bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2022–01–16
57 papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Regulation of adult neurogenesis by the endocannabinoid-producing enzyme diacylglycerol lipase alpha (DAGLa).
  2. Differential Alterations to the Metabolic Connectivity of the Cortical and Subcortical Regions in Rat Brain During Ketamine-Induced Unconsciousness.
  3. Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis.
  4. Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
  5. The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression.
  6. Covering the Role of PGC-1α in the Nervous System.
  7. Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
  8. Divergent Effect of Central Incretin Receptors Inhibition in a Rat Model of Sporadic Alzheimer's Disease.
  9. Nutritional Supplementation Reduces Lesion Size and Neuroinflammation in a Sex-Dependent Manner in a Mouse Model of Perinatal Hypoxic-Ischemic Brain Injury.
  10. Metabolic Abnormalities in the Basal Ganglia and Cerebellum in Bipolar Disorder: A Multi-modal MR Study.
  11. AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.
  12. Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies.
  13. Electroacupuncture Relieves Hippocampal Injury by Heme Oxygenase-1 to Improve Mitochondrial Function.
  14. Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery.
  15. Infantile onset carnitine palmitoyltransferase 2 deficiency: Cortical polymicrogyria, schizencephaly, and gray matter heterotopias in an adolescent with normal development.
  16. Novel Probable Glance at Inflammatory Scenario Development in Autistic Pathology.
  17. Glutathione in Brain Disorders and Aging.
  18. Guanidinoacetate-creatine in secondary progressive multiple sclerosis: a case report.
  19. Suicidal behaviour: What's the brain up to?
  20. Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
  21. Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.
  22. Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.
  23. Double-edge sword roles of iron in driving energy production versus instigating ferroptosis.
  24. High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates With Lower Survival.
  25. Neuroimaging brain growth charts: A road to mental health.
  26. A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe Syndrome.
  27. Structural and functional neuroimaging of the effects of the gut microbiome.
  28. The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer's Cholinergic Atrophy.
  29. Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.
  30. Developmental iron deficiency dysregulates TET activity and DNA hydroxymethylation in the rat hippocampus and cerebellum.
  31. The Role of Glial Cells in Regulating Feeding Behavior: Potential Relevance to Anorexia Nervosa.
  32. Improving Brain Creatine Uptake by Klotho Protein Stimulation: Can Diet Hit the Big Time?
  33. Oxidized low-density lipoprotein receptor 1: a novel potential therapeutic target for intracerebral hemorrhage.
  34. A Long-Term Energy-Rich Diet Increases Prefrontal BDNF in Sprague-Dawley Rats.
  35. The Influence of Mitochondrial-DNA-Driven Inflammation Pathways on Macrophage Polarization: A New Perspective for Targeted Immunometabolic Therapy in Cerebral Ischemia-Reperfusion Injury.
  36. Reduction of Deuterium Level Supports Resistance of Neurons to Glucose Deprivation and Hypoxia: Study in Cultures of Neurons and on Animals.
  37. Effects of vitamin D (VD3) supplementation on the brain mitochondrial function of male rats, in the 6-OHDA-induced model of Parkinson's disease.
  38. Circadian Transcription Factor NPAS2 and the NAD+-Dependent Deacetylase SIRT1 Interact in the Mouse Nucleus Accumbens and Regulate Reward.
  39. Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.
  40. Restricting feeding to dark phase fails to entrain circadian activity and energy expenditure oscillations in Pitx3-mutant Aphakia mice.
  41. Orexin, serotonin, and energy balance.
  42. Mitochondrial repair as potential pharmacological target in cerebral ischemia.
  43. Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors.
  44. A Whole-Brain Connectivity Map of VTA and SNc Glutamatergic and GABAergic Neurons in Mice.
  45. The glutamatergic synapse - A key hub in neuronal metabolism, signalling and plasticity.
  46. Metabolic Sex Dimorphism of the Brain at the Gene, Cell, and Tissue Level.
  47. Brain Signaling of Indispensable Amino Acid Deficiency.
  48. TOM70 in Glial Cells as a Potential Target for Treatment of COVID-19.
  49. Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.
  50. Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice.
  51. Glucose fluxes in glycolytic and oxidative pathways detected in vivo by deuterium magnetic resonance spectroscopy reflect proliferation in mouse glioblastoma.
  52. Insulin signaling in clock neurons regulates sleep in Drosophila.
  53. Monocarboxylate transporter functions and neuroprotective effects of valproic acid in experimental models of amyotrophic lateral sclerosis.
  54. Protective effect of mesenchymal stem cell-derived exosomal treatment of hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury.
  55. Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease.
  56. Mapping an Extended Metabolic Profile of Gliomas Using High-Resolution 31P MRSI at 7T.
  57. Neuroimmunometabolism: A new pathological nexus underlying neurodegenerative disorders.
  1. Sci Rep. 2022 Jan 12. 12(1): 633
    Regulation of adult neurogenesis by the endocannabinoid-producing enzyme diacylglycerol lipase alpha (DAGLa).
    Lena-Louise Schuele, Britta Schuermann, Andras Bilkei-Gorzo, Sara Gorgzadeh, Andreas Zimmer, Este Leidmaa.
      The endocannabinoid system modulates adult hippocampal neurogenesis by promoting the proliferation and survival of neural stem and progenitor cells (NSPCs). This is demonstrated by the disruption of adult neurogenesis under two experimental conditions: (1) NSPC-specific deletion of cannabinoid receptors and (2) constitutive deletion of the enzyme diacylglycerol lipase alpha (DAGLa) which produces the endocannabinoid 2-arachidonoylglycerol (2-AG). However, the specific cell types producing 2-AG relevant to neurogenesis remain unknown. Here we sought to identify the cellular source of endocannabinoids in the subgranular zone of the dentate gyrus (DG) in hippocampus, an important neurogenic niche. For this purpose, we used two complementary Cre-deleter mouse strains to delete Dagla either in neurons, or in astroglia and NSPCs. Surprisingly, neurogenesis was not altered in mice bearing a deletion of Dagla in neurons (Syn-Dagla KO), although neurons are the main source for the endocannabinoids in the brain. In contrast, a specific inducible deletion of Dagla in NPSCs and astrocytes (GLAST-CreERT2-Dagla KO) resulted in a strongly impaired neurogenesis with a 50% decrease in proliferation of newborn cells. These results identify Dagla in NSPCs in the DG or in astrocytes as a prominent regulator of adult hippocampal neurogenesis. We also show a reduction of Daglb expression in GLAST-CreERT2-Dagla KO mice, which may have contributed to the neurogenesis phenotype.
    DOI:  https://doi.org/10.1038/s41598-021-04600-1
  2. Anesth Analg. 2022 Jan 10.
    Differential Alterations to the Metabolic Connectivity of the Cortical and Subcortical Regions in Rat Brain During Ketamine-Induced Unconsciousness.
    Yali Chen, Siyang Li, Xia Liang, Jun Zhang.
       BACKGROUND: Ketamine anesthesia increased glucose metabolism in most brain regions compared to another intravenous anesthetic propofol. However, whether the changes in cerebral metabolic networks induced by ketamine share the same mechanism with propofol remains to be explored. The purpose of the present study was to identify specific features of metabolic network in rat brains during ketamine-induced subanesthesia state and anesthesia state compared to awake state.
    METHODS: We acquired fluorodeoxyglucose positron emission tomography (FDG-PET) images in 20 healthy adult Sprague-Dawley rats that were intravenously administrated saline and ketamine to achieve different conscious states: awake (normal saline), subanesthesia (30 mg kg-1 h-1), and anesthesia (160 mg kg-1 h-1). Based on the FDG-PET data, the alterations in cerebral glucose metabolism and metabolic topography were investigated by graph-theory analysis.
    RESULTS: The baseline metabolism in rat brains was found significantly increased during ketamine-induced subanesthesia and anesthesia. The graph-theory analysis manifested a reduction in metabolism connectivity and network global/local efficiency across cortical regions and an increase across subcortical regions during ketamine-induced anesthesia (nonparametric permutation test: global efficiency between awake and anesthesia, cortex: P = .016, subcortex: P = .015; global efficiency between subanesthesia and anesthesia, subcortex: P = .012).
    CONCLUSIONS: Ketamine broadly increased brain metabolism alongside decreased metabolic connectivity and network efficiency of cortex network. Modulation of these cortical metabolic networks may be a candidate mechanism underlying general anesthesia-induced loss of consciousness.
    DOI:  https://doi.org/10.1213/ANE.0000000000005869
  3. Front Nutr. 2021 ;8 783659
    Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis.
    Angela M Poff, Sara Moss, Maricel Soliven, Dominic P D'Agostino.
      Diverse neurological disorders are associated with a deficit in brain energy metabolism, often characterized by acute or chronic glucose hypometabolism. Ketones serve as the brain's only significant alternative fuel and can even become the primary fuel in conditions of limited glucose availability. Thus, dietary supplementation with exogenous ketones represents a promising novel therapeutic strategy to help meet the energetic needs of the brain in an energy crisis. Preliminary evidence suggests ketosis induced by exogenous ketones may attenuate damage or improve cognitive and motor performance in neurological conditions such as seizure disorders, mild cognitive impairment, Alzheimer's disease, and neurotrauma.
    Keywords:  brain metabolism; energy deficit; exogenous ketone; ketogenic diet; ketone
    DOI:  https://doi.org/10.3389/fnut.2021.783659
  4. Brain. 2022 Jan 13. pii: awab488. [Epub ahead of print]
    Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
    Zhenyu Chen, Eric Chai, Yongchao Mou, Ricardo H Roda, Craig Blackstone, Xue-Jun Li.
      Hereditary spastic paraplegias (HSPs) are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive HSPs, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons (PNs) and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament (NF) aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates NF disruption in both SPG11 and SPG48 knockdown cortical PNs, confirming the contribution of HSP gene deficiency to subsequent NF and mitochondrial defects. Strikingly, NF aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical PNs. Reduced ATP levels and accumulated NF aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wildtype SPG11 in cortical PNs derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and NF aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.
    Keywords:  axonal degeneration; cortical projection neuron; cytoskeletal organization; hereditary spastic paraplegias; mitochondrial dynamics
    DOI:  https://doi.org/10.1093/brain/awab488
  5. Cells. 2021 Dec 29. pii: 90. [Epub ahead of print]11(1):
    The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression.
    Sónia Sá Santos, João B Moreira, Márcia Costa, Rui S Rodrigues, Ana M Sebastião, Sara Xapelli, Susana Solá.
      Neural stem cells (NSCs), crucial for memory in the adult brain, are also pivotal to buffer depressive behavior. However, the mechanisms underlying the boost in NSC activity throughout life are still largely undiscovered. Here, we aimed to explore the role of deacetylase Sirtuin 3 (SIRT3), a central player in mitochondrial metabolism and oxidative protection, in the fate of NSC under aging and depression-like contexts. We showed that chronic treatment with tert-butyl hydroperoxide induces NSC aging, markedly reducing SIRT3 protein. SIRT3 overexpression, in turn, restored mitochondrial oxidative stress and the differentiation potential of aged NSCs. Notably, SIRT3 was also shown to physically interact with the long chain acyl-CoA dehydrogenase (LCAD) in NSCs and to require its activation to prevent age-impaired neurogenesis. Finally, the SIRT3 regulatory network was investigated in vivo using the unpredictable chronic mild stress (uCMS) paradigm to mimic depressive-like behavior in mice. Interestingly, uCMS mice presented lower levels of neurogenesis and LCAD expression in the same neurogenic niches, being significantly rescued by physical exercise, a well-known upregulator of SIRT3 and lipid metabolism. Our results suggest that targeting NSC metabolism, namely through SIRT3, might be a suitable promising strategy to delay NSC aging and confer stress resilience.
    Keywords:  SIRT3; aging; depression; lipid metabolism; mitochondria; neural stem cells
    DOI:  https://doi.org/10.3390/cells11010090
  6. Cells. 2021 Dec 30. pii: 111. [Epub ahead of print]11(1):
    Covering the Role of PGC-1α in the Nervous System.
    Zuzanna Kuczynska, Erkan Metin, Michal Liput, Leonora Buzanska.
      The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.
    Keywords:  PGC-1α; central nervous system; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/cells11010111
  7. Autophagy. 2022 Jan 14. 1-2
    Ceramide-induced mitophagy impairs ß-oxidation-linked energy production in PINK1 deficiency.
    Melissa Vos, Christine Klein.
      Mitophagy and energy production are two functionalities in which PINK1 plays a key role. Loss of PINK1 is one of the genetic causes of Parkinson disease (PD), suggesting both processes are important in PD pathogenesis. Nonetheless, it remains unclear whether these processes are connected or independent of one another. Sphingolipids, including ceramide, have recently emerged as an important new player in the development of PD, however, how alterations in ceramide levels are mechanistically linked to PD remained elusive. In a recently published study, we demonstrated that ceramide accumulates in mitochondria and initiates ceramide-induced mitophagy, thereby compensating for the lack of PINK1-dependent mitophagy upon PINK1 deficiency. However, ceramide accumulation negatively affects ß-oxidation, further aggravating the electron transport chain (ETC) defect caused by PINK1 deficiency and resulting in an additional requirement for mitophagy. Thus, we showed that ceramide serves as a link between the ETC and mitophagy upon PINK1 deficiency. Interruption of this vicious cycle via stimulation of ß-oxidation or reduction of ceramide levels can provide a novel therapeutic target in the treatment of PINK1-related PD.
    Keywords:  PINK1; Parkinson’s disease; ceramide; mitophagy; ß-oxidation
    DOI:  https://doi.org/10.1080/15548627.2022.2027193
  8. Int J Mol Sci. 2022 Jan 04. pii: 548. [Epub ahead of print]23(1):
    Divergent Effect of Central Incretin Receptors Inhibition in a Rat Model of Sporadic Alzheimer's Disease.
    Jelena Osmanovic Barilar, Ana Knezovic, Jan Homolak, Ana Babic Perhoc, Melita Salkovic-Petrisic.
      The incretin system is an emerging new field that might provide valuable contributions to the research of both the pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the roles of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain, as well as on the levels of these incretins, insulin, and glucose via inhibition of the central incretin receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer's disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.
    Keywords:  Alzheimer’s disease; gastric inhibitory polypeptide; glucagon-like peptide-1; hippocampus; hypothalamus
    DOI:  https://doi.org/10.3390/ijms23010548
  9. Nutrients. 2021 Dec 30. pii: 176. [Epub ahead of print]14(1):
    Nutritional Supplementation Reduces Lesion Size and Neuroinflammation in a Sex-Dependent Manner in a Mouse Model of Perinatal Hypoxic-Ischemic Brain Injury.
    Myrna J V Brandt, Cora H Nijboer, Isabell Nessel, Tatenda R Mutshiya, Adina T Michael-Titus, Danielle S Counotte, Lidewij Schipper, Niek E van der Aa, Manon J N L Benders, Caroline G M de Theije.
      Perinatal hypoxia-ischemia (HI) is a major cause of neonatal brain injury, leading to long-term neurological impairments. Medical nutrition can be rapidly implemented in the clinic, making it a viable intervention to improve neurodevelopment after injury. The omega-3 (n-3) fatty acids docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), uridine monophosphate (UMP) and choline have previously been shown in rodents to synergistically enhance brain phospholipids, synaptic components and cognitive performance. The objective of this study was to test the efficacy of an experimental diet containing DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 in a mouse model of perinatal HI. Male and female C57Bl/6 mice received the experimental diet or an isocaloric control diet from birth. Hypoxic ischemic encephalopathy was induced on postnatal day 9 by ligation of the right common carotid artery and systemic hypoxia. To assess the effects of the experimental diet on long-term motor and cognitive outcome, mice were subjected to a behavioral test battery. Lesion size, neuroinflammation, brain fatty acids and phospholipids were analyzed at 15 weeks after HI. The experimental diet reduced lesion size and neuroinflammation specifically in males. In both sexes, brain n-3 fatty acids were increased after receiving the experimental diet. The experimental diet also improved novel object recognition, but no significant effects on motor performance were observed. Current data indicates that early life nutritional supplementation with a combination of DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 may provide neuroprotection after perinatal HI.
    Keywords:  DHA; EPA; UMP; choline; diet; fish oil; hypoxic-ischemic encephalopathy; iodide; mouse; neonate; neurodevelopment; neuroinflammation; vitamin B12; zinc
    DOI:  https://doi.org/10.3390/nu14010176
  10. J Affect Disord. 2022 Jan 11. pii: S0165-0327(22)00056-8. [Epub ahead of print]
    Metabolic Abnormalities in the Basal Ganglia and Cerebellum in Bipolar Disorder: A Multi-modal MR Study.
    Vincent A Magnotta, Jia Xu, Jess G Fiedorowicz, Aislinn Williams, Joseph Shaffer, Gary Christensen, Jeffrey D Long, Eric Taylor, Leela Sathyaputri, Jenny Gringer Richards, Gail Harmata, John Wemmie.
       AIMS: Bipolar type I disorder (BD) is characterized by severe mood swings and occurs in about 1% of the population. The mechanisms underlying the disorder remain unknown. Prior studies have suggested abnormalities in brain metabolism using 1H and 31P magnetic resonance spectroscopy (MRS). Supporting altered metabolism, in previous studies we found T1ρ relaxation times in the cerebellum were elevated in participants with BD. In addition, T1ρ relaxation times in the basal ganglia were lower in participants with BD experiencing depressed mood. Based on these findings, this study sought to probe brain metabolism with a focus of extending these assessments to the cerebellum.
    METHODS: This study collected data from 64 participants with Bipolar type I disorder (BD) and 42 controls. Subjects were scanned at both 3T (anatomical, functional, and T1ρ imaging data) and 7T (31P and 1H spectroscopy). Regions of interest defined by the 1H MRS data were used to explore metabolic and functional changes in the cerebellar vermis and putamen.
    RESULTS: Elevated concentrations of n-Acetyl-L-aspartate (NAA), glutamate, glutathione, taurine, and creatine were found in the cerebellar vermis along with decreased intra-cellular pH. Similar trends were observed in the right putamen for glutamate, creatine, and pH. We also observed a relationship between T1ρ relaxation times and mood in the putamen. We did not observe a significant effect of medications on these measures.
    LIMITATIONS: The study was cross sectional in design and employed a naturalistic approach for assessing the impact of medications on the results.
    CONCLUSION: This study supports prior findings of reduced pH in mitochondrial dysfunction in BD while also showing that these differences extend to the cerebellum.
    Keywords:  Basal Ganglia; Bipolar disorder; Brain Metabolism; Cerebellum; MR Spectroscopy
    DOI:  https://doi.org/10.1016/j.jad.2022.01.052
  11. Int J Mol Sci. 2022 Jan 04. pii: 528. [Epub ahead of print]23(1):
    AGC1 Deficiency: Pathology and Molecular and Cellular Mechanisms of the Disease.
    Beatriz Pardo, Eduardo Herrada-Soler, Jorgina Satrústegui, Laura Contreras, Araceli Del Arco.
      AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named "early infantile epileptic encephalopathy 39" (EIEE 39, OMIM # 612949) characterized by epilepsy, hypotonia, arrested psychomotor neurodevelopment, hypo myelination and a drastic drop in brain aspartate (Asp) and N-acetylaspartate (NAA). Current evidence suggest that neurons are the main brain cell type expressing Aralar. However, paradoxically, glial functions such as myelin and Glutamine (Gln) synthesis are markedly impaired in AGC1 deficiency. Herein, we discuss the role of the AGC1/Aralar-MAS pathway in neuronal functions such as Asp and NAA synthesis, lactate use, respiration on glucose, glutamate (Glu) oxidation and other neurometabolic aspects. The possible mechanism triggering the pathophysiological findings in AGC1 deficiency, such as epilepsy and postnatal hypomyelination observed in humans and mice, are also included. Many of these mechanisms arise from findings in the aralar-KO mice model that extensively recapitulate the human disease including the astroglial failure to synthesize Gln and the dopamine (DA) mishandling in the nigrostriatal system. Epilepsy and DA mishandling are a direct consequence of the metabolic defect in neurons due to AGC1/Aralar deficiency. However, the deficits in myelin and Gln synthesis may be a consequence of neuronal affectation or a direct effect of AGC1/Aralar deficiency in glial cells. Further research is needed to clarify this question and delineate the transcellular metabolic fluxes that control brain functions. Finally, we discuss therapeutic approaches successfully used in AGC1-deficient patients and mice.
    Keywords:  AGC1/Aralar deficiency; malate-aspartate shuttle; mitochondrial aspartate-glutamate carrier; mitochondrial disorders; mitochondrial function
    DOI:  https://doi.org/10.3390/ijms23010528
  12. Front Mol Neurosci. 2021 ;14 778569
    Effects of Mdivi-1 on Neural Mitochondrial Dysfunction and Mitochondria-Mediated Apoptosis in Ischemia-Reperfusion Injury After Stroke: A Systematic Review of Preclinical Studies.
    Nguyen Thanh Nhu, Qing Li, Yijie Liu, Jian Xu, Shu-Yun Xiao, Shin-Da Lee.
      This systematic review sought to determine the effects of Mitochondrial division inhibitor-1 (Mdivi-1) on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in ischemia/reperfusion (I/R) injury after ischemic stroke. Pubmed, Web of Science, and EMBASE databases were searched through July 2021. The studies published in English language that mentioned the effects of Mdivi-1 on neural mitochondrial dysfunction and neural mitochondria-mediated apoptosis in I/R-induced brain injury were included. The CAMARADES checklist (for in vivo studies) and the TOXRTOOL checklist (for in vitro studies) were used for study quality evaluation. Twelve studies were included (median CAMARADES score = 6; TOXRTOOL scores ranging from 16 to 18). All studies investigated neural mitochondrial functions, providing that Mdivi-1 attenuated the mitochondrial membrane potential dissipation, ATP depletion, and complexes I-V abnormalities; enhanced mitochondrial biogenesis, as well as inactivated mitochondrial fission and mitophagy in I/R-induced brain injury. Ten studies analyzed neural mitochondria-mediated apoptosis, showing that Mdivi-1 decreased the levels of mitochondria-mediated proapoptotic factors (AIF, Bax, cytochrome c, caspase-9, and caspase-3) and enhanced the level of antiapoptotic factor (Bcl-2) against I/R-induced brain injury. The findings suggest that Mdivi-1 can protect neural mitochondrial functions, thereby attenuating neural mitochondria-mediated apoptosis in I/R-induced brain injury. Our review supports Mdivi-1 as a potential therapeutic compound to reduce brain damage in ischemic stroke (PROSPERO protocol registration ID: CRD42020205808). Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/], identifier [CRD42020205808].
    Keywords:  Mdivi-1; apoptosis; ischemia-reperfusion injury; mitochondrial function; stroke
    DOI:  https://doi.org/10.3389/fnmol.2021.778569
  13. J Surg Res. 2022 Jan 08. pii: S0022-4804(21)00741-1. [Epub ahead of print]273 15-23
    Electroacupuncture Relieves Hippocampal Injury by Heme Oxygenase-1 to Improve Mitochondrial Function.
    Rui Mu, Na Li, Jian-Bo Yu, Li-Rong Gong, Shu-An Dong, Jia Shi, Yuan Zhang, Zi-Lei Xie.
       INTRODUCTION: Electroacupuncture (EA) treatment has been demonstrated to have the potential to prevent sepsis-induced hippocampal injury; however, the mechanisms underlying the protective effects of EA against such injury remain unclear. Herein, to elucidate these mechanisms, we constructed a mouse model of lipopolysaccharide (LPS)-induced hippocampal injury to investigate the protection mechanism of EA and to determine whether heme oxygenase-1 (HO-1)-mediated mitochondrial function is involved in the protective effect of EA.
    MATERIALS AND METHODS: The sepsis model of hippocampal injury was induced by administering LPS. The Zusanli and Baihui acupoints were stimulated using EA for 30 min once a day, for 5 d before LPS exposure and the first day after administering LPS. Hippocampal injury was investigated by hematoxylin and eosin staining and Nissl staining. HO-1 levels were measured using Western blotting. Mitochondrial metabolism was validated by assessing adenosine triphosphate, superoxide dismutase, malondialdehyde levels, reactive oxygen species production, and mitochondrial respiratory chain activity. Mitochondrial morphology was analyzed by transmission electron microscopy.
    RESULTS: EA treatment alleviated neuronal injury, impeded oxidative stress, and improved mitochondrial respiratory function, energy metabolism, and mitochondrial morphology in LPS-exposed mice. In addition, HO-1 knockout aggravated LPS-induced hippocampal injury, aggravated oxidative stress, and reduced mitochondrial respiratory function and aggravated mitochondrial swelling, crest relaxation, and vacuole degeneration. Moreover, EA was unable to reverse the hippocampal damage and mitochondrial dysfunction caused by LPS exposure after HO-1 knockout.
    CONCLUSIONS: EA improves LPS-induced hippocampal injury by regulating HO-1-mediated mitochondrial function. Furthermore, HO-1 plays a critical role in maintaining mitochondrial function and resisting oxidative injury.
    Keywords:  Electroacupuncture; Heme oxygenase-1; Hippocampal injury; Lipopolysaccharide; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.jss.2021.12.013
  14. Neural Regen Res. 2022 Aug;17(8): 1814-1820
    Reducing host aldose reductase activity promotes neuronal differentiation of transplanted neural stem cells at spinal cord injury sites and facilitates locomotion recovery.
    Kun Zhang, Wen-Can Lu, Ming Zhang, Qian Zhang, Pan-Pan Xian, Fang-Fang Liu, Zhi-Yang Chen, Chung Sookja Kim, Sheng-Xi Wu, Hui-Ren Tao, Ya-Zhou Wang.
      Neural stem cell (NSC) transplantation is a promising strategy for replacing lost neurons following spinal cord injury. However, the survival and differentiation of transplanted NSCs is limited, possibly owing to the neurotoxic inflammatory microenvironment. Because of the important role of glucose metabolism in M1/M2 polarization of microglia/macrophages, we hypothesized that altering the phenotype of microglia/macrophages by regulating the activity of aldose reductase (AR), a key enzyme in the polyol pathway of glucose metabolism, would provide a more beneficial microenvironment for NSC survival and differentiation. Here, we reveal that inhibition of host AR promoted the polarization of microglia/macrophages toward the M2 phenotype in lesioned spinal cord injuries. M2 macrophages promoted the differentiation of NSCs into neurons in vitro. Transplantation of NSCs into injured spinal cords either deficient in AR or treated with the AR inhibitor sorbinil promoted the survival and neuronal differentiation of NSCs at the injured spinal cord site and contributed to locomotor functional recovery. Our findings suggest that inhibition of host AR activity is beneficial in enhancing the survival and neuronal differentiation of transplanted NSCs and shows potential as a treatment of spinal cord injury.
    Keywords:  aldose reductase; functional recovery; inflammation; macrophage; microglia; neural stem cell transplantation; neuronal differentiation; polarization; spinal cord injury
    DOI:  https://doi.org/10.4103/1673-5374.330624
  15. JIMD Rep. 2022 Jan;63(1): 3-10
    Infantile onset carnitine palmitoyltransferase 2 deficiency: Cortical polymicrogyria, schizencephaly, and gray matter heterotopias in an adolescent with normal development.
    Ivan Shelihan, Elsa Rossignol, Jean-Claude Décarie, Jean-Paul Bonnefont, Michèle Brivet, Catherine Brunel-Guitton, Grant A Mitchell.
       Objective: To report an adolescent with infantile-onset carnitine palmitoyltransferase 2 (CPT2) deficiency and cerebral malformations and to review the occurrence of brain malformations in CPT2 deficiency. The patient presented clinically at age 5 months with dehydration and hepatomegaly. He also has an unrelated condition, X-linked nephrogenic diabetes insipidus. He had recurrent rhabdomyolysis but normal psychomotor development. At age 17 years, he developed spontaneous focal seizures. Cerebral magnetic resonance imaging revealed extensive left temporo-parieto-occipital polymicrogyria, white matter heterotopias, and schizencephaly. Neuronal migration defects were previously reported in lethal neonatal CPT2 deficiency but not in later-onset forms.
    Design and Methods: We searched PubMed, Google Scholar, and the bibliographies of the articles found by these searches, for cerebral malformations in CPT2 deficiency. All antenatal, neonatal, infantile, and adult-onset cases were included. Exclusion criteria included insufficient information about age of clinical onset and lack of confirmation of CPT2 deficiency by enzymatic assay or genetic testing. For each report, we noted the presence of cerebral malformations on brain imaging or pathological examination.
    Results: Of 26 neonatal-onset CPT2-deficient patients who met the inclusion criteria, brain malformations were reported in 16 (61.5%). In 19 infantile-onset cases, brain malformations were not reported, but only 3 of the 19 reports (15.8%) include brain imaging or neuropathology data. In 276 adult-onset cases, no brain malformations were reported.
    Conclusion: To the best of our knowledge, this is the first report of cerebral malformations in an infantile onset CPT2-deficient patient. Brain imaging should be considered in patients with CPTII deficiency and neurological manifestations, even in those with later clinical onset.
    Keywords:  CPT2; carnitine; cerebral; heterotopias; infantile; malformation; palmitoyltransferase; polymicrogyria
    DOI:  https://doi.org/10.1002/jmd2.12243
  16. Front Psychiatry. 2021 ;12 788779
    Novel Probable Glance at Inflammatory Scenario Development in Autistic Pathology.
    Aida A Harutyunyan, Hayk A Harutyunyan, Konstantin B Yenkoyan.
      Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication and restricted-repetitive patterns of behavior, interests, or activities. ASD is generally associated with chronic inflammatory states, which are linked to immune system dysfunction and/or hyperactivation. The latter might be considered as one of the factors damaging neuronal cells. Several cell types trigger and sustain such neuroinflammation. In this study, we traced different markers of immune system activation on both cellular (immune cell phenotypes) and mediatory levels (production of cytokines) alongside adverse hematology and biochemistry screening in a group of autistic children. In addition, we analyzed the main metabolic pathways potentially involved in ASD development: energy (citric acid cycle components), porphyrin, and neurotransmitter metabolism. Several ASD etiological factors, like heavy metal intoxication, and risk factors-genetic polymorphisms of the relevant neurotransmitters and vitamin D receptors-were also analyzed. Finally, broad linear regression analysis allowed us to elucidate the possible scenario that led to the development of chronic inflammation in ASD patients. Obtained data showed elevated levels of urinary cis-aconitate, isocitrate, alfa-ketoglutarate, and HMG. There were no changes in levels of metabolites of monoamine neurotransmitters, however, the liver-specific tryptophan kinurenine pathway metabolites showed increased levels of quinolinate (QUIN) and picolinate, whereas the level of kynurenate remained unchanged. Abovementioned data demonstrate the infringement in energy metabolism. We found elevated levels of lead in red blood cells, as well as altered porphyrin metabolism, which support the etiological role of heavy metal intoxication in ASD. Lead intoxication, the effect of which is intensified by a mutation of the VDR-Taq and MAO-A, leads to quinolinic acid increase, resulting in energy metabolism depletion and mitochondrial dysfunction. Moreover, our data backing the CD4+CD3+ T-cell dependence of mitochondrial dysfunction development in ASD patients reported in our previous study leads us to the conclusion that redox-immune cross-talk is considered a main functional cell damaging factor in ASD patients.
    Keywords:  MAO-A; TNF-alfa; VDR Taq; autism spectrum disorders; energy metabolism; lead; mitochondria; monocytes
    DOI:  https://doi.org/10.3389/fpsyt.2021.788779
  17. Molecules. 2022 Jan 05. pii: 324. [Epub ahead of print]27(1):
    Glutathione in Brain Disorders and Aging.
    Igor Y Iskusnykh, Anastasia A Zakharova, Dhruba Pathak.
      Glutathione is a remarkably functional molecule with diverse features, which include being an antioxidant, a regulator of DNA synthesis and repair, a protector of thiol groups in proteins, a stabilizer of cell membranes, and a detoxifier of xenobiotics. Glutathione exists in two states-oxidized and reduced. Under normal physiological conditions of cellular homeostasis, glutathione remains primarily in its reduced form. However, many metabolic pathways involve oxidization of glutathione, resulting in an imbalance in cellular homeostasis. Impairment of glutathione function in the brain is linked to loss of neurons during the aging process or as the result of neurological diseases such as Huntington's disease, Parkinson's disease, stroke, and Alzheimer's disease. The exact mechanisms through which glutathione regulates brain metabolism are not well understood. In this review, we will highlight the common signaling cascades that regulate glutathione in neurons and glia, its functions as a neuronal regulator in homeostasis and metabolism, and finally a mechanistic recapitulation of glutathione signaling. Together, these will put glutathione's role in normal aging and neurological disorders development into perspective.
    Keywords:  aging; brain; disorders; glutathione; neuron
    DOI:  https://doi.org/10.3390/molecules27010324
  18. J Int Med Res. 2022 Jan;50(1): 3000605211073305
    Guanidinoacetate-creatine in secondary progressive multiple sclerosis: a case report.
    Sergej M Ostojic, Jelena Ostojic, Dragana Zanini, Tatjana Jezdimirovic, Valdemar Stajer.
      Acute secondary progressive multiple sclerosis (SPMS) is characterized by escalating neurological disability, with limited disease-modifying therapeutic options. A 48-year-old woman with acute SPMS being treated with interferon beta-1a and oral corticosteroids presented as a clinical outpatient with no disease-modifying effects after treatment. A decision was made to treat her with a combination of guanidinoacetate and creatine for 21 days. She had made clinical progress at follow-up, with the intensity of fatigue dropping from severe to mild. Magnetic resonance spectroscopy revealed increased brain choline, creatine, N-acetylaspartate, and glutathione. Patients with SPMS may benefit from guanidinoacetate-creatine treatment in terms of patient- and clinician-reported outcomes; this requires additional study.
    Keywords:  Multiple sclerosis; brain metabolism; case report; creatine; guanidinoacetic acid; patient outcome
    DOI:  https://doi.org/10.1177/03000605211073305
  19. J Psychiatr Res. 2021 Dec 28. pii: S0022-3956(21)00763-9. [Epub ahead of print]146 210-218
    Suicidal behaviour: What's the brain up to?
    Shubhangi Parkar, Natasha Kate, Karishma Rupani, Gaurav Malhotra, Trupti Upadhye, Ramesh Asopa.
       BACKGROUND: Individuals with suicidal behaviours are increasingly recognized as having impairments in brain metabolism. However, these are not well delineated.
    AIM: To evaluate regional cerebral glucose metabolism (rCMglu) in subjects with suicidal behaviours and assess differences in rCMglu between depressed and non-depressed suicidal subjects.
    METHODS: Thirty-three subjects with suicidal behaviours were assessed using Columbia Suicide Severity Rating scale (CSSRS) and Beck's Depression Inventory (BDI). Brain metabolism was assessed using [18F]Fluoro,Deoxy-Glucose Positron Emission Tomography (FDG-PET).
    RESULTS: Of 33 subjects, eighteen had depression. FDG-PET findings revealed that in comparison to mean asymptomatic controls, subjects had decreased rCMglu in right inferior frontal, left Broca's, left inferiolateral andsuperiolateral temporal, right inferior parietal and left posterior cingulate cortex. Increased rCMglu was seen in bilateral superior and medial frontal, right inferiolateral and posteriomedial temporal cortex, and midbrain. CSSRS total intensity inversely correlated with rCMglu in medial frontal cortex, left Broca's and superiolateral temporal cortex and directly correlated with rCMglu in right cerebellum. There was no significant difference in rCMglu between depressed and non depressed group.
    CONCLUSIONS: Significant differences exist in rCMglu of suicidal individuals, chiefly in frontal and temporal regions. Understanding these would help us identify individuals more at risk for suicidal behaviours.
    DOI:  https://doi.org/10.1016/j.jpsychires.2021.12.052
  20. Front Cell Dev Biol. 2021 ;9 767407
    Genetic and Mitochondrial Metabolic Analyses of an Atypical Form of Leigh Syndrome.
    Martine Uittenbogaard, Kuntal Sen, Matthew Whitehead, Christine A Brantner, Yue Wang, Lee-Jun Wong, Andrea Gropman, Anne Chiaramello.
      In this study, we aimed to establish the mitochondrial etiology of the proband's progressive neurodegenerative disease suggestive of an atypical Leigh syndrome, by determining the proband's pathogenic variants. Brain MRI showed a constellation of multifocal temporally disparate lesions in the cerebral deep gray nuclei, brainstem, cerebellum, spinal cord along with rhombencephalic atrophy, and optic nerve atrophy. Single voxel 1H MRS performed concurrently over the left cerebral deep gray nuclei showed a small lactate peak, increased glutamate and citrate elevation, elevating suspicion of a mitochondrial etiology. Whole exome sequencing revealed three heterozygous nuclear variants mapping in three distinct genes known to cause Leigh syndrome. Our mitochondrial bioenergetic investigations revealed an impaired mitochondrial energy metabolism. The proband's overall ATP deficit is further intensified by an ineffective metabolic reprogramming between oxidative phosphorylation and glycolysis. The deficient metabolic adaptability and global energy deficit correlate with the proband's neurological symptoms congruent with an atypical Leigh syndrome. In conclusion, our study provides much needed insights to support the development of molecular diagnostic and therapeutic strategies for atypical Leigh syndrome.
    Keywords:  combined oxidative phosphorylation deficiency; leigh syndrome; metabolic adaptability; mitochondrial energy metabolism; nuclear variants; whole exome sequencing
    DOI:  https://doi.org/10.3389/fcell.2021.767407
  21. Int J Mol Sci. 2021 Dec 22. pii: 102. [Epub ahead of print]23(1):
    Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.
    Giulia Sierri, Roberta Dal Magro, Barbara Vergani, Biagio Eugenio Leone, Beatrice Formicola, Lorenzo Taiarol, Stefano Fagioli, Marcelo Kravicz, Lucio Tremolizzo, Laura Calabresi, Francesca Re.
      The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood-brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.
    Keywords:  ABCA1; Alzheimer disease; HDL; apoA-I nanodiscs; astrocytes; brain cholesterol; nanoparticles
    DOI:  https://doi.org/10.3390/ijms23010102
  22. Int J Mol Sci. 2021 Dec 29. pii: 363. [Epub ahead of print]23(1):
    Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.
    Viktoriia Bazylianska, Akhil Sharma, Heli Chauhan, Bernard Schneider, Anna Moszczynska.
      Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson's disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction and whether parkin regulates complex I, an enzymatic complex downregulated in PD. To determine this, we separately assessed the effects of METH or DA alone on electron transport chain (ETC) complexes and the protein parkin in isolated striatal mitochondria. We show that METH decreases the levels of selected complex I, II, and III subunits (NDUFS3, SDHA, and UQCRC2, respectively), whereas DA decreases the levels only of the NDUFS3 subunit in our preparations. We also show that the selected subunits are not decreased in synaptosomal mitochondria under similar experimental conditions. Finally, we found that parkin overexpression does not influence the levels of the NDUFS3 subunit in rat striatum. The presented results indicate that METH itself is a factor promoting dysfunction of striatal mitochondria; therefore, it is a potential drug target against METH neurotoxicity. The observed decreases in ETC complex subunits suggest that DA and METH decrease activities of the ETC complexes via oxidative damage to their subunits and that synaptosomal mitochondria may be somewhat "resistant" to DA- and METH-induced disruption in mitochondrial ETC complexes than perikaryal mitochondria. The results also suggest that parkin does not regulate NDUFS3 turnover in rat striatum.
    Keywords:  dopamine; electron transport chain complexes; methamphetamine; parkin
    DOI:  https://doi.org/10.3390/ijms23010363
  23. Cell Death Dis. 2022 01 10. 13(1): 40
    Double-edge sword roles of iron in driving energy production versus instigating ferroptosis.
    Shuping Zhang, Wei Xin, Gregory J Anderson, Ruibin Li, Ling Gao, Shuguang Chen, Jiajun Zhao, Sijin Liu.
      Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-021-04490-1
  24. Front Mol Biosci. 2021 ;8 752404
    High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates With Lower Survival.
    Kimberly M Stanke, Carrick Wilson, Srivatsan Kidambi.
      Glioblastoma (GBM), the most aggressive brain tumor, is associated with a median survival at diagnosis of 16-20 months and limited treatment options. The key hallmark of GBM is altered tumor metabolism and marked increase in the rate of glycolysis. Aerobic glycolysis along with elevated glucose consumption and lactate production supports rapid cell proliferation and GBM growth. In this study, we examined the gene expression profile of metabolic targets in GBM samples from patients with lower grade glioma (LGG) and GBM. We found that gene expression of glycolytic enzymes is up-regulated in GBM samples and significantly associated with an elevated risk for developing GBM. Our findings of clinical outcomes showed that GBM patients with high expression of HK2 and PKM2 in the glycolysis related genes and low expression of genes involved in mitochondrial metabolism-SDHB and COX5A related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), respectively, was associated with poor patient overall survival. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in GBM compared to LGG but was lower compared to normal brain. The fact that in GBM the expression levels of TCA cycle and OXPHOS-related genes are higher than those in LGG patients suggests the metabolic shift in GBM cells when progressing from LGG to GBM. These results are an important step forward in our understanding of the role of metabolic reprogramming in glioma as drivers of the tumor and could be potential prognostic targets in GBM therapies.
    Keywords:  aerobic glycolysis; brain; glioblastoma; glucose metabolism; the Warburg effect
    DOI:  https://doi.org/10.3389/fmolb.2021.752404
  25. Psychoradiology. 2021 Dec;1(4): 272-286
    Neuroimaging brain growth charts: A road to mental health.
    Li-Zhen Chen, Avram J Holmes, Xi-Nian Zuo, Qi Dong.
      Mental disorders are common health concerns and contribute to a heavy global burden on our modern society. It is challenging to identify and treat them timely. Neuroimaging evidence suggests the incidence of various psychiatric and behavioral disorders is closely related to the atypical development of brain structure and function. The identification and understanding of atypical brain development provide chances for clinicians to detect mental disorders earlier, perhaps even prior to onset, and treat them more precisely. An invaluable and necessary method in identifying and monitoring atypical brain development are growth charts of typically developing individuals in the population. The brain growth charts can offer a series of standard references on typical neurodevelopment, representing an important resource for the scientific and medical communities. In the present paper, we review the relationship between mental disorders and atypical brain development from a perspective of normative brain development by surveying the recent progress in the development of brain growth charts, including four aspects on growth chart utility: 1) cohorts, 2) measures, 3) mechanisms, and 4) clinical translations. In doing so, we seek to clarify the challenges and opportunities in charting brain growth, and to promote the application of brain growth charts in clinical practice.
    Keywords:  development; growth chart; mental health; neuroimaging; reliability
    DOI:  https://doi.org/10.1093/psyrad/kkab022
  26. Biol Open. 2022 Jan 13. pii: bio.059066. [Epub ahead of print]
    A human stem cell resource to decipher the biochemical and cellular basis of neurodevelopmental defects in Lowe Syndrome.
    Bilal M Akhtar, Priyanka Bhatia, Shubhra Acharya, Sanjeev Sharma, Yojet Sharma, B S Aswathy, Kavina Ganapathy, Anil Vasudevan, Padinjat Raghu.
      Human brain development is a complex process where multiple cellular and developmental events are co-ordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS), is a X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1 that encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated, but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a "disease-in-a-dish" model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development.
    Keywords:  Human disease; Lipid phosphatase; Neural development; PI(4,5)P2; Phosphoinositides; hiPSC-stem cells
    DOI:  https://doi.org/10.1242/bio.059066
  27. Eur Radiol. 2022 Jan 14.
    Structural and functional neuroimaging of the effects of the gut microbiome.
    Rodrigo A Montoro, Ajay P Singh, John-Paul J Yu.
      Interactions between intestinal microbiota and the central nervous system profoundly influence brain structure and function. Over the past 15 years, intense research efforts have uncovered the significant association between gut microbial dysbiosis and neurologic, neurodegenerative, and psychiatric disorders; however, our understanding of the effect of gut microbiota on quantitative neuroimaging measures of brain microstructure and function remains limited. Many current gut microbiome studies specifically focus on discovering correlations between specific microbes and neurologic disease states that, while important, leave critical mechanistic questions unanswered. To address this significant gap in knowledge, quantitative structural and functional brain imaging has emerged as a vital bridge and as the next step in understanding how the gut microbiome influences the brain. In this review, we examine the current state-of-the-art, raise awareness of this important topic, and aim to highlight immense new opportunities-in both research and clinical imaging-for the imaging community in this emerging field of study. Our review also highlights the potential for preclinical imaging of germ-free and gnotobiotic models to significantly advance our understanding of the causal mechanisms by which the gut microbiome alters neural microstructure and function. KEY POINTS: • Alterations to the gut microbiome can significantly influence brain structure and function in health and disease. • Quantitative neuroimaging can help elucidate the effect of gut microbiota on the brain and with future translational advances, neuroimaging will be critical for both diagnostic assessment and therapeutic monitoring.
    Keywords:  Diffusion tensor imaging; Gut microbiome; Gut-brain axis; Magnetic resonance imaging; fMRI
    DOI:  https://doi.org/10.1007/s00330-021-08486-5
  28. Cells. 2021 Dec 22. pii: 16. [Epub ahead of print]11(1):
    The Nerve Growth Factor Metabolic Pathway Dysregulation as Cause of Alzheimer's Cholinergic Atrophy.
    Sonia Do Carmo, Benjamin Kannel, A Claudio Cuello.
      The cause of the loss of basal forebrain cholinergic neurons (BFCNs) and their terminal synapses in the cerebral cortex and hippocampus in Alzheimer's disease (AD) has provoked a decades-long controversy. The cholinergic phenotype of this neuronal system, involved in numerous cognitive mechanisms, is tightly dependent on the target-derived nerve growth factor (NGF). Consequently, the loss of BFCNs cholinergic phenotype in AD was initially suspected to be due to an NGF trophic failure. However, in AD there is a normal NGF synthesis and abundance of the NGF precursor (proNGF), therefore the NGF trophic failure hypothesis for the atrophy of BCNs was abandoned. In this review, we discuss the history of NGF-dependency of BFCNs and the atrophy of these neurons in Alzheimer's disease (AD). Further to it, we propose that trophic factor failure explains the BFCNs atrophy in AD. We discuss evidence of the occurrence of a brain NGF metabolic pathway, the dysregulation of which, in AD explains the severe deficiency of NGF trophic support for the maintenance of BFCNs cholinergic phenotype. Finally, we revise recent evidence that the NGF metabolic dysregulation in AD pathology starts at preclinical stages. We also propose that the alteration of NGF metabolism-related markers in body fluids might assist in the AD preclinical diagnosis.
    Keywords:  Alzheimer’s disease; Down syndrome; NGF metabolic cascade; basal forebrain cholinergic nuclei; cholinergic system; nerve growth factor; trophic support
    DOI:  https://doi.org/10.3390/cells11010016
  29. Neural Regen Res. 2022 Aug;17(8): 1645-1651
    Phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer's disease.
    Angie K Torres, Bastián I Rivera, Catalina M Polanco, Claudia Jara, Cheril Tapia-Rojas.
      During normal aging, there is a decline in all physiological functions in the organism. One of the most affected organs is the brain, where neurons lose their proper synaptic function leading to cognitive impairment. Aging is one of the main risk factors for the development of neurodegenerative diseases, such as Alzheimer's disease. One of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming aggregates. The most studied brain aggregates are the senile plaques, formed by Aβ peptide; however, the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their toxicity. It is reported that neurons undergo severe mitochondrial dysfunction with age, with a decrease in adenosine 5'-triphosphate production, loss of the mitochondrial membrane potential, redox imbalance, impaired mitophagy, and loss of calcium buffer capacity. Interestingly, abnormal tau protein interacts with several mitochondrial proteins, suggesting that it could induce mitochondrial dysfunction. Nevertheless, whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown. A recent study of our laboratory shows that phosphorylated tau at Ser396/404 (known as PHF-1), an epitope commonly related to pathology, accumulates inside mitochondria during normal aging. This accumulation occurs preferentially in synaptic mitochondria, which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged individuals. Here, we review the main tau modifications promoting mitochondrial dysfunction, and the possible mechanism involved. Also, we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in aging. Finally, we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer's disease, which could be considered as an early event in the neurodegenerative process. Thus, phosphorylated tau PHF-1 inside the mitochondria could be considered such a potential therapeutic target to prevent or attenuate age-related cognitive impairment.
    Keywords:  Alzheimer’s disease; PHF-1; age pathology; aging; hippocampus; memory; mitochondria; phosphorylated tau; synaptic mitochondria; tau
    DOI:  https://doi.org/10.4103/1673-5374.332125
  30. Dev Neurosci. 2022 Jan 11.
    Developmental iron deficiency dysregulates TET activity and DNA hydroxymethylation in the rat hippocampus and cerebellum.
    Amanda K Barks, Montana M Beeson, Timothy C Hallstrom, Michael K Georgieff, Phu V Tran.
      Iron deficiency (ID) during neurodevelopment is associated with lasting cognitive and socioemotional deficits, and increased risk for neuropsychiatric disease throughout the lifespan. These neurophenotypical changes are underlain by gene dysregulation in the brain that outlasts the period of ID; however, the mechanisms by which ID establishes and maintains gene expression changes are incompletely understood. The epigenetic modification 5-hydroxymethylcytosine (5hmC), or DNA hydroxymethylation, is one candidate mechanism because of its dependence on iron-containing TET enzymes. The aim of the present study was to determine the effect of fetal-neonatal ID on regional brain TET activity, Tet expression, and 5hmC in the developing rat hippocampus and cerebellum, and to determine whether changes are reversible with dietary iron treatment. Timed pregnant Sprague-Dawley rats were fed iron deficient diet (ID; 4 mg/kg Fe) from gestational day (G)2 to generate iron deficient anemic (IDA) offspring. Control dams were fed iron sufficient diet (IS; 200 mg/kg Fe). At postnatal day (P)7, a subset of ID-fed litters was randomized to IS diet, generating treated IDA (TIDA) offspring. At P15, hippocampus and cerebellum were isolated for subsequent analysis. TET activity was quantified by ELISA from nuclear proteins. Expression of Tet1, Tet2, and Tet3 was quantified by qPCR from total RNA. Global %5hmC was quantified by ELISA from genomic DNA. ID increased DNA hydroxymethylation (p=0.0105), with a corresponding increase in TET activity (p<0.0001) and Tet3 expression (p<0.0001) in the P15 hippocampus. In contrast, ID reduced TET activity (p=0.0016) in the P15 cerebellum, with minimal effect on DNA hydroxymethylation. Neonatal dietary iron treatment resulted in partial normalization of these changes in both brain regions. These results demonstrate that the TET/DNA hydroxymethylation system is disrupted by developmental ID in a brain region-specific manner. Differential regional disruption of this epigenetic system may contribute to the lasting neural circuit dysfunction and neurobehavioral dysfunction associated with developmental ID.
    DOI:  https://doi.org/10.1159/000521704
  31. J Clin Med. 2021 Dec 30. pii: 186. [Epub ahead of print]11(1):
    The Role of Glial Cells in Regulating Feeding Behavior: Potential Relevance to Anorexia Nervosa.
    Linda Frintrop, Stefanie Trinh, Jochen Seitz, Markus Kipp.
      Eating behavior is controlled by hypothalamic circuits in which agouti-related peptide-expressing neurons when activated in the arcuate nucleus, promote food intake while pro-opiomelanocortin-producing neurons promote satiety. The respective neurotransmitters signal to other parts of the hypothalamus such as the paraventricular nucleus as well as several extra-hypothalamic brain regions to orchestrate eating behavior. This complex process of food intake may be influenced by glia cells, in particular astrocytes and microglia. Recent studies showed that GFAP+ astrocyte cell density is reduced in the central nervous system of an experimental anorexia nervosa model. Anorexia nervosa is an eating disorder that causes, among the well-known somatic symptoms, brain volume loss which was associated with neuropsychological deficits while the underlying pathophysiology is unknown. In this review article, we summarize the findings of glia cells in anorexia nervosa animal models and try to deduce which role glia cells might play in the pathophysiology of eating disorders, including anorexia nervosa. A better understanding of glia cell function in the regulation of food intake and eating behavior might lead to the identification of new drug targets.
    Keywords:  anorexia nervosa; astrocyte; glia cells; hypothalamus
    DOI:  https://doi.org/10.3390/jcm11010186
  32. Front Nutr. 2021 ;8 795599
    Improving Brain Creatine Uptake by Klotho Protein Stimulation: Can Diet Hit the Big Time?
    Sergej M Ostojic, Dagrun Engeset.
      
    Keywords:  CT1; Klotho (KL); brain; creatine; curcumin; low-calorie high-protein diet; phosphate-restricted diet; vitamin D2
    DOI:  https://doi.org/10.3389/fnut.2021.795599
  33. Neural Regen Res. 2022 Aug;17(8): 1795-1801
    Oxidized low-density lipoprotein receptor 1: a novel potential therapeutic target for intracerebral hemorrhage.
    Hui-Yuan Zhang, Xi Lu, Yue-Han Hao, Ling Tang, Zhi-Yi He.
      Oxidized low-density lipoprotein receptor 1 (OLR1) is upregulated in neurons and participates in hypertension-induced neuronal apoptosis. OLR1 deletion exerts protective effects on cerebral damage induced by hypertensive-induced stroke. Therefore, OLR1 is likely involved in the progress of intracerebral hemorrhage. In this study, we examined the potential role of OLR1 in intracerebral hemorrhage using a rat model. OLR1 small interfering RNA (10 μL; 50 pmol/μL) was injected into the right basal ganglia to knock down OLR1. Twenty-four hours later, 0.5 U collagenase type VII was injected to induce intracerebral hemorrhage. We found that knockdown of OLR1 attenuated neurological behavior impairment in rats with intracerebral hemorrhage and reduced hematoma, neuron loss, inflammatory reaction, and oxidative stress in rat brain tissue. We also found that silencing of OLR1 suppressed ferroptosis induced by intracerebral hemorrhage and the p38 signaling pathway. Therefore, silencing OLR1 exhibits protective effects against secondary injury of intracerebral hemorrhage. These findings suggest that OLR1 may be a novel potential therapeutic target for intracerebral hemorrhage.
    Keywords:  ferroptosis; inflammation; intracerebral hemorrhage; neurological behavior; neuroprotection; novel therapeutic target; oxidative stress; oxidized low-density lipoprotein receptor 1; p38 signaling pathway; secondary brain injury
    DOI:  https://doi.org/10.4103/1673-5374.332157
  34. Nutrients. 2021 Dec 28. pii: 126. [Epub ahead of print]14(1):
    A Long-Term Energy-Rich Diet Increases Prefrontal BDNF in Sprague-Dawley Rats.
    Alessandro Virtuoso, Pernille Tveden-Nyborg, Anne Marie Voigt Schou-Pedersen, Jens Lykkesfeldt, Heidi Kaastrup Müller, Betina Elfving, Dorte Bratbo Sørensen.
      Findings of the effect of high-fat feeding including "Cafeteria Diets" (CAF) on brain-derived neurotrophic factor (BDNF) in the hippocampus (HIP) and prefrontal cortex (PFC) in rodents are conflicting. CAF is a non-standardized, highly palatable energy-rich diet composed by everyday food items for human consumption and is known to induce metabolic syndrome and obesity in rats. However, the highly palatable nature of CAF may counteract a negative effect of chronic stress on anticipatory behavior and synaptic plasticity in the hippocampus, hence represent a confounding factor (e.g., when evaluating functional effects on the brain). This study investigated the effects of a chronic, restricted access to CAF on BDNF, monoamine neurotransmitters, and redox imbalance in HIP and PFC in male rats. Our results show that CAF induced BDNF and its receptor TrkB in PFC compared to the controls (p < 0.0005). No differences in monoamine neurotransmitters were detected in either PFC or HIP. CAF increased dehydroascorbic acid and decreased malondialdehyde in PFC (p < 0.05), suggesting an early redox imbalance insufficient to induce lipid peroxidation. This study supports that a chronic CAF on a restricted schedule increases BDNF levels in the PFC of rats, highlighting that this may be a suboptimal feeding regime when investigating the effects of diet-induced obesity in the brain and emphasizing this as a point of attention when comparing the findings.
    Keywords:  BDNF; Cafeteria Diet; diet-induced obesity; experimental animal models
    DOI:  https://doi.org/10.3390/nu14010126
  35. Int J Mol Sci. 2021 Dec 23. pii: 135. [Epub ahead of print]23(1):
    The Influence of Mitochondrial-DNA-Driven Inflammation Pathways on Macrophage Polarization: A New Perspective for Targeted Immunometabolic Therapy in Cerebral Ischemia-Reperfusion Injury.
    Sihang Yu, Jiaying Fu, Jian Wang, Yuanxin Zhao, Buhan Liu, Jiahang Wei, Xiaoyu Yan, Jing Su.
      Cerebral ischemia-reperfusion injury is related to inflammation driven by free mitochondrial DNA. At the same time, the pro-inflammatory activation of macrophages, that is, polarization in the M1 direction, aggravates the cycle of inflammatory damage. They promote each other and eventually transform macrophages/microglia into neurotoxic macrophages by improving macrophage glycolysis, transforming arginine metabolism, and controlling fatty acid synthesis. Therefore, we propose targeting the mtDNA-driven inflammatory response while controlling the metabolic state of macrophages in brain tissue to reduce the possibility of cerebral ischemia-reperfusion injury.
    Keywords:  STING; cerebral ischemia-reperfusion; immune metabolism; inflammation; macrophages; mtDNA
    DOI:  https://doi.org/10.3390/ijms23010135
  36. Molecules. 2021 Dec 31. pii: 243. [Epub ahead of print]27(1):
    Reduction of Deuterium Level Supports Resistance of Neurons to Glucose Deprivation and Hypoxia: Study in Cultures of Neurons and on Animals.
    Alexandr Kravtsov, Stanislav Kozin, Alexandr Basov, Elena Butina, Mikhail Baryshev, Vadim Malyshko, Arkady Moiseev, Anna Elkina, Stepan Dzhimak.
      The effect of a reduced deuterium (D) content in the incubation medium on the survival of cultured neurons in vitro and under glucose deprivation was studied. In addition, we studied the effect of a decrease in the deuterium content in the rat brain on oxidative processes in the nervous tissue, its antioxidant protection, and training of rats in the T-shaped maze test under hypoxic conditions. For experiments with cultures of neurons, 7-8-day cultures of cerebellar neurons were used. Determination of the rate of neuronal death in cultures was carried out using propidium iodide. Acute hypoxia with hypercapnia was simulated in rats by placing them in sealed vessels with a capacity of 1 L. The effect on oxidative processes in brain tissues was assessed by changes in the level of free radical oxidation and malondialdehyde. The effect on the antioxidant system of the brain was assessed by the activity of catalase. The study in the T-maze was carried out in accordance with the generally accepted methodology, the skill of alternating right-sided and left-sided loops on positive reinforcement was developed. This work has shown that a decrease in the deuterium content in the incubation medium to a level of -357‱ has a neuroprotective effect, increasing the survival rate of cultured neurons under glucose deprivation. When exposed to hypoxia, a preliminary decrease in the deuterium content in the rat brain to -261‱ prevents the development of oxidative stress in their nervous tissue and preserves the learning ability of animals in the T-shaped maze test at the level of the control group. A similar protective effect during the modification of the 2H/1H internal environment of the body by the consumption of DDW can potentially be used for the prevention of pathological conditions associated with the development of oxidative stress with damage to the central nervous system.
    Keywords:  deuterium depleted water; hypoxia; neuron; rats
    DOI:  https://doi.org/10.3390/molecules27010243
  37. Neurochem Int. 2022 Jan 10. pii: S0197-0186(22)00005-5. [Epub ahead of print] 105280
    Effects of vitamin D (VD3) supplementation on the brain mitochondrial function of male rats, in the 6-OHDA-induced model of Parkinson's disease.
    Ludmila Araújo de Lima, Pedro Lourenzo Oliveira Cunha, Iana Bantim Felicio Calou, Kelly Rose Tavares Neves, Heberty Tarso Facundo, Glauce Socorro de Barros Viana.
      Mitochondria dysfunction is an important factor involved in PD pathogenesis. We reported neuroprotective actions of vitamin D (VD3) on a PD model, and now we investigated the VD3 effects on the brain mitochondrial function. We focused on oxygen consumption, respiratory control ratio (RCR), ADP/O ratio, mitochondria swelling, H2O2 production, and SOD activity. Additionally, immunohistochemistry assays for the dopamine system markers (TH and DAT) and mitochondrial markers (VDAC1 and Hsp60) were also carried out in the striata. Young adult male Wistar rats (250 g, 2.5 months age) were anesthetized and subjected to stereotaxic surgery and injection of saline (SO group) or 6-OHDA, into the right striatum. Brain mitochondria were isolated from the groups: sham-operated (SO), 6-OHDA, 6-OHDA pretreated with VD3 for 7, days before the 6-OHDA lesion (6-OHDA+VD3, pre-) or treated with VD3 for 14 days, after the 6-OHDA lesion (6-OHDA+VD3, post-). VD3 prevented decreases in oxygen consumption, RCR, and ADP/O ratio observed after 6-OHDA injury. Noteworthy, a very low (oxygen consumption and RCR) or no improvement (ADP/O) were observed in the 6-OHDA+VD3 post- group. VD3 also prevented the increased mitochondria swelling and H2O2 production and a decrease in SOD activity, respectively, in the 6-OHDA injured mitochondria. Also, VD3 supplementation protected the hemiparkinsonian brain from decreases in TH and DAT expressions and decreased the upregulation of mitochondrial markers, as VDAC 1 and Hsp60. In conclusion, VD3 showed neuroprotective actions on brain mitochondria injured by 6-OHDA and should stimulate translational studies focusing on its use as a therapeutic strategy for the treatment of neurodegenerative diseases as PD.
    Keywords:  6-OHDA-model of PD; Mitochondria; Oxidative stress; VD3; Vitamin D
    DOI:  https://doi.org/10.1016/j.neuint.2022.105280
  38. Eur J Neurosci. 2022 Jan 09.
    Circadian Transcription Factor NPAS2 and the NAD+-Dependent Deacetylase SIRT1 Interact in the Mouse Nucleus Accumbens and Regulate Reward.
    Darius D Becker-Krail, Puja K Parekh, Kyle D Ketchesin, Shintaro Yamaguchi, Jun Yoshino, Mariah A Hildebrand, Brandon Dunham, Madhavi K Ganapathiraiu, Ryan W Logan, Colleen A McClung.
      Substance use disorders are associated with disruptions to both circadian rhythms and cellular metabolic state. At the molecular level, the circadian molecular clock and cellular metabolic state may be interconnected through interactions with the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, Sirtuin 1 (SIRT1). In the nucleus accumbens (NAc), a region important for reward, both SIRT1 and the circadian transcription factor neuronal PAS domain protein 2 (NPAS2) are highly enriched, and both are regulated by the metabolic cofactor NAD+. Substances of abuse, like cocaine, greatly disrupt cellular metabolism and promote oxidative stress; however, their effects on NAD+ in the brain remain unclear. Interestingly, cocaine also induces NAc expression of both NPAS2 and SIRT1, and both have independently been shown to regulate cocaine reward in mice. However, whether NPAS2 and SIRT1 interact in the NAc and/or whether together they regulate reward is unknown. Here, we demonstrate diurnal expression of Npas2, Sirt1, and NAD+ in the NAc, which is altered by cocaine-induced upregulation. Additionally, co-immunoprecipitation reveals NPAS2 and SIRT1 interact in the NAc, and cross-analysis of NPAS2 and SIRT1 chromatin immunoprecipitation sequencing reveals several reward-relevant and metabolic-related pathways enriched among shared gene targets. Notably, NAc-specific Npas2 knock-down or a functional Npas2 mutation in mice attenuates SIRT1-mediated increases in cocaine preference. Together, our data reveal an interaction between NPAS2 and SIRT1 in the NAc which may serve to integrate cocaine's effects on circadian and metabolic factors, leading to regulation of drug reward.
    Keywords:  Circadian; Cocaine; NPAS2; Nucleus Accumbens; Reward; SIRT1
    DOI:  https://doi.org/10.1111/ejn.15596
  39. Am J Physiol Endocrinol Metab. 2022 Jan 10.
    Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis.
    Brian Maunze, Katherine Wood Bruckner, Nikhil Nilesh Desai, Christopher Chen, Fanghong Chen, David Baker, SuJean Choi.
      Pituitary adenylate cyclase activating polypeptide (PACAP) exerts pleiotropic effects on ventromedial nuclei (VMN) of the hypothalamus and its control of feeding and energy expenditure through the Type I PAC1 receptor. However, the endogenous role of PAC1R's in the VMN and the downstream signaling responsible for PACAP's effects on energy balance are unknown. Numerous studies have revealed that PAC1Rs are coupled to both Gas/ adenylate cyclase/protein kinase A (Gas/AC/PKA) and Gaq/phospholipase C/protein kinase C (Gaq/PLC/PKC), while also undergoing trafficking following stimulation. To determine the endogenous role PAC1R's and downstream signaling that may explain PACAP's pleiotropic effects, we used RNA interference to knockdown VMN PAC1Rs and pharmacologically inhibited PKA, PKC and PAC1R trafficking. Knocking down PAC1Rs increased meal sizes, reduced total number of meals, and induced body weight gain. Inhibition of either PKA or PKC alone in awake male Sprague Dawley rats, attenuated PACAP's hypophagic and anorectic effects during the dark phase. However, PKA or PKC inhibition potentiated PACAP's thermogenic effects during the light phase. Analysis of locomotor activity revealed that PKA inhibition augmented PACAP's locomotor effects, however, PKC inhibition had no effect. Finally, PACAP infusion in the VMN induces surface PAC1R trafficking into the cytosol which was blocked by endocytosis inhibitors. Subsequently, inhibition of PAC1R trafficking into the cytosol attenuated PACAP-induced hypophagia. These results revealed that endogenous PAC1Rs uniquely engage PKA, PKC and receptor trafficking to mediate PACAP's pleiotropic effects in VMN control of feeding and metabolism.
    Keywords:  Feeding; PAC1R; PACAP; energy expenditure; rat
    DOI:  https://doi.org/10.1152/ajpendo.00320.2021
  40. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01750-2. [Epub ahead of print]38(2): 110241
    Restricting feeding to dark phase fails to entrain circadian activity and energy expenditure oscillations in Pitx3-mutant Aphakia mice.
    Antonio Fernández-Pérez, Adrián Sanz-Magro, Rosario Moratalla, Mario Vallejo.
      Metabolic homeostasis is under circadian regulation to adapt energy requirements to light-dark cycles. Feeding cycles are regulated by photic stimuli reaching the suprachiasmatic nucleus via retinohypothalamic axons and by nutritional information involving dopaminergic neurotransmission. Previously, we reported that Pitx3-mutant Aphakia mice with altered development of the retinohypothalamic tract and the dopaminergic neurons projecting to the striatum, are resistant to locomotor and metabolic entrainment by time-restricted feeding. In their Matters Arising article, Scarpa et al. (2022) challenge this conclusion using mice from the same strain but following a different experimental paradigm involving calorie restriction. Here, we address their concerns by extending the analyses of our previous data, by identifying important differences in the experimental design between both studies and by presenting additional results on the dopaminergic deficit in the brain of Aphakia mice. This Matters Arising Response article addresses the Matters Arising article by Scarpa et al. (2022), published concurrently in Cell Reports.
    Keywords:  Pitx3(ak); calorie restriction; circadian clock; dopamine; energy metabolism; retinohypothalamic tract; striatum; suprachiasmatic nucleus; time-restricted feeding; ventral tegmental area
    DOI:  https://doi.org/10.1016/j.celrep.2021.110241
  41. WIREs Mech Dis. 2022 Jan;14(1): e1536
    Orexin, serotonin, and energy balance.
    Vijayakumar Mavanji, Brianna Pomonis, Catherine M Kotz.
      The lateral hypothalamus is critical for the control of ingestive behavior and spontaneous physical activity (SPA), as lesion or stimulation of this region alters these behaviors. Evidence points to lateral hypothalamic orexin neurons as modulators of feeding and SPA. These neurons affect a broad range of systems, and project to multiple brain regions such as the dorsal raphe nucleus, which contains serotoninergic neurons (DRN) important to energy homeostasis. Physical activity is comprised of intentional exercise and SPA. These are opposite ends of a continuum of physical activity intensity and structure. Non-goal-oriented behaviors, such as fidgeting, standing, and ambulating, constitute SPA in humans, and reflect a propensity for activity separate from intentional activity, such as high-intensity voluntary exercise. In animals, SPA is activity not influenced by rewards such as food or a running wheel. Spontaneous physical activity in humans and animals burns calories and could theoretically be manipulated pharmacologically to expend calories and protect against obesity. The DRN neurons receive orexin inputs, and project heavily onto cortical and subcortical areas involved in movement, feeding and energy expenditure (EE). This review discusses the function of hypothalamic orexin in energy-homeostasis, the interaction with DRN serotonin neurons, and the role of this orexin-serotonin axis in regulating food intake, SPA, and EE. In addition, we discuss possible brain areas involved in orexin-serotonin cross-talk; the role of serotonin receptors, transporters and uptake-inhibitors in the pathogenesis and treatment of obesity; animal models of obesity with impaired serotonin-function; single-nucleotide polymorphisms in the serotonin system and obesity; and future directions in the orexin-serotonin field. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
    Keywords:  energy expenditure; orexin; physical activity; serotonin
    DOI:  https://doi.org/10.1002/wsbm.1536
  42. Mitochondrion. 2022 Jan 06. pii: S1567-7249(22)00001-0. [Epub ahead of print]63 23-31
    Mitochondrial repair as potential pharmacological target in cerebral ischemia.
    Ms Mandeep Kaur, Dr Saurabh Sharma.
      Cerebral ischemia and its consequences like transient ischemic attack, aneurysm and stroke are the common and devastating conditions which remain the leading cause of mortality after coronary heart disease in developed countries and are the greatest cause of disability, leaving 50% of survivors permanently disabled. Despite recognition of risk factors and mechanisms involved in the pathology of the disease, treatment of ischemic disorders is limited to thrombolytic drugs like recombinant tissue plasminogen activator (rt-PA) and clinical rendition of the neuroprotective agents have not been so successful. Recent studies evidenced the role of mitochondrial dysfunction in neuronal damage that occurred after cerebral ischemia. This review article will focus on the various fundamental mechanisms responsible for neuronal damage because of mitochondrial dysfunction including cell signaling pathways, autophagy, apoptosis/necrosis, generation of reactive oxygen species, calcium overload, the opening of membrane permeability transition pore (mPTP), mitochondrial dynamics and biogenesis. Recent studies have concerned the significant role of mitochondrial biogenesis in mitochondrial repair and transfer of healthy mitochondria from astrocytes to the damaged neurons, providing neuroprotection and neural recovery following ischemia. Novel and influential studies have evidenced the significant role of mitochondria transfer and mitochondrial transplantation in reviving cell energy and in replacement of impaired or dysfunctional mitochondria with healthy mitochondria after ischemic episode. This review article will focus on recent advances in mitochondrial interventions and exogenous therapeutic modalities like mitochondria transfer technique, employment of stem cells, mitochondrial transplantation, miRNA inhibition and mitochondrial-targeted Sirtuin1 activator for designing novel and promising treatment for cerebral ischemia induced pathological states.
    Keywords:  Cerebral ischemia; Mitochondrial transfer; Mitochondrial transplantation; Mitochondrial dysfunction; Mitophagy; Reactive oxygen species; miRNA inhibition
    DOI:  https://doi.org/10.1016/j.mito.2022.01.001
  43. Free Radic Biol Med. 2022 Jan 06. pii: S0891-5849(22)00001-6. [Epub ahead of print]180 33-51
    Cannabinol inhibits oxytosis/ferroptosis by directly targeting mitochondria independently of cannabinoid receptors.
    Zhibin Liang, David Soriano-Castell, Devin Kepchia, Brendan M Duggan, Antonio Currais, David Schubert, Pamela Maher.
      The oxytosis/ferroptosis regulated cell death pathway recapitulates many features of mitochondrial dysfunction associated with the aging brain and has emerged as a potential key mediator of neurodegeneration. It has thus been proposed that the oxytosis/ferroptosis pathway can be used to identify novel drug candidates for the treatment of age-associated neurodegenerative diseases that act by preserving mitochondrial function. Previously, we identified cannabinol (CBN) as a potent neuroprotector. Here, we demonstrate that not only does CBN protect nerve cells from oxytosis/ferroptosis in a manner that is dependent on mitochondria and it does so independently of cannabinoid receptors. Specifically, CBN directly targets mitochondria and preserves key mitochondrial functions including redox regulation, calcium uptake, membrane potential, bioenergetics, biogenesis, and modulation of fusion/fission dynamics that are disrupted following induction of oxytosis/ferroptosis. These protective effects of CBN are at least partly mediated by the promotion of endogenous antioxidant defenses and the activation of AMP-activated protein kinase (AMPK) signaling. Together, our data highlight the potential of mitochondrially-targeted compounds such as CBN as novel oxytotic/ferroptotic inhibitors to rescue mitochondrial dysfunction as well as opportunities for the discovery and development of future neurotherapeutics.
    Keywords:  AMPK; Aging; Antioxidant defense; Cannabinoid; Mitochondrial dysfunction; Neurodegenerative disease; Neurotherapeutics; Oxytosis/ferroptosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.001
  44. Front Neuroanat. 2021 ;15 818242
    A Whole-Brain Connectivity Map of VTA and SNc Glutamatergic and GABAergic Neurons in Mice.
    Sile An, Xiangning Li, Lei Deng, Peilin Zhao, Zhangheng Ding, Yutong Han, Yue Luo, Xin Liu, Anan Li, Qingming Luo, Zhao Feng, Hui Gong.
      The glutamatergic and GABAergic neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) mediated diverse brain functions. However, their whole-brain neural connectivity has not been comprehensively mapped. Here we used the virus tracers to characterize the whole-brain inputs and outputs of glutamatergic and GABAergic neurons in VTA and SNc. We found that these neurons received similar inputs from upstream brain regions, but some quantitative differences were also observed. Neocortex and dorsal striatum provided a greater share of input to VTA glutamatergic neurons. Periaqueductal gray and lateral hypothalamic area preferentially innervated VTA GABAergic neurons. Specifically, superior colliculus provided the largest input to SNc glutamatergic neurons. Compared to input patterns, the output patterns of glutamatergic and GABAergic neurons in the VTA and SNc showed significant preference to different brain regions. Our results laid the anatomical foundation for understanding the functions of cell-type-specific neurons in VTA and SNc.
    Keywords:  cell-type-specific; substantia nigra pars compacta (SNc); three-dimension; ventral tegmental area (VTA); virus tracers; whole brain
    DOI:  https://doi.org/10.3389/fnana.2021.818242
  45. Neuropharmacology. 2022 Jan 06. pii: S0028-3908(22)00004-1. [Epub ahead of print]207 108945
    The glutamatergic synapse - A key hub in neuronal metabolism, signalling and plasticity.
    Bruno G Frenguelli.
      The Special Issue of Neuropharmacology on the glutamatergic synapse is one of a series of Special Issues celebrating the 40th anniversary of Dick Evans and Jeff Watkins's seminal review on excitatory amino acids (Watkins and Evans, 1981). Through a careful appraisal of the literature extending several decades prior to the 1980s, and their own development and use of ligands for excitatory amino acid receptors, Dick and Jeff provided incontrovertible proof for the veracity and importance of glutamate as a neurotransmitter in the central nervous system. While other Special Issues in this series examine the receptors activated by glutamate (AMPA, NMDA, Kainate, mGluR and Delta/Orphan glutamate receptors) this Special Issue examines the glutamatergic synapse itself, and considers its evolution, metabolism, structure, properties and plasticity that have placed it so firmly at the centre of neuronal signalling in the central nervous system.
    DOI:  https://doi.org/10.1016/j.neuropharm.2022.108945
  46. J Immunol. 2022 Jan 15. 208(2): 212-220
    Metabolic Sex Dimorphism of the Brain at the Gene, Cell, and Tissue Level.
    Jun Won Lee, Martin Profant, Chao Wang.
      The palpable observation in the sex bias of disease prevalence in the CNS has fascinated scientists for several generations. Brain sex dimorphism has been visualized by imaging and analytical tools at the tissue, cellular, and molecular levels. Recent work highlighted the specificity of such sex bias in the brain and its subregions, offering a unique lens through which disease pathogenesis can be investigated. The brain is the largest consumer of energy in the body and provides a unique metabolic environment for diverse lineages of cells. Immune cells are increasingly recognized as an integral part of brain physiology, and their function depends on metabolic homeostasis. This review focuses on metabolic sex dimorphism in brain tissue, resident, and infiltrating immune cells. In this context, we highlight the relevance of recent advances in metabolomics and RNA sequencing technologies at the single cell resolution and the development of novel computational approaches.
    DOI:  https://doi.org/10.4049/jimmunol.2100853
  47. J Clin Med. 2021 Dec 30. pii: 191. [Epub ahead of print]11(1):
    Brain Signaling of Indispensable Amino Acid Deficiency.
    Dorothy W Gietzen.
      Our health requires continual protein synthesis for maintaining and repairing tissues. For protein synthesis to function, all the essential (indispensable) amino acids (IAAs) must be available in the diet, along with those AAs that the cells can synthesize (the dispensable amino acids). Here we review studies that have shown the location of the detector for IAA deficiency in the brain, specifically for recognition of IAA deficient diets (IAAD diets) in the anterior piriform cortex (APC), with subsequent responses in downstream brain areas. The APC is highly excitable, which makes is uniquely suited to serve as an alarm for reductions in IAAs. With a balanced diet, these neurons are kept from over-excitation by GABAergic inhibitory neurons. Because several transporters and receptors on the GABAergic neurons have rapid turnover times, they rely on intact protein synthesis to function. When an IAA is missing, its unique tRNA cannot be charged. This activates the enzyme General Control Nonderepressible 2 (GCN2) that is important in the initiation phase of protein synthesis. Without the inhibitory control supplied by GABAergic neurons, excitation in the circuitry is free to signal an urgent alarm. Studies in rodents have shown rapid recognition of IAA deficiency by quick rejection of the IAAD diet.
    Keywords:  GCN2; anterior piriform cortex; neural signaling; protein synthesis initiation; transfer RNA
    DOI:  https://doi.org/10.3390/jcm11010191
  48. Front Cell Neurosci. 2021 ;15 811376
    TOM70 in Glial Cells as a Potential Target for Treatment of COVID-19.
    Yorran Hardman Araújo Montenegro, Geancarlo Zanatta, André Quincozes-Santos, Guilhian Leipnitz.
      
    Keywords:  COVID-19; SARS-CoV-2; TOM70; glial cells; mitochondria; neurological symptoms
    DOI:  https://doi.org/10.3389/fncel.2021.811376
  49. Proc Natl Acad Sci U S A. 2022 Jan 18. pii: e2115082119. [Epub ahead of print]119(3):
    Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice.
    Min Hee Park, Kang Ho Park, Byung Jo Choi, Wan Hui Han, Hee Ji Yoon, Hye Yoon Jung, Jihoon Lee, Im-Sook Song, Dong Yu Lim, Min-Koo Choi, Yang-Ha Lee, Cheol-Min Park, Ming Wang, Jihoon Jo, Hee-Jin Kim, Seung Hyun Kim, Edward H Schuchman, Hee Kyung Jin, Jae-Sung Bae.
      Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.
    Keywords:  ASM direct inhibitor; Alzheimer’s disease; GHSR1 alpha agonist; memory improvement; small compound
    DOI:  https://doi.org/10.1073/pnas.2115082119
  50. Free Radic Biol Med. 2022 Jan 06. pii: S0891-5849(22)00002-8. [Epub ahead of print]180 1-12
    Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice.
    Liuji Chen, Nawab John Dar, Ren Na, Kirsten Danae McLane, Kwangsun Yoo, Xianlin Han, Qitao Ran.
      Oxidative damage including lipid peroxidation is widely reported in Alzheimer's disease (AD) with the peroxidation of phospholipids in membranes being the driver of ferroptosis, an iron-dependent oxidative form of cell death. However, the importance of ferroptosis in AD remains unclear. This study tested whether ferroptosis inhibition ameliorates AD. 5xFAD mice, a widely used AD mouse model with cognitive impairment and robust neurodegeneration, exhibit markers of ferroptosis including increased lipid peroxidation, elevated lyso-phospholipids, and reduced level of Gpx4, the master defender against ferroptosis. To determine if enhanced defense against ferroptosis retards disease development, we generated 5xFAD mice that overexpress Gpx4, i.e., 5xFAD/GPX4 mice. Consistent with enhanced defense against ferroptosis, neurons from 5xFAD/GPX4 mice showed an augmented capacity to reduce lipid reactive oxygen species. In addition, compared with control 5xFAD mice, 5xFAD/GPX4 mice showed significantly improved learning and memory abilities and had reduced neurodegeneration. Moreover, 5xFAD/GPX4 mice exhibited attenuated markers of ferroptosis. Our results indicate that enhanced defense against ferroptosis is effective in ameliorating cognitive impairment and decreasing neurodegeneration of 5xFAD mice. The findings support the notion that ferroptosis is a key contributor to AD pathogenesis.
    Keywords:  5xFAD mice; Alzheimer's disease; Cognition impairment; Ferroptosis; Gpx4; Lipid peroxidation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.01.002
  51. Neuroimage Clin. 2022 Jan 05. pii: S2213-1582(21)00376-4. [Epub ahead of print]33 102932
    Glucose fluxes in glycolytic and oxidative pathways detected in vivo by deuterium magnetic resonance spectroscopy reflect proliferation in mouse glioblastoma.
    Rui V Simões, Rafael N Henriques, Beatriz M Cardoso, Francisca F Fernandes, Tânia Carvalho, Noam Shemesh.
       OBJECTIVES: Glioblastoma multiforme (GBM), the most aggressive glial brain tumors, can metabolize glucose through glycolysis and mitochondrial oxidation pathways. While specific dependencies on those pathways are increasingly associated with treatment response, detecting such GBM subtypes in vivo remains elusive. Here, we develop a dynamic glucose-enhanced deuterium spectroscopy (DGE 2H-MRS) approach for differentially assessing glucose turnover rates through glycolysis and mitochondrial oxidation in mouse GBM and explore their association with histologic features of the tumor and its microenvironment.
    MATERIALS AND METHODS: GL261 and CT2A glioma allografts were induced in immunocompetent mice and scanned in vivo at 9.4 Tesla, harnessing DGE 2H-MRS with volume selection and Marchenko-Pastur PCA (MP-PCA) denoising to achieve high temporal resolution. Each tumor was also classified by histopathologic analysis and assessed for cell proliferation (Ki67 immunostaining), while the respective cell lines underwent in situ extracellular flux analysis to assess mitochondrial function.
    RESULTS: MP-PCA denoising of in vivo DGE 2H-MRS data significantly improved the time-course detection (~2-fold increased Signal-to-Noise Ratio) and fitting precision (-19 ± 1 % Cramér-Rao Lower Bounds) of 2H-labelled glucose, and glucose-derived glutamate-glutamine (Glx) and lactate pools in GL261 and CT2A orthotopic tumors. Kinetic modeling further indicated inter-tumor heterogeneity of glucose consumption rate for glycolysis and oxidation during a defined epoch of active proliferation in both cohorts (19 ± 1 days post-induction), with consistent volumes (38.3 ± 3.4 mm3) and perfusion properties prior to marked necrosis. Histopathologic analysis of these tumors revealed clear differences in tumor heterogeneity between the two GBM models, aligned with metabolic differences of the respective cell lines monitored in situ. Importantly, glucose oxidation (i.e. Glx synthesis and elimination rates: 0.40 ± 0.08 and 0.12 ± 0.03 mM min-1, respectively) strongly correlated with cell proliferation across the pooled cohorts (R = 0.82, p = 0.001; and R = 0.80, p = 0.002, respectively), regardless of tumor morphologic features or in situ metabolic characteristics of each GBM model.
    CONCLUSIONS: Our fast DGE 2H-MRS enables the quantification of glucose consumption rates through glycolysis and mitochondrial oxidation in mouse GBM, which is relevant for assessing their modulation in vivo according to tumor microenvironment features such as cell proliferation. This novel application augurs well for non-invasive metabolic characterization of glioma or other cancers with mitochondrial oxidation dependencies.
    Keywords:  Deuterium magnetic resonance spectroscopy; Glioblastoma; Glycolysis; Magnetic resonance imaging; Mitochondrial oxidation
    DOI:  https://doi.org/10.1016/j.nicl.2021.102932
  52. Biochem Biophys Res Commun. 2021 Dec 28. pii: S0006-291X(21)01752-6. [Epub ahead of print]591 44-49
    Insulin signaling in clock neurons regulates sleep in Drosophila.
    Sho T Yamaguchi, Jun Tomita, Kazuhiko Kume.
      Sleep relates to numerous biological functions, including metabolism. Both dietary conditions and genes related to metabolism are known to affect sleep behavior. Insulin signaling is well conserved across species including the fruit fly and relates to both metabolism and sleep. However, the neural mechanism of sleep regulation by insulin signaling is poorly understood. Here, we report that insulin signaling in specific neurons regulates sleep in Drosophila melanogaster. We analyzed the sleep behavior of flies with the mutation in insulin-like ligands expressed in the brain and found that three insulin-like ligands participate in sleep regulation with some redundancy. We next used 21 Gal4 drivers to express a dominant-negative form of the insulin receptor (InR DN) in various neurons including circadian clock neurons, which express the clock gene, and the pars intercerebralis (PI). Inhibition of insulin signaling in the anterior dorsal neuron group 1 (DN1a) decreased sleep. Additionally, the same manipulation in PI also decreased sleep. Pan-neuronal induced expression of InR DN also decreased sleep. These results suggested that insulin signaling in DN1a and PI regulates sleep.
    Keywords:  Drosophila; Insulin; Insulin receptor; Metabolism; Sleep
    DOI:  https://doi.org/10.1016/j.bbrc.2021.12.100
  53. J Biomed Sci. 2022 Jan 10. 29(1): 2
    Monocarboxylate transporter functions and neuroprotective effects of valproic acid in experimental models of amyotrophic lateral sclerosis.
    Asmita Gyawali, Sana Latif, Seung-Hye Choi, Seung Jae Hyeon, Hoon Ryu, Young-Sook Kang.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devasting neurodegenerative disorder for which no successful therapeutics are available. Valproic acid (VPA), a monocarboxylate derivative, is a known antiepileptic drug and a histone deacetylase inhibitor.
    METHODS: To investigate whether monocarboxylate transporter 1 (MCT1) and sodium-coupled MCT1 (SMCT1) are altered in ALS cell and mouse models, a cellular uptake study, quantitative real time polymerase chain reaction and western blot parameters were used. Similarly, whether VPA provides a neuroprotective effect in the wild-type (WT; hSOD1WT) and ALS mutant-type (MT; hSOD1G93A) NSC-34 motor neuron-like cell lines was determined through the cell viability assay.
    RESULTS: [3H]VPA uptake was dependent on time, pH, sodium and concentration, and the uptake rate was significantly lower in the MT cell line than the WT cell line. Interestingly, two VPA transport systems were expressed, and the VPA uptake was modulated by SMCT substrates/inhibitors in both cell lines. Furthermore, MCT1 and SMCT1 expression was significantly lower in motor neurons of ALS (G93A) model mice than in those of WT mice. Notably, VPA ameliorated glutamate- and hydrogen peroxide-induced neurotoxicity in both the WT and MT ALS cell lines.
    CONCLUSIONS: Together, the current findings demonstrate that VPA exhibits a neuroprotective effect regardless of the dysfunction of an MCT in ALS, which could help develop useful therapeutic strategies for ALS.
    Keywords:  Amyotrophic lateral sclerosis; Monocarboxylate transporter 1; Neuroprotection; Sodium-coupled monocarboxylate transporter; Valproic acid
    DOI:  https://doi.org/10.1186/s12929-022-00785-3
  54. World J Emerg Med. 2022 ;13(1): 46-53
    Protective effect of mesenchymal stem cell-derived exosomal treatment of hippocampal neurons against oxygen-glucose deprivation/reperfusion-induced injury.
    Xiao-Fang Guo, Shuang-Shuang Gu, Jun Wang, Hao Sun, Yu-Juan Zhang, Peng-Fei Yu, Jin-Song Zhang, Lei Jiang.
       BACKGROUND: Individuals who survive a cardiac arrest often sustain cognitive impairments due to ischemia-reperfusion injury. Mesenchymal stem cell (MSC) transplantation is used to reduce tissue damage, but exosomes are more stable and highly conserved than MSCs. This study was conducted to investigate the therapeutic effects of MSC-derived exosomes (MSC-Exo) on cerebral ischemia-reperfusion injury in an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R), and to explore the underlying mechanisms.
    METHODS: Primary hippocampal neurons obtained from 18-day Sprague-Dawley rat embryos were subjected to OGD/R treatment, with or without MSC-Exo treatment. Exosomal integration, cell viability, mitochondrial membrane potential, and generation of reactive oxygen species (ROS) were examined. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) staining was performed to detect neuronal apoptosis. Moreover, mitochondrial function-associated gene expression, Nrf2 translocation, and expression of downstream antioxidant proteins were determined.
    RESULTS: MSC-Exo attenuated OGD/R-induced neuronal apoptosis and decreased ROS generation (P<0.05). The exosomes reduced OGD/R-induced Nrf2 translocation into the nucleus (2.14±0.65 vs. 5.48±1.09, P<0.01) and increased the intracellular expression of antioxidative proteins, including superoxide dismutase and glutathione peroxidase (17.18±0.97 vs. 14.40±0.62, and 20.65±2.23 vs. 16.44±2.05, respectively; P<0.05 for both). OGD/R significantly impaired the mitochondrial membrane potential and modulated the expression of mitochondrial function-associated genes, such as PINK, DJ1, LRRK2, Mfn-1, Mfn-2, and OPA1. The abovementioned changes were partially reversed by exosomal treatment of the hippocampal neurons.
    CONCLUSIONS: MSC-Exo treatment can alleviate OGD/R-induced oxidative stress and dysregulation of mitochondrial function-associated genes in hippocampal neurons. Therefore, MSC-Exo might be a potential therapeutic strategy to prevent OGD/R-induced neuronal injury.
    Keywords:  Exosomes; Mesenchymal stem cells; Mitochondria; Oxygen-glucose deprivation/reperfusion; Reactive oxygen species
    DOI:  https://doi.org/10.5847/wjem.j.1920-8642.2022.015
  55. Nat Commun. 2022 Jan 10. 13(1): 159
    Altered succinylation of mitochondrial proteins, APP and tau in Alzheimer's disease.
    Yun Yang, Victor Tapias, Diana Acosta, Hui Xu, Huanlian Chen, Ruchika Bhawal, Elizabeth T Anderson, Elena Ivanova, Hening Lin, Botir T Sagdullaev, Jianer Chen, William L Klein, Kirsten L Viola, Sam Gandy, Vahram Haroutunian, M Flint Beal, David Eliezer, Sheng Zhang, Gary E Gibson.
      Abnormalities in brain glucose metabolism and accumulation of abnormal protein deposits called plaques and tangles are neuropathological hallmarks of Alzheimer's disease (AD), but their relationship to disease pathogenesis and to each other remains unclear. Here we show that succinylation, a metabolism-associated post-translational protein modification (PTM), provides a potential link between abnormal metabolism and AD pathology. We quantified the lysine succinylomes and proteomes from brains of individuals with AD, and healthy controls. In AD, succinylation of multiple mitochondrial proteins declined, and succinylation of small number of cytosolic proteins increased. The largest increases occurred at critical sites of amyloid precursor protein (APP) and microtubule-associated tau. We show that in vitro, succinylation of APP disrupted its normal proteolytic processing thereby promoting Aβ accumulation and plaque formation and that succinylation of tau promoted its aggregation to tangles and impaired microtubule assembly. In transgenic mouse models of AD, elevated succinylation associated with soluble and insoluble APP derivatives and tau. These findings indicate that a metabolism-linked PTM may be associated with AD.
    DOI:  https://doi.org/10.1038/s41467-021-27572-2
  56. Front Neurol. 2021 ;12 735071
    Mapping an Extended Metabolic Profile of Gliomas Using High-Resolution 31P MRSI at 7T.
    Andreas Korzowski, Nina Weckesser, Vanessa L Franke, Johannes Breitling, Steffen Goerke, Heinz-Peter Schlemmer, Mark E Ladd, Peter Bachert, Daniel Paech.
      Phosphorus magnetic resonance spectroscopic imaging (31P MRSI) is of particular interest for investigations of patients with brain tumors as it enables to non-invasively assess altered energy and phospholipid metabolism in vivo. However, the limited sensitivity of 31P MRSI hampers its broader application at clinical field strengths. This study aimed to identify the additional value of 31P MRSI in patients with glioma at ultra-high B 0 = 7T, where the increase in signal-to-noise ratio may foster its applicability for clinical research. High-quality, 3D 31P MRSI datasets with an effective voxel size of 5.7 ml were acquired from the brains of seven patients with newly diagnosed glioma. An optimized quantification model was implemented to reliably extract an extended metabolic profile, including low-concentrated metabolites such as extracellular inorganic phosphate, nicotinamide adenine dinucleotide [NAD(H)], and uridine diphosphoglucose (UDPG), which may act as novel tumor markers; a background signal was extracted as well, which affected measures of phosphomonoesters beneficially. Application of this model to the MRSI datasets yielded high-resolution maps of 12 different 31P metabolites, showing clear metabolic differences between white matter (WM) and gray matter, and between healthy and tumor tissues. Moreover, differences between tumor compartments in patients with high-grade glioma (HGG), i.e., gadolinium contrast-enhancing/necrotic regions (C+N) and peritumoral edema, could also be suggested from these maps. In the group of patients with HGG, the most significant changes in metabolite intensities were observed in C+N compared to WM, i.e., for phosphocholine +340%, UDPG +54%, glycerophosphoethanolamine -45%, and adenosine-5'-triphosphate -29%. Furthermore, a prominent signal from mobile phospholipids appeared in C+N. In the group of patients with low-grade glioma, only the NAD(H) intensity changed significantly by -28% in the tumor compared to WM. Besides the potential of 31P MRSI at 7T to provide novel insights into the biochemistry of gliomas in vivo, the attainable spatial resolutions improve the interpretability of 31P metabolite intensities obtained from malignant tissues, particularly when only subtle differences compared to healthy tissues are expected. In conclusion, this pilot study demonstrates that 31P MRSI at 7T has potential value for the clinical research of glioma.
    Keywords:  31P; 7T; MRSI; UHF; brain; glioma; phosphorus; tumor
    DOI:  https://doi.org/10.3389/fneur.2021.735071
  57. J Neurosci. 2022 Jan 13. pii: JN-RV-0998-21. [Epub ahead of print]
    Neuroimmunometabolism: A new pathological nexus underlying neurodegenerative disorders.
    Swarup Mitra, Avijit Banik, Sumit Saurabh, Malabika Maulik, Shailesh N Khatri.
      Neuroimmunometabolism is an emerging field that examines the intersection of immunological and metabolic cascades in the brain. Neuroinflammatory conditions often involve differential metabolic reprogramming in neuronal and glial cells through their immunometabolic sensors. The impact of such bioenergetic adaptation on general brain function is poorly understood, but this cross-talk becomes increasingly important in neurodegenerative disorders that exhibit reshaping of neuroimmunometabolic pathways. Here we summarize the intrinsic balance of neuroimmunometabolic substrates and sensors in the healthy brain and how their dysregulation can contribute to the pathophysiology of various neurodegenerative disorders. This review also proposes possible avenues for disease management through neuroimmunometabolic profiling and therapeutics to bridge translational gaps and guide future treatment strategies.SIGNIFICANCE STATEMENTNeuroimmunometabolism intersects with neuroinflammation and immunometabolic regulation of neurons and glial cells in the CNS. There is emerging evidence that neuroimmunometabolism plays an essential role in the manifestation of CNS degeneration. This review highlights how neuroimmunometabolic homeostasis is disrupted in various neurodegenerative conditions and could be a target for new therapeutic strategies.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0998-21.2022
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