy. Furthermore, the data suggest that SIRT3 dysfunction may predispose females to age-related metabolic and cognitive impairment.

DOI: https://doi.org/10.1523/JNEUROSCI.1259-22.2023
Amyotroph Lateral Scler Frontotemporal Degener. 2023 Feb 08. 1-10

FDG-PET shows weak correlation between focal motor weakness and brain metabolic alterations in ALS.

Stefan Sennfält, Marco Pagani, Fang Fang, Irina Savitcheva, Ulrika Estenberg, Caroline Ingre.

  Objective: Amyotrophic lateral sclerosis (ALS) is a clinically heterogenous disease, typically presenting with focal motor weakness that eventually generalizes. Weather there is a correlation between focal motor weakness and metabolic alterations in specific areas of the brain has not been thoroughly explored. This study aims to systematically investigate this by using fluorodeoxyglucose-positron emission tomography (FDG-PET), including longitudinal imaging. Methods: This observational imaging study included 131 ALS patients diagnosed and examined with FDG-PET at the ALS Clinical Research Center at the Karolinska University Hospital in Stockholm, Sweden. Thirteen ALS patients had a second scan and were analyzed longitudinally. The findings were compared to 39 healthy controls examined at the University Medical Center of Gröningen, the Netherlands. Results: There was a general pattern of brain metabolic alterations consistent with previously reported findings in ALS, namely hypometabolism in frontal regions and hypermetabolism in posterior regions. A higher symptom burden was associated with increased hypometabolism and decreased hypermetabolism. However, there was no clear correlation between focal motor weakness and specific metabolic alterations, neither when analyzing focal motor weakness with concomitant upper motor neuron signs or when including all focal motor weakness. Longitudinal FDG-PET imaging showed inconsistent results with little correlation between progression of motor weakness and metabolic alterations. Conclusion: Our results support the disease model of ALS as a diffuse process since no clear correlation was seen between focal motor weakness and specific metabolic alterations. However, there is need for further research on a larger number of patients, particularly including longitudinal imaging.

Keywords:  ALS; Amyotrophic lateral sclerosis; FDG-PET; glucose metabolism; weakness

DOI:  https://doi.org/10.1080/21678421.2023.2174881
J Mol Biol. 2023 Feb 08. pii: S0022-2836(23)00056-6. [Epub ahead of print] 168000

Role of ceramides and sphingolipidsin Parkinson's disease.

Melissa Vos, Christine Klein, Andrew A Hicks.

  Sphingolipids, including the basic ceramide, are a subset of bioactive lipids that consist of many different species. Sphingolipids are indispensable for proper neuronal function, and an increasing number of studies have emerged on the complexity and importance of these lipids in (almost) all biological processes. These include regulation of mitochondrial function, autophagy, and endosomal trafficking, which are affected in Parkinson's disease (PD). PD is the second most common neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Currently, PD cannot be cured due to the lack of knowledge of the exact pathogenesis. Nonetheless, important advances have identified molecular changes in mitochondrial function, autophagy, and endosomal function. Furthermore, recent studies have identified ceramide alterations in patients suffering from PD, and in PD models, suggesting a critical interaction between sphingolipids and related cellular processes in PD. For instance, autosomal recessive forms of PD cause mitochondrial dysfunction, including energy production or mitochondrial clearance, that is directly influenced by manipulating sphingolipids. Additionally, endo-lysosomal recycling is affected by genes that cause autosomal dominant forms of the disease, such as VPS35 and SNCA. Furthermore, endo-lysosomal recycling is crucial for transporting sphingolipids to different cellular compartments where they will execute their functions. This review will discuss mitochondrial dysfunction, defects in autophagy, and abnormal endosomal activity in PD and the role sphingolipids play in these vital molecular processes.

Keywords:  Parkinson’s disease; Sphingolipids; autophagy; ceramide; endosome; mitochondria

DOI:  https://doi.org/10.1016/j.jmb.2023.168000
Nat Commun. 2023 Feb 09. 14(1): 729

Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice.

Shan Yao, Min-Dong Xu, Ying Wang, Shen-Ting Zhao, Jin Wang, Gui-Fu Chen, Wen-Bing Chen, Jian Liu, Guo-Bin Huang, Wen-Juan Sun, Yan-Yan Zhang, Huan-Li Hou, Lei Li, Xiang-Dong Sun.

Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca2+-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.

DOI: https://doi.org/10.1038/s41467-023-36209-5
Hum Brain Mapp. 2023 Feb 10.

Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.

Parker L La, Julie M Joyce, Tiffany K Bell, Micaela Mauthner, William Craig, Quynh Doan, Miriam H Beauchamp, Roger Zemek, Keith Owen Yeates, Ashley D Harris.

  Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N-acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo-Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L-DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post-injury (median 10 days post-injury, range 2-33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow-up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L-DLPFC. We suggest that at 2 weeks post-injury in a general pediatric concussion population, brain metabolites in the L-DLPFC are not specifically affected by brain injury.

Keywords:  brain metabolites; concussion; magnetic resonance spectroscopy; multi-site; multi-vendor; orthopedic injury control; pediatric mTBI

DOI:  https://doi.org/10.1002/hbm.26226
Biophys J. 2023 Feb 06. pii: S0006-3495(23)00095-4. [Epub ahead of print]

A combined computational-biophysical approach to understanding fatty acid binding to FABP7.

Iulia Bodnariuc, Stefan Lenz, Margaret Renaud-Young, Tanille Shandro, Hiroaki Ishida, Hans J Vogel, Justin L MacCallum.

Members of the fatty acid binding protein (FABP) family function as intracellular transporters of long chain fatty acids and other hydrophobic molecules to different cellular compartments. Brain fatty acid binding protein (FABP7) exhibits ligand-directed differences in cellular transport. For example, when FABP7 binds to docosahexaenoic acid (DHA), the complex relocates to the nucleus and influences transcriptional activity, whereas FABP7 bound with monosaturated fatty acids remains in the cytosol. Preferential binding of FABP7 to polyunsaturated fatty acids like DHA has been previously observed and is thought to play a role in differential localization. However, we find that at 37°C, FABP7 does not display strong selectivity, suggesting that the conformational ensemble of FABP7 and its perturbation upon binding may be important. We use molecular dynamics simulations, NMR, and a variety of biophysical techniques to better understand the conformational ensemble of FABP7, how it is perturbed by fatty acid binding, and how this may be related to ligand-directed transport. We find that FABP7 has high degree of confrontational heterogeneity that is substantially reduced upon ligand binding. We also observe substantial heterogeneity in ligand binding poses, which is consistent with our finding that ligand binding is resistant to mutations in key polar residues in the binding pocket. Our NMR experiments show that DHA binding leads to chemical shift perturbations in residues near the nuclear localization signal, which may point toward a mechanism of differential transport.

DOI: https://doi.org/10.1016/j.bpj.2023.02.003
J Cell Sci. 2023 Feb 01. pii: jcs260370. [Epub ahead of print]136(3):

DRP1 mutations associated with EMPF1 encephalopathy alter mitochondrial membrane potential and metabolic programs.

Gabriella L Robertson, Stellan Riffle, Mira Patel, Caroline Bodnya, Andrea Marshall, Heather K Beasley, Edgar Garza-Lopez, Jianqiang Shao, Zer Vue, Antentor Hinton, Maria S Stoll, Sholto de Wet, Rensu P Theart, Ram Prosad Chakrabarty, Ben Loos, Navdeep S Chandel, Jason A Mears, Vivian Gama.

  Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) - a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.

Keywords:  Cristae; DRP1; Fibroblast; Glycolysis; Mitochondria; Oxidative phosphorylation; Peroxisome

DOI:  https://doi.org/10.1242/jcs.260370
Int J Mol Sci. 2023 Feb 02. pii: 2950. [Epub ahead of print]24(3):

The Protective Role of Glutathione on Zinc-Induced Neuron Death after Brain Injuries.

Min Kyu Park, Bo Young Choi, A Ra Kho, Song Hee Lee, Dae Ki Hong, Beom Seok Kang, Si Hyun Lee, Sang Won Suh.

  Glutathione (GSH) is necessary for maintaining physiological antioxidant function, which is responsible for maintaining free radicals derived from reactive oxygen species at low levels and is associated with improved cognitive performance after brain injury. GSH is produced by the linkage of tripeptides that consist of glutamic acid, cysteine, and glycine. The adequate supplementation of GSH has neuroprotective effects in several brain injuries such as cerebral ischemia, hypoglycemia, and traumatic brain injury. Brain injuries produce an excess of reactive oxygen species through complex biochemical cascades, which exacerbates primary neuronal damage. GSH concentrations are known to be closely correlated with the activities of certain genes such as excitatory amino acid carrier 1 (EAAC1), glutamate transporter-associated protein 3-18 (Gtrap3-18), and zinc transporter 3 (ZnT3). Following brain-injury-induced oxidative stress, EAAC1 function is negatively impacted, which then reduces cysteine absorption and impairs neuronal GSH synthesis. In these circumstances, vesicular zinc is also released into the synaptic cleft and then translocated into postsynaptic neurons. The excessive influx of zinc inhibits glutathione reductase, which inhibits GSH's antioxidant functions in neurons, resulting in neuronal damage and ultimately in the impairment of cognitive function. Therefore, in this review, we explore the overall relationship between zinc and GSH in terms of oxidative stress and neuronal cell death. Furthermore, we seek to understand how the modulation of zinc can rescue brain-insult-induced neuronal death after ischemia, hypoglycemia, and traumatic brain injury.

Keywords:  excitatory amino acid carrier 1; glutathione; neuronal death; oxidative stress; zinc; zinc transporter 3

DOI:  https://doi.org/10.3390/ijms24032950
Physiol Behav. 2023 Feb 03. pii: S0031-9384(23)00036-7. [Epub ahead of print] 114108

Tanycyte, the neuron whisperer.

Rafik Dali, Judith Estrada-Meza, Fanny Langlet.

  Reciprocal communication between neurons and glia is essential for normal brain functioning and adequate physiological functions, including energy balance. In vertebrates, the homeostatic process that adjusts food intake and energy expenditure in line with physiological requirements is tightly controlled by numerous neural cell types located within the hypothalamus and the brainstem and organized in complex networks. Within these neural networks, peculiar ependymoglial cells called tanycytes are nowadays recognized as multifunctional players in the physiological mechanisms of appetite control, partly by modulating orexigenic and anorexigenic neurons. Here, we review recent advances in tanycytes' impact on hypothalamic neuronal activity, emphasizing on arcuate neurons.

Keywords:  Arcuate nucleus; energy balance; glia-neuron communication; hypothalamus; tanycytes

DOI:  https://doi.org/10.1016/j.physbeh.2023.114108
J Cereb Blood Flow Metab. 2023 Feb 11. 271678X231157298

Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke.

Sanna H Loppi, Marco A Tavera-Garcia, Danielle A Becktel, Boaz K Maiyo, Kristos E Johnson, Thuy-Vi V Nguyen, Rick G Schnellmann, Kristian P Doyle.

  The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naïve and sham mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid β-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naïve controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. Spatial transcriptomics and RNA in situ hybridization localized these alterations to microglia within the area of axonal degeneration. These results indicate that chronic metabolic differences exist between stroked and control brains, including alterations in fatty acid metabolism and glycolysis within microglia in areas of degenerating white matter for at least 12 weeks after stroke.

Keywords:  glycolysis; itaconate; metabolism; stroke; β-Oxidation

DOI:  https://doi.org/10.1177/0271678X231157298
bioRxiv. 2023 Jan 28. pii: 2023.01.27.525748. [Epub ahead of print]

Cross-species transcriptomic analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.

Ryan H Purcell, Esra Sefik, Erica Werner, Alexia T King, Trenell J Mosley, Megan E Merritt-Garza, Pankaj Chopra, Zachary T McEachin, Sridhar Karne, Nisha Raj, Kedamawit Tilahun, Maxine Robinette, Stephen T Warren, Zhexing Wen, Victor Faundez, Steven A Sloan, Gary J Bassell, Jennifer G Mulle.

Recent advances in the genetics of schizophrenia (SCZ) have identified rare variants that confer high disease risk, including a 1.6 Mb deletion at chromosome 3q29 with a staggeringly large effect size (O.R. > 40). Understanding the impact of the 3q29 deletion (3q29Del) on the developing CNS may therefore lead to insights about the pathobiology of schizophrenia. To gain clues about the molecular and cellular perturbations caused by the 3q29 deletion, we interrogated transcriptomic effects in two experimental model systems with complementary advantages: isogenic human forebrain cortical organoids and isocortex from the 3q29Del mouse model. We first created isogenic lines by engineering the full 3q29Del into an induced pluripotent stem cell line from a neurotypical individual. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 months and 12 months, as well as day p7 perinatal mouse isocortex, all at single cell resolution. Differential expression analysis by genotype in each cell-type cluster revealed that more than half of the differentially expressed genes identified in mouse cortex were also differentially expressed in human cortical organoids, and strong correlations were observed in mouse-human differential gene expression across most major cell-types. We systematically filtered differentially expressed genes to identify changes occurring in both model systems. Pathway analysis on this filtered gene set implicated dysregulation of mitochondrial function and energy metabolism, although the direction of the effect was dependent on developmental timepoint. Transcriptomic changes were validated at the protein level by analysis of oxidative phosphorylation protein complexes in mouse brain tissue. Assays of mitochondrial function in human heterologous cells further confirmed robust mitochondrial dysregulation in 3q29Del cells, and these effects are partially recapitulated by ablation of the 3q29Del gene PAK2 . Taken together these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species. These results converge with data from other rare SCZ-associated variants as well as idiopathic schizophrenia, suggesting that mitochondrial dysfunction may be a significant but overlooked contributing factor to the development of psychotic disorders. This cross-species scRNA-seq analysis of the SCZ-associated 3q29 deletion reveals that this copy number variant may produce early and persistent changes in cellular metabolism that are relevant to human neurodevelopment.

DOI: https://doi.org/10.1101/2023.01.27.525748
NPJ Parkinsons Dis. 2023 Feb 04. 9(1): 19

Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1.

Julie Jacquemyn, Sabine Kuenen, Jef Swerts, Benjamin Pavie, Vinoy Vijayan, Ayse Kilic, Dries Chabot, Yu-Chun Wang, Nils Schoovaerts, Nikky Corthout, Patrik Verstreken.

Recent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinson's disease, but the mechanisms are not resolved. Here, we generated a new Drosophila knock-in model of DNAJC6/Auxilin and find that the pathogenic mutation causes synaptic dysfunction, neurological defects and neurodegeneration, as well as specific lipid metabolism alterations. In these mutants, membrane lipids containing long-chain polyunsaturated fatty acids, including phosphatidylinositol lipid species that are key for synaptic vesicle recycling and organelle function, are reduced. Overexpression of another protein mutated in Parkinson's disease, Synaptojanin-1, known to bind and metabolize specific phosphoinositides, rescues the DNAJC6/Auxilin lipid alterations, the neuronal function defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinsonism and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival.

DOI: https://doi.org/10.1038/s41531-023-00459-3
J Investig Med High Impact Case Rep. 2023 Jan-Dec;11:11 23247096231154438

Creatine Transporter Deficiency Presenting as Failure to Thrive: A Case Report of a Novel SLC6A8 Variant Causing a Treatable but Likely Underdiagnosed Genetic Disorder.

Christina G Tise, Melinda J Palma, Kristina P Cusmano-Ozog, Dena R Matalon.

  Cerebral creatine deficiency syndromes (CCDS) are a rare group of inherited metabolic disorders (IMDs) that often present with nonspecific findings including global developmental delay (GDD), intellectual disability (ID), seizures, hypotonia, and behavioral differences. Creatine transporter (CRTR) deficiency is the most common CCDS, exhibiting X-linked inheritance and an estimated prevalence as high as 2.6% in individuals with neurodevelopmental disorders. Here, we present a 20-month-old boy with worsening failure to thrive (FTT) and GDD admitted for evaluation. He was found to have persistently low serum creatinine levels and a family history notable for a mother with learning disabilities and a maternal male cousin with GDD. Urine analyses revealed a marked elevation of creatine and elevated creatine:creatinine ratio suggestive of CRTR deficiency. Molecular genetic testing of SLC6A8 identified a maternally inherited hemizygous variant and brain magnetic resonance spectroscopy (MRS) showed diffusely diminished creatine peaks, further supporting the diagnosis of CRTR deficiency. The proband was started on creatine, arginine, and glycine supplementation and has demonstrated improved development. This case highlights that CRTR deficiency should be considered in all patients presenting with FTT and abnormal neurodevelopmental features, particularly if creatinine levels are low on serum chemistry studies. The nonspecific presentation of this condition in males and females likely has resulted in CRTR deficiency being underdiagnosed. There are existing therapies for individuals affected with CRTR deficiency and other CCDS, highlighting the importance of early diagnosis and intervention for affected individuals.

Keywords:  case report; creatine transporter deficiency; developmental delay; failure to thrive; intellectual disability; neurodevelopmental disorder; newborn screening

DOI:  https://doi.org/10.1177/23247096231154438
Int J Mol Sci. 2023 Jan 30. pii: 2576. [Epub ahead of print]24(3):

Ketogenic Diet and Ketone Bodies against Ischemic Injury: Targets, Mechanisms, and Therapeutic Potential.

Ciara I Makievskaya, Vasily A Popkov, Nadezda V Andrianova, Xinyu Liao, Dmitry B Zorov, Egor Y Plotnikov.

  The ketogenic diet (KD) has been used as a treatment for epilepsy since the 1920s, and its role in the prevention of many other diseases is now being considered. In recent years, there has been an intensive investigation on using the KD as a therapeutic approach to treat acute pathologies, including ischemic ones. However, contradictory data are observed for the effects of the KD on various organs after ischemic injury. In this review, we provide the first systematic analysis of studies conducted from 1980 to 2022 investigating the effects and main mechanisms of the KD and its mimetics on ischemia-reperfusion injury of the brain, heart, kidneys, liver, gut, and eyes. Our analysis demonstrated a high diversity of both the composition of the used KD and the protocols for the treatment of animals, which could be the reason for contradictory effects in different studies. It can be concluded that a true KD or its mimetics, such as β-hydroxybutyrate, can be considered as positive exposure, protecting the organ from ischemia and its negative consequences, whereas the shift to a rather similar high-calorie or high-fat diet leads to the opposite effect.

Keywords:  acetoacetate; beta-hydroxybutyrate; ischemia; ketogenic diet; ketone bodies; reperfusion

DOI:  https://doi.org/10.3390/ijms24032576
Transl Psychiatry. 2023 Feb 04. 13(1): 41

Blood glutamate scavenging as a novel glutamate-based therapeutic approach for post-traumatic brain injury anxiety and social impairment.

Dmitry Frank, Benjamin F Gruenbaum, Ilan Shelef, Vladislav Zvenigorodsky, Olena Severynovska, Ilya Fleidervish, Boris Knyazer, Amit Frenkel, Alexander Zlotnik, Ora Kofman, Matthew Boyko.

Traumatic brain injury (TBI) is a serious condition that is associated with an increased risk of severe, long-term psychiatric consequences. Drugs that target the glutamatergic system have proven successful in treating both TBI and many of its psychiatric sequelae. Blood glutamate scavengers (BGS) cause a decrease in blood glutamate levels, leading to a reduction in glutamate's concentration gradient from the brain to the blood and decreased levels of brain glutamate. This study evaluated the BGS pyruvate as a treatment for TBI-related neuropsychiatric conditions in a rat model. 213 rats were divided into four groups in a 2 × 2 design: Sham or TBI rats treated with pyruvate or control treatment. Magnetic resonance imaging, neurological status, brain glutamate and blood glutamate levels were assessed following the injury. Four weeks after the start of treatment, all rats underwent behavioral tests to assess anxious behavior and social impairment (aggressive and hierarchical behavior). Rats responded positively to pyruvate in several tasks, lowering brain glutamate levels and reducing anxiety and depression, as well as modulating TBI-related changes in social behavior. Glutamate scavenging with pyruvate may be an effective therapeutic option for post-TBI behavioral changes by reducing associated elevations in brain glutamate levels.

DOI: https://doi.org/10.1038/s41398-023-02329-1
Epilepsy Behav. 2023 Feb 04. pii: S1525-5050(23)00024-0. [Epub ahead of print]140 109106

The effects of ketogenic diet on beta-hydroxybutyrate, arachidonic acid, and oxidative stress in pediatric epilepsy.

Bita Poorshiri, Mohammad Barzegar, Mohammadreza Afghan, Siamak Shiva, Parviz Shahabi, Zahra Golchinfar, Hamid Reza Yousefi Nodeh, Sina Raeisi.

  The exact mechanism of a ketogenic diet (KD) as a suitable alternative therapeutic approach for drug-resistant epilepsy (DRE) in alleviating seizures is not yet fully understood. The present study aimed to evaluate the role of the KD in reducing oxidative stress (OS) by increasing the ketone body beta-hydroxybutyrate (BHB) and Arachidonic acid (ARA), an essential polyunsaturated fatty acid, as a possible mechanism in relieving seizure attacks in children with DRE. Forty children with refractory epilepsy were included in the present study. The serum levels of BHB, ARA, and OS markers, malondialdehyde (MDA), and 8-hydroxyl-deoxyguanosine (8-OHdG), were evaluated in children with DRE and compared before and after the three months of KD therapy. Thirty-four of 40 included children could complete the three-month KD therapy. Twenty-one (61.76%) patients had more than a 50% reduction in seizure frequency after the KD (responders). The remaining 13 children were considered non-responders to the diet. The serum levels of ARA and BHB significantly (p < 0.05) increased after the KD therapy. The serum levels of OS parameters MDA and 8-OHdG before the diet therapy were significantly (p < 0.05) higher than those after the administration. The serum levels of BHB and MDA after the KD therapy in the responders were respectively higher and lower than those in the non-responders (p < 0.001). Ketogenic diet might reduce brain OS by increasing BHB and ARA. The role of BHB in diminishing OS and seizure might be more remarkable than ARA.

Keywords:  Arachidonic acid; Beta-hydroxybutyrate; Drug-resistant epilepsy; Ketogenic diet; Oxidative stress

DOI:  https://doi.org/10.1016/j.yebeh.2023.109106
Mitochondrion. 2023 Feb 08. pii: S1567-7249(23)00014-4. [Epub ahead of print]

Hemispheric analysis of mitochondrial Complex I and II activity in the mouse model of ischemia-reperfusion-induced injury.

Ksenija Lucija Bahire, Reinis Maļuhins, Fiona Bello, Susana Valero Freitag, Iļja Jeļisejevs, Renāte Gile, Jolanta Upīte, Nikolaus Plesnila, Baiba Jansone.

  Brain ischemia/reperfusion injury results in a variable mixture of cellular damage, but little is known about possible patterns of mitochondrial dysfunction from the scope of hemispheric processes. The current study used high-resolution fluorespirometry to compare ipsi- and contralateral hemispheres' linked respiration and ROS emission after 60-minutes of filament induced middle cerebral artery occlusion (fMCAo) and 2, 24, 72, and 168 hours after reperfusion in mice. Our findings highlight that experimental ischemic stroke resulted in higher mitochondrial respiration in the contralateral compared to the ipsilateral hemisphere and highest ROS emission in ipsilateral hemisphere. The largest difference between the ipsilateral and contralateral hemispheres was observed 2 hours after reperfusion in Complex I and II ETS state. Oxygen flux returns to near baseline 72 hours after reperfusion without any changes thereafter in Complex I and II respiration. Studying the effects of brain mitochondrial functionality after ischemic stroke in each cerebral hemisphere separately provides a better understanding about the molecular and compensatory processes of the contralateral hemisphere, a region of the brain often neglected in stroke research.

Keywords:  ROS; hemispheric analysis; high-resolution fluorespirometry; ischemia; mitochondria; reperfusion

DOI:  https://doi.org/10.1016/j.mito.2023.02.005
Nat Commun. 2023 Feb 06. 14(1): 638

The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.

Rakesh Ganji, Joao A Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S Clemen, Conrad C Weihl, John G Purdy, Steve P Gygi, Malavika Raman.

The intimate association between the endoplasmic reticulum (ER) and mitochondrial membranes at ER-Mitochondria contact sites (ERMCS) is a platform for critical cellular processes, particularly lipid synthesis. How contacts are remodeled and the impact of altered contacts on lipid metabolism remains poorly understood. We show that the p97 AAA-ATPase and its adaptor ubiquitin-X domain adaptor 8 (UBXD8) regulate ERMCS. The p97-UBXD8 complex localizes to contacts and its loss increases contacts in a manner that is dependent on p97 catalytic activity. Quantitative proteomics and lipidomics of ERMCS demonstrates alterations in proteins regulating lipid metabolism and a significant change in membrane lipid saturation upon UBXD8 deletion. Loss of p97-UBXD8 increased membrane lipid saturation via SREBP1 and the lipid desaturase SCD1. Aberrant contacts can be rescued by unsaturated fatty acids or overexpression of SCD1. We find that the SREBP1-SCD1 pathway is negatively impacted in the brains of mice with p97 mutations that cause neurodegeneration. We propose that contacts are exquisitely sensitive to alterations to membrane lipid composition and saturation.

DOI: https://doi.org/10.1038/s41467-023-36298-2
Sci Rep. 2023 Feb 08. 13(1): 2246

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.

Marilena M DeMayo, Alexander McGirr, Ben Selby, Frank P MacMaster, Chantel T Debert, Ashley D Harris.

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo-inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo-inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

DOI: https://doi.org/10.1038/s41598-023-29190-y
Curr Opin Neurobiol. 2023 Feb 06. pii: S0959-4388(23)00009-0. [Epub ahead of print]79 102684

Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease.

Robert W Mahley.

Apolipoprotein (apo) E4 sets the stage for neuropathology in Alzheimer's disease (AD) by causing mitochondrial dysfunction and altering mitochondria-associated membranes. Contact and apposition of mitochondrial-endoplasmic reticulum membranes are enhanced in brain cells in AD and associated with increases in tethering and spacing proteins that modulate many cellular processes. Contact site protein levels are higher in apoE4 cells. In apoE4 neurons, the NAD+/NADH ratio is lowered, reactive oxygen species are increased, and NAD/NADH pathway components and redox proteins are decreased. Oxidative phosphorylation is impaired and reserve ATP generation capacity is lacking. ApoE4 neurons have ∼50% fewer respiratory complex subunits (e.g., ATP synthase) and may increase translocase levels of the outer and inner mitochondrial membranes to facilitate delivery of nucleus-encoded complex subunits. Respiratory complex assembly relies on mitochondrial cristae organizing system subunits that are altered in apoE4 cells, and apoE4 increases mitochondrial proteases that control respiratory subunit composition for complex assembly.

DOI: https://doi.org/10.1016/j.conb.2023.102684
Front Mol Neurosci. 2022 ;15 1053411

Lipidomic changes of cerebral cortex in aldehyde dehydrogenase-2 knock-in heterozygote mice after chronic alcohol exposure.

Li Xiao, Jin Xiang, Xinyu Liu, Lin Yang, Ying Wei, Shiyong Fang, Jing Li, Yi Ye.

  Introduction: Alcohol is the main legal drug in the world, and excessive consumption of alcohol seriously damages the morphological structure and function of various organs. The insufficiency of an essential enzyme in ethanol metabolism, aldehyde dehydrogenase-2 (ALDH2), will aggravate the alcohol-induced brain injury. The effect of ALDH2 after chronic alcohol exposure on global lipid profiling of the brain remains unclear.Methods: In this study, ALDH2*2 knock-in mice were fed the Lieber-DeCarli liquid diet containing ethanol for 8 weeks. Blood alcohol and acetaldehyde levels were examined, and the mice were tested through novel object recognition and the Y-maze test to evaluate cognitive impairment toward the end of the study. The lipidome profiling of cerebral cortex samples was investigated using a lipidomics method based on ultra-high performance liquid tandem chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOFMS).
Results and Discussion: Compared with similarly treated wild-type (WT) mice, ALDH2*2 mice exhibited poor cognitive performance, though the result did not achieve statistical significance. The lipidomics results indicated that 74 differential lipid species were selected in WT mice, of which 57 species were up-regulated, and 17 were down-regulated. Moreover, 99 differential lipids were identified in ALDH2*2 mice, of which 73 were up-regulated, and 26 were down-regulated. For ALDH2*2 mice, the number of changed significantly glycerophospholipids (GPs) subtypes was lower than that of WT mice. Interestingly, compared with WT mice, a lower proportion of polyunsaturated fatty acids (PUFAs) was found in ALDH2*2 mice. Collectively, the results provide clear evidence for a lipidomic signature of marked changes in the cerebral cortex of ALDH2*2 mice after chronic alcohol exposure.
Highlights: • The cerebral cortex of heterozygous ALDH2*2 mice showed more significant changes in lipidome profiles after chronic alcohol exposure than wild-type mice.• Most lipids were significantly up-regulated in both groups of mice, whereas the increase in TAG was restricted to WT mice.• For ALDH2*2 mice, GPs substances changed significantly, and SHexCer and SM subclasses in sphingolipids also deserved attention.

Keywords:  ALDH2; cerebral cortex; chronic alcohol exposure; knock-in; lipidomics

DOI:  https://doi.org/10.3389/fnmol.2022.1053411
ACS Chem Neurosci. 2023 Feb 08.

UBA52 Attunes VDAC1-Mediated Mitochondrial Dysfunction and Dopaminergic Neuronal Death.

Shubhangini Tiwari, Abhishek Singh, Parul Gupta, Amrutha K, Sarika Singh.

  Mitochondrial homeostasis regulates energy metabolism, calcium buffering, cell function, and apoptosis. The present study has been conducted to investigate the implications of the ubiquitin-encoding gene UBA52 in mitochondrial physiology. Transient expression of Myc-UBA52 in neurons significantly inhibited the rotenone-induced increase in reactive oxygen species generation, nitrite level, and depleted glutathione level. Mass spectrometric and coimmunoprecipitation data suggested the profound interaction of UBA52 with mitochondrial outer membrane channel protein, VDAC1 in both the wild-type and Myc-α-synuclein overexpressed neuronal cells and in the Parkinson's disease (PD)-specific substantia nigra and striatal region of the rat brain. In vitro ubiquitylation assay revealed that UBA52 participates in the ubiquitylation of VDAC1 through E3 ligase CHIP. Myc-UBA52 overexpression in neurons further improved the mitochondrial functionality and cell viability by preventing the alteration in mitochondrial membrane potential, mitochondrial complex I activity, and translocation of cytochrome c and p-Nrf2 along with the effect on intracellular calcium uptake, thus collectively inhibiting the opening of mitochondrial permeability transition pore. Additionally, Myc-UBA52 expression in neuronal cells offered protection against apoptotic and autophagic cell death. Altogether, our findings delineate a functional association between UBA52 and mitochondrial homeostasis, providing new insights into the deterrence of dopaminergic cell death during acute PD pathogenesis.

Keywords:  Parkinson’s disease; autophagic cell death; mitochondrial homeostasis; ubiquitin-60S ribosomal protein L40 (UBA52); ubiquitylation; voltage-dependent anion channel 1 (VDAC1)

DOI:  https://doi.org/10.1021/acschemneuro.2c00579
Hippocampus. 2023 Feb 10.

Layer-specific mitochondrial diversity across hippocampal CA2 dendrites.

Katy E Pannoni, Daniela Gil, Mikel L Cawley, Mayd M Alsalman, Logan A Campbell, Shannon Farris.

  CA2 is an understudied subregion of the hippocampus that is critical for social memory. Previous studies identified multiple components of the mitochondrial calcium uniporter (MCU) complex as selectively enriched in CA2. The MCU complex regulates calcium entry into mitochondria, which in turn regulates mitochondrial transport and localization to active synapses. We found that MCU is strikingly enriched in CA2 distal apical dendrites, precisely where CA2 neurons receive entorhinal cortical input carrying social information. Furthermore, MCU-enriched mitochondria in CA2 distal dendrites are larger compared to mitochondria in CA2 proximal apical dendrites and neighboring CA1 apical dendrites, which was confirmed in CA2 with genetically labeled mitochondria and electron microscopy. MCU overexpression in neighboring CA1 led to a preferential localization of MCU in the proximal dendrites of CA1 compared to the distal dendrites, an effect not seen in CA2. Our findings demonstrate that mitochondria are molecularly and structurally diverse across hippocampal cell types and circuits, and suggest that MCU can be differentially localized within dendrites, possibly to meet local energy demands.

Keywords:  dendrites; entorhinal cortex; hippocampal CA2; mitochondrial calcium uniporter; mitochondrial localization; mitochondrial morphology

DOI:  https://doi.org/10.1002/hipo.23512
Sci Rep. 2023 Feb 06. 13(1): 2102

Ketogenic diet for epilepsy control and enhancement in adaptive behavior.

Omnia Fathy El-Rashidy, May Fouad Nassar, Wafaa Abdelwahab Shokair, Yasmin Gamal Abdou El Gendy.

The Ketogenic Diet (KD) is gaining attention as a management line in childhood drug resistant epilepsy (DRE). The objective of this study was to highlight KD benefits for Ain Shams University (ASU) Children's Hospital patients. This cross-sectional study included all patients at the Ketoclinic of ASU Children's Hospital since it started. Anthropometric measurements and laboratory data were recorded. Chalfont severity score and daily frequency of epileptic attacks were used to evaluate KD efficacy. Vineland test was used to demonstrate the adaptive behavior of a selected group of patients. ASU Children's Hospital Ketoclinic records included 143 patients. During KD therapy, the weight and height/length assessment showed significant increase with significant decrease in the severity of seizures and its frequency. There were no significant changes in the lipid profile of the patients. Vineland test showed significant improvement in the adaptive behavior in 65% of patients. The Ketoclinic data proves that KD is a tolerable, safe, and effective line of therapy for DRE in children without significant negative impact on their anthropometric measurements or lipid profile. Furthermore, the enhancement in adaptive behavior is a promising finding. It is prudent to recommend wider scale studies for longer duration to demonstrate additional cognitive benefits of KD in pediatric age group.

DOI: https://doi.org/10.1038/s41598-023-27373-1
Nutrients. 2023 Jan 31. pii: 722. [Epub ahead of print]15(3):

Association of Fatty Acid Desaturase 1 rs174547 Polymorphism with the Composition of Long-Chain Polyunsaturated Fatty Acids in Serum Glycerophospholipids during Pregnancy.

Terue Kawabata, Hideoki Fukuoka, Michiru Harada, Kumiko Shoji, Yoshinori Kubo, Chisato Mori, Kenichi Sakurai, Takeshi Ohkubo, Kyoichi Oshida, Yuichiro Yamashiro.

  The increase in fetal requirements of long-chain polyunsaturated fatty acids (LCPUFAs) during pregnancy alters maternal fatty acid metabolism, and therefore, fatty acid desaturase (FADS) gene polymorphisms may change blood fatty acid composition or concentration differently during pregnancy. We investigated the relationship between a FADS1 single-nucleotide polymorphism (SNP) and maternal serum LCPUFA levels in Japanese pregnant women during the first and third trimesters and at delivery. Two hundred and fifty-three pregnant women were included, and fatty acid compositions of glycerophospholipids in serum (weight %) and the FADS1 SNP rs174547 (T/C) were analyzed. LCPUFAs, including arachidonic acid (ARA) and docosahexaenoic acid (DHA), significantly decreased from the first to the third trimester of pregnancy. Furthermore, DHA significantly decreased from the third trimester of pregnancy to delivery. At all gestational stages, linoleic acid (LA) and α-linolenic acid were significantly higher with the number of minor FADS1 SNP alleles, whereas γ-linolenic acid and ARA and the ARA/LA ratio were significantly lower. DHA was significantly lower with the number of minor FADS1 SNP alleles only in the third trimester and at delivery, suggesting that genotype effects become more obvious as pregnancy progresses.

Keywords:  docosahexaenoic acids; fatty acid desaturase 1; pregnancy; trimester

DOI:  https://doi.org/10.3390/nu15030722
Integr Cancer Ther. 2023 Jan-Dec;22:22 15347354221150787

The Role of Ketogenic Diet in the Treatment of Neuroblastoma.

Rangarirai Makuku, Zeinab Sinaei Far, Neda Khalili, Alistar Moyo, Sepideh Razi, Mahsa Keshavarz-Fathi, Maryam Mahmoudi, Nima Rezaei.

  The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimer's disease, Parkinson's disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumor in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.

Keywords:  Neuroblastoma; Warburg Effect; adjuvant therapy; childhood malignancies; ketogenic diet; nutritional therapy

DOI:  https://doi.org/10.1177/15347354221150787
Cells. 2023 Jan 20. pii: 385. [Epub ahead of print]12(3):

Alternations of Lipoprotein Profiles in the Plasma as Biomarkers of Huntington's Disease.

Kuo-Hsuan Chang, Mei-Ling Cheng, Chi-Jen Lo, Chun-Ming Fan, Yih-Ru Wu, Chiung-Mei Chen.

  Alterations in lipid composition and disturbed lipoprotein metabolism are involved in the pathomechanism of Huntington's disease (HD). Here, we measured 112 lipoprotein subfractions and components in the plasma of 20 normal controls, 24 symptomatic (sympHD) and 9 presymptomatic (preHD) HD patients. Significant changes were found in 30 lipoprotein subfractions and components in all HD patients. Plasma levels of total cholesterol (CH), apolipoprotein (Apo)B, ApoB-particle number (PN), and components of low-density lipoprotein (LDL) were lower in preHD and sympHD patients. Components of LDL4, LDL5, LDL6 and high-density lipoprotein (HDL)4 demonstrated lower levels in preHD and sympHD patients compared with controls. Components in LDL3 displayed lower levels in sympHD compared with the controls, whereas components in very low-density lipoprotein (VLDL)5 were higher in sympHD patients compared to the controls. The levels of components in HDL4 and VLDL5 demonstrated correlation with the scores of motor assessment, independence scale or functional capacity of Unified Huntington's Disease Rating Scale. These findings indicate the potential of components of VLDL5, LDL3, LDL4, LDL5 and HDL4 to serve as the biomarkers for HD diagnosis and disease progression, and demonstrate substantial evidence of the involvement of lipids and apolipoproteins in HD pathogenesis.

Keywords:  Huntington’s disease; biomarker; high-density lipoprotein; lipoprotein; low-density lipoprotein; very low-density lipoprotein

DOI:  https://doi.org/10.3390/cells12030385
Neural Regen Res. 2023 Aug;18(8): 1763-1769

Sphingosine 1-phosphate receptor 1 regulates blood-brain barrier permeability in epileptic mice.

Li-Xiang Yang, Yuan-Yuan Yao, Jiu-Rong Yang, Hui-Lin Cheng, Xin-Jian Zhu, Zhi-Jun Zhang.

  Destruction of the blood-brain barrier is a critical component of epilepsy pathology. Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity. However, its effect on blood-brain barrier permeability in epileptic mice remains unclear. In this study, we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice. S1P1 expression was increased in the hippocampus after status epilepticus, whereas tight junction protein expression was decreased in epileptic mice compared with controls. Intraperitoneal injection of SEW2871, a specific agonist of sphingosine-1-phosphate receptor 1, decreased the level of tight junction protein in the hippocampus of epileptic mice, increased blood-brain barrier leakage, and aggravated the severity of seizures compared with the control. W146, a specific antagonist of sphingosine-1-phosphate receptor 1, increased the level of tight junction protein, attenuated blood-brain barrier disruption, and reduced seizure severity compared with the control. Furthermore, sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1β and tumor necrosis factor-α and caused astrocytosis. Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline, a neuroinflammation inhibitor. Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors. Additionally, specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage, seizure severity, and epilepsy-associated depression-like behaviors. Taken together, our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.

Keywords:  adeno-associated virus; astrocytes; blood-brain barrier; epilepsy; epilepsy-associated depression-like behavior; neuroinflammation; pentylenetetrazol; pilocarpine; tight junction

DOI:  https://doi.org/10.4103/1673-5374.360263
Curr Opin Neurobiol. 2023 Feb 03. pii: S0959-4388(23)00010-7. [Epub ahead of print]79 102685

How astrocytic ATP shapes neuronal activity and brain circuits.

Jonathan Lezmy.

Astrocytes play a key role in processing information at synapses, by controlling synapse formation, modulating synapse strength and terminating neurotransmitter action. They release ATP to shape brain activity but it is unclear how, as astrocyte processes contact many targets and ATP-mediated effects are diverse and numerous. Here, I review recent studies showing how astrocytic ATP modulates cellular mechanisms in nearby neurons and glia in the grey and white matter, how it affects signal transmission in these areas, and how it modulates behavioural outputs. I attempt to provide a flowchart of astrocytic ATP signalling, showing that it tends to inhibit neural circuits to match energy demands.

DOI: https://doi.org/10.1016/j.conb.2023.102685
Cell Chem Biol. 2023 Feb 07. pii: S2451-9456(23)00028-4. [Epub ahead of print]

Selective and brain-penetrant lanosterol synthase inhibitors target glioma stem-like cells by inducing 24(S),25-epoxycholesterol production.

Thu P Nguyen, Wentian Wang, Alex C Sternisha, Chase D Corley, Hua-Yu Leo Wang, Xiaoyu Wang, Francisco Ortiz, Sang-Kyun Lim, Kalil G Abdullah, Luis F Parada, Noelle S Williams, Samuel K McBrayer, Jeffrey G McDonald, Jef K De Brabander, Deepak Nijhawan.

  Glioblastoma (GBM) is an aggressive adult brain cancer with few treatment options due in part to the challenges of identifying brain-penetrant drugs. Here, we investigated the mechanism of MM0299, a tetracyclic dicarboximide with anti-glioblastoma activity. MM0299 inhibits lanosterol synthase (LSS) and diverts sterol flux away from cholesterol into a "shunt" pathway that culminates in 24(S),25-epoxycholesterol (EPC). EPC synthesis following MM0299 treatment is both necessary and sufficient to block the growth of mouse and human glioma stem-like cells by depleting cellular cholesterol. MM0299 exhibits superior selectivity for LSS over other sterol biosynthetic enzymes. Critical for its application in the brain, we report an MM0299 derivative that is orally bioavailable, brain-penetrant, and induces the production of EPC in orthotopic GBM tumors but not normal mouse brain. These studies have implications for the development of an LSS inhibitor to treat GBM or other neurologic indications.

Keywords:  LSS; epoxycholesterol; glioblastoma; lanosterol synthase inhibitors; shunt pathway

DOI:  https://doi.org/10.1016/j.chembiol.2023.01.005
Eur J Neurosci. 2023 Feb 07.

Decreased β-hydroxybutyrate and ketogenic amino acid levels in depressed human adults.

Shiho Sato, Zhiqian Yu, Mai Sakai, Ikuko N Motoike, Daisuke Saigusa, Ryo Hirayama, Yoshie Kikuchi, Takaaki Abe, Kengo Kinoshita, Seizo Koshiba, Hiroaki Tomita.

  β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analyzed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5,722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the liver and prefrontal cortex at 2 h and 6 h, respectively. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly increased in the liver and PFC after acute SDS exposure and decreased after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.

Keywords:  Mitochondria; Monocarboxylic acid transporter 1; Social defeat stress; Voltage-dependent anion-selective channel 1; β-Hydroxybutyrate

DOI:  https://doi.org/10.1111/ejn.15931
Front Pharmacol. 2023 ;14 1121819

Cholesterol metabolism in the regulation of inflammatory responses.

Rebekka Bauer, Bernhard Brüne, Tobias Schmid.

  The importance of biologically active lipid mediators, such as prostanoids, leukotrienes, and specialized pro-resolving mediators, in the regulation of inflammation is well established. While the relevance of cholesterol in the context of atherosclerosis is also widely accepted, the role of cholesterol and its biosynthetic precursors on inflammatory processes is less comprehensively described. In the present mini-review, we summarize the current understanding of the inflammation-regulatory properties of cholesterol and relevant biosynthetic intermediates taking into account the implications of different subcellular distributions. Finally, we discuss the inflammation-regulatory effect of cholesterol homeostasis in the context of SARS-CoV-2 infections.

Keywords:  COVID-19; SARS-CoV-2; cholesterol; immunometabolism; inflammation

DOI:  https://doi.org/10.3389/fphar.2023.1121819