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Regulation and Deregulation of Cell Metabolism in the Brain: Molecular...
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Regulation and Deregulation of Cell Metabolism in the Brain: Molecular Aspects, Functional Outcomes

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 20736

Special Issue Editors

Dr. Marco Segatto

E-Mail Website
Guest Editor
Department of Biosciences and Territory, University of Molise, Pesche (Is), Italy
Interests: cholesterol; cell metabolism; neurotrophins; neurodegeneration; neurogenesis; epigenetics; skeletal muscle; inflammation; autophagy; cell signaling
Special Issues, Collections and Topics in MDPI journals
Dr. Piergiorgio La Rosa

E-Mail Website
Co-Guest Editor
1. Division of Neuroscience, Department of Psychology, University La Sapienza, Rome, Italy
2. European Center for Brain Research, IRCCS Fondazione Santa Lucia, Rome, Italy
Interests: neurodegenerative diseases; neurodevelopment; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Clleagues,

Metabolism comprises the enzyme-mediated chemical processes that regulate the synthesis and degradation of biological molecules required for cellular viability. A tight regulation of metabolic processes is of paramount importance in the cell, especially in the brain, where homeostasis maintenance is highly dynamic. Although the central nervous system only accounts for 2% of the body mass, the energy demand is one of the highest in the whole organism. Lipids, such as long-chain polyunsaturated fatty acids and cholesterol, play pivotal structural and functional roles in brain cells. Furthermore, spatial and temporal regulation of protein homeostasis is essential for proper brain functioning and development. Thus, it is not surprising that alterations of the processes regulating ATP, redox status, glucose, lipids, and protein metabolism can lead to severe neurodevelopmental and neurodegenerative disorders. For instance, reactive oxygen/nitrogen species (ROS/RNS) imbalance during development or in the adult brain is a defect observed in most of neurologic conditions. Similarly, impairments of lipid synthesis/trafficking or lysosome-mediated protein degradation can lead to neuronal death and the subsequent onset of syndromes distinguishable from the primary cause, but with common secondary alterations.

The aim of this Special Issue is to gather reviews and research papers focused on the regulation of the brain metabolism in health and pathologic conditions, highlighting new insights into the molecular pathways, and the therapeutic approaches aimed at restoring these processes.

Dr. Marco Segatto
Guest Editor
Dr. Piergiorgio La Rosa
Co-Guest Editor

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Keywords

  • cell metabolism
  • lipids
  • glucose
  • energy homeostasis
  • oxidative stress
  • protein metabolism
  • brain
  • nervous system
  • neurodegeneration
  • neurodevelopmental disorders

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Published Papers (5 papers)

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Research

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18 pages, 3103 KiB  
Article
Protective Potential of β-Hydroxybutyrate against Glucose-Deprivation-Induced Neurotoxicity Involving the Modulation of Autophagic Flux and the Monomeric Aβ Level in Neuro-2a Cells
by Yi-Fen Chiang, Ngan Thi Kim Nguyen, Shih-Min Hsia, Hsin-Yuan Chen, Shyh-Hsiang Lin and Ching-I Lin
Biomedicines 2023, 11(3), 698; https://doi.org/10.3390/biomedicines11030698 - 24 Feb 2023
Cited by 4 | Viewed by 1755
Abstract
Hypoglycemia has been known as a potential contributory factor to neurodegenerative diseases, such as Alzheimer’s disease. There may be shared pathogenic mechanisms underlying both conditions, and the ketone body, β-hydroxybutyrate (BHB), as an alternative substrate for glucose may exert neuroprotection against hypoglycemia-induced injury. [...] Read more.
Hypoglycemia has been known as a potential contributory factor to neurodegenerative diseases, such as Alzheimer’s disease. There may be shared pathogenic mechanisms underlying both conditions, and the ketone body, β-hydroxybutyrate (BHB), as an alternative substrate for glucose may exert neuroprotection against hypoglycemia-induced injury. To investigate this, Neuro-2a cells were subjected to a 24 h period of glucose deprivation with or without the presence of BHB. Cell viability, reactive oxygen species (ROS) production, apoptosis, autophagy, and adenosine triphosphate (ATP) and beta-amyloid peptide (Aβ) levels were evaluated. The results show that Neuro-2a cells deprived of glucose displayed a significant loss of cell survival with a corresponding decrease in ATP levels, suggesting that glucose deprivation was neurotoxic. This effect was likely attributed to the diverse mechanisms including raised ROS, defective autophagic flux and reduced basal Aβ levels (particularly monomeric Aβ). The presence of BHB could partially protect against the loss of cell survival induced by glucose deprivation. The mechanisms underlying the neuroprotective actions of BHB might be mediated, at least in part, through restoring ATP, and modulating ROS production, autophagy flux efficacy and the monomeric Aβ level. Results imply that a possible link between the basal monomeric Aβ and glucose deprivation neurotoxicity, and treatments designed for the prevention of energy impairment, such as BHB, may be beneficial for rescuing surviving cells in relation to neurodegeneration. Full article
(This article belongs to the Special Issue Regulation and Deregulation of Cell Metabolism in the Brain: Molecular Aspects, Functional Outcomes)
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Review

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26 pages, 1530 KiB  
Review
Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich’s Ataxia Pre-Clinical Models and Clinical Trials
by Jessica Tiberi, Marco Segatto, Maria Teresa Fiorenza and Piergiorgio La Rosa
Biomedicines 2023, 11(5), 1293; https://doi.org/10.3390/biomedicines11051293 - 27 Apr 2023
Cited by 6 | Viewed by 2285
Abstract
Friedreich’s ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in [...] Read more.
Friedreich’s ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies. Full article
(This article belongs to the Special Issue Regulation and Deregulation of Cell Metabolism in the Brain: Molecular Aspects, Functional Outcomes)
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18 pages, 10708 KiB  
Review
Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease
by Yuanxin Zhao, Buhan Liu, Jian Wang, Long Xu, Sihang Yu, Jiaying Fu, Xiaoyu Yan and Jing Su
Biomedicines 2022, 10(8), 1800; https://doi.org/10.3390/biomedicines10081800 - 27 Jul 2022
Cited by 15 | Viewed by 4707
Abstract
One of the most striking hallmarks shared by various neurodegenerative diseases, including Alzheimer’s disease (AD), is microglia-mediated neuroinflammation. The main pathological features of AD are extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. Amyloid-β (Aβ) peptide and tau protein [...] Read more.
One of the most striking hallmarks shared by various neurodegenerative diseases, including Alzheimer’s disease (AD), is microglia-mediated neuroinflammation. The main pathological features of AD are extracellular amyloid-β (Aβ) plaques and intracellular tau-containing neurofibrillary tangles in the brain. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles. The crosstalk between microglia and neurons helps maintain brain homeostasis, and the metabolic phenotype of microglia determines its polarizing phenotype. There are currently many research and development efforts to provide disease-modifying therapies for AD treatment. The main targets are Aβ and tau, but whether there is a causal relationship between neurodegenerative proteins, including Aβ oligomer and tau oligomer, and regulation of microglia metabolism in neuroinflammation is still controversial. Currently, the accumulation of Aβ and tau by exosomes or other means of propagation is proposed as a regulator in neurological disorders, leading to metabolic disorders of microglia that can play a key role in the regulation of immune cells. In this review, we propose that the accumulation of Aβ oligomer and tau oligomer can propagate to adjacent microglia through exosomes and change the neuroinflammatory microenvironment by microglia metabolic reprogramming. Clarifying the relationship between harmful proteins and microglia metabolism will help people to better understand the mechanism of crosstalk between neurons and microglia, and provide new ideas for the development of AD drugs. Full article
(This article belongs to the Special Issue Regulation and Deregulation of Cell Metabolism in the Brain: Molecular Aspects, Functional Outcomes)
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15 pages, 1542 KiB  
Review
New Insights into the Neurodegeneration Mechanisms Underlying Riboflavin Transporter Deficiency (RTD): Involvement of Energy Dysmetabolism and Cytoskeletal Derangement
by Fiorella Colasuonno, Chiara Marioli, Marco Tartaglia, Enrico Bertini, Claudia Compagnucci and Sandra Moreno
Biomedicines 2022, 10(6), 1329; https://doi.org/10.3390/biomedicines10061329 - 6 Jun 2022
Cited by 9 | Viewed by 4540
Abstract
Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment [...] Read more.
Riboflavin transporter deficiency (RTD) is a rare genetic disorder characterized by motor, sensory and cranial neuropathy. This childhood-onset neurodegenerative disease is caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3 genes, resulting in insufficient supply of riboflavin (vitamin B2) and consequent impairment of flavoprotein-dependent metabolic pathways. Current therapy, empirically based high-dose riboflavin supplementation, ameliorates the progression of the disease, even though response to treatment is variable and partial. Recent studies have highlighted concurrent pathogenic contribution of cellular energy dysmetabolism and cytoskeletal derangement. In this context, patient specific RTD models, based on induced pluripotent stem cell (iPSC) technology, have provided evidence of redox imbalance, involving mitochondrial and peroxisomal dysfunction. Such oxidative stress condition likely causes cytoskeletal perturbation, associated with impaired differentiation of RTD motor neurons. In this review, we discuss the most recent findings obtained using different RTD models. Relevantly, the integration of data from innovative iPSC-derived in vitro models and invertebrate in vivo models may provide essential information on RTD pathophysiology. Such novel insights are expected to suggest custom therapeutic strategies, especially for those patients unresponsive to high-dose riboflavin treatments. Full article
(This article belongs to the Special Issue Regulation and Deregulation of Cell Metabolism in the Brain: Molecular Aspects, Functional Outcomes)
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21 pages, 2708 KiB  
Review
One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome
by Romana Vulturar, Adina Chiș, Sebastian Pintilie, Ilinca Maria Farcaș, Alina Botezatu, Cristian Cezar Login, Adela-Viviana Sitar-Taut, Olga Hilda Orasan, Adina Stan, Cecilia Lazea, Camelia Al-Khzouz, Monica Mager, Mihaela Adela Vințan, Simona Manole and Laura Damian
Biomedicines 2022, 10(6), 1249; https://doi.org/10.3390/biomedicines10061249 - 26 May 2022
Cited by 8 | Viewed by 6303
Abstract
Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive [...] Read more.
Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood–brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes’ Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches. Full article
(This article belongs to the Special Issue Regulation and Deregulation of Cell Metabolism in the Brain: Molecular Aspects, Functional Outcomes)
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