bims-medebr 2022-03-13 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒03‒13
34 papers selected by
Regina F. Fernández
Johns Hopkins University

Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age.
The Implication of Physiological Ketosis on The Cognitive Brain: A Narrative Review.
The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation.
Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer's Disease.
Acute inhibition of OGA sex-dependently alters the networks associated with bioenergetics, autophagy, and neurodegeneration.
The relevance of migraine in the clinical spectrum of mitochondrial disorders.
Homeostatic Regulation of Glucose Metabolism by the Central Nervous System.
Neurons undergo pathogenic metabolic reprogramming in models of familial ALS.
Mitochondrial complex I as a therapeutic target for Alzheimer's disease.
Editorial: Metabolic Alterations in Neurodegenerative Disorders.
Ghrelin Regulates Expression of the Transcription Factor Pax6 in Hypoxic Brain Progenitor Cells and Neurons.
The mitochondrial proteomic changes of rat hippocampus induced by 28-day simulated microgravity.
Representing Stimulus Information in an Energy Metabolism Pathway.
Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence.
Neuroprotective effects of ATPase inhibitory factor 1 preventing mitochondrial dysfunction in Parkinson's disease.
ASIC1a senses lactate uptake to regulate metabolism in neurons.
Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function.
Deficient mitochondrial respiration in astrocytes impairs trace fear conditioning and increases naloxone-precipitated aversion in morphine-dependent mice.
One-Carbon Metabolism in Alzheimer's Disease and Parkinson's Disease Brain Tissue.
Dual Effects of Korean Red Ginseng on Astrocytes and Neural Stem Cells in Traumatic Brain Injury: The HO-1-Tom20 Axis as a Putative Target for Mitochondrial Function.
Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit.
Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.
Schizophrenia: a disorder of broken brain bioenergetics.
Perilipins at a glance.
Gel-Based and Gel-Free Phosphoproteomics to Measure and Characterize Mitochondrial Phosphoproteins.
The Vannucci Model of Hypoxic-Ischemic Injury in the Neonatal Rodent: 40 years later.
Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD+ balance as a therapeutic strategy.
Choline Kinetics in Neonatal Liver, Brain and Lung-Lessons from a Rodent Model for Neonatal Care.
Imaging and analysis of neuronal mitochondria in murine acute brain slices.
Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.
Role of Specialized Pro-resolving Mediators in Reducing Neuroinflammation in Neurodegenerative Disorders.
Protein methylation in mitochondria.
Ghrelin Acylation-A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis.
L-Acetylcarnitine causes analgesia in mice modeling Fabry disease by up-regulating type-2 metabotropic glutamate receptors.

Int J Mol Sci. 2022 Feb 25. pii: 2579. [Epub ahead of print]23(5):

Acute Prenatal Hypoxia in Rats Affects Physiology and Brain Metabolism in the Offspring, Dependent on Sex and Gestational Age.

Anastasia V Graf, Maria V Maslova, Artem V Artiukhov, Alexander L Ksenofontov, Vasily A Aleshin, Victoria I Bunik.

  Hypoxia is damaging to the fetus, but the developmental impact may vary, with underlying molecular mechanisms unclear. We demonstrate the dependence of physiological and biochemical effects of acute prenatal hypoxia (APH) on sex and gestational age. Compared to control rats, APH on the 10th day of pregnancy (APH-10) increases locomotion in both the male and female offspring, additionally increasing exploratory activity and decreasing anxiety in the males. Compared to APH-10, APH on the 20th day of pregnancy (APH-20) induces less behavioral perturbations. ECG is changed similarly in all offspring only by APH-10. Sexual dimorphism in the APH outcome on behavior is also observed in the brain acetylation system and 2-oxoglutarate dehydrogenase reaction, essential for neurotransmitter metabolism. In view of the perturbed behavior, more biochemical parameters in the brains are assessed after APH-20. Of the six enzymes, APH-20 significantly decreases the malic enzyme activity in both sexes. Among 24 amino acids and dipeptides, APH-20 increases the levels of only three amino acids (Phe, Thr, and Trp) in male offspring, and of seven amino acids (Glu, Gly, Phe, Trp, Ser, Thr, Asn) and carnosine in the female offspring. Thus, a higher reactivity of the brain metabolism to APH stabilizes the behavior. The behavior and brain biochemistry demonstrate sexually dimorphic responses to APH at both gestational stages, whereas the APH effects on ECG depend on gestational age rather than sex.

Keywords:  2-oxoglutarate dehydrogenase; brain neurotransmitter metabolism; malic enzyme; sex-specific effects of acute prenatal hypoxia

DOI:  https://doi.org/10.3390/ijms23052579
Nutrients. 2022 Jan 25. pii: 513. [Epub ahead of print]14(3):

The Implication of Physiological Ketosis on The Cognitive Brain: A Narrative Review.

Mansour Altayyar, Jennifer A Nasser, Dimitra Thomopoulos, Michael Bruneau.

  Optimal cognitive functions are necessary for activities of daily living and self-independence. Cognitive abilities are acquired during early childhood as part of progressive neurodevelopmental milestones; unfortunately, regressive changes can occur as part of physiological aging, or more ominously, pathological diseases, such as Alzheimer's disease (AD). Cases of AD and its milder subset, mild cognitive impairment (MCI), are rising and would impose a burdensome impact beyond the individual level. Various dietary and nutritional approaches have potential for promising results in managing cognitive deterioration. Glucose is the core source of bioenergy in the body; however, glucose brain metabolism could be affected in aging cells or due to disease development. Ketone bodies are an efficient alternate fuel source that could compensate for the deficient glycolytic metabolism upon their supra-physiologic availability in the blood (ketosis), which, in turn, could promote cognitive benefits and tackle disease progression. In this review, we describe the potential of ketogenic approaches to produce cognitive benefits in healthy individuals, as well as those with MCI and AD. Neurophysiological changes of the cognitive brain in response to ketosis through neuroimaging modalities are also described in this review to provide insight into the ketogenic effect on the brain outside the framework of purely molecular explanations.

Keywords:  cognition; intermittent fasting; ketogenic diet; ketone bodies; ketosis; medium-chain triglycerides; neuroimaging

DOI:  https://doi.org/10.3390/nu14030513
Int J Mol Sci. 2022 Feb 28. pii: 2717. [Epub ahead of print]23(5):

The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation.

Mohamed Ashraf Virmani, Maria Cirulli.

  Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. l-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. l-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. l-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like l-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of l-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.

Keywords:  beta oxidation; diabetes; fatty acid oxidation; glycolysis; ketogenesis; l-carnitine; liver disease; metabolic inflexibility; mitochondrial function; neurodegeneration

DOI:  https://doi.org/10.3390/ijms23052717
J Cell Immunol. 2021 ;3(6): 397-412

Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer's Disease.

Tyler C Hammond, Xin Xing, Lucy M Yanckello, Arnold Stromberg, Ya-Hsuan Chang, Peter T Nelson, Ai-Ling Lin.

Alzheimer's disease (AD) is the most common form of dementia with hallmarks of β-amyloid (Aβ) plaques, tau tangles, and neurodegeneration. Studies have shown that neurodegeneration components, especially brain metabolic deficits, are more predictable for AD severity than Aβ and tau. However, detailed knowledge of the biochemical composition of AD brain tissue vs. normal brain tissue remains unclear. In this study, we performed a metabolomics analysis on the brain tissue of 158 community-based older adults in the University of Kentucky AD Research Center brain bank to characterize the biochemical profiles of brains with and without AD based on white/gray matter type, apolipoprotein E genotype (ε3 vs ε4 variants), and disease stage (early vs late) as all these factors influence metabolic processes. We also used machine learning to rank the top metabolites separating controls and AD in gray and white matter. Compared with control samples, we found that glutamate and creatine metabolism were more critical for predicting AD in the gray matter, while glycine, fatty acid, pyrimidine, tricarboxylic acid (TCA) cycle, and phosphatidylcholine metabolism were more critical in the white matter. In ε4 carriers, metabolites associated with the TCA cycle and oxidative phosphorylation were prominent in advanced stages compared to the early stages. In ε3 carriers, metabolites related to oxidative DNA damage, changes in inhibitory neurotransmitters, and disruptions of neuronal membranes were prominent in advanced stages compared to the early stages. In early disease, ε4 carriers had metabolites related to poor kidney function and altered neuronal sterol metabolism compared to ε3 carriers, but there were few differences between genotypes in late disease. Our results indicate that metabolism plays a pivotal role in differentiating APOE- and stage-dependent changes in AD and may facilitate precision lifestyle and dietary interventions to mitigate AD risk in the early stages, especially for ε4 carriers.

DOI: https://doi.org/10.33696/immunology.3.123
Mol Brain. 2022 Mar 05. 15(1): 22

Acute inhibition of OGA sex-dependently alters the networks associated with bioenergetics, autophagy, and neurodegeneration.

Van N Huynh, Gloria A Benavides, Michelle S Johnson, Xiaosen Ouyang, Balu K Chacko, Edie Osuma, Toni Mueller, John Chatham, Victor M Darley-Usmar, Jianhua Zhang.

  The accumulation of neurotoxic proteins characteristic of age-related neurodegenerative pathologies such as Alzheimer's and Parkinson's diseases is associated with the perturbation of metabolism, bioenergetics, and mitochondrial quality control. One approach to exploit these interactions therapeutically is to target the pathways that regulate metabolism. In this respect, the nutrient-sensing hexosamine biosynthesis pathway is of particular interest since it introduces a protein post-translational modification known as O-GlcNAcylation, which modifies different proteins in control versus neurodegenerative disease postmortem brains. A potent inhibitor of the O-GlcNAcase enzyme that removes the modification from proteins, Thiamet G (TG), has been proposed to have potential benefits in Alzheimer's disease. We tested whether key factors in the O-GlcNAcylation are correlated with mitochondrial electron transport and proteins related to the autophagy/lysosomal pathways in the cortex of male and female mice with and without exposure to TG (10 mg/kg i.p.). Mitochondrial complex activities were measured in the protein homogenates, and a panel of metabolic, autophagy/lysosomal proteins and O-GlcNAcylation enzymes were assessed by either enzyme activity assay or by western blot analysis. We found that the networks associated with O-GlcNAcylation enzymes and activities with mitochondrial parameters, autophagy-related proteins as well as neurodegenerative disease-related proteins exhibited sex and TG dependent differences. Taken together, these studies provide a framework of interconnectivity for multiple O-GlcNAc-dependent pathways in mouse brain of relevance to aging and sex/age-dependent neurodegenerative pathogenesis and response to potential therapies.

Keywords:  Autophagy; Cortex; Glycolysis; Mitochondria; Neurodegenerative disease; O-GlcNAc; OGA; Synapse; TCA cycle

DOI:  https://doi.org/10.1186/s13041-022-00906-x
Sci Rep. 2022 Mar 10. 12(1): 4222

The relevance of migraine in the clinical spectrum of mitochondrial disorders.

Alberto Terrin, Luca Bello, Maria Lucia Valentino, Leonardo Caporali, Gianni Sorarù, Valerio Carelli, Ferdinando Maggioni, Massimo Zeviani, Elena Pegoraro.

Recent scientific evidence suggests a link between migraine and brain energy metabolism. In fact, migraine is frequently observed in mitochondrial disorders. We studied 46 patients affected by mitochondrial disorders, through a headache-focused semi-structured interview, to evaluate the prevalence of migraine among patients affected by mitochondrial disorders, the possible correlations between migraine and neuromuscular genotype or phenotype, comorbidities, lactate acid levels and brain magnetic resonance spectroscopy. We explored migraine-related disability, analgesic and prophylactic treatments. Diagnoses were achieved according to International Classification of Headache Disorders, 3rd edition. Lifetime prevalence of migraine was 61% (28/46), with high values in both sexes (68% in females, 52% in males) and higher than the values found in both the general population and previous literature. A maternal inheritance pattern was reported in 57% of cases. MIDAS and HIT6 scores revealed a mild migraine-related disability. The high prevalence of migraine across different neuromuscular phenotypes and genotypes suggests that migraine itself may be a common clinical manifestation of brain energy dysfunction. Our results provide new relevant indications in favour of migraine as the result of brain energy unbalance.

DOI: https://doi.org/10.1038/s41598-022-08206-z
Endocrinol Metab (Seoul). 2022 Feb;37(1): 9-25

Homeostatic Regulation of Glucose Metabolism by the Central Nervous System.

Jong Han Choi, Min-Seon Kim.

  Evidence for involvement of the central nervous system (CNS) in the regulation of glucose metabolism dates back to the 19th century, although the majority of the research on glucose metabolism has focused on the peripheral metabolic organs. Due to recent advances in neuroscience, it has now become clear that the CNS is indeed vital for maintaining glucose homeostasis. To achieve normoglycemia, specific populations of neurons and glia in the hypothalamus sense changes in the blood concentrations of glucose and of glucoregulatory hormones such as insulin, leptin, glucagon-like peptide 1, and glucagon. This information is integrated and transmitted to other areas of the brain where it eventually modulates various processes in glucose metabolism (i.e., hepatic glucose production, glucose uptake in the brown adipose tissue and skeletal muscle, pancreatic insulin and glucagon secretion, renal glucose reabsorption, etc.). Errors in these processes lead to hyper- or hypoglycemia. We here review the current understanding of the brain regulation of glucose metabolism.

Keywords:  Central nervous system; Glucose; Metabolism

DOI:  https://doi.org/10.3803/EnM.2021.1364
Mol Metab. 2022 Mar 03. pii: S2212-8778(22)00037-0. [Epub ahead of print] 101468

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS.

Sean-Patrick Riechers, Jelena Mojsilovic-Petrovic, Tayler B Belton, Ram P Chakrabarty, Mehraveh Garjani, Valentina Medvedeva, Casey Dalton, Yvette C Wong, Navdeep S Chandel, Gerald Dienel, Robert G Kalb.

Normal cellular function requires a rate of ATP production sufficient to meet demand. In most neurodegenerative diseases (including Amyotrophic Lateral Sclerosis, ALS), mitochondrial dysfunction is postulated raising the possibility of impaired ATP production and a need for compensatory maneuvers to sustain the ATP production/demand balance. We find in our rodent models of familial ALS (fALS), a reduction in neuronal lactate production with maintained or enhanced activity of the neuronal citric acid cycle. This rewiring of metabolism is associated with normal ATP levels, bioenergetics and redox status, supporting the notion that gross mitochondrial function is not compromised in neurons soon after expressing fALS genes. Genetic loss-of-function manipulation of individual steps in the glycolysis and the pentose phosphate pathway blunt the negative phenotypes seen in various fALS models. We propose that neurons adjust fuel utilization in the setting of neurodegenerative disease-associated alteration in mitochondrial function in a baleful manner and targeting this process can be healthful.

DOI: https://doi.org/10.1016/j.molmet.2022.101468
Acta Pharm Sin B. 2022 Feb;12(2): 483-495

Mitochondrial complex I as a therapeutic target for Alzheimer's disease.

Eugenia Trushina, Sergey Trushin, Md Fayad Hasan.

  Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.

Keywords:  AD, Alzheimer's disease; ADP, adenosine diphosphate; AIDS, acquired immunodeficiency syndrome; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; APP/PS1, amyloid precursor protein/presenilin 1; ATP, adenosine triphosphate; Alzheimer's disease; Aβ, amyloid beta; BBB, blood‒brain barrier; BDNF, brain-derived neurotrophic factor; CP2, tricyclic pyrone compound two; Complex I inhibitors; ER, endoplasmic reticulum; ETC, electron transport chain; FADH2, flavin adenine dinucleotide; FDG-PET, fluorodeoxyglucose-positron emission tomography; GWAS, genome-wide association study; HD, Huntington's disease; HIF-1α, hypoxia induced factor 1 α; Healthy aging; ISR, integrated stress response; Integrated stress response; LTP, long term potentiation; MCI, mild cognitive impairment; MPTP, 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine; Mitochondria; Mitochondria signaling; Mitochondria targeted therapeutics; NAD+ and NADH, nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NRF2, nuclear factor E2-related factor 2; Neuroprotection; OXPHOS, oxidative phosphorylation; PD, Parkinson's disease; PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PMF, proton-motive force; RNAi, RNA interference; ROS, reactive oxygen species; T2DM, type II diabetes mellitus; TCA, the tricarboxylic acid cycle; mtDNA, mitochondrial DNA; mtUPR, mitochondrial unfolded protein response; pTau, hyper-phosphorylated Tau protein; ΔpH, proton gradient; Δψm, mitochondrial membrane potential

DOI:  https://doi.org/10.1016/j.apsb.2021.11.003
Front Aging Neurosci. 2022 ;14 833109

Editorial: Metabolic Alterations in Neurodegenerative Disorders.

Kristine K Freude, Ines Moreno-Gonzalez, Carlos J Rodriguez-Ortiz, David Baglietto-Vargas.



Keywords:  anesthesia; astrocytes; blood-brain barrier; ceramides; hyperlipidemia; metabolism; neurodegenerative disorders; probiotics

DOI:  https://doi.org/10.3389/fnagi.2022.833109
Cells. 2022 Feb 23. pii: 782. [Epub ahead of print]11(5):

Ghrelin Regulates Expression of the Transcription Factor Pax6 in Hypoxic Brain Progenitor Cells and Neurons.

Irina I Stoyanova, Andrii Klymenko, Jeannette Willms, Thorsten R Döppner, Anton B Tonchev, David Lutz.

  The nature of brain impairment after hypoxia is complex and recovery harnesses different mechanisms, including neuroprotection and neurogenesis. Experimental evidence suggests that hypoxia may trigger neurogenesis postnatally by influencing the expression of a variety of transcription factors. However, the existing data are controversial. As a proof-of-principle, we subjected cultured cerebral cortex neurons, cerebellar granule neurons and organotypic cerebral cortex slices from rat brains to hypoxia and treated these cultures with the hormone ghrelin, which is well-known for its neuroprotective functions. We found that hypoxia elevated the expression levels and stimulated nuclear translocation of ghrelin's receptor GHSR1 in the cultured neurons and the acute organotypic slices, whereas ghrelin treatment reduced the receptor expression to normoxic levels. GHSR1 expression was also increased in cerebral cortex neurons of mice with induced experimental stroke. Additional quantitative analyses of immunostainings for neuronal proliferation and differentiation markers revealed that hypoxia stimulated the proliferation of neuronal progenitors, whereas ghrelin application during the phase of recovery from hypoxia counteracted these effects. At the mechanistic level, we provide a link between the described post-ischemic phenomena and the expression of the transcription factor Pax6, an important regulator of neural progenitor cell fate. In contrast to the neurogenic niches in the brain where hypoxia is known to increase Pax6 expression, the levels of the transcription factor in cultured hypoxic cerebral cortex cells were downregulated. Moreover, the application of ghrelin to hypoxic neurons normalised the expression levels of these factors. Our findings suggest that ghrelin stimulates neurogenic factors for the protection of neurons in a GHSR1-dependent manner in non-neurogenic brain areas such as the cerebral cortex after exposure to hypoxia.

Keywords:  GHSR1; ghrelin; hypoxia; neurogenesis; progenitor cells; transcription factors

DOI:  https://doi.org/10.3390/cells11050782
PLoS One. 2022 ;17(3): e0265108

The mitochondrial proteomic changes of rat hippocampus induced by 28-day simulated microgravity.

Guohua Ji, Hui Chang, Mingsi Yang, Hailong Chen, Tingmei Wang, Xu Liu, Ke Lv, Yinghui Li, Bo Song, Lina Qu.

A large number of aerospace practices have confirmed that the aerospace microgravity environment can lead to cognitive function decline. Mitochondria are the most important energy metabolism organelles, and some studies demonstrate that the areospace microgravity environment can cause mitochondrial dysfunction. However, the relationships between cognitive function decline and mitochondrial dysfunction in the microgravity environment have not been elucidated. In this study, we simulated the microgravity environment in the Sprague-Dawley (SD) rats by -30° tail suspension for 28 days. We then investigated the changes of mitochondrial morphology and proteomics in the hippocampus. The electron microscopy results showed that the 28-day tail suspension increased the mitochondria number and size of rat hippocampal neuronal soma. Using TMT-based proteomics analysis, we identified 163 differentially expressed proteins (DEPs) between tail suspension and control samples, and among them, 128 proteins were upregulated and 35 proteins were downregulated. Functional and network analyses of the DEPs indicated that several of mitochondrial metabolic processes including the tricarboxylic acid (TCA) cycle were altered by simulating microgravity (SM). We verified 3 upregulated proteins, aconitate hydratase (ACO2), dihydrolipoamide S-succinyltransferase (DLST), and citrate synthase (CS), in the TCA cycle process by western blotting and confirmed their differential expressions between tail suspension and control samples. Taken together, our results demonstrate that 28-day tail suspension can cause changes in the morphology and metabolic function of hippocampus mitochondria, which might represent a mechanism of cognitive disorder caused by aerospace microgravity.

DOI: https://doi.org/10.1371/journal.pone.0265108
J Theor Biol. 2022 Mar 07. pii: S0022-5193(22)00088-1. [Epub ahead of print] 111090

Representing Stimulus Information in an Energy Metabolism Pathway.

Jay S Coggan, Daniel Keller, Henry Markram, Felix Schürmann, Pierre J Magistretti.

  We explored a computational model of astrocytic energy metabolism and demonstrated the theoretical plausibility that this type of pathway might be capable of coding information about stimuli in addition to its known functions in cellular energy and carbon budgets. Simulation results indicate that glycogenolytic glycolysis triggered by activation of adrenergic receptors can capture the intensity and duration features of a neuromodulator waveform and can respond in a dose-dependent manner, including non-linear state changes that are analogous to action potentials. We show how this metabolic pathway can translate information about external stimuli to production profiles of energy-carrying molecules such as lactate with a precision beyond simple signal transduction or non-linear amplification. The results suggest the operation of a metabolic state-machine from the spatially discontiguous yet interdependent metabolite elements. Such metabolic pathways might be well-positioned to code an additional level of salient information about a cell's environmental demands to impact its function. Our hypothesis has implications for the computational power and energy efficiency of the brain.

Keywords:  biochemical networks; cellular information; dynamical systems; ligand pulse; metabolic states; synthetic biology

DOI:  https://doi.org/10.1016/j.jtbi.2022.111090
Stem Cell Rev Rep. 2022 Mar 08.

Metabolic Regulation: A Potential Strategy for Rescuing Stem Cell Senescence.

Wenxin Zhang, Jiayu Li, Yuchi Duan, Yanlin Li, Yanan Sun, Hui Sun, Xiao Yu, Xingyu Gao, Chang Zhang, Haiying Zhang, Yingai Shi, Xu He.

  Stem cell senescence and exhaustion are closely related to organ failure and individual aging, which not only induces age-related diseases, but also hinders stem cell applications in regenerative medicine. Thus, it's imminent to find effective ways to delay and retrieve stem cell senescence. Metabolic abnormalities are one of the main characteristics of age-associated declines in stem cell function. Understanding the underlying mechanisms may reveal potential strategies for ameliorating age-associated phenotypes and treating age-related diseases. This review focuses on recent advances in the association between metabolism including glucose, lipid, glutamine and NAD+ metabolism and stem cell senescence, as well as the other properties like proliferation and differentiation. Layers of studies are summarized to demonstrate how metabolism varies in senescent stem cells and how metabolic reprogramming regulates stem cell senescence. Additionally, we mentioned some recent progress in therapeutic strategies to rejuvenate dysfunctional aged stem cells. Finally, a brief conclusion about the prospect of metabolic regulation as a potential strategy for rescuing stem cell senescence is displayed. Stem cell senescence is induced by the metabolic reprogramming. The metabolic alterations of glucose, lipid, glutamine and NAD+ can conversely facilitate or inhibit stem cell senescence. Glycolysis, OXPHOS and PPP are all attenuated. But gluconeogenesis alterations still remain unclear. In lipid metabolisms, both FAO and DNL are suppressed. As for the glutamine metabolism, stem cells' dependence on glutamine is enhanced. Last, NAD+ metabolism undergoes a down-regulated synthesis and up-regulated consumption. All these alterations can be potential targets for reversing stem cell senescence.

Keywords:  NAD+ metabolism; age-related diseases; glucose metabolism; glutamine metabolism; lipid metabolism; stem cell senescence

DOI:  https://doi.org/10.1007/s12015-022-10348-6
Sci Rep. 2022 Mar 09. 12(1): 3874

Neuroprotective effects of ATPase inhibitory factor 1 preventing mitochondrial dysfunction in Parkinson's disease.

InHyeok Chung, Han-A Park, Jun Kang, Heyyoung Kim, Su Min Hah, Juhee Lee, Hyeon Soo Kim, Won-Seok Choi, Ji Hyung Chung, Min-Jeong Shin.

Mitochondrial dysfunction is a key element in the progression of Parkinson's disease (PD). The inefficient operation of the electron transport chain (ETC) impairs energy production and enhances the generation of oxidative stress contributing to the loss of dopaminergic cells in the brain. ATPase inhibitory factor 1 (IF1) is a regulator of mitochondrial energy metabolism. IF1 binds directly to the F1Fo ATP synthase and prevents ATP wasting during compromised energy metabolism. In this study, we found treatment with IF1 protects mitochondria against PD-like insult in vitro. SH-SY5Y cells treated with IF1 were resistant to loss of ATP and mitochondrial inner membrane potential during challenge with rotenone, an inhibitor of complex I in the ETC. We further demonstrated that treatment with IF1 reversed rotenone-induced superoxide production in mitochondria and peroxide accumulation in whole cells. Ultimately, IF1 decreased protein levels of pro-apoptotic Bax, cleaved caspase-3, and cleaved PARP, rescuing SH-SY5Y cells from rotenone-mediated apoptotic death. Administration of IF1 significantly improved the results of pole and hanging tests performed by PD mice expressing human α-synuclein. This indicates that IF1 mitigates PD-associated motor deficit. Together, these findings suggest that IF1 exhibits a neuroprotective effect preventing mitochondrial dysfunction in PD pathology.

DOI: https://doi.org/10.1038/s41598-022-07851-8
Redox Biol. 2022 Jan 29. pii: S2213-2317(22)00025-8. [Epub ahead of print]51 102253

ASIC1a senses lactate uptake to regulate metabolism in neurons.

Ivana Savic Azoulay, Xin Qi, Maya Rozenfeld, Fan Liu, Qin Hu, Tsipi Ben Kasus Nissim, Alexandra Stavsky, Michael X Zhu, Tian-Le Xu, Israel Sekler.

  Lactate is a major metabolite largely produced by astrocytes that nourishes neurons. ASIC1a, a Na+ and Ca2+-permeable channel with an extracellular proton sensing domain, is thought to be activated by lactate through chelation of divalent cations, including Ca2+, Mg2+ and Zn2+, that block the channel pore. Here, by monitoring lactate-evoked H+ and Ca2+ transport in cultured mouse cortical and hippocampal neurons, we find that stereo-selective neuronal uptake of L-lactate results in rapid intracellular acidification that triggers H+ extrusion to activate plasma membrane ASIC1a channels, leading to propagating Ca2+ waves into the cytosol and mitochondria. We show that lactate activates ASIC1a at its physiological concentrations, far below that needed to chelate divalent cations. The L-isomer of lactate exerts a much greater effect on ASIC1a-mediated activity than the d-isomer and this stereo-selectivity arises from lactate transporters, which prefer the physiologically common L-lactate. The lactate uptake in turn results in intracellular acidification, which is then followed by a robust acid extrusion. The latter response sufficiently lowers the pH in the vicinity of the extracellular domain of ASIC1a to trigger its activation, resulting in cytosolic and mitochondrial Ca2+ signals that accelerate mitochondrial respiration. Furthermore, blocking ASIC1a led to a robust mitochondrial ROS production induced by L-lactate. Together our results indicate that ASIC1a is a metabolic sensor, which by sensing extracellular pH drop triggered by neuronal lactate uptake with subsequent proton extrusion, transmits a Ca2+ response that is propagated to mitochondria to enhance lactate catabolism and suppress ROS production.

Keywords:  ASIC1a; Acidification; Cytosolic Ca(2+) signaling; Cytosolic Na(+) signaling; Lactate; Mitochondrial Ca(2+) signaling; Mitochondrial Na(+) signaling; NCLX

DOI:  https://doi.org/10.1016/j.redox.2022.102253
Neuropathol Appl Neurobiol. 2022 Mar 10.

Extracellular tau oligomers affect extracellular glutamate handling by astrocytes through downregulation of GLT-1 expression and impairment of NKA1A2 function.

Domenica Donatella Li Puma, Cristian Ripoli, Giulia Puliatti, Francesco Pastore, Giacomo Lazzarino, Barbara Tavazzi, Ottavio Arancio, Roberto Piacentini, Claudio Grassi.

  AIMS: Several studies reported that astrocytes support neuronal communication by the release of gliotransmitters, including ATP and glutamate. Astrocytes also play a fundamental role in buffering extracellular glutamate in the synaptic cleft, thus limiting the risk of excitotoxicity in neurons. We previously demonstrated that extracellular tau oligomers (ex-oTau), by specifically targeting astrocytes, affect glutamate-dependent synaptic transmission via a reduction in gliotransmitter release. The aim of this work was to determine if ex-oTau also impair the ability of astrocytes to uptake extracellular glutamate, thus further contributing to ex-oTau-dependent neuronal dysfunction.METHODS: Primary cultures of astrocytes and organotypic brain slices were exposed to ex-oTau (200 nM) for 1 hour. Extracellular glutamate buffering by astrocytes was studied by: Na+ imaging; electrophysiological recordings; high-performance liquid chromatography; Western blot and immunofluorescence. Experimental paradigms avoiding ex-oTau internalization (i.e., heparin pre-treatment and amyloid precursor protein knockout astrocytes) were used to dissect intracellular vs. extracellular effects of oTau.
RESULTS: Ex-oTau uploading in astrocytes significantly affected glutamate-transporter-1 expression and function, thus impinging on glutamate buffering activity. Ex-oTau also reduced Na-K-ATPase activity because of pump mislocalization on the plasma membrane, with no significant changes in expression. This effect was independent of oTau internalization and it caused Na+ overload and membrane depolarization in ex-oTau-targeted astrocytes.
CONCLUSIONS: Ex-oTau exerted a complex action on astrocytes, at both intracellular and extracellular levels. The net effect was dysregulated glutamate signalling in terms of both release and uptake that relied on reduced expression of glutamate-transporter-1, altered function and localization of NKA1A1, and NKA1A2. Consequently, Na+ gradients and all Na+ -dependent transports were affected.

Keywords:  Amyloid Precursor Protein; GLT-1; NKA; astrocytes; glutamate; tau oligomers

DOI:  https://doi.org/10.1111/nan.12811
Glia. 2022 Mar 11.

Deficient mitochondrial respiration in astrocytes impairs trace fear conditioning and increases naloxone-precipitated aversion in morphine-dependent mice.

Kateryna Murlanova, Yan Jouroukhin, Shovgi Huseynov, Olga Pletnikova, Michael J Morales, Yun Guan, Jay M Baraban, Dwight E Bergles, Mikhail V Pletnikov.

  Mitochondria are abundant in the fine processes of astrocytes, however, potential roles for astrocyte mitochondria remain poorly understood. In the present study, we performed a systematic examination of the effects of abnormal oxidative phosphorylation in astrocytes on several mouse behaviors. Impaired astrocyte oxidative phosphorylation was produced by astrocyte-specific deletion of the nuclear mitochondrial gene, Cox10, that encodes an accessory protein of complex IV, the protoheme:heme-O-farnesyl transferase. As expected, conditional deletion of the Cox10 gene in mice (cKO mice) significantly reduced expression of COX10 and Cytochrome c oxidase subunit I (MTCO1) of Complex IV, resulting in decreased oxidative phosphorylation without significantly affecting glycolysis. No effects of the deletion were observed on locomotor activity, anxiety-like behavior, nociception, or spontaneous alternation. Cox10 cKO female mice exhibited mildly impaired novel object recognition, while Cox10 cKO male mice were moderately deficient in trace fear conditioning. No group-related changes were observed in conditional place preference (CPP) that assessed effects of morphine on reward. In contrast to CPP, Cox10 cKO mice demonstrated significantly increased aversive behaviors produced by naloxone-precipitated withdrawal following chronic exposure to morphine, that is, jumping and avoidance behavior as assessed by conditional place aversion (CPA). Our study suggests that astrocyte oxidative phosphorylation may contribute to behaviors associated with greater cognitive load and/or aversive and stressful conditions.

Keywords:  astrocytes; fear conditioning; mitochondria; morphine withdrawal; naloxone

DOI:  https://doi.org/10.1002/glia.24169
Nutrients. 2022 Jan 29. pii: 599. [Epub ahead of print]14(3):

One-Carbon Metabolism in Alzheimer's Disease and Parkinson's Disease Brain Tissue.

Karel Kalecký, Paula Ashcraft, Teodoro Bottiglieri.

  Disruptions in one-carbon metabolism and elevated homocysteine have been previously implicated in the development of dementia associated with Alzheimer's disease (AD) and Parkinson's disease (PD). Moreover, a PD diagnosis itself carries substantial risk for the development of dementia. This is the first study that explores alterations in one-carbon metabolism in AD and PD directly in the human brain frontal cortex, the primary center of cognition. Applying targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS), we analyzed post-mortem samples obtained from 136 subjects (35 AD, 65 PD, 36 controls). We found changes in one-carbon metabolites that indicate inefficient activation of cystathionine β-synthase (CBS) in AD and PD subjects with dementia, the latter seemingly accompanied by a restricted re-methylation flow. Levodopa-carbidopa is known to reduce available vitamin B6, which would explain the hindered CBS activity. We present evidence of temporary non-protein-bound homocysteine accumulation upon levodopa intake in the brain of PD subjects with dementia but not in non-demented PD subjects. Importantly, this homocysteine elevation is not related to levodopa dosage, disease progression, or histopathological markers but exclusively to the dementia status. We hypothesize that this levodopa-induced effect is a direct cause of dementia in PD in susceptible subjects with reduced re-methylation capacity. Furthermore, we show that betaine best correlates with cognitive score even among PD subjects alone and discuss nutritional recommendations to improve one-carbon metabolism function.

Keywords:  Alzheimer’s disease; Parkinson’s disease; betaine; brain frontal cortex; dementia; homocysteine; levodopa; metabolomics; one-carbon metabolism

DOI:  https://doi.org/10.3390/nu14030599
Cells. 2022 Mar 04. pii: 892. [Epub ahead of print]11(5):

Dual Effects of Korean Red Ginseng on Astrocytes and Neural Stem Cells in Traumatic Brain Injury: The HO-1-Tom20 Axis as a Putative Target for Mitochondrial Function.

Minsu Kim, Sunhong Moon, Hui Su Jeon, Sueun Kim, Seong-Ho Koh, Mi-Sook Chang, Young-Myeong Kim, Yoon Kyung Choi.

  Astrocytes display regenerative potential in pathophysiologic conditions. In our previous study, heme oxygenase-1 (HO-1) promoted astrocytic mitochondrial functions in mice via the peroxisome-proliferator-activating receptor-γ coactivator-1α (PGC-1α) pathway on administering Korean red ginseng extract (KRGE) after traumatic brain injury (TBI). In this study, KRGE promoted astrocytic mitochondrial functions, assessed with oxygen consumption and adenosine triphosphate (ATP) production, which could be regulated by the translocase of the outer membrane of mitochondria 20 (Tom20) pathway with a PGC-1α-independent pathway. The HO-1-Tom20 axis induced an increase in mitochondrial functions, detected with cytochrome c oxidase subunit 2 and cytochrome c. HO-1 crosstalk with nicotinamide phosphoribosyltransferase was concomitant with the upregulated nicotinamide adenine dinucleotide (NAD)/NADH ratio, thereby upregulating NAD-dependent class I sirtuins. In adult neural stem cells (NSCs), KRGE-treated, astrocyte-conditioned media increased oxygen consumption and Tom20 levels through astrocyte-derived HO-1. HO inactivation by Sn(IV) protoporphyrin IX dichloride in TBI mice administered KRGE decreased neuronal markers, together with Tom20. Thus, astrocytic HO-1 induced astrocytic mitochondrial functions. HO-1-related, astrocyte-derived factors may also induce neuronal differentiation and mitochondrial functions of adult NSCs after TBI. KRGE-mediated astrocytic HO-1 induction may have a key role in repairing neurovascular function post-TBI in peri-injured regions by boosting astrocytic and NSC mitochondrial functions.

Keywords:  Korean red ginseng extract; animal study; astrocyte; heme oxygenase-1; neurology; traumatic brain injury

DOI:  https://doi.org/10.3390/cells11050892
Cells. 2022 Feb 25. pii: 813. [Epub ahead of print]11(5):

Metabolic Contribution and Cerebral Blood Flow Regulation by Astrocytes in the Neurovascular Unit.

Shinichi Takahashi.

  The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20-25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU.

Keywords:  astrocyte; astrocyte-neuron lactate shuttle; astroglia; functional hyperemia; glucose; lactate

DOI:  https://doi.org/10.3390/cells11050813
Int J Mol Sci. 2022 Feb 23. pii: 2474. [Epub ahead of print]23(5):

Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.

Ricardo Cabezas, Cynthia Martin-Jiménez, Martha Zuluaga, Andrés Pinzón, George E Barreto, Janneth González.

  Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues which involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, severely detrimental to cellular homeostasis and viability. In brain, lipotoxicity affects both neurons and other cell types, notably astrocytes, leading to neurodegenerative processes, such as Alzheimer (AD) and Parkinson diseases (PD). In this study, we performed for the first time, a whole lipidomic characterization of Normal Human Astrocytes cultures exposed to toxic concentrations of palmitic acid and the protective compound tibolone, to establish and identify the set of potential metabolites that are modulated under these experimental treatments. The study covered 3843 features involved in the exo- and endo-metabolome extracts obtained from astrocytes with the mentioned treatments. Through multivariate statistical analysis such as PCA (principal component analysis), partial least squares (PLS-DA), clustering analysis, and machine learning enrichment analysis, it was possible to determine the specific metabolites that were affected by palmitic acid insult, such as phosphoethanolamines, phosphoserines phosphocholines and glycerophosphocholines, with their respective metabolic pathways impact. Moreover, our results suggest the importance of tibolone in the generation of neuroprotective metabolites by astrocytes and may be relevant to the development of neurodegenerative processes.

Keywords:  astrocytes; lipidomics; palmitic acid; tibolone

DOI:  https://doi.org/10.3390/ijms23052474
Mol Psychiatry. 2022 Mar 09.

Schizophrenia: a disorder of broken brain bioenergetics.

Nicholas D Henkel, Xiajoun Wu, Sinead M O'Donovan, Emily A Devine, Jessica M Jiron, Laura M Rowland, Zoltan Sarnyai, Amy J Ramsey, Zhexing Wen, Margaret K Hahn, Robert E McCullumsmith.

A substantial and diverse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.

DOI: https://doi.org/10.1038/s41380-022-01494-x
J Cell Sci. 2022 Mar 01. pii: jcs259501. [Epub ahead of print]135(5):

Perilipins at a glance.

Charles P Najt, Mahima Devarajan, Douglas G Mashek.

  Lipid droplets (LDs) are ubiquitous organelles that store and supply lipids for energy metabolism, membrane synthesis and production of lipid-derived signaling molecules. While compositional differences in the phospholipid monolayer or neutral lipid core of LDs impact their metabolism and function, the proteome of LDs has emerged as a major influencer in all aspects of LD biology. The perilipins (PLINs) are the most studied and abundant proteins residing on the LD surface. This Cell Science at a Glance and the accompanying poster summarize our current knowledge of the common and unique features of the mammalian PLIN family of proteins, the mechanisms through which they affect cell metabolism and signaling, and their links to disease.

Keywords:  Lipid droplets; Lipid metabolism; Lipid signaling; Perilipins

DOI:  https://doi.org/10.1242/jcs.259501
Curr Protoc. 2022 Mar;2(3): e390

Gel-Based and Gel-Free Phosphoproteomics to Measure and Characterize Mitochondrial Phosphoproteins.

Visith Thongboonkerd, Sakdithep Chaiyarit.

  The mitochondrion is a key intracellular organelle regulating metabolic processes, oxidative stress, energy production, calcium homeostasis, and cell survival. Protein phosphorylation plays an important role in regulating mitochondrial functions and cellular signaling pathways. Dysregulation of protein phosphorylation status can cause protein malfunction and abnormal signal transduction, leading to organ dysfunction and disease. Investigating the mitochondrial phosphoproteins is therefore crucial to better understand the molecular and pathogenic mechanisms of many metabolic disorders. Conventional analyses of phosphoproteins, for instance, via western blotting, can be done only for proteins for which specific antibodies to their phosphorylated forms are available. Moreover, such an approach is not suitable for large-scale study of phosphoproteins. Currently, proteomics represents an important tool for large-scale analysis of proteins and their post-translational modifications, including phosphorylation. Here, we provide step-by-step protocols for the proteomics analysis of mitochondrial phosphoproteins (the phosphoproteome), using renal tubular cells as an example. These protocols include methods to effectively isolate mitochondria and to validate the efficacy of mitochondrial enrichment as well as its purity. We also provide detailed protocols for performing both gel-based and gel-free phosphoproteome analyses. The gel-based analysis involves two-dimensional gel electrophoresis and phosphoprotein-specific staining, followed by protein identification via mass spectrometry, whereas the gel-free approach is based on in-solution mass spectrometric identification of specific phosphorylation sites and residues. In all, these approaches allow large-scale analyses of mitochondrial phosphoproteins that can be applied to other cells and tissues of interest. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Mitochondrial isolation/purification from renal tubular cells Support Protocol: Validation of enrichment efficacy and purity of mitochondrial isolation Basic Protocol 2: Gel-based phosphoproteome analysis Basic Protocol 3: Gel-free phosphoproteome analysis.

Keywords:  PTMs ; mass spectrometry; mitochondria; phosphoproteome; phosphorylation; proteome; proteomics

DOI:  https://doi.org/10.1002/cpz1.390
Dev Neurosci. 2022 Mar 09.

The Vannucci Model of Hypoxic-Ischemic Injury in the Neonatal Rodent: 40 years later.

Susan J Vannucci, Stephen A Back.

Perinatal hypoxic-ischemic (HI) brain damage has long been a major cause of acute mortality and chronic neurologic morbidity in infants and children. Experimental animal models are essential to gain insights into the pathogenesis and management of perinatal HI brain damage. Prior to 1980 only large animal models were available. The first small animal model was developed in the postnatal 7 (P7) rat in 1981, now known as the Vannucci model. This model combines unilateral carotid artery ligation with subsequent hypoxia to produce transient hemispheric hypoxia-ischemia in the hemisphere ipsilateral to the ligation while the contralateral hemisphere is exposed to hypoxia only. This model has been characterized with studies of cerebral hemodynamics, cerebral metabolic changes, and acute and chronic neuropathology. Over the past 40 year this animal model has been utilized in numerous laboratories around the world, has been adapted to the immature mouse, as well as to immature rodents at various stages of development. This brief review describes the validation and characterization studies of the original model and some of the adaptations. A discussion of all of the studies focused on specific cell types is beyond the scope of this review. Rather, we present the application of the model to the study of a specific cell type, the pre-oligodendrocyte, and the role this cell plays in the development of white matter injury in the preterm brain.

DOI: https://doi.org/10.1159/000523990
Sci Rep. 2022 Mar 11. 12(1): 4287

Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD+ balance as a therapeutic strategy.

Mukesh Gautam, Aksu Gunay, Navdeep S Chandel, P Hande Ozdinler.

Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected in upper motor neurons (UMNs) with TDP-43 pathology, a pathology that is predominantly present in both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). While same mitochondrial problems are present in the UMNs of ALS patients with TDP-43 pathology and UMNs of TDP-43 mouse models, and since pathologies are shared at a cellular level, regardless of species, we first analyzed the metabolite profile of both healthy and diseased motor cortex to investigate whether metabolomic changes occur with respect to TDP-43 pathology. High-performance liquid chromatography, high-resolution mass spectrometry and tandem mass spectrometry (HPLC-MS/MS) for metabolite profiling began to suggest that reduced levels of NAD+ is one of the underlying causes of metabolomic problems. Since nicotinamide mononucleotide (NMN) was reported to restore NAD+ levels, we next investigated whether NMN treatment would improve the health of diseased corticospinal motor neurons (CSMN, a.k.a. UMN in mice). prpTDP-43A315T-UeGFP mice, the CSMN reporter line with TDP-43 pathology, allowed cell-type specific responses of CSMN to NMN treatment to be assessed in vitro. Our results show that metabolomic defects occur early in ALS motor cortex and establishing NAD+ balance could offer therapeutic benefit to UMNs with TDP-43 pathology.

DOI: https://doi.org/10.1038/s41598-022-08068-5
Nutrients. 2022 Feb 08. pii: 720. [Epub ahead of print]14(3):

Choline Kinetics in Neonatal Liver, Brain and Lung-Lessons from a Rodent Model for Neonatal Care.

Wolfgang Bernhard, Marco Raith, Anna Shunova, Stephan Lorenz, Katrin Böckmann, Michaela Minarski, Christian F Poets, Axel R Franz.

  Choline requirements are high in the rapidly growing fetus and preterm infant, mainly serving phosphatidylcholine (PC) synthesis for parenchymal growth and one-carbon metabolism via betaine. However, choline metabolism in critical organs during rapid growth is poorly understood. Therefore, we investigated the kinetics of D9-choline and its metabolites in the liver, plasma, brain and lung in 14 d old rats. Animals were intraperitoneally injected with 50 mg/kg D9-choline chloride and sacrificed after 1.5 h, 6 h and 24 h. Liver, plasma, lungs, cerebrum and cerebellum were analyzed for D9-choline metabolites, using tandem mass spectrometry. In target organs, D9-PC and D9-betaine comprised 15.1 ± 1.3% and 9.9 ± 1.2% of applied D9-choline at 1.5 h. D9-PC peaked at 1.5 h in all organs, and decreased from 1.5-6 h in the liver and lung, but not in the brain. Whereas D9-labeled PC precursors were virtually absent beyond 6 h, D9-PC increased in the brain and lung from 6 h to 24 h (9- and 2.5-fold, respectively) at the expense of the liver, suggesting PC uptake from the liver via plasma rather than local synthesis. Kinetics of D9-PC sub-groups suggested preferential hepatic secretion of linoleoyl-PC and acyl remodeling in target organs. D9-betaine showed rapid turnover and served low-level endogenous (D3-)choline synthesis. In conclusion, in neonatal rats, exogenous choline is rapidly metabolized to PC by all organs. The liver supplies the brain and lung directly with PC, followed by organotypic acyl remodeling. A major fraction of choline is converted to betaine, feeding the one-carbon pool and this must be taken into account when calculating choline requirements.

Keywords:  betaine; brain; choline; liver; lung; phospholipids; preterm infant; stable isotope labelling; tandem mass spectrometry

DOI:  https://doi.org/10.3390/nu14030720
J Neurosci Methods. 2022 Mar 07. pii: S0165-0270(22)00085-1. [Epub ahead of print] 109558

Imaging and analysis of neuronal mitochondria in murine acute brain slices.

Bimala Malla, Anja Hauser, Raluca Niesner, Carmen Infante-Duarte.

  BACKGROUND: Mitochondrial alterations are common to many inflammatory, degenerative as well as metabolic diseases. However, due to the vulnerability of mitochondria in explanted tissue, there is a general lack of ex vivo models, especially of CNS tissue, that preserve mitochondria and allow investigation of mitochondrial dynamics.NEW METHODS: Here, we present a model of acute hippocampal slices to study neuronal mitochondria ex vivo. We used two-photon microscopy to image CFP fluorescent neuronal mitochondria in B6.Cg-Tg(Thy1-CFP/COX8A)S2Lich mice brain slices. To define the optimal processing and culturing conditions, we compared mitochondrial morphology and motility with three different sets of slicing and incubation solutions. The investigation of mitochondrial dynamics was performed on deconvoluted images. For morphological investigation, images were segmented into three different categories according to the shape of mitochondria, while motility was investigated using semi-automated tracking.
RESULTS: The imaging of acute brain slices by two-photon microscopy represented a suitable tool to monitor neuronal mitochondria ex vivo. We observed that mitochondrial dynamics were better preserved in slices incubated with HEPES aCSF, maintaining elongated rod-shaped morphology and the motility.
COMPARISON WITH EXISTING METHODS: We showed for the first time a method that allows live imaging of mitochondria and its quantification, while the existing in vitro protocol are not suitable to investigate mitochondria in live tissue.
CONCLUSION: We have established the best incubation conditions and microscopy tools to investigate living mitochondria in acute slices. We showed that preventing initial swelling with HEPES and addition of glucose, pyruvate, ascorbate and thiourea preserved mitochondria in adult brain slices, which could be monitored by two-photon microscopy.

Keywords:  Acute brain slices; HEPES aCSF; N-Methyl-D-glucamin (NMDG) aCSF; mitochondria; sucrose cutting solution; two-photon microscopy

DOI:  https://doi.org/10.1016/j.jneumeth.2022.109558
Int J Mol Sci. 2022 Feb 26. pii: 2606. [Epub ahead of print]23(5):

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.

Henry H C Lee, Gabrielle E McGinty, Phillip L Pearl, Alexander Rotenberg.

  Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSADHD therapies. We conclude with a description of a novel SSADHD mouse model that enables 'on-demand' SSADH restoration, allowing proof-of-concept studies to fine-tune SSADH restoration in preparation for eventual human trials.

Keywords:  ALDH5A1; GABA receptors; enzyme replacement therapy; epilepsy; gene therapy; inhibition; mouse model; plasticity; succinic semialdehyde dehydrogenase deficiency (SSADHD); γ-aminobutyric acid (GABA); γ-hydroxybutyrate (GHB)

DOI:  https://doi.org/10.3390/ijms23052606
Front Aging Neurosci. 2022 ;14 780811

Role of Specialized Pro-resolving Mediators in Reducing Neuroinflammation in Neurodegenerative Disorders.

Jana Ponce, Arzu Ulu, Corrine Hanson, Erin Cameron-Smith, John Bertoni, Jenna Wuebker, Alfred Fisher, Ka-Chun Siu, Vivien Marmelat, Jiri Adamec, Danish Bhatti.

  Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders that affect millions of individuals worldwide. As incidence of these conditions increases with age, there will undoubtedly be an increased prevalence of cases in the near future. Neuroinflammation is a hallmark in the development and progression of neurodegenerative diseases and prevention or resolution of chronic neuroinflammation may represent a novel approach to treatment. The present review highlights the potential of the anti-inflammatory and pro-resolving effects of polyunsaturated fatty acid (PUFA)-derived mediators (Specialized Pro-resolving Mediators-SPM) in neurodegenerative disorders. PUFA-derived SPM are biosynthesized in response to chemicals produced from acute inflammatory responses. Preclinical studies from both AD and PD models suggest a dysregulation of SPM and their receptors in neurological disorders. Decreased SPM may be due to inadequate substrate, an imbalance between SPM and pro-inflammatory mediators or a disruption in SPM synthesis. SPMs hold great promise for neuroprotection in AD by altering expression of pro-inflammatory genes, modulating macrophage function, serving as a biomarker for AD status, and promoting resolution of neuroinflammation. In PD, data suggest SPM are able to cross the blood-brain barrier, inhibit microglial activation and decrease induced markers of inflammation, possibly as a result of their ability to downregulate NFκB signaling pathways. Several in vivo and in vitro studies suggest a benefit from administration of SPMs in both neurodegenerative disorders. However, extrapolation of these outcomes to humans is difficult as no models are able to replicate all features of AD or PD. Minimal data evaluating these PUFA-derived metabolites in humans with neurodegenerative disorders are available and a gap in knowledge exists regarding behavior of SPM and their receptors in patients with these conditions. There is also large gap in our knowledge regarding which lipid mediator would be most effective in which model of AD or PD and how dietary intake or supplementation can impact SPM levels. Future direction should include focused, translational efforts to investigate SPM as an add-on (in addition to standard treatment) or as standalone agents in patients with neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Parkinson’s disease; neurodegenerative disorder; neuroinflammation; omega-3 fatty acids; omega-6 fatty acid; polyunsaturated fatty acids; specialized pro-resolving lipid mediator (SPM)

DOI:  https://doi.org/10.3389/fnagi.2022.780811
J Biol Chem. 2022 Mar 02. pii: S0021-9258(22)00231-9. [Epub ahead of print] 101791

Protein methylation in mitochondria.

Jędrzej M Małecki, Erna Davydova, Pål Ø Falnes.

  Many proteins are modified by post-translational methylation, introduced by a number of methyltransferases (MTases). Protein methylation plays important roles in modulating protein function, and thus in optimizing and regulating cellular and physiological processes. Research has mainly focused on nuclear and cytosolic protein methylation, but it has been known for many years that also mitochondrial proteins are methylated. During the last decade, significant progress has been made on identifying the MTases responsible for mitochondrial protein methylation and addressing its functional significance. In particular, several novel human MTases have been uncovered that methylate lysine, arginine, histidine, and glutamine residues in various mitochondrial substrates. Several of these substrates are key components of the bioenergetics machinery, e.g. respiratory Complex I, citrate synthase and the ATP synthase. In the present review we report the status of the field of mitochondrial protein methylation, with a particular emphasis on recently discovered human MTases. We also discuss evolutionary aspects and functional significance of mitochondrial protein methylation, and present an outlook for this emergent research field.

Keywords:  ATP synthase; bioenergetics; electron transport chain; methyltransferase; mitochondria; oxidative phosphorylation; protein methylation

DOI:  https://doi.org/10.1016/j.jbc.2022.101791
Cells. 2022 Feb 22. pii: 765. [Epub ahead of print]11(5):

Ghrelin Acylation-A Post-Translational Tuning Mechanism Regulating Adult Hippocampal Neurogenesis.

Martina Sassi, Alwena H Morgan, Jeffrey S Davies.

  Adult hippocampal neurogenesis-the generation of new functional neurones in the adult brain-is impaired in aging and many neurodegenerative disorders. We recently showed that the acylated version of the gut hormone ghrelin (acyl-ghrelin) stimulates adult hippocampal neurogenesis while the unacylated form of ghrelin inhibits it, thus demonstrating a previously unknown function of unacyl-ghrelin in modulating hippocampal plasticity. Analysis of plasma samples from Parkinson's disease patients with dementia demonstrated a reduced acyl-ghrelin:unacyl-ghrelin ratio compared to both healthy controls and cognitively intact Parkinson's disease patients. These data, from mouse and human studies, suggest that restoring acyl-ghrelin signalling may promote the activation of pathways to support memory function. In this short review, we discuss the evidence for ghrelin's role in regulating adult hippocampal neurogenesis and the enzymes involved in ghrelin acylation and de-acylation as targets to treat mood-related disorders and dementia.

Keywords:  APT1; BChE; acyl-ghrelin; dementia; neurodegeneration; neurogenesis; unacyl-ghrelin

DOI:  https://doi.org/10.3390/cells11050765
Mol Pain. 2022 Mar 07. 17448069221087033

L-Acetylcarnitine causes analgesia in mice modeling Fabry disease by up-regulating type-2 metabotropic glutamate receptors.

Francesco Formaggio, Roberto Rimondini, Cecilia Delprete, Leonardo Scalia, Emilio Merlo Pich, Rocco Liguori, Ferdinando Nicoletti, Marco Caprini.

  Fabry disease (FD) is a X-linked lysosomal storage disorder caused by deficient function of the alpha-galactosidase A (α-GalA) enzyme. α-GalA deficiency leads to multisystemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide (Gb3). A hallmark symptom of FD patients is neuropathic pain that appears in the early stage of the disease as a result of peripheral small fiber damage. Previous studies have shown that Acetyl-L-carnitine (ALC) has neuroprotective, neurotrophic, and analgesic activity in animal models of neuropathic pain. To study the action of ALC on neuropathic pain associated with FD, we treated α-GalA gene null mice (α-GalA(-/0)) with ALC for 30 days. In α-Gal KO mice ALC treatment induced acute and long-lasting analgesia, which persisted 1 month after drug withdrawal. This effect was antagonized by single administration of LY341495, an orthosteric antagonist of mGlu2/3 metabotropic glutamate receptors. We also found an up-regulation of mGlu2 receptors in cultured DRG neurons isolated from 30-day ALC treated α-GalA KO mice. However, the up-regulation of mGlu2 receptors was no longer present in DRG neurons isolated 30 days after the end of treatment. Taken together, these findings suggest that ALC induces analgesia in an animal model of FD by up-regulating mGlu2 receptors, and that analgesia is maintained by additional mechanisms after ALC withdrawal. ALC might represent a valuable pharmacological strategy to reduce pain in FD patients.

Keywords:  Fabri disease; Ion channels; Mouse model; Pain; mGlu Receptors

DOI:  https://doi.org/10.1177/17448069221087033