bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022‒05‒29
forty-one papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases.
  2. Sex-specific lipid dysregulation in the Abca7 knockout mouse brain.
  3. Intranasal Administration of Nanovectorized Docosahexaenoic Acid (DHA) Improves Cognitive Function in Two Complementary Mouse Models of Alzheimer's Disease.
  4. Transcriptomes Suggest That Pinniped and Cetacean Brains Have a High Capacity for Aerobic Metabolism While Reducing Energy-Intensive Processes Such as Synaptic Transmission.
  5. Phospholipid Profiles Are Selectively Altered in the Putamen and White Frontal Cortex of Huntington's Disease.
  6. Blocking mitochondrial Zn2+ accumulation after ischemia reduces mitochondrial dysfunction and neuronal injury.
  7. Metabolic Profiling of the Hypothalamus of Mice during Short-Term Food Deprivation.
  8. Brain Glucose Hypometabolism and Iron Accumulation in Different Brain Regions in Alzheimer's and Parkinson's Diseases.
  9. Zebrafish: A New Promise to Study the Impact of Metabolic Disorders on the Brain.
  10. Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation.
  11. Analysis of hemisphere-dependent effects of unilateral intrastriatal injection of α-synuclein pre-formed fibrils on mitochondrial protein levels, dynamics, and function.
  12. A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress.
  13. The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis.
  14. Plppr5 gene inactivation causes a more severe neurological phenotype and abnormal mitochondrial homeostasis in a mouse model of juvenile seizure.
  15. Triplication of HSA21 on alterations in structure and function of mitochondria.
  16. Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.
  17. Mechanisms of Mitochondrial Malfunction in Alzheimer's Disease: New Therapeutic Hope.
  18. Automated Quantification and Network Analysis of Redox Dynamics in Neuronal Mitochondria.
  19. Cell type-specific biotin labeling in vivo resolves regional neuronal and astrocyte proteomic differences in mouse brain.
  20. Metabolic Shades of S-D-Lactoylglutathione.
  21. Defining mitochondrial protein functions through deep multiomic profiling.
  22. Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update.
  23. Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights.
  24. SREBP and central nervous system disorders: genetic overlaps revealed by in silico analysis.
  25. Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission.
  26. Loss of neurexin-1 in Drosophila melanogaster results in altered energy metabolism and increased seizure susceptibility.
  27. Interplay between metabolic energy regulation and memory pathways in Drosophila.
  28. New Evidence of Central Nervous System Damage in Diabetes Mellitus: Impairment of Fine Visual Discrimination.
  29. Prophylactic role of Korean Red Ginseng in astrocytic mitochondrial biogenesis through HIF-1α.
  30. Modulating Insulin Signaling and Trafficking at the Blood-Brain Barrier Endothelium Using Lipid Based Nanoemulsions.
  31. The Effect of Methylene Blue and Its Metabolite-Azure I-on Bioenergetic Parameters of Intact Mouse Brain Mitochondria.
  32. Docosahexaenoic acid enhances hippocampal insulin sensitivity to promote cognitive function of aged rats on a high-fat diet.
  33. Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism.
  34. PPARα Signaling: A Candidate Target in Psychiatric Disorder Management.
  35. A ferret brain slice model of oxygen-glucose deprivation captures regional responses to perinatal injury and treatment associated with specific microglial phenotypes.
  36. Neonatal Hypoxic-Ischemic Brain Injury Alters Brain Acylcarnitine Levels in a Mouse Model.
  37. Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis.
  38. The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington's Disease Model by Acting on the Expression of Carnitine-Related Genes.
  39. Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation.
  40. CDDO-Me Attenuates CA1 Neuronal Death by Facilitating RalBP1-Mediated Mitochondrial Fission and 4-HNE Efflux in the Rat Hippocampus Following Status Epilepticus.
  41. Small Extracellular Vesicles in Milk Cross the Blood-Brain Barrier in Murine Cerebral Cortex Endothelial Cells and Promote Dendritic Complexity in the Hippocampus and Brain Function in C57BL/6J Mice.
  1. Front Endocrinol (Lausanne). 2022 ;13 873301
    Significance of Brain Glucose Hypometabolism, Altered Insulin Signal Transduction, and Insulin Resistance in Several Neurological Diseases.
    Enrique Blázquez, Verónica Hurtado-Carneiro, Yannick LeBaut-Ayuso, Esther Velázquez, Luis García-García, Francisca Gómez-Oliver, Juan Miguel Ruiz-Albusac, Jesús Ávila, Miguel Ángel Pozo.
      Several neurological diseases share pathological alterations, even though they differ in their etiology. Neuroinflammation, altered brain glucose metabolism, oxidative stress, mitochondrial dysfunction and amyloidosis are biological events found in those neurological disorders. Altered insulin-mediated signaling and brain glucose hypometabolism are characteristic signs observed in the brains of patients with certain neurological diseases, but also others such as type 2 diabetes mellitus and vascular diseases. Thus, significant reductions in insulin receptor autophosphorylation and Akt kinase activity, and increased GSK-3 activity and insulin resistance, have been reported in these neurological diseases as contributing to the decline in cognitive function. Supporting this relationship is the fact that nasal and hippocampal insulin administration has been found to improve cognitive function. Additionally, brain glucose hypometabolism precedes the unmistakable clinical manifestations of some of these diseases by years, which may become a useful early biomarker. Deficiencies in the major pathways of oxidative energy metabolism have been reported in patients with several of these neurological diseases, which supports the hypothesis of their metabolic background. This review remarks on the significance of insulin and brain glucose metabolism alterations as keystone common pathogenic substrates for certain neurological diseases, highlighting new potential targets.
    Keywords:  altered insulin signaling; brain; glucose hypometabolism; insulin resistance; neurological disorders
    DOI:  https://doi.org/10.3389/fendo.2022.873301
  2. Brain Commun. 2022 ;4(3): fcac120
    Sex-specific lipid dysregulation in the Abca7 knockout mouse brain.
    YuHong Fu, Ying He, Katherine Phan, Russell Pickford, Young-Bum Kim, Nicolas Dzamko, Glenda M Halliday, Woojin Scott Kim.
      Alzheimer's disease is a devastating neurodegenerative disease that affects more women than men. The pathomechanism underlying the sex disparity, especially in the brain, is unclear. ABCA7 is one of the strongest susceptibility genes for Alzheimer's disease. It mediates the transport of lipids across membranes and is associated with pathways related to amyloid-β neuropathology. However, the role of ABCA7 in the regulation of brain lipids is largely unknown. Sex-specific differences in the pathological link between brain lipid dysregulation and amyloid-β are also unknown. Here, we undertook quantitative discovery lipidomics of male and female Abca7 knockout (n = 52) and wild type (n = 35) mouse brain using sophisticated liquid chromatography/mass spectrometry. We identified 61 lipid subclasses in the mouse brain and found sex-specific differences in lipids that were altered with Abca7 deletion. The altered lipids belong to cellular pathways that control cell signalling, sterol metabolism, mitochondrial function and neuroprotection. We also investigated the relationship between lipids and amyloid-β levels in the Abca7 knockout mice and found elevated free cholesterol only in female mice that was significantly correlated with amyloid-β42 levels. In male Abca7 knockout mice, the neuroprotective ganglioside GD1a levels were elevated and inversely correlated with amyloid-β42 levels. Collectively, these results demonstrate that Abca7 deletion leads to sex-specific lipid dysregulation in the brain, providing insight into the underlying sex disparity in the aetiology of Alzheimer's disease.
    Keywords:  ABCA7; Alzheimer’s disease; cholesterol; lipid dysregulation; lipidomics
    DOI:  https://doi.org/10.1093/braincomms/fcac120
  3. Antioxidants (Basel). 2022 Apr 25. pii: 838. [Epub ahead of print]11(5):
    Intranasal Administration of Nanovectorized Docosahexaenoic Acid (DHA) Improves Cognitive Function in Two Complementary Mouse Models of Alzheimer's Disease.
    Charleine Zussy, Rijo John, Théo Urgin, Léa Otaegui, Claire Vigor, Niyazi Acar, Geoffrey Canet, Mathieu Vitalis, Françoise Morin, Emmanuel Planel, Camille Oger, Thierry Durand, Shinde L Rajshree, Laurent Givalois, Padma V Devarajan, Catherine Desrumaux.
      Polyunsaturated fatty acids (PUFAs) are a class of fatty acids that are closely associated with the development and function of the brain. The most abundant PUFA is docosahexaenoic acid (DHA, 22:6 n-3). In humans, low plasmatic concentrations of DHA have been associated with impaired cognitive function, low hippocampal volumes, and increased amyloid deposition in the brain. Several studies have reported reduced brain DHA concentrations in Alzheimer's disease (AD) patients' brains. Although a number of epidemiological studies suggest that dietary DHA consumption may protect the elderly from developing cognitive impairment or dementia including AD, several review articles report an inconclusive association between omega-3 PUFAs intake and cognitive decline. The source of these inconsistencies might be because DHA is highly oxidizable and its accessibility to the brain is limited by the blood-brain barrier. Thus, there is a pressing need for new strategies to improve DHA brain supply. In the present study, we show for the first time that the intranasal administration of nanovectorized DHA reduces Tau phosphorylation and restores cognitive functions in two complementary murine models of AD. These results pave the way for the development of a new approach to target the brain with DHA for the prevention or treatment of this devastating disease.
    Keywords:  Alzheimer’s disease; Tau protein; amyloid-β peptide; cognitive impairment; curcumin; docosahexaenoic acid; intranasal; microemulsion; omega-3 fatty acids
    DOI:  https://doi.org/10.3390/antiox11050838
  4. Front Mol Neurosci. 2022 ;15 877349
    Transcriptomes Suggest That Pinniped and Cetacean Brains Have a High Capacity for Aerobic Metabolism While Reducing Energy-Intensive Processes Such as Synaptic Transmission.
    Cornelia Geßner, Alena Krüger, Lars P Folkow, Wilfrid Fehrle, Bjarni Mikkelsen, Thorsten Burmester.
      The mammalian brain is characterized by high energy expenditure and small energy reserves, making it dependent on continuous vascular oxygen and nutritional supply. The brain is therefore extremely vulnerable to hypoxia. While neurons of most terrestrial mammals suffer from irreversible damage after only short periods of hypoxia, neurons of the deep-diving hooded seal (Cystophora cristata) show a remarkable hypoxia-tolerance. To identify the molecular mechanisms underlying the intrinsic hypoxia-tolerance, we excised neurons from the visual cortices of hooded seals and mice (Mus musculus) by laser capture microdissection. A comparison of the neuronal transcriptomes suggests that, compared to mice, hooded seal neurons are endowed with an enhanced aerobic metabolic capacity, a reduced synaptic transmission and an elevated antioxidant defense. Publicly available whole-tissue brain transcriptomes of the bowhead whale (Balaena mysticetus), long-finned pilot whale (Globicephala melas), minke whale (Balaenoptera acutorostrata) and killer whale (Orcinus orca), supplemented with 2 newly sequenced long-finned pilot whales, suggest that, compared to cattle (Bos taurus), the cetacean brain also displays elevated aerobic capacity and reduced synaptic transmission. We conclude that the brain energy balance of diving mammals is preserved during diving, due to reduced synaptic transmission that limits energy expenditure, while the elevated aerobic capacity allows efficient use of oxygen to restore energy balance during surfacing between dives.
    Keywords:  brain; cetacean; diving; hooded seal; hypoxia; marine mammals; neurons; transcriptome
    DOI:  https://doi.org/10.3389/fnmol.2022.877349
  5. Nutrients. 2022 May 16. pii: 2086. [Epub ahead of print]14(10):
    Phospholipid Profiles Are Selectively Altered in the Putamen and White Frontal Cortex of Huntington's Disease.
    Gabrielle R Phillips, Sarah E Hancock, Andrew M Jenner, Catriona McLean, Kelly A Newell, Todd W Mitchell.
      Huntington's disease (HD) is a genetic, neurodegenerative illness that onsets in late adulthood as a series of progressive and terminal cognitive, motor, and psychiatric deficits. The disease is caused by a polyQ mutation in the Huntingtin gene (HTT), producing a polyglutamine expansion in the Huntingtin protein (HTT). HTT interacts with phospholipids in vitro; however, its interactions are changed when the protein is mutated in HD. Emerging evidence suggests that the susceptibility of brain regions to pathological stimuli is influenced by lipid composition. This study aimed to identify where and how phospholipids are changed in human HD brain tissue. Phospholipids were extracted using a modified MTBE method from the post-mortem brain of 13 advanced-stage HD patients and 13 age- and sex-matched controls. Targeted precursor ion scanning mass spectrometry was used to detect phospholipid species. In the white cortex of HD patients, there was a significantly lower abundance of phosphatidylcholine (PC) and phosphatidylserine (PS), but no difference in phosphatidylethanolamine (PE). In HD putamen, ester-linked 22:6 was lower in all phospholipid classes promoting a decrease in the relative abundance of ester polyunsaturated fatty acids in PE. No differences in phospholipid composition were identified in the caudate, grey cortex or cerebellum. Ether-linked PE fatty acids appear protected in the HD brain, as no changes were identified. The nature of phospholipid alterations in the HD brain is dependent on the lipid (subclass, species, and bond type) and the location.
    Keywords:  Huntington’s disease; cortex; lipids; phospholipids; striatum; white matter
    DOI:  https://doi.org/10.3390/nu14102086
  6. J Neurosci. 2022 May 27. pii: JN-RM-0874-21. [Epub ahead of print]
    Blocking mitochondrial Zn2+ accumulation after ischemia reduces mitochondrial dysfunction and neuronal injury.
    Yuliya V Medvedeva, Hong Z Yin, Afsheen Bazrafkan, Andriy Yeromin, Sung G Ji, Eli J Weiss-Hung, Edward Sharman, Alyssa P Avilez, Niki Maki, Masih A Rafi, Guilian Tian, Yama Akbari, John H Weiss.
      Zn2+ is an important contributor to ischemic brain injury and recent studies support the hypothesis that mitochondria are key sites of its injurious effects. In murine hippocampal slices (both sexes) subjected to oxygen glucose deprivation (OGD), we found that Zn2+ accumulation and its entry into mitochondria precedes and contributes to the induction of acute neuronal death. In addition, if the ischemic episode is short (and sublethal), there is ongoing Zn2+ accumulation in CA1 mitochondria after OGD that may contribute to their delayed dysfunction. Using this slice model of sublethal OGD, we have now examined Zn2+ contributions to the progression of changes evoked by OGD and occurring over 4-5 hours. We detected progressive mitochondrial depolarization occurring from ∼ 2 hours after ischemia, a large increase in spontaneous synaptic activity between 2-3 hours, and mitochondrial swelling and fragmentation at 4 hours. Blockade of the primary route for Zn2+ entry, the mitochondrial Ca2+ uniporter (MCU; with ruthenium red, RR) or Zn2+ chelation shortly after OGD withdrawal substantially attenuated the mitochondrial depolarization and the changes in synaptic activity. RR also largely reversed the mitochondrial swelling. Finally, using an in vivo rat (male) asphyxial cardiac arrest (CA) model of transient global ischemia, we found that ∼8 min asphyxia induces considerable injury of CA1 neurons 4 hours later that is associated with strong Zn2+ accumulation within many damaged mitochondria. These effects were substantially attenuated by infusion of RR upon reperfusion. Our findings highlight mitochondrial Zn2+ accumulation after ischemia as a possible target for neuroprotective therapy.SIGNIFICANCE STATEMENT:Brain ischemia is a leading cause of mortality and long-term disability that still lacks effective treatment. After transient ischemia delayed death of neurons occurs in vulnerable brain regions. There is a critical need to understand mechanisms of this delayed neurodegeneration which can be targeted for neuroprotection. We found progressive and long-lasting mitochondrial Zn2+ accumulation to occur in highly vulnerable CA1 neurons after ischemia. Here we demonstrate that this Zn2+ accumulation contributes strongly to deleterious events occurring after ischemia including mitochondrial dysfunction, swelling and structural changes. We suggest that this mitochondrial Zn2+ entry may constitute a promising target for development of therapeutic interventions to be delivered after termination of an episode of transient global ischemia.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0874-21.2022
  7. Metabolites. 2022 Apr 29. pii: 407. [Epub ahead of print]12(5):
    Metabolic Profiling of the Hypothalamus of Mice during Short-Term Food Deprivation.
    Ye Jin Kim, Dasol Kang, Hye Rim Yang, Byong Seo Park, Thai Hien Tu, Bora Jeong, Byung Ju Lee, Jae Kwang Kim, Jae Geun Kim.
      Nutrient availability and utilization in hypothalamic cells are directly associated with the regulation of whole-body energy homeostasis. Thus, establishing metabolic profiling in the hypothalamus in response to metabolic shift is valuable to better understand the underlying mechanism of appetite regulation. In the present study, we evaluate the alteration of lipophilic and hydrophilic metabolites in both the hypothalamus and serum of fasted mice. Fasted mice displayed an elevated ketone body and decreased lactate levels in the hypothalamus. In support of the metabolite data, we further confirmed that short-term food deprivation resulted in the altered expression of genes involved in cellular metabolic processes, including the shuttling of fuel sources and the production of monocarboxylates in hypothalamic astrocytes. Overall, the current study provides useful information to close the gap in our understanding of the molecular and cellular mechanisms underlying hypothalamic control of whole-body energy metabolism.
    Keywords:  astrocyte; food deprivation; hypothalamus; metabolites; monocarboxylate
    DOI:  https://doi.org/10.3390/metabo12050407
  8. Pharmaceuticals (Basel). 2022 Apr 29. pii: 551. [Epub ahead of print]15(5):
    Brain Glucose Hypometabolism and Iron Accumulation in Different Brain Regions in Alzheimer's and Parkinson's Diseases.
    Indira Y Rao, Leah R Hanson, Julia C Johnson, Michael H Rosenbloom, William H Frey.
      The aim of this study was to examine the relationship between the presence of glucose hypometabolism (GHM) and brain iron accumulation (BIA), two potential pathological mechanisms in neurodegenerative disease, in different regions of the brain in people with late-onset Alzheimer's disease (AD) or Parkinson's disease (PD). Studies that conducted fluorodeoxyglucose positron emission tomography (FDG-PET) to map GHM or quantitative susceptibility mapping-magnetic resonance imaging (QSM-MRI) to map BIA in the brains of patients with AD or PD were reviewed. Regions of the brain where GHM or BIA were reported in each disease were compared. In AD, both GHM and BIA were reported in the hippocampus, temporal, and parietal lobes. GHM alone was reported in the cingulate gyrus, precuneus and occipital lobe. BIA alone was reported in the caudate nucleus, putamen and globus pallidus. In PD, both GHM and BIA were reported in thalamus, globus pallidus, putamen, hippocampus, and temporal and frontal lobes. GHM alone was reported in cingulate gyrus, caudate nucleus, cerebellum, and parietal and occipital lobes. BIA alone was reported in the substantia nigra and red nucleus. GHM and BIA are observed independent of one another in various brain regions in both AD and PD. This suggests that GHM is not always necessary or sufficient to cause BIA and vice versa. Hypothesis-driven FDG-PET and QSM-MRI imaging studies, where both are conducted on individuals with AD or PD, are needed to confirm or disprove the observations presented here about the potential relationship or lack thereof between GHM and BIA in AD and PD.
    Keywords:  Alzheimer’s disease; FDG-PET; Parkinson’s disease; QSM–MRI; brain iron accumulation; glucose hypometabolism; intranasal deferoxamine; intranasal insulin
    DOI:  https://doi.org/10.3390/ph15050551
  9. Int J Mol Sci. 2022 May 11. pii: 5372. [Epub ahead of print]23(10):
    Zebrafish: A New Promise to Study the Impact of Metabolic Disorders on the Brain.
    Batoul Ghaddar, Nicolas Diotel.
      Zebrafish has become a popular model to study many physiological and pathophysiological processes in humans. In recent years, it has rapidly emerged in the study of metabolic disorders, namely, obesity and diabetes, as the regulatory mechanisms and metabolic pathways of glucose and lipid homeostasis are highly conserved between fish and mammals. Zebrafish is also widely used in the field of neurosciences to study brain plasticity and regenerative mechanisms due to the high maintenance and activity of neural stem cells during adulthood. Recently, a large body of evidence has established that metabolic disorders can alter brain homeostasis, leading to neuro-inflammation and oxidative stress and causing decreased neurogenesis. To date, these pathological metabolic conditions are also risk factors for the development of cognitive dysfunctions and neurodegenerative diseases. In this review, we first aim to describe the main metabolic models established in zebrafish to demonstrate their similarities with their respective mammalian/human counterparts. Then, in the second part, we report the impact of metabolic disorders (obesity and diabetes) on brain homeostasis with a particular focus on the blood-brain barrier, neuro-inflammation, oxidative stress, cognitive functions and brain plasticity. Finally, we propose interesting signaling pathways and regulatory mechanisms to be explored in order to better understand how metabolic disorders can negatively impact neural stem cell activity.
    Keywords:  brain plasticity; diabetes; metabolic disorders; neural stem cell; obesity; zebrafish
    DOI:  https://doi.org/10.3390/ijms23105372
  10. Metabolites. 2022 May 21. pii: 465. [Epub ahead of print]12(5):
    Lactate Neuroprotection against Transient Ischemic Brain Injury in Mice Appears Independent of HCAR1 Activation.
    Lara Buscemi, Melanie Price, Julia Castillo-González, Jean-Yves Chatton, Lorenz Hirt.
      Lactate can protect against damage caused by acute brain injuries both in rodents and in human patients. Besides its role as a metabolic support and alleged preferred neuronal fuel in stressful situations, an additional signaling mechanism mediated by the hydroxycarboxylic acid receptor 1 (HCAR1) was proposed to account for lactate's beneficial effects. However, the administration of HCAR1 agonists to mice subjected to middle cerebral artery occlusion (MCAO) at reperfusion did not appear to exert any relevant protective effect. To further evaluate the involvement of HCAR1 in the protection against ischemic damage, we looked at the effect of HCAR1 absence. We subjected wild-type and HCAR1 KO mice to transient MCAO followed by treatment with either vehicle or lactate. In the absence of HCAR1, the ischemic damage inflicted by MCAO was less pronounced, with smaller lesions and a better behavioral outcome than in wild-type mice. The lower susceptibility of HCAR1 KO mice to ischemic injury suggests that lactate-mediated protection is not achieved or enhanced by HCAR1 activation, but rather attributable to its metabolic effects or related to other signaling pathways. Additionally, in light of these results, we would disregard HCAR1 activation as an interesting therapeutic strategy for stroke patients.
    Keywords:  HCAR1; MCAO; ischemia; lactate; neuroprotection; stroke
    DOI:  https://doi.org/10.3390/metabo12050465
  11. Acta Neuropathol Commun. 2022 May 23. 10(1): 78
    Analysis of hemisphere-dependent effects of unilateral intrastriatal injection of α-synuclein pre-formed fibrils on mitochondrial protein levels, dynamics, and function.
    Rose B Creed, Adeel A Memon, Sindhu P Komaragiri, Sandeep K Barodia, Matthew S Goldberg.
      Genetic and neuropathological evidence strongly implicates aberrant forms of α-synuclein in neurodegeneration. Antibodies specific for α-synuclein phosphorylated at serine 129 (pS129) are selective for the pathological protein aggregates that are characteristic of Parkinson's disease (PD) and other synucleinopathies, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the etiology of most synucleinopathies remains uncertain, a large body of evidence points to mitochondrial dysfunction. The recent development of animal models based on intracranial injection of α-synuclein pre-formed fibrils (PFFs) has provided a valuable experimental system in which to study the spread and neurotoxicity of α-synuclein aggregates, yet the effects of PFF-induced protein aggregates on mitochondrial function and dynamics have not been rigorously examined in vivo. To help fill this knowledge gap, we injected the striatum of mice unilaterally with well-characterized small length (< 30 nm) PFFs or monomeric α-synuclein control and measured the distribution and extent of pS129 α-synuclein-immunoreactive aggregates, the loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra, the abundance of mitochondrial proteins, and the activity of mitochondrial respiratory chain components at 3 months and 6 months post injection. Intrastriatal injection of small length PFFs, but not monomeric α-synuclein control, induced robust pS129 α-synuclein immunoreactive inclusions in the cortex, ventral midbrain, and striatum, as well as in rarely reported brain regions, such as the hippocampus, as early as 3 months post injection. Significant loss of nigral tyrosine hydroxylase-immunoreactive neurons was observed in the PFF-injected hemisphere at 3 months and 6 months post injection. The unilateral striatal injection of small length PFFs also caused hemisphere-dependent and treatment-dependent changes in the cortical levels of mitochondrial proteins such as VDAC1, COX-IV, and DRP-1, as well as functional changes in mitochondrial complex I activity in the contralateral striatum. Together, these data demonstrate that intrastriatal injection of mice with small length PFFs induces extensive bilateral protein aggregates, significant unilateral nigral cell loss, and altered contralateral levels of mitochondrial proteins and respiratory chain activity. Our data suggest this animal model may be useful for studying the role of mitochondrial dysfunction in α-synucleinopathies, for studying the hemisphere-dependent effects of α-synuclein aggregates, and for testing neuroprotective therapies that target mitochondrial dysfunction and protein aggregation.
    Keywords:  Aggregation; Lewy bodies; Mitochondria; Parkinson’s disease; Pre-formed fibrils; Synuclein
    DOI:  https://doi.org/10.1186/s40478-022-01374-z
  12. Front Behav Neurosci. 2022 ;16 885849
    A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress.
    Dávid Csabai, Abigél Sebők-Tornai, Ove Wiborg, Boldizsár Czéh.
      Exposure to severe, uncontrollable and long-lasting stress is a strong risk factor for the development of numerous mental and somatic disorders. Animal studies document that chronic stress can alter neuronal morphology and functioning in limbic brain structures such as the prefrontal cortex. Mitochondria are intracellular powerhouses generating chemical energy for biochemical reactions of the cell. Recent findings document that chronic stress can lead to changes in mitochondrial function and metabolism. Here, we studied putative mitochondrial damage in response to chronic stress in neurons of the medial prefrontal cortex. We performed a systematic quantitative ultrastructural analysis to examine the consequences of 9-weeks of chronic mild stress on mitochondria number and morphology in the infralimbic cortex of adult male rats. In this preliminary study, we analyzed 4,250 electron microscopic images and 67000 mitochondria were counted and examined in the brains of 4 control and 4 stressed rats. We found significantly reduced number of mitochondria in the infralimbic cortex of the stressed animals, but we could not detect any significant alteration in mitochondrial morphology. These data support the concept that prolonged stress can lead to mitochondrial loss. This in turn may result in impaired energy production. Reduced cellular energy may sensitize the neurons to additional injuries and may eventually trigger the development of psychopathologies.
    Keywords:  animal model for depression; chronic mild stress (CMS); electron microscope; infralimbic cortex; medial prefrontal cortex (mPFC); mitochondria; quantitative analysis; ultrastructure
    DOI:  https://doi.org/10.3389/fnbeh.2022.885849
  13. Cell Biosci. 2022 May 26. 12(1): 71
    The ventromedial hypothalamic nucleus: watchdog of whole-body glucose homeostasis.
    Longlong Tu, Makoto Fukuda, Qingchun Tong, Yong Xu.
      The brain, particularly the ventromedial hypothalamic nucleus (VMH), has been long known for its involvement in glucose sensing and whole-body glucose homeostasis. However, it is still not fully understood how the brain detects and responds to the changes in the circulating glucose levels, as well as brain-body coordinated control of glucose homeostasis. In this review, we address the growing evidence implicating the brain in glucose homeostasis, especially in the contexts of hypoglycemia and diabetes. In addition to neurons, we emphasize the potential roles played by non-neuronal cells, as well as extracellular matrix in the hypothalamus in whole-body glucose homeostasis. Further, we review the ionic mechanisms by which glucose-sensing neurons sense fluctuations of ambient glucose levels. We also introduce the significant implications of heterogeneous neurons in the VMH upon glucose sensing and whole-body glucose homeostasis, in which sex difference is also addressed. Meanwhile, research gaps have also been identified, which necessities further mechanistic studies in future.
    Keywords:  Counterregulatory response; Diabetes; Glucose sensing; Hypoglycemia; Sex difference; VMH; Whole-body glucose homeostasis
    DOI:  https://doi.org/10.1186/s13578-022-00799-2
  14. Epilepsy Res. 2022 May 20. pii: S0920-1211(22)00095-X. [Epub ahead of print]183 106944
    Plppr5 gene inactivation causes a more severe neurological phenotype and abnormal mitochondrial homeostasis in a mouse model of juvenile seizure.
    Dandan Wang, Yueying Liu, Dongjing Zhao, Meifang Jin, Lili Li, Hong Ni.
      Mice with inactivation of the Plppr5 gene (Plppr5-/-) had aggravated hypoxic-ischemic damage and partially weakened neuroprotection of melatonin (a mitochondrial targeted antioxidant), suggesting that abnormal mitochondrial homeostasis contributes to neurological abnormalities in these mice. We examined the hypothesis that Plppr5 inactivation disturbs mitochondrial homeostasis, which may cause long-term adverse consequences on behavior and cognition. We studied the long-term effects of Plppr5 knockout (KO) in both wild-type (WT) and Plppr5-null mice using a combination of neurobehavior, cognition, and standard cellular glutamate-induced excitotoxicity techniques. The change in mitochondrial membrane potential was determined by detecting MitoTracker Green FM and MitoTracker Red CMXROS with a Gallios flow cytometer. Our results suggest that Plppr5 gene knockout aggravated the impairment of exploratory behavior (open field test) and memory (novel object recognition and passive avoidance tests) in Plppr5-null mice following juvenile seizures. Furthermore, Plppr5 gene silencing aggravated the decrease in the cell survival rate of HT22 cells treated with glutamate for 24 h and further resulted in a decrease in superoxide dismutase (SOD) levels and the ratio of active mitochondria and a parallel increase in the reactive oxygen species (ROS) content. Interestingly, silencing the Plppr5 gene alone in vitro is sufficient to reduce the cell survival rate, aggravate oxidative stress damage, reduce the proportion of surviving mitochondria, and upregulate mitophagy activity. In summary, the present data reveal the first direct link between Plppr5 KO and neurobehavioral and cognitive impairment following juvenile seizures and provide a potential mechanistic explanation for the adverse consequences. Given that silencing the Plppr5 gene is sufficient to upregulate mitophagy activity and aggravate oxidative stress neuronal damage, our results suggest that Plppr5 substrates and/or mitophagy-based treatments may provide valuable new targets for the treatment of developmental convulsive brain injury.
    Keywords:  HT22 cell; Juvenile seizure; Mitochondrial homeostasis; Neurological phenotype; Plppr5
    DOI:  https://doi.org/10.1016/j.eplepsyres.2022.106944
  15. Mitochondrion. 2022 May 24. pii: S1567-7249(22)00048-4. [Epub ahead of print]
    Triplication of HSA21 on alterations in structure and function of mitochondria.
    Bani Bandana Ganguly, Nitin N Kadam.
      Triplication of genes encoded in human chromosome 21 (HSA21) is responsible for the phenotypes of Down syndrome (DS). The dosage-imbalance of the nuclear genes and the extra-nuclear mitochondrial DNA (mtDNA) jointly contributes to patho-mechanisms in DS. The mitochondrial organelles are the power house of cells for generation of ATP and maintaining cellular calcium and redox homeostasis, and cellular energy-metabolism processes. Each cell contains hundreds to thousands of mitochondria depending on their energy consumption. The dynamic structure of mitochondria is maintained with continuous fission and fusion events, and thus, content of mtDNA and its genetic composition are widely variable among cells. Cells of brain and heart tissues of DS patients and DS-mouse models have demonstrated elevated number but reduced amount of mtDNA due to higher fission process. This mechanism perturbs the oxidative phosphorylation (OXPHOS) and generates more free radicals such as reactive oxygen species (ROS), suggesting contribution of mtDNA in proliferation and protection of cells from endogenous toxic environment and external stressors. Gene-dosage in DS population collectively contributes to mitochondrial dysfunction by lowering energy production and respiratory capacity via the impaired OXPHOS, and damaged redox homeostasis and mitochondrial dynamics in all types of cells in DS. The context is highly complex and affects the functioning of all organs. The effect in brain and heart tissues promotes myriads of neurodegenerative diseases and cardiac complexities in individuals with DS. Crosstalk between trisomic nuclear and mitochondrial genome has been crucial for identification of potential therapeutic targets.
    Keywords:  Down syndrome; bioenergetics and biogenesis of mitochondria; mitochondrial dynamics; mitochondrial dysfunction and oxidative stress; mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2022.05.007
  16. Mol Neurobiol. 2022 May 25.
    Bisphenol-A Mediated Impaired DRP1-GFER Axis and Cognition Restored by PGC-1α Upregulation Through Nicotinamide in the Rat Brain Hippocampus.
    Shweta Goyal, Saurabh Tiwari, Brashket Seth, Phoolmala, Ankit Tandon, Rajnish Kumar Chaturvedi.
      The regulatory network of mitochondrial biogenesis and dynamics is vital for mitochondrial functions and cellular homeostasis. Any impairment in the mitochondrial network leads to neurodegenerative disorders. Our earlier studies suggest that environmental toxicant Bisphenol-A (BPA) exposure reduces neurogenesis by abnormal mitochondrial dynamics and mitochondrial biogenesis through impairment of mitochondrial fission factor dynamin-related protein (DRP1) and mitochondrial import protein GFER, which leads to demyelination, neurodegeneration, and cognitive deficits in the rats. In the present study, we found that chronic BPA exposure reduces PGC-1α levels (master regulator of mitochondrial biogenesis), alters mitochondrial localization of DRP1 and GFER, and reduces the number of PGC-1α/NeuN+ and PGC-1α/β-tubulin+ neurons in the rat hippocampus, suggesting reduced PGC-1α-mediated neurogenesis. Nicotinamide significantly increased PGC-1α protein levels, PGC-1α/NeuN+ co-labeled cells in BPA-treated rat hippocampus and PGC-1α/β-tubulin+ co-labeled cells in neuron culture derived from hippocampal neural stem cells. Interestingly, PGC-1α upregulation by nicotinamide also resulted in increased GFER levels and restored mitochondrial localization of GFER (increased GFER/TOMM20 co-labeled cells) in vitro and in vivo following BPA treatment. Nicotinamide also reduced DRP1 levels and prevented DRP1 mitochondrial localization in BPA-treated neuronal cultures and hippocampus, suggesting reduced mitochondrial fission. This resulted in reduced cytochrome c levels in neuronal culture and reduced hippocampal neurodegeneration (reduced caspase-3/NeuN+ co-labeled neurons) following nicotinamide treatment in BPA-treated group. Consequently, activation of PGC-1α by nicotinamide restored BPA-mediated cognitive deficits in rats. Results suggest that the treatment of nicotinamide has therapeutic potential and rescues BPA-mediated neuronal death and cognitive deficits by upregulating the PGC-1α and GFER-DRP1 link, thus balancing mitochondrial homeostasis.
    Keywords:  Bisphenol-A; Cognition; DRP1; GFER; Hippocampus; Mitochondria; Nicotinamide; PGC-1α
    DOI:  https://doi.org/10.1007/s12035-022-02862-y
  17. Oxid Med Cell Longev. 2022 ;2022 4759963
    Mechanisms of Mitochondrial Malfunction in Alzheimer's Disease: New Therapeutic Hope.
    Showkat Ul Nabi, Andleeb Khan, Ehraz Mehmood Siddiqui, Muneeb U Rehman, Saeed Alshahrani, Azher Arafah, Sidharth Mehan, Rana M Alsaffar, Athanasios Alexiou, Bairong Shen.
      Mitochondria play a critical role in neuron viability or death as it regulates energy metabolism and cell death pathways. They are essential for cellular energy metabolism, reactive oxygen species production, apoptosis, Ca++ homeostasis, aging, and regeneration. Mitophagy and mitochondrial dynamics are thus essential processes in the quality control of mitochondria. Improvements in several fundamental features of mitochondrial biology in susceptible neurons of AD brains and the putative underlying mechanisms of such changes have made significant progress. AD's etiology has been reported by mitochondrial malfunction and oxidative damage. According to several recent articles, a continual fusion and fission balance of mitochondria is vital in their normal function maintenance. As a result, the shape and function of mitochondria are inextricably linked. This study examines evidence suggesting that mitochondrial dysfunction plays a significant early impact on AD pathology. Furthermore, the dynamics and roles of mitochondria are discussed with the link between mitochondrial malfunction and autophagy in AD has also been explored. In addition, recent research on mitochondrial dynamics and mitophagy in AD is also discussed in this review. It also goes into how these flaws affect mitochondrial quality control. Furthermore, advanced therapy techniques and lifestyle adjustments that lead to improved management of the dynamics have been demonstrated, hence improving the conditions that contribute to mitochondrial dysfunction in AD.
    DOI:  https://doi.org/10.1155/2022/4759963
  18. Methods Mol Biol. 2022 ;2399 261-274
    Automated Quantification and Network Analysis of Redox Dynamics in Neuronal Mitochondria.
    Felix T Kurz, Michael O Breckwoldt.
      Mitochondria are complex organelles with multifaceted roles in cell biology, acting as signaling hubs that implicate them in cellular physiology and pathology. Mitochondria are both the target and the origin of multiple signaling events, including redox processes and calcium signaling which are important for organellar function and homeostasis. One way to interrogate mitochondrial function is by live cell imaging. Elaborated approaches perform imaging of single mitochondrial dynamics in living cells and animals. Imaging mitochondrial signaling and function can be challenging due to the sheer number of mitochondria, and the speed, propagation, and potential short half-life of signals. Moreover, mitochondria are organized in functionally coupled interorganellar networks. Therefore, advanced analysis and postprocessing tools are needed to enable automated analysis to fully quantitate mitochondrial signaling events and decipher their complex spatiotemporal connectedness. Herein, we present a protocol for recording and automating analyses of signaling in neuronal mitochondrial networks.
    Keywords:  Computational wavelet analysis; Fluorescence microscopy; Grx1-roGFP2; Mitochondria; Mitochondrial cluster; Redox potential
    DOI:  https://doi.org/10.1007/978-1-0716-1831-8_12
  19. Nat Commun. 2022 May 25. 13(1): 2927
    Cell type-specific biotin labeling in vivo resolves regional neuronal and astrocyte proteomic differences in mouse brain.
    Sruti Rayaprolu, Sara Bitarafan, Juliet V Santiago, Ranjita Betarbet, Sydney Sunna, Lihong Cheng, Hailian Xiao, Ruth S Nelson, Prateek Kumar, Pritha Bagchi, Duc M Duong, Annie M Goettemoeller, Viktor János Oláh, Matt Rowan, Allan I Levey, Levi B Wood, Nicholas T Seyfried, Srikant Rangaraju.
      Proteomic profiling of brain cell types using isolation-based strategies pose limitations in resolving cellular phenotypes representative of their native state. We describe a mouse line for cell type-specific expression of biotin ligase TurboID, for in vivo biotinylation of proteins. Using adenoviral and transgenic approaches to label neurons, we show robust protein biotinylation in neuronal soma and axons throughout the brain, allowing quantitation of over 2000 neuron-derived proteins spanning synaptic proteins, transporters, ion channels and disease-relevant druggable targets. Next, we contrast Camk2a-neuron and Aldh1l1-astrocyte proteomes and identify brain region-specific proteomic differences within both cell types, some of which might potentially underlie the selective vulnerability to neurological diseases. Leveraging the cellular specificity of proteomic labeling, we apply an antibody-based approach to uncover differences in neuron and astrocyte-derived signaling phospho-proteins and cytokines. This approach will facilitate the characterization of cell-type specific proteomes in a diverse number of tissues under both physiological and pathological states.
    DOI:  https://doi.org/10.1038/s41467-022-30623-x
  20. Antioxidants (Basel). 2022 May 20. pii: 1005. [Epub ahead of print]11(5):
    Metabolic Shades of S-D-Lactoylglutathione.
    Miklós Péter Kalapos, Cinzia Antognelli, Lidia de Bari.
      S-D-lactoylglutathione (SDL) is an intermediate of the glutathione-dependent metabolism of methylglyoxal (MGO) by glyoxalases. MGO is an electrophilic compound that is inevitably produced in conjunction with glucose breakdown and is essentially metabolized via the glyoxalase route. In the last decades, MGO metabolism and its cytotoxic effects have been under active investigation, while almost nothing is known about SDL. This article seeks to fill the gap by presenting an overview of the chemistry, biochemistry, physiological role and clinical importance of SDL. The effects of intracellular SDL are investigated in three main directions: as a substrate for post-translational protein modifications, as a reservoir for mitochondrial reduced glutathione and as an energy currency. In essence, all three approaches point to one direction, namely, a metabolism-related regulatory role, enhancing the cellular defense against insults. It is also suggested that an increased plasma concentration of SDL or its metabolites may possibly serve as marker molecules in hemolytic states, particularly when the cause of hemolysis is a disturbance of the pay-off phase of the glycolytic chain. Finally, SDL could also represent a useful marker in such metabolic disorders as diabetes mellitus or ketotic states, in which its formation is expected to be enhanced. Despite the lack of clear-cut evidence underlying the clinical and experimental findings, the investigation of SDL metabolism is a promising field of research.
    Keywords:  N-lact(o)ylation; S-D-lactoylglutathione; S-glutathionylation; cytoskeleton; glyoxalases; methylglyoxal
    DOI:  https://doi.org/10.3390/antiox11051005
  21. Nature. 2022 May 25.
    Defining mitochondrial protein functions through deep multiomic profiling.
    Jarred W Rensvold, Evgenia Shishkova, Yuriy Sverchkov, Ian J Miller, Arda Cetinkaya, Angela Pyle, Mateusz Manicki, Dain R Brademan, Yasemin Alanay, Julian Raiman, Adam Jochem, Paul D Hutchins, Sean R Peters, Vanessa Linke, Katherine A Overmyer, Austin Z Salome, Alexander S Hebert, Catherine E Vincent, Nicholas W Kwiecien, Matthew J P Rush, Michael S Westphall, Mark Craven, Nurten A Akarsu, Robert W Taylor, Joshua J Coon, David J Pagliarini.
      Mitochondria are epicentres of eukaryotic metabolism and bioenergetics. Pioneering efforts in recent decades have established the core protein componentry of these organelles1 and have linked their dysfunction to more than 150 distinct disorders2,3. Still, hundreds of mitochondrial proteins lack clear functions4, and the underlying genetic basis for approximately 40% of mitochondrial disorders remains unresolved5. Here, to establish a more complete functional compendium of human mitochondrial proteins, we profiled more than 200 CRISPR-mediated HAP1 cell knockout lines using mass spectrometry-based multiomics analyses. This effort generated approximately 8.3 million distinct biomolecule measurements, providing a deep survey of the cellular responses to mitochondrial perturbations and laying a foundation for mechanistic investigations into protein function. Guided by these data, we discovered that PIGY upstream open reading frame (PYURF) is an S-adenosylmethionine-dependent methyltransferase chaperone that supports both complex I assembly and coenzyme Q biosynthesis and is disrupted in a previously unresolved multisystemic mitochondrial disorder. We further linked the putative zinc transporter SLC30A9 to mitochondrial ribosomes and OxPhos integrity and established RAB5IF as the second gene harbouring pathogenic variants that cause cerebrofaciothoracic dysplasia. Our data, which can be explored through the interactive online MITOMICS.app resource, suggest biological roles for many other orphan mitochondrial proteins that still lack robust functional characterization and define a rich cell signature of mitochondrial dysfunction that can support the genetic diagnosis of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41586-022-04765-3
  22. Int J Mol Sci. 2022 May 16. pii: 5574. [Epub ahead of print]23(10):
    Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update.
    Flavia Agata Cimini, Marzia Perluigi, Ilaria Barchetta, Maria Gisella Cavallo, Eugenio Barone.
      Insulin signaling is a conserved pathway that orchestrates glucose and lipid metabolism, energy balance, and inflammation, and its dysregulation compromises the homeostasis of multiple systems. Insulin resistance is a shared hallmark of several metabolic diseases, including obesity, metabolic syndrome, and type 2 diabetes, and has been associated with cognitive decline during aging and dementia. Numerous mechanisms promoting the development of peripheral and central insulin resistance have been described, although most of them were not completely clarified. In the last decades, several studies have highlighted that biliverdin reductase-A (BVR-A), over its canonical role in the degradation of heme, acts as a regulator of insulin signaling. Evidence from human and animal studies show that BVR-A alterations are associated with the aberrant activation of insulin signaling, metabolic syndrome, liver steatosis, and visceral adipose tissue inflammation in obese and diabetic individuals. In addition, recent findings demonstrated that reduced BVR-A levels or impaired BVR-A activation contribute to the development of brain insulin resistance and metabolic alterations in Alzheimer's disease. In this narrative review, we will provide an overview on the literature by focusing on the role of BVR-A in the regulation of insulin signaling and how BVR-A alterations impact on cell dysfunctions in both metabolic and neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; biliverdin reductase A; dementia; insulin signaling; metabolic disorders; neurodegenerative diseases; obesity; type 2 diabetes
    DOI:  https://doi.org/10.3390/ijms23105574
  23. Int J Mol Sci. 2022 May 12. pii: 5390. [Epub ahead of print]23(10):
    Roles of the Unsaturated Fatty Acid Docosahexaenoic Acid in the Central Nervous System: Molecular and Cellular Insights.
    Ana B Petermann, Mauricio Reyna-Jeldes, Lorena Ortega, Claudio Coddou, Gonzalo E Yévenes.
      Fatty acids (FAs) are essential components of the central nervous system (CNS), where they exert multiple roles in health and disease. Among the FAs, docosahexaenoic acid (DHA) has been widely recognized as a key molecule for neuronal function and cell signaling. Despite its relevance, the molecular pathways underlying the beneficial effects of DHA on the cells of the CNS are still unclear. Here, we summarize and discuss the molecular mechanisms underlying the actions of DHA in neural cells with a special focus on processes of survival, morphological development, and synaptic maturation. In addition, we examine the evidence supporting a potential therapeutic role of DHA against CNS tumor diseases and tumorigenesis. The current results suggest that DHA exerts its actions on neural cells mainly through the modulation of signaling cascades involving the activation of diverse types of receptors. In addition, we found evidence connecting brain DHA and ω-3 PUFA levels with CNS diseases, such as depression, autism spectrum disorders, obesity, and neurodegenerative diseases. In the context of cancer, the existing data have shown that DHA exerts positive actions as a coadjuvant in antitumoral therapy. Although many questions in the field remain only partially resolved, we hope that future research may soon define specific pathways and receptor systems involved in the beneficial effects of DHA in cells of the CNS, opening new avenues for innovative therapeutic strategies for CNS diseases.
    Keywords:  CNS tumors; DHA; GPR40; cell survival; docosahexaenoic acid; neural morphology; synaptic function
    DOI:  https://doi.org/10.3390/ijms23105390
  24. J Integr Neurosci. 2022 May 16. 21(3): 95
    SREBP and central nervous system disorders: genetic overlaps revealed by in silico analysis.
    Mary Jasmin Ang, Changjong Moon.
      BACKGROUND: The central nervous system (CNS) is enriched in lipids; despite this, studies exploring the functional roles of lipids in the brain are still limited. Sterol regulatory element binding protein (SREBP) signaling is a transcriptomic pathway that predominantly participates in the maintenance of lipid homeostasis; however, its involvement in the CNS dysfunction is not well-established. In this study, we aimed to characterize and pinpoint specific genes of the SREBP pathway which may be implicated in neurodegenerative, neurological, and neuropsychiatric diseases.METHODS: In silico bioinformatic analysis was performed using the open-source databases DisGeNET and MSigDB. Protein-protein interaction data were visualized and analyzed using STRING, after which GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses were conducted via DAVID (Database for Annotation, Visualization and Integrated Discovery).
    RESULTS: Several common genes were identified between the SREBP pathway and CNS disorders. In GO enrichment analysis, the most enriched biological processes included lipid, cholesterol, and steroid biosynthetic processes; the most enriched molecular functions were transcription factor-related; and the most enriched subcellular compartments revealed that the genes involved in CNS disorders were mainly associated with the enzyme complexes of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). In KEGG enrichment analysis, the most enriched pathway was the AMP-activated protein kinase (AMPK) signaling pathway, and the top-ranked genes significantly enriched under this pathway were ACACA, ACACB, FASN, HMGCR, MTOR, PPARGC1A, PRKAA1, SCD, SIRT1, and SREBF1.
    CONCLUSIONS: The findings of this study strengthen the evidence linking the involvement of lipid homeostasis in CNS functions. We suggest herein the roles of downstream ACC and FASN enzymes and upstream AMPK signaling in the SREBP pathway as mechanisms underlying neurodegenerative, neurological, and neuropsychiatric CNS disorders.
    Keywords:  AMPK; Lipids; Neurodegenerative; Neurological; Neuropsychiatric; SREBP
    DOI:  https://doi.org/10.31083/j.jin2103095
  25. Front Oncol. 2022 ;12 893396
    Loss of PTEN-Induced Kinase 1 Regulates Oncogenic Ras-Driven Tumor Growth By Inhibiting Mitochondrial Fission.
    Dantong Zhu, Fengtong Han, Liuke Sun, Sandeep K Agnihotri, Ying Hu, Hansruedi Büeler.
      Mitochondrial metabolism and dynamics (fission and fusion) critically regulate cell survival and proliferation, and abnormalities in these pathways are implicated in both neurodegenerative disorders and cancer. Mitochondrial fission is necessary for the growth of mutant Ras-dependent tumors. Here, we investigated whether loss of PTEN-induced kinase 1 (PINK1) - a mitochondrial kinase linked to recessive familial Parkinsonism - affects the growth of oncogenic Ras-induced tumor growth in vitro and in vivo. We show that RasG12D-transformed embryonic fibroblasts (MEFs) from PINK1-deficient mice display reduced growth in soft agar and in nude mice, as well as increased necrosis and decreased cell cycle progression, compared to RasG12D-transformed MEFs derived from wildtype mice. PINK1 re-expression (overexpression) at least partially rescues these phenotypes. Neither PINK1 deletion nor PINK1 overexpression altered Ras expression levels. Intriguingly, PINK1-deficient Ras-transformed MEFs exhibited elongated mitochondria and altered DRP1 phosphorylation, a key event in regulating mitochondrial fission. Inhibition of DRP1 diminished PINK1-regulated mitochondria morphological changes and tumor growth suggesting that PINK1 deficiency primarily inhibits Ras-driven tumor growth through disturbances in mitochondrial fission and associated cell necrosis and cell cycle defects. Moreover, we substantiate the requirement of PINK1 for optimal growth of Ras-transformed cells by showing that human HCT116 colon carcinoma cells (carrying an endogenous RasG13D mutation) with CRISPR/Cas9-introduced PINK1 gene deletions also show reduced mitochondrial fission and decreased growth. Our results support the importance of mitochondrial function and dynamics in regulating the growth of Ras-dependent tumor cells and provide insight into possible mechanisms underlying the lower incidence of cancers in Parkinson's disease and other neurodegenerative disorders.
    Keywords:  PTEN-induced kinase-1 (PINK1); Ras protein; Ras-induced tumors; cell cycle; dynamin-related protein 1 (DRP1); mitochondrial dynamics; mitochondrial metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.893396
  26. Hum Mol Genet. 2022 May 25. pii: ddac115. [Epub ahead of print]
    Loss of neurexin-1 in Drosophila melanogaster results in altered energy metabolism and increased seizure susceptibility.
    Kyra A Levy, Eliana D Weisz, Thomas A Jongens.
      While autism is typically characterized by differences in language, social interaction, and restrictive, repetitive behaviors, it is becoming more well known in the field that alterations in energy metabolism and mitochondrial function are a comorbid disorder in autism. The synaptic cell adhesion molecule, neurexin-1 (NRXN1), has previously been implicated in autism, and here we show that in Drosophila melanogaster, the homologue of NRXN1, called Nrx-1, regulates energy metabolism and nutrient homeostasis. First, we show that Nrx-1-null flies exhibit decreased resistance to nutrient deprivation and heat stress compared to wildtype controls. Additionally, Nrx-1 mutants exhibit a significantly altered metabolic profile characterized by decreased lipid and carbohydrate stores. Nrx-1-null Drosophila also exhibit diminished levels of nicotinamide adenine dinucleotide (NAD+), an important coenzyme in major energy metabolism pathways. Moreover, loss of Nrx-1 resulted in striking abnormalities in mitochondrial morphology in the flight muscle of Nrx-1-null Drosophila, as well as impaired flight ability in these flies. Further, following a mechanical shock Nrx-1-null flies exhibited seizure-like activity, a phenotype previously linked to defects in mitochondrial metabolism and a common symptom of patients with NRXN1 deletions. The current studies indicate a novel role for neurexin-1 in the regulation of energy metabolism as well as uncover a clinically relevant seizure phenotype in Drosophila lacking Nrx-1.
    DOI:  https://doi.org/10.1093/hmg/ddac115
  27. Trends Neurosci. 2022 May 18. pii: S0166-2236(22)00081-9. [Epub ahead of print]
    Interplay between metabolic energy regulation and memory pathways in Drosophila.
    Noemi Sgammeglia, Simon G Sprecher.
      Regulating energy metabolism is critical to maintain homeostasis of cellular and systemic functions. In the brain, specialised centres for energy storage regulation finely communicate with the periphery and integrate signals about internal states. As a result, the behavioural responses can be directly adjusted accordingly to the energetic demands. In the fruit fly Drosophila melanogaster, one of these regulatory centres is the mushroom bodies (MBs), a brain region involved in olfactory memory. The integration of metabolic cues by the MBs has a crucial impact on learned behaviour. In this review, we explore recent advances supporting the interplay between energy metabolism and memory establishment, as well as the instructive role of energy during the switch between memory phases.
    Keywords:  Drosophila melanogaster; energy metabolism; energy storage centres; learning and memory; neural coding
    DOI:  https://doi.org/10.1016/j.tins.2022.04.007
  28. Diabetes. 2022 May 25. pii: db210715. [Epub ahead of print]
    New Evidence of Central Nervous System Damage in Diabetes Mellitus: Impairment of Fine Visual Discrimination.
    He Chen, Menghan Wang, Lin Xia, Jiong Dong, Guangwei Xu, Ziyi Wang, Lixia Feng, Yifeng Zhou.
      Diabetes can damage both the peripheral sensory organs, causing retinopathy, as well as the central visual system, leading to contrast sensitivity and impaired color vision in patients without retinopathy. Orientation discrimination is important for shape recognition by the visual system. Our psychophysical findings in this study show diminished orientation discrimination in diabetic patients without retinopathy. To reveal the underlying mechanism, we established a diabetic mouse model and recorded in vivo electrophysiological data in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (V1). Reduced orientation selectivity was observed in both individual and populations of neurons in V1 and dLGN, which increased in severity with disease duration. This diabetes-associated neuronal dysfunction appeared earlier in the V1 than dLGN. Additionally, neuronal activity and signal-to-noise ratio is reduced in V1 neurons of diabetic mice, leading to a decreased capacity for information processing by V1 neurons. Notably, the V1 in diabetic mice exhibits reduced excitatory neuronal activity and lower levels of phosphorylated mammalian target of rapamycin (mTOR). Our findings show that altered responses of both populations and single V1 neurons may impair fine vision, thus expanding our understanding of the underlying causes of diabetes-related impairment of the central nervous system.
    DOI:  https://doi.org/10.2337/db21-0715
  29. J Ginseng Res. 2022 May;46(3): 408-417
    Prophylactic role of Korean Red Ginseng in astrocytic mitochondrial biogenesis through HIF-1α.
    Jinhong Park, Minjae Lee, Minsu Kim, Sunhong Moon, Seunghee Kim, Sueun Kim, Seong-Ho Koh, Young-Myeong Kim, Yoon Kyung Choi.
      Background: Korean Red Ginseng extract (KRGE) has been used as a health supplement and herbal medicine. Astrocytes are one of the key cells in the central nervous system (CNS) and have bioenergetic potential as they stimulate mitochondrial biogenesis. They play a critical role in connecting the brain vasculature and nerves in the CNS.Methods: Brain samples from KRGE-administered mice were tested using immunohistochemistry. Treatment of human brain astrocytes with KRGE was subjected to assays such as proliferation, cytotoxicity, Mitotracker, ATP production, and O2 consumption rate as well as western blotting to demonstrate the expression of proteins related to mitochondria functions. The expression of hypoxia-inducible factor-1α (HIF-1α) was diminished utilizing siRNA transfection.
    Results: Brain samples from KRGE-administered mice harbored an increased number of GFAP-expressing astrocytes. KRGE triggered the proliferation of astrocytes in vitro. Enhanced mitochondrial biogenesis induced by KRGE was detected using Mitotracker staining, ATP production, and O2 consumption rate assays. The expression of proteins related to mitochondrial electron transport was increased in KRGE-treated astrocytes. These effects were blocked by HIF-1α knockdown. The factors secreted from KRGE-treated astrocytes were determined, revealing the expression of various cytokines and growth factors, especially those related to angiogenesis and neurogenesis. KRGE-treated astrocyte conditioned media enhanced the differentiation of adult neural stem cells into mature neurons, increasing the migration of endothelial cells, and these effects were reduced in the background of HIF-1α knockdown.
    Conclusion: Our findings suggest that KRGE exhibits prophylactic potential by stimulating astrocyte mitochondrial biogenesis through HIF-1α, resulting in improved neurovascular function.
    Keywords:  Angiogenesis; Astrocytic mitochondrial biogenesis; Hypoxia-inducible factor-1α; Korean Red Ginseng; Neural stem cell differentiation
    DOI:  https://doi.org/10.1016/j.jgr.2021.07.003
  30. Int J Pharm. 2022 May 20. pii: S0378-5173(22)00378-7. [Epub ahead of print] 121823
    Modulating Insulin Signaling and Trafficking at the Blood-Brain Barrier Endothelium Using Lipid Based Nanoemulsions.
    Lushan Wang, Timothy S Wiedmann, Karunya K Kandimalla.
      The compositionally distinct lipid rafts present in the plasma membrane regulates the restrictive trafficking and signal transduction in the blood-brain barrier (BBB) endothelium. Several metabolic and neurodegenerative diseases are associated with lipid homeostasis disruption within the BBB endothelium. Here, we hypothesized that the delivery of lipid triglyceride based nanoemulsions containing unsaturated fatty acids (UFAs) provides a novel non-pharmacological approach to modulate lipid raft integrity and rectify the aberrant trafficking and signal transduction. The current study has shown that soybean oil nanoemulsions (SNEs) altered the morphology of lipid rafts that are stained by Alex Fluor 647 labelled cholera toxin (AF647-CTX) in polarized hCMEC/D3 cell monolayers. Moreover, western blot and flow cytometry analysis showed that SNEs containing polyunsaturated fatty acids (PUFAs) increased phospo-AKT (p-AKT) expression, a marker for the stimulation of metabolic arm of the insulin signaling, and insulin uptake in human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. However, olive oil nanoemulsions (ONEs) containing monounsaturated fatty acids (MUFAs) had no detectable impact on lipid raft integrity, AKT phosphorylation, or insulin uptake. These findings provided direct evidence that SNEs containing PUFAs can upregulate insulin-pAKT pathway, facilitate insulin trafficking at the BBB, and thereby address cerebrovascular dysfunction in metabolic and neurodegenerative diseases.
    Keywords:  Insulin resistance; Insulin signaling; Insulin trafficking; Lipid rafts; Nanoemulsions; Olive oil; Soybean oil; Unsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.ijpharm.2022.121823
  31. Biochem Mosc Suppl B Biomed Chem. 2022 ;16(2): 148-153
    The Effect of Methylene Blue and Its Metabolite-Azure I-on Bioenergetic Parameters of Intact Mouse Brain Mitochondria.
    A P Gureev, N A Samoylova, D V Potanina, V N Popov.
      Methylene blue, a phenothiazine dye, that is widely used in medicine and is under clinical trials as an agent for treatment of Alzheimer's disease. One of the factors of the unique therapeutic effect of methylene blue is its redox properties, allowing implementation of alternative electron transport: the dye accepts electrons from reducing equivalents in mitochondria and transfer them to other components of the respiratory chain or molecular oxygen. Azure I, an N-dimethylated metabolite of methylene blue, is potentially a more effective compound than methylene blue, but its ability for alternative electron transport has not been studied yet. We have shown that in contrast to methylene blue, azure I is unable to restore the membrane potential in isolated mouse brain mitochondria, inhibited by rotenone and, therefore, is unable to perform bypass of the respiratory chain complex I. Moreover, addition of azure I does not affect the rate of mitochondrial respiration in contrast to methylene blue, which increases the rate of non-phosphorylation respiration. At the same time, both dyes stimulate an increase in H2O2 production. Thus, only methylene blue is capable of alternative electron transport, while azure I does not produce complex I bypass. This limits its therapeutic application only as a mitochondrial-targeted agent, but does not question its antidepressant effects.
    Keywords:  alternative electron transport; azure I; methylene blue; mitochondria
    DOI:  https://doi.org/10.1134/S1990750822020044
  32. J Adv Res. 2022 Apr 30. pii: S2090-1232(22)00111-4. [Epub ahead of print]
    Docosahexaenoic acid enhances hippocampal insulin sensitivity to promote cognitive function of aged rats on a high-fat diet.
    Jiqu Xu, Ben Ni, Congcong Ma, Shuang Rong, Hui Gao, Li Zhang, Xia Xiang, Qingde Huang, Qianchun Deng, Fenghong Huang.
      INTRODUCTION: Diminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function.OBJECTIVES: This study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD).
    METHODS: Eight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested.
    RESULTS: DHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aβ burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein.
    CONCLUSION: DHA improves cognitive function by enhancing hippocampal insulin sensitivity.
    Keywords:  Aging; Cognitive function; Docosahexaenoic acid; High-fat diet; Hippocampus; Insulin resistance
    DOI:  https://doi.org/10.1016/j.jare.2022.04.015
  33. Metabolites. 2022 Apr 21. pii: 377. [Epub ahead of print]12(5):
    Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism.
    Dylan E Jones, Elizabeth A Jennings, Robert O Ryan.
      A growing number of inborn errors of metabolism (IEM) have been identified that manifest 3-methylglutaconic (3MGC) aciduria as a phenotypic feature. In primary 3MGC aciduria, IEM-dependent deficiencies in leucine pathway enzymes prevent catabolism of trans-3MGC CoA. Consequently, this metabolite is converted to 3MGC acid and excreted in urine. In secondary 3MGC aciduria, however, no leucine metabolism pathway enzyme deficiencies exist. These IEMs affect mitochondrial membrane structure, electron transport chain function or ATP synthase subunits. As a result, acetyl CoA oxidation via the TCA cycle slows and acetyl CoA is diverted to trans-3MGC CoA, and then to 3MGC acid. Whereas the trans diastereomer of 3MGC CoA is the only biologically relevant diastereomer, the urine of affected subjects contains both cis- and trans-3MGC acids. Studies have revealed that trans-3MGC CoA is susceptible to isomerization to cis-3MGC CoA. Once formed, cis-3MGC CoA undergoes intramolecular cyclization, forming an anhydride that, upon hydrolysis, yields cis-3MGC acid. Alternatively, cis-3MGC anhydride can acylate protein lysine side chains. Once formed, cis-3MGCylated proteins can be deacylated by the NAD+-dependent enzyme, sirtuin 4. Taken together, the excretion of 3MGC acid in secondary 3MGC aciduria represents a barometer of defective mitochondrial function.
    Keywords:  3-methylglutaconic acid; acetyl CoA; inborn errors of metabolism; leucine; mitochondria; organic aciduria; sirtuin 4
    DOI:  https://doi.org/10.3390/metabo12050377
  34. Biomolecules. 2022 May 20. pii: 723. [Epub ahead of print]12(5):
    PPARα Signaling: A Candidate Target in Psychiatric Disorder Management.
    Simona Scheggi, Graziano Pinna, Giulia Braccagni, Maria Graziella De Montis, Carla Gambarana.
      Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD.
    Keywords:  N-acylethanolamines; anhedonia; autism; dopamine; endocannabinoids; fenofibrate; major depression; neuroinflammation; neurosteroids; schizophrenia
    DOI:  https://doi.org/10.3390/biom12050723
  35. Bioeng Transl Med. 2022 May;7(2): e10265
    A ferret brain slice model of oxygen-glucose deprivation captures regional responses to perinatal injury and treatment associated with specific microglial phenotypes.
    Thomas R Wood, Kate Hildahl, Hawley Helmbrecht, Kylie A Corry, Daniel H Moralejo, Sarah E Kolnik, Katherine E Prater, Sandra E Juul, Elizabeth Nance.
      Organotypic brain slice models are an ideal technological platform to investigate therapeutic options for hypoxic-ischemic (HI) brain injury, a leading cause of morbidity and mortality in neonates. The brain exhibits regional differences in the response to HI injury in vivo. This can be modeled using organotypic brain slices, which maintain three-dimensional regional structures and reflect the regional differences in injury response. Here, we developed an organotypic whole hemisphere (OWH) slice culture model of HI injury using the gyrencephalic ferret brain at a developmental stage equivalent to a full-term human infant in order to better probe region-specific cellular responses to injury. Each slice encompassed the cortex, corpus callosum, subcortical white matter, hippocampus, basal ganglia, and thalamus. Regional responses to treatment with either erythropoietin (Epo) or the ketone body acetoacetate (AcAc) were highly heterogenous. While both treatments suppressed global injury responses and oxidative stress, significant neuroprotection was only seen in a subset of regions, with others displaying no response or potential exacerbation of injury. Similar regional heterogeneity was seen in the morphology and response of microglia to injury and treatment, which mirrored those seen after injury in vivo. Within each region, machine-learning-based classification of microglia morphological shifts in response to injury predicted the neuroprotective response to each therapy, with different morphologies associated with different treatment responses. This suggests that the ferret OWH slice culture model provides a platform for examining regional responses to injury in the gyrencephalic brain, as well as for screening combinations of therapeutics to provide global neuroprotection after injury.
    Keywords:  ferret; machine learning; microglia; neonatal; neuroprotection; organotypic brain slice; therapeutic screening
    DOI:  https://doi.org/10.1002/btm2.10265
  36. Metabolites. 2022 May 22. pii: 467. [Epub ahead of print]12(5):
    Neonatal Hypoxic-Ischemic Brain Injury Alters Brain Acylcarnitine Levels in a Mouse Model.
    Amanda M Dave, Thiago C Genaro-Mattos, Zeljka Korade, Eric S Peeples.
      Hypoxic-ischemic brain injury (HIBI) leads to depletion of ATP, mitochondrial dysfunction, and enhanced oxidant formation. Measurement of acylcarnitines may provide insight into mitochondrial dysfunction. Plasma acylcarnitine levels are altered in neonates after an HIBI, but individual acylcarnitine levels in the brain have not been evaluated. Additionally, it is unknown if plasma acylcarnitines reflect brain acylcarnitine changes. In this study, postnatal day 9 CD1 mouse pups were randomized to HIBI induced by carotid artery ligation, followed by 30 min at 8% oxygen, or to sham surgery and normoxia, with subgroups for tissue collection at 30 min, 24 h, or 72 h after injury (12 animals/group). Plasma, liver, muscle, and brain (dissected into the cortex, cerebellum, and striatum/thalamus) tissues were collected for acylcarnitine analysis by LC-MS. At 30 min after HIBI, acylcarnitine levels were significantly increased, but the differences resolved by 24 h. Palmitoylcarnitine was increased in the cortex, muscle, and plasma, and stearoylcarnitine in the cortex, striatum/thalamus, and cerebellum. Other acylcarnitines were elevated only in the muscle and plasma. In conclusion, although plasma acylcarnitine results in this study mimic those seen previously in humans, our data suggest that the plasma acylcarnitine profile was more reflective of muscle changes than brain changes. Acylcarnitine metabolism may be a target for therapeutic intervention after neonatal HIBI, though the lack of change after 30 min suggests a limited therapeutic window.
    Keywords:  asphyxia; biomarker; carnitine; encephalopathy; plasma
    DOI:  https://doi.org/10.3390/metabo12050467
  37. Metabolites. 2022 Apr 20. pii: 371. [Epub ahead of print]12(5):
    Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis.
    Danielle Brister, Brianna A Werner, Geoffrey Gideon, Patrick J McCarty, Alison Lane, Brian T Burrows, Sallie McLees, P David Adelson, Jorge I Arango, William Marsh, Angelea Flores, Matthew T Pankratz, Ngoc Han Ly, Madison Flood, Danni Brown, David Carpentieri, Yan Jin, Haiwei Gu, Richard E Frye.
      Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite-metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.
    Keywords:  amino acid metabolism; autism spectrum disorder; cerebrospinal fluid; cis-cis-muconic acid; developmental delay; energy metabolism; epilepsy; mass spectrometry; metabolomics; redox metabolism; shikimic acid; vitamins
    DOI:  https://doi.org/10.3390/metabo12050371
  38. Molecules. 2022 May 13. pii: 3125. [Epub ahead of print]27(10):
    The Reversible Carnitine Palmitoyltransferase 1 Inhibitor (Teglicar) Ameliorates the Neurodegenerative Phenotype in a Drosophila Huntington's Disease Model by Acting on the Expression of Carnitine-Related Genes.
    Carla Bertapelle, Maria Rosaria Carillo, Nunzio Antonio Cacciola, Yulii V Shidlovskii, Gianfranco Peluso, Filomena Anna Digilio.
      Huntington's disease (HD) is a dramatic neurodegenerative disorder caused by the abnormal expansion of a CAG triplet in the huntingtin gene, producing an abnormal protein. As it leads to the death of neurons in the cerebral cortex, the patients primarily present with neurological symptoms, but recently metabolic changes resulting from mitochondrial dysfunction have been identified as novel pathological features. The carnitine shuttle is a complex consisting of three enzymes whose function is to transport the long-chain fatty acids into the mitochondria. Here, its pharmacological modification was used to test the hypothesis that shifting metabolism to lipid oxidation exacerbates the HD symptoms. Behavioural and transcriptional analyses were carried out on HD Drosophila model, to evaluate the involvement of the carnitine cycle in this pathogenesis. Pharmacological inhibition of CPT1, the rate-limiting enzyme of the carnitine cycle, ameliorates the HD symptoms in Drosophila, likely acting on the expression of carnitine-related genes.
    Keywords:  Drosophila melanogaster; Huntington’s disease; L-carnitine; carnitine shuttle; mitochondria; neurodegeneration; β-oxidation
    DOI:  https://doi.org/10.3390/molecules27103125
  39. Sci Rep. 2022 May 24. 12(1): 8718
    Persistent elevation of lysophosphatidylcholine promotes radiation brain necrosis with microglial recruitment by P2RX4 activation.
    Natsuko Kondo, Yoshinori Sakurai, Takushi Takata, Kuniyuki Kano, Kyo Kume, Munetoshi Maeda, Nobuhiko Takai, Shugo Suzuki, Fumihiro Eto, Kenji Kikushima, Hideki Wanibuchi, Shin-Ichi Miyatake, Takayuki Kajihara, Shoji Oda, Mitsutoshi Setou, Junken Aoki, Minoru Suzuki.
      Brain radiation necrosis (RN) or neurocognitive disorder is a severe adverse effect that may occur after radiation therapy for malignant brain tumors or head and neck cancers. RN accompanies inflammation which causes edema or micro-bleeding, and no fundamental treatment has been developed. In inflammation, lysophospholipids (LPLs) are produced by phospholipase A2 and function as bioactive lipids involved in sterile inflammation in atherosclerosis or brain disorders. To elucidate its underlying mechanisms, we investigated the possible associations between lysophospholipids (LPLs) and RN development in terms of microglial activation with the purinergic receptor P2X purinoceptor 4 (P2RX4). We previously developed a mouse model of RN and in this study, measured phospholipids and LPLs in the brains of RN model by liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses. We immune-stained microglia and the P2RX4 in the brains of RN model with time-course. We treated RN model mice with ivermectin, an allosteric modulator of P2RX4 and investigate the effect on microglial activation with P2RX4 and LPLs' production, and resulting effects on overall survival and working memory. We revealed that LPLs (lysophosphatidylcholine (LPC), lysophosphatidyl acid, lysophosphatidylserine, lysophosphatidylethanolamine, lysophosphatidylinositol, and lysophosphatidylglycerol) remained at high levels during the progression of RN with microglial accumulation, though phospholipids elevations were limited. Both microglial accumulation and activation of the P2RX4 were attenuated by ivermectin. Moreover, the elevation of all LPLs except LPC was also attenuated by ivermectin. However, there was limited prolongation of survival time and improvement of working memory disorders. Our findings suggest that uncontrollable increased LPC, even with ivermectin treatment, promoted the development of RN and working memory disorders. Therefore, LPC suppression will be essential for controlling RN and neurocognitive disorder after radiation therapy.
    DOI:  https://doi.org/10.1038/s41598-022-12293-3
  40. Antioxidants (Basel). 2022 May 18. pii: 985. [Epub ahead of print]11(5):
    CDDO-Me Attenuates CA1 Neuronal Death by Facilitating RalBP1-Mediated Mitochondrial Fission and 4-HNE Efflux in the Rat Hippocampus Following Status Epilepticus.
    Ji-Eun Kim, Duk-Shin Lee, Tae-Hyun Kim, Tae-Cheon Kang.
      Ras-related protein Ral-A (RalA)-binding protein 1 (RalBP1, also known as Ral-interacting protein of 76 kDa (RLIP76) or Ral-interacting protein 1 (RLIP1 or RIP1)) is involved in the efflux of 4-hydroxynonenal (4-HNE, an end product of lipid peroxidation), as well as mitochondrial fission. In the present study, we found that 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) attenuated CA1 neuronal death and aberrant mitochondrial elongations in these neurons coupled with enhanced RalBP1 expression and reduced 4-HNE levels following status epilepticus (SE). RalBP1 knockdown did not affect mitochondrial dynamics and CA1 neuronal death under physiological and post-SE conditions. Following SE, however, cotreatment of RalBP1 siRNA diminished the effect of CDDO-Me on 4-HNE levels, mitochondrial hyperfusion in CA1 neurons, and CA1 neuronal death. These findings indicate that CDDO-Me may ameliorate CA1 neuronal death by facilitating RalBP1-mediated 4-HNE efflux and mitochondrial fission following SE. Therefore, our findings suggest that increased RalBP1 expression/activity may be one of the considerable targets to protect neurons from SE.
    Keywords:  FJB; mitochondrial dynamics; mitochondrial elongation; mitochondrial fragmentation; oxidative stress; seizure
    DOI:  https://doi.org/10.3390/antiox11050985
  41. Front Nutr. 2022 ;9 838543
    Small Extracellular Vesicles in Milk Cross the Blood-Brain Barrier in Murine Cerebral Cortex Endothelial Cells and Promote Dendritic Complexity in the Hippocampus and Brain Function in C57BL/6J Mice.
    Fang Zhou, Pearl Ebea, Ezra Mutai, Haichuan Wang, Sonal Sukreet, Shya Navazesh, Haluk Dogan, Wenhao Li, Juan Cui, Peng Ji, Denise M O Ramirez, Janos Zempleni.
      Human milk contains large amounts of small extracellular vesicles (sEVs) and their microRNA cargos, whereas infant formulas contain only trace amounts of sEVs and microRNAs. We assessed the transport of sEVs across the blood-brain barrier (BBB) and sEV accumulation in distinct regions of the brain in brain endothelial cells and suckling mice. We further assessed sEV-dependent gene expression profiles and effects on the dendritic complexity of hippocampal granule cells and phenotypes of EV depletion in neonate, juvenile and adult mice. The transfer of sEVs across the BBB was assessed by using fluorophore-labeled bovine sEVs in brain endothelial bEnd.3 monolayers and dual chamber systems, and in wild-type newborn pups fostered to sEV and cargo tracking (ECT) dams that express sEVs labeled with a CD63-eGFP fusion protein for subsequent analysis by serial two-photon tomography and staining with anti-eGFP antibodies. Effects of EVs on gene expression and dendritic architecture of granule cells was analyzed in hippocampi from juvenile mice fed sEV and RNA-depleted (ERD) and sEV and RNA-sufficient (ERS) diets by using RNA-sequencing analysis and Golgi-Cox staining followed by integrated neuronal tracing and morphological analysis of neuronal dendrites, respectively. Spatial learning and severity of kainic acid-induced seizures were assessed in mice fed ERD and ERS diets. bEnd.3 cells internalized sEVs by using a saturable transport mechanism and secreted miR-34a across the basal membrane. sEVs penetrated the entire brain in fostering experiments; major regions of accumulation included the hippocampus, cortex and cerebellum. Two hundred ninety-five genes were differentially expressed in hippocampi from mice fed ERD and ERS diets; high-confidence gene networks included pathways implicated in axon guidance and calcium signaling. Juvenile pups fed the ERD diet had reduced dendritic complexity of dentate granule cells in the hippocampus, scored nine-fold lower in the Barnes maze test of spatial learning and memory, and the severity of seizures was 5-fold higher following kainic acid administration in adult mice fed the ERD diet compared to mice fed the ERS diet. We conclude that sEVs cross the BBB and contribute toward optimal neuronal development, spatial learning and memory, and resistance to kainic acid-induced seizures in mice.
    Keywords:  blood brain barrier; gene expression; milk exosomes; neuronal development; serial two-photon tomography
    DOI:  https://doi.org/10.3389/fnut.2022.838543
This page is being maintained by Thomas Krichel. It was last updated on 2022‒06‒03 at 19:38:06.