bims-brabim 2022-01-23 papers

bims-brabim

Biomed News

on Brain bioenergetics and metabolism

Issue of 2022–01–23
thirty papers selected by
João Victor Cabral-Costa, University of São Paulo

Cyanidin 3-O-β-Galactoside Alleviated Cognitive Impairment in Mice by Regulating Brain Energy Metabolism During Aging.
Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
Effects of Endurance Training on the Coenzyme Q Redox State in Rat Heart, Liver, and Brain at the Tissue and Mitochondrial Levels: Implications for Reactive Oxygen Species Formation and Respiratory Chain Remodeling.
In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics.
Mitophagy mechanisms in neuronal physiology and pathology during ageing.
NRF2 Activation Ameliorates Oxidative Stress and Improves Mitochondrial Function and Synaptic Plasticity, and in A53T α-Synuclein Hippocampal Neurons.
Role of Bioactive Compounds in the Regulation of Mitochondrial Dysfunctions in Brain and Age-Related Neurodegenerative Diseases.
Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.
Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain.
Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone.
Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency.
Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus.
Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System.
OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.
The Protective Effects of Mogroside V Against Neuronal Damages by Attenuating Mitochondrial Dysfunction via Upregulating Sirtuin3.
Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease.
Dengzhan Xixin injection derived from a traditional Chinese herb Erigeron breviscapus ameliorates cerebral ischemia/reperfusion injury in rats via modulation of mitophagy and mitochondrial apoptosis.
MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle.
Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ homeostasis.
The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner.
Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs.
The detrimental effects of APOE4 on risk for Alzheimer's disease may result from altered dendritic spine density, synaptic proteins, and estrogen receptor alpha.
Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.
Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice.
Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons.
Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis.
Design and Evaluation of a Lactate Microbiosensor: Toward Multianalyte Monitoring of Neurometabolic Markers In Vivo in the Brain.
Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats.
Voluntary Behavior and Training Conditions Modulate in vivo Extracellular Glucose and Lactate in the Mouse Primary Motor Cortex.
Regional Brain Analysis of Modified Amino Acids and Dipeptides during the Sleep/Wake Cycle.

J Agric Food Chem. 2022 Jan 18.

Cyanidin 3-O-β-Galactoside Alleviated Cognitive Impairment in Mice by Regulating Brain Energy Metabolism During Aging.

Zhuoyan Fan, Haichao Wen, Xiaoxu Zhang, Jingming Li, Jiachen Zang.

  Metabolic disorder, which commonly happens among senile people worldwide, is an important sign of aging. The early symptoms of neurodegenerative diseases include a decrease in energy metabolism and mitochondrial dysfunction. Comparably, early dietary intervention may be more effective in preventing or delaying brain aging, owing to its role in regulating metabolism. Polyphenol intake has shown its potential in preventing Alzheimer's disease. However, whether there are close connections between polyphenols and the energy metabolism of the brain during aging remains unclear. This study sought to evaluate whether cyanidin 3-O-β-galactoside from black chokeberry (Aronia melanocarpa (Michx.) Elliott) has positive effects on energy metabolism, as well as cognitive function in aging mice. Intragastrical administration of cyanidin 3-O-β-galactoside (25 and 50 mg/kg/day) for 8 weeks effectively alleviated the decline in brain glucose uptake (decline rate 18.29% versus 1.05%, 7.63%) of aging mice. Moreover, cyanidin 3-O-β-galactoside also alleviated neuronal damage in the hippocampus (number of neurons 212.33 ± 16.19 versus 285.33 ± 29.53, 301.67 ± 10.07; p < 0.05) and cortex (number of neurons 82.00 ± 4.58 versus 111.67 ± 6.51, 112.00 ± 1.00; p < 0.05). Furthermore, cyanidin 3-O-β-galactoside reduced β-amyloid load in the brain and significantly increased the crossing-platform number (0.92 ± 1.11 versus 1.83 ± 0.68, 2.08 ± 0.58; p < 0.05) in the Morris water maze test. We further determined that protein kinase B (AKT) might be the target of cyanidin 3-O-β-galactoside, which played a beneficial role in controlling the energy metabolism of the brain. These results suggested that early intervention of anthocyanins could promote neuroprotection under the challenge of brain energy metabolism.

Keywords:  Alzheimer’s disease; aging; cognitive impairment; cyanidin 3-O-β-galactoside; energy metabolism

DOI:  https://doi.org/10.1021/acs.jafc.1c06240
Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]

Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.

Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.

  Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.

Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
Int J Mol Sci. 2022 Jan 14. pii: 896. [Epub ahead of print]23(2):

Effects of Endurance Training on the Coenzyme Q Redox State in Rat Heart, Liver, and Brain at the Tissue and Mitochondrial Levels: Implications for Reactive Oxygen Species Formation and Respiratory Chain Remodeling.

Karolina Dominiak, Lukasz Galganski, Adrianna Budzinska, Andrzej Woyda-Ploszczyca, Jerzy A Zoladz, Wieslawa Jarmuszkiewicz.

  Sixteen adult, 4-month-old male Wistar rats were randomly assigned to the training group (n = 8) or the control group (n = 8). We elucidated the effects of 8 weeks of endurance training on coenzyme Q (Q) content and the formation of reactive oxygen species (ROS) at the tissue level and in isolated mitochondria of the rat heart, liver and brain. We demonstrated that endurance training enhanced mitochondrial biogenesis in all tested organs, while a significant increase in the Q redox state was observed in the heart and brain, indicating an elevated level of QH2 as an antioxidant. Moreover, endurance training increased the mQH2 antioxidant pool in the mitochondria of the heart and liver, but not in the brain. At the tissue and isolated mitochondria level, an increase in ROS formation was only observed in the heart. ROS formation observed in the mitochondria of individual rat tissues after training may be associated with changes in the activity/amount of individual components of the oxidative phosphorylation system and its molecular organization, as well as with the size of the oxidized pool of mitochondrial Q acting as an electron carrier in the respiratory chain. Our results indicate that tissue-dependent changes induced by endurance training in the cellular and mitochondrial QH2 pool acting as an antioxidant and in the mitochondrial Q pool serving the respiratory chain may serve important roles in energy metabolism, redox homeostasis and the level of oxidative stress.

Keywords:  coenzyme Q; endurance training; mitochondrial energetics; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms23020896
Environ Sci Technol. 2022 Jan 18. 56(2): 1113-1124

In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics.

Danielle F Mello, Laura L Maurer, Ian T Ryde, Dong Hoon Songr, Stella M Marinakos, Chuanjia Jiang, Mark R Wiesner, Heileen Hsu-Kim, Joel N Meyer.

  Silver nanoparticles (AgNPs) are extensively used in consumer products and biomedical applications, thus guaranteeing both environmental and human exposures. Despite extensive research addressing AgNP safety, there are still major knowledge gaps regarding AgNP toxicity mechanisms, particularly in whole organisms. Mitochondrial dysfunction is frequently described as an important cytotoxicity mechanism for AgNPs; however, it is still unclear if mitochondria are the direct targets of AgNPs. To test this, we exposed the nematodeCaenorhabditis elegans to sublethal concentrations of AgNPs and assessed specific mitochondrial parameters as well as organismal-level endpoints that are highly reliant on mitochondrial function, such as development and chemotaxis behavior. All AgNPs tested significantly delayed nematode development, disrupted mitochondrial bioenergetics, and blocked chemotaxis. However, silver was not preferentially accumulated in mitochondria, indicating that these effects are likely not due to direct mitochondria-AgNP interactions. Mutant nematodes with deficiencies in mitochondrial dynamics displayed both greater and decreased susceptibility to AgNPs compared to wild-type nematodes, which was dependent on the assay and AgNP type. Our study suggests that AgNPs indirectly promote mitochondrial dysfunction, leading to adverse outcomes at the organismal level, and reveals a role of gene-environment interactions in the susceptibility to AgNPs. Finally, we propose a novel hypothetical adverse outcome pathway for AgNP effects to guide future research.

Keywords:  invertebrates; mitochondrial dynamics; mitochondrial metabolism; nanomaterials; nanotoxicity

DOI:  https://doi.org/10.1021/acs.est.1c05915
Biophys Rev. 2021 Dec;13(6): 955-965

Mitophagy mechanisms in neuronal physiology and pathology during ageing.

Maria Markaki, Dikaia Tsagkari, Nektarios Tavernarakis.

  Ageing in diverse species ranging from the simple nematode Caenorhabditis elegans to humans is associated with a marked decrease of neuronal function and increased susceptibility to neurodegeneration. Accumulating findings also indicate that alterations in neuronal functionality with age are associated with a decline in mitochondrial integrity and function. The rate at which a mitochondrial population is refreshed is determined by the coordination of mitochondrial biogenesis with mitophagy, a selective type of autophagy targeting damaged or superfluous mitochondria for degradation. Coupling of these opposing processes is crucial for maintaining cellular energy homeostasis, which eventually contributes to health span. Here, we focus on the role of mitophagy in nervous system function in the context of normal physiology and disease. First, we consider the progress that has been made over the last decade in elucidating the mechanisms that govern and regulate mitophagy, placing emphasis on the PINK1/Parkin-mediated mitophagy. We further discuss the contribution of mitophagy to the maintenance of neuronal homeostasis and health as well as recent findings implicating impaired mitophagy in age-related decline of the nervous system function and consequently in the pathogenesis of neurodegenerative diseases.

Keywords:  Ageing; Energy homeostasis; Mitophagy; Neurodegeneration; Neuron; Neuronal health

DOI:  https://doi.org/10.1007/s12551-021-00894-7
Antioxidants (Basel). 2021 Dec 24. pii: 26. [Epub ahead of print]11(1):

NRF2 Activation Ameliorates Oxidative Stress and Improves Mitochondrial Function and Synaptic Plasticity, and in A53T α-Synuclein Hippocampal Neurons.

Mikah S Brandes, Jonathan A Zweig, Anita Tang, Nora E Gray.

  In Parkinson's disease (PD), brain oxidative stress and mitochondrial dysfunction contribute to neuronal loss as well as motor and cognitive deficits. The transcription factor NRF2 has emerged as a promising therapeutic target in PD because it sits at the intersection of antioxidant and mitochondrial pathways. Here, we investigate the effects of modulating NRF2 activity in neurons isolated from a A53T α-synuclein (A53TSyn) mouse model of synucleinopathy. Embryonic hippocampal neurons were isolated from A53TSyn mice and their wild type (WT) littermates. Neurons were treated with either the NRF2 activator dimethyl fumarate (DMF) or the NRF2 inhibitor ML385. Reactive oxygen species (ROS), dendritic arborization and dendritic spine density were quantified. Mitochondrial bioenergetics were also profiled in these neurons. A53TSyn neurons had increased ROS and reduced basal and maximal mitochondrial respiration relative to WT neurons. A53TSyn neurons also displayed decreased dendritic arborization and reduced spine density. Treatment with DMF reduced ROS levels and improved both mitochondrial function and arborization, while inhibition of NRF2 with ML385 exacerbated these endpoints. Modulation of NRF2 activity had a significant effect on mitochondrial function, oxidative stress, and synaptic plasticity in A53TSyn neurons. These data suggest that NRF2 may be a viable target for therapeutic interventions in PD.

Keywords:  NRF2; Parkinson’s disease; alpha-synuclein; dimethyl fumarate

DOI:  https://doi.org/10.3390/antiox11010026
Cells. 2022 Jan 13. pii: 257. [Epub ahead of print]11(2):

Role of Bioactive Compounds in the Regulation of Mitochondrial Dysfunctions in Brain and Age-Related Neurodegenerative Diseases.

Khadidja Kessas, Zhor Chouari, Imen Ghzaiel, Amira Zarrouk, Mohamed Ksila, Taoufik Ghrairi, Adil El Midaoui, Gérard Lizard, Omar Kharoubi.

  Mitochondria are multifunctional organelles that participate in a wide range of metabolic processes, including energy production and biomolecule synthesis. The morphology and distribution of intracellular mitochondria change dynamically, reflecting a cell's metabolic activity. Oxidative stress is defined as a mismatch between the body's ability to neutralise and eliminate reactive oxygen and nitrogen species (ROS and RNS). A determination of mitochondria failure in increasing oxidative stress, as well as its implications in neurodegenerative illnesses and apoptosis, is a significant developmental process of focus in this review. The neuroprotective effects of bioactive compounds linked to neuronal regulation, as well as related neuronal development abnormalities, will be investigated. In conclusion, the study of secondary components and the use of mitochondrial features in the analysis of various neurodevelopmental diseases has enabled the development of a new class of mitochondrial-targeted pharmaceuticals capable of alleviating neurodegenerative disease states and enabling longevity and healthy ageing for the vast majority of people.

Keywords:  ageing; antioxidant therapy; energy metabolism; mitochondria; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells11020257
Brain Sci. 2022 Jan 06. pii: 83. [Epub ahead of print]12(1):

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.

Bruna L Zampieri, Alberto C S Costa.

  For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure "neurocentric" vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

Keywords:  Ts65Dn; astrocytes; down syndrome; glycolysis; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.3390/brainsci12010083
Nutrients. 2022 Jan 12. pii: 300. [Epub ahead of print]14(2):

Oral Administration of Nicotinamide Mononucleotide Increases Nicotinamide Adenine Dinucleotide Level in an Animal Brain.

Chidambaram Ramanathan, Thomas Lackie, Drake H Williams, Paul S Simone, Yufeng Zhang, Richard J Bloomer.

  As a redox-sensitive coenzyme, nicotinamide adenine dinucleotide (NAD+) plays a central role in cellular energy metabolism and homeostasis. Low NAD+ levels are linked to multiple disease states, including age-related diseases, such as metabolic and neurodegenerative diseases. Consequently, restoring/increasing NAD+ levels in vivo has emerged as an important intervention targeting age-related neurodegenerative diseases. One of the widely studied approaches to increase NAD+ levels in vivo is accomplished by using NAD+ precursors, such as nicotinamide mononucleotide (NMN). Oral administration of NMN has been shown to successfully increase NAD+ levels in a variety of tissues; however, it remains unclear whether NMN can cross the blood-brain barrier to increase brain NAD+ levels. This study evaluated the effects of oral NMN administration on NAD+ levels in C57/B6J mice brain tissues. Our results demonstrate that oral gavage of 400 mg/kg NMN successfully increases brain NAD+ levels in mice after 45 min. These findings provide evidence that NMN may be used as an intervention to increase NAD+ levels in the brain.

Keywords:  NAD+; NMN; brain; mice; oral gavage

DOI:  https://doi.org/10.3390/nu14020300
Antioxidants (Basel). 2021 Dec 28. pii: 62. [Epub ahead of print]11(1):

Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone.

Daniela Valenti, Fiorenza Stagni, Marco Emili, Sandra Guidi, Renata Bartesaghi, Rosa Anna Vacca.

  Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3-P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3-P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

Keywords:  7,8-dihydroxyflavone; Down syndrome; Ts65Dn mice; brain mitochondria; mitochondrial respiratory chain; oxidative phosphorylation

DOI:  https://doi.org/10.3390/antiox11010062
Genes (Basel). 2022 Jan 11. pii: 127. [Epub ahead of print]13(1):

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency.

Jing Wang, Gudrun A Rappold, Henning Fröhlich.

  Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/- mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/- hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/- mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Keywords:  FOXP1 syndrome; Foxp1+/− mouse; associative learning; autism spectrum disorder; hippocampus; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/genes13010127
Front Cell Neurosci. 2021 ;15 788262

Neuronal Loss of the Glutamate Transporter GLT-1 Promotes Excitotoxic Injury in the Hippocampus.

Theresa S Rimmele, Shaomin Li, Jens Velde Andersen, Emil W Westi, Alexander Rotenberg, Jianlin Wang, Blanca Irene Aldana, Dennis J Selkoe, Chiye J Aoki, Chris G Dulla, Paul Allen Rosenberg.

  GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20-25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.

Keywords:  Alzheimer’s disease; aging; excitotoxicity glutamatergic; homeostasis; mitochondria; neurodegeneration; repair

DOI:  https://doi.org/10.3389/fncel.2021.788262
Front Mol Neurosci. 2021 ;14 808603

Farnesoid X Receptor Activation in Brain Alters Brown Adipose Tissue Function via the Sympathetic System.

Benjamin Deckmyn, Dorothée Domenger, Chloé Blondel, Sarah Ducastel, Emilie Nicolas, Emilie Dorchies, Emilie Caron, Julie Charton, Emmanuelle Vallez, Benoit Deprez, Jean-Sébastien Annicotte, Sophie Lestavel, Anne Tailleux, Christophe Magnan, Bart Staels, Kadiombo Bantubungi.

  The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.

Keywords:  FXR; brain; brown adipose tissue; energy homeostasis; hypothalamus

DOI:  https://doi.org/10.3389/fnmol.2021.808603
Front Cell Dev Biol. 2021 ;9 774108

OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.

Benjamín Cartes-Saavedra, Josefa Macuada, Daniel Lagos, Duxan Arancibia, María E Andrés, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.

  Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+]mito). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1 -/- MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+]cyto) needed for a prompt [Ca2+]mito rise. Finally, OPA1 mutants' overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1 -/- MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.

Keywords:  ADOA; OPA1; calcium; endoplasmic reticulum; mitochondria

DOI:  https://doi.org/10.3389/fcell.2021.774108
Mol Neurobiol. 2022 Jan 18.

The Protective Effects of Mogroside V Against Neuronal Damages by Attenuating Mitochondrial Dysfunction via Upregulating Sirtuin3.

Hanjiang Luo, Caixia Peng, Xiaofeng Xu, Yuntao Peng, Fang Shi, Qinghua Li, Jianghui Dong, Min Chen.

  Mitochondrial dysfunction and oxidative stress are thought to play a dominant role in the pathogenesis of Parkinson's disease (PD). Mogroside V (MV), extracted from Siraitia grosvenorii, exhibits antioxidant-like activities. The aim of this study was to investigate the function of MV in neuroprotection in PD and to reveal its mechanism of action. To that end, we firstly set up mice models of PD with unilateral striatum injection of 0.25 mg/kg rotenone (Rot) and co-treated with 2.5 mg/kg, 5 mg/kg, and 10 mg/kg MV by gavage. Results showed that Rot-induced motor impairments and dopaminergic neuronal damage were reversed by treatment of 10 mg/kg MV. Then, we established cellular models of PD using Rot-treated SH-SY5Y cells, which were divided into six groups, including control, Rot, and co-enzyme Q10 (CQ10), as well as MV groups, MV25, MV50, and MV100 treated with 25 μM, 50 μM, and 100 μM MV doses, respectively. Results demonstrated that MV effectively attenuates Rot neurotoxicity through a ROS-related intrinsic mitochondrial pathway. MV reduced overproduction of reactive oxygen species (ROS), recovered the mitochondrial membrane potential (MMP), and increased the oxygen consumption rate and adenosine triphosphate (ATP) production in a dose-dependent manner. Hence, treatment with MV led to a reduction in the number of apoptotic cells, as reflected by Annexin-V/propidium iodide co-staining using flow cytometry and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. In addition, the Sirtuin3 (SIRT3) protein level and activity were decreased upon exposure to Rot both in substantia nigra (SN) of mice and SH-SY5Y cells. SIRT3 impairment hyperacetylated a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2). MV alleviates SIRT3 and SOD2 molecular changes. However, after successfully inhibiting SIRT3 by its specific inhibitor 3-1H-1, 2, 3-triazol-4-yl pyridine (3TYP), MV was not able to reduce ROS levels, reverse abnormal MMP, or decrease apoptotic cells. Motor impairments and dopaminergic neuronal injury in the SN were alleviated with the oral administration of MV in Rot-treated PD mice, indicating a relationship between protection against defective motility and preservation of dopaminergic neurons. Therefore, we conclude that MV can alleviate Rot-induced neurotoxicity in a PD model, and that SIRT3 may be an important regulator in the protection of MV.

Keywords:  Mitochondria-dependent apoptosis; Mogroside V; Parkinson’s disease; Rotenone; Sirtuin3

DOI:  https://doi.org/10.1007/s12035-021-02689-z
Antioxidants (Basel). 2022 Jan 17. pii: 170. [Epub ahead of print]11(1):

Neuroprotection and Disease Modification by Astrocytes and Microglia in Parkinson Disease.

Shinichi Takahashi, Kyoko Mashima.

  Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.

Keywords:  Toll-like receptor 4; astrocyte; astroglia; glutathione; lactate; microglia

DOI:  https://doi.org/10.3390/antiox11010170
J Ethnopharmacol. 2022 Jan 12. pii: S0378-8741(22)00022-8. [Epub ahead of print] 114988

Dengzhan Xixin injection derived from a traditional Chinese herb Erigeron breviscapus ameliorates cerebral ischemia/reperfusion injury in rats via modulation of mitophagy and mitochondrial apoptosis.

Lu Yang, Yiwen Tao, Liuling Luo, Yi Zhang, Xiaobo Wang, Xianli Meng.

   ETHNOPHARMACOLOGICAL RELEVANCE: Dengzhan Xixin injection (DX), a preparation of extracts from traditional Chinese medicine Erigeron breviscapus (Vaniot) Hand.-Mazz., has been widely used in clinical treatment of cerebral ischemia sequelae in China for a long history. However, its underlying mechanisms remain unclear.
AIM OF THE STUDY: The objective of this present study aimed to investigate the therapeutic effects of DX on cerebral ischemia/reperfusion (I/R) injury in a rat model. Meanwhile, its underlying molecular mechanisms on mitochondrial protection were further interpreted.
MATERIALS AND METHODS: The major components of DX were detected by high-performance liquid chromatography analysis. The model of cerebral I/R injury was established by middle cerebral artery occlusion (MCAO) in SD rats. We firstly performed neurobehavioral score, the regional cerebral blood flow (rCBF) assay, and TTC, HE and Nissl staining for evaluating the effects of DX on I/R injury. And then, the cortical levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) were determined by commercial kits. Whereafter, real time-PCR and transmission electron microscopy were employed to investigate the relative copy number of mitochondrial DNA (mtDNA) and neuronal ultrastructure changes, respectively. Further, the potential interactions of major components in DX with mitophagy/apoptosis-related proteins were predicted by Schrodinger molecular docking. The expression of mitophagy-related proteins LC3, p62, TOM20, PINK1 and Parkin was estimated by western blot and immunofluorescence analyses. Furthermore, TUNEL staining and western blot were used to detect the apoptotic phenomenon and the protein expression of Bax, Bcl-2, Cytochrome c (Cyto-c) and cleaved Caspase-3.
RESULTS: DX mainly contains scutellarin, 3,4-O-dicaffeoylquinic acid, 3,5-O-dicaffeoylquinic acid, 4,5-O-dicaffeoylquinic acid, caffeic acid and 5-O-caffeoylquinic acid. Compared with the model group, DX could remarkably relieve ischemia-provoked neurological deficit, rCBF deficiency and cerebral infarction. Pathological changes and neuronal loss in a MCAO model of rats were memorably ameliorated by DX administration. Meanwhile, DX reduced the surged ROS and MDA, while increased the level of SOD. Notably, DX treatment conversed the collapse of ATP and MMP, along with decreased in the relative copy number of mtDNA, contributing to the maintaining of mitochondrial ultrastructure via the increased number of autophagy lysosomes. The representative ingredients in DX had a potential bind with the active sites of mitophagy/apoptosis-related proteins. DX stimulated the protein expression of LC3, PINK1 and Parkin, while reduced the levels of p62 and TOM20. In addition, DX confined TUNEL-positive cell rate with the decreased expressions of Bax, Cyto-c and cleaved Caspase-3 as well as the increased Bcl-2 level.
CONCLUSIONS: We demonstrated that the protection of DX against brain ischemia could attribute to alleviating mitochondrial damage by upregulating mitophagy and inhibiting mitochondria-mediated apoptosis.

Keywords:  Dengzhan xixin injection; Ischemic stroke; Mitochondria-mediated apoptosis; Mitochondrial damage; Mitophagy

DOI:  https://doi.org/10.1016/j.jep.2022.114988
Biochim Biophys Acta Bioenerg. 2022 Jan 18. pii: S0005-2728(22)00001-9. [Epub ahead of print] 148532

MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle.

Thibaut Molinié, Elodie Cougouilles, Claudine David, Edern Cahoreau, Jean-Charles Portais, Arnaud Mourier.

  The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other respiratory chain (RC) complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organization would favour NADH oxidation. Unexpectedly, characterization of heart and liver mitochondria demonstrates that the RC systematically favours electrons provided by the 'respirasome free' complex II. Our results demonstrate that the preferential succinate driven respiration is tightly controlled by OAA levels, and that OAA feedback inhibition of complex II rewires RC fuelling increasing NADH oxidation capacity. This new regulatory mechanism synergistically increases RC's NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favour oxidation of cytosolic malate. This regulatory mechanism synergistically adjusts RC and TCA fuelling in response to extramitochondrial malate produced by the MAS.

Keywords:  Bioenergetics; MDH2; Malate aspartate shuttle; Mitochondria; NADH redox homeostasis; Oxaloacetate; Respirasomes; Respiratory chain supercomplexes

DOI:  https://doi.org/10.1016/j.bbabio.2022.148532
Commun Biol. 2022 Jan 20. 5(1): 76

Citrin mediated metabolic rewiring in response to altered basal subcellular Ca2+ homeostasis.

Zhanat Koshenov, Furkan E Oflaz, Martin Hirtl, Benjamin Gottschalk, Rene Rost, Roland Malli, Wolfgang F Graier.

In contrast to long-term metabolic reprogramming, metabolic rewiring represents an instant and reversible cellular adaptation to physiological or pathological stress. Ca2+ signals of distinct spatio-temporal patterns control a plethora of signaling processes and can determine basal cellular metabolic setting, however, Ca2+ signals that define metabolic rewiring have not been conclusively identified and characterized. Here, we reveal the existence of a basal Ca2+ flux originating from extracellular space and delivered to mitochondria by Ca2+ leakage from inositol triphosphate receptors in mitochondria-associated membranes. This Ca2+ flux primes mitochondrial metabolism by maintaining glycolysis and keeping mitochondria energized for ATP production. We identified citrin, a well-defined Ca2+-binding component of malate-aspartate shuttle in the mitochondrial intermembrane space, as predominant target of this basal Ca2+ regulation. Our data emphasize that any manipulation of this ubiquitous Ca2+ system has the potency to initiate metabolic rewiring as an instant and reversible cellular adaptation to physiological or pathological stress.

DOI: https://doi.org/10.1038/s42003-022-03019-2
J Neurosci Res. 2022 Jan 18.

The serotonin reuptake transporter modulates mitochondrial copy number and mitochondrial respiratory complex gene expression in the frontal cortex and cerebellum in a sexually dimorphic manner.

Bryony N Thorne, Bart A Ellenbroek, Darren J Day.

  Neuropsychiatric and neurodevelopmental disorders such as major depressive disorder (MDD) and autism spectrum disorder (ASD) are complex conditions attributed to both genetic and environmental factors. There is a growing body of evidence showing that serotonergic signaling and mitochondrial dysfunction contribute to the pathophysiology of these disorders and are linked as signaling through specific serotonin (5-HT) receptors drives mitochondrial biogenesis. The serotonin transporter (SERT) is important in these disorders as it regulates synaptic serotonin and therapeutically is the target of selective serotonin reuptake inhibitors which are a major class of anti-depressant drug. Human allelic variants of the serotonin transporter-linked polymorphic region (5-HTTLPR) such as the S/S variant, are associated with reduced SERT expression and increased susceptibility for developing neuropsychiatric disorders. Using a rat model that is haploinsufficient for SERT and displays reduced SERT expression similar to the human S/S variant, we demonstrate that reduced SERT expression modulates mitochondrial copy number and expression of respiratory chain electron transfer components in the brain. In the frontal cortex, genotype-related trends were opposing for males and females, such that reduced SERT expression led to increased expression of the Complex I subunit mt-Nd1 in males but reduced expression in females. Our findings suggest that SERT expression and serotonergic signaling have a role in regulating mitochondrial biogenesis and adenosine triphosphate (ATP) production in the brain. We speculate that the sexual dimorphism in mitochondrial abundance and gene expression contributes to the sex bias found in the incidence of neuropsychiatric disorders such as MDD and ASD.

Keywords:  SERT; mitochondrial biogenesis; neuropsychiatric disorders; serotonin

DOI:  https://doi.org/10.1002/jnr.25010
J Proteome Res. 2022 Jan 19.

Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs.

Micaela Kalani Roy, Francesca La Carpia, Francesca Cendali, Sebastian Fernando, Chiara Moriconi, Boguslaw S Wojczyk, Lin Wang, Travis Nemkov, Eldad A Hod, Angelo D'Alessandro.

  Investigating the metabolic effects of radiation is critical to understand the impact of radiotherapy, space travel, and exposure to environmental radiation. In patients undergoing hemopoietic stem cell transplantation, iron overload is a common risk factor for poor outcomes. However, no studies have interrogated the multiorgan effects of these treatments concurrently. Herein, we use a model that recapitulates transfusional iron overload, a condition often observed in chronically transfused patients. We applied an omics approach to investigate the impact of both the iron load and irradiation on the host metabolome. The results revealed dose-dependent effects of irradiation in the red blood cells, plasma, spleen, and liver energy and redox metabolism. Increases in polyamines and purine salvage metabolites were observed in organs with high oxygen consumption including the heart, kidneys, and brain. Irradiation also impacted the metabolism of the duodenum, colon, and stool, suggesting a potential effect on the microbiome. Iron infusion affected the response to radiation in the organs and blood, especially in erythrocyte polyamines and spleen antioxidant metabolism, and affected glucose, methionine, and glutathione systems and tryptophan metabolism in the liver, stool, and the brain. Together, the results suggest that radiation impacts metabolism on a multiorgan level with a significant interaction of the host iron status.

Keywords:  iron; mass spectrometry; metabolism; methionine; organs; polyamine; radiation

DOI:  https://doi.org/10.1021/acs.jproteome.1c00912
Neurobiol Aging. 2021 Dec 24. pii: S0197-4580(21)00362-6. [Epub ahead of print]112 74-86

The detrimental effects of APOE4 on risk for Alzheimer's disease may result from altered dendritic spine density, synaptic proteins, and estrogen receptor alpha.

Lisa R Taxier, Sarah M Philippi, Jason M York, Mary Jo LaDu, Karyn M Frick.

  Women carriers of APOE4, the greatest genetic risk factor for late-onset Alzheimer's disease (AD), are at highest risk of developing AD, yet factors underlying interactions between APOE4 and sex are not well characterized. Here, we examined how sex and APOE3 or APOE4 genotypes modulate object and spatial memory, dendritic spine density and branching, and protein expression in 6-month-old male and female E3FAD and E4FAD mice (APOE+/+/5xFAD+/-). APOE4 negatively impacted object recognition and spatial memory, with male E3FADs exhibiting the best memory across 2 object-based tasks. In both sexes, APOE4 reduced basal dendritic spine density in the medial prefrontal cortex and dorsal hippocampus. APOE4 reduced dorsal hippocampal levels of PDS-95, synaptophysin, and phospho-CREB, yet increased levels of ERα. E4FAD females exhibited strikingly increased GFAP levels, in addition to the lowest levels of PSD-95 and pCREB. Overall, our results suggest that APOE4 negatively impacts object memory, dendritic spine density, and levels of hippocampal synaptic proteins and ERα. However, the general lack of sex differences or sex by genotype interactions suggests that the sex-specific effects of APOE4 on AD risk may be related to factors unexplored in the present study.

Keywords:  APOE4; Alzheimer's disease; Apolipoprotein E; Hippocampus; Medial prefrontal cortex; Object recognition; Spatial memory

DOI:  https://doi.org/10.1016/j.neurobiolaging.2021.12.006
Metabolites. 2022 Jan 10. pii: 56. [Epub ahead of print]12(1):

Metabolomic Analysis of Carbohydrate and Amino Acid Changes Induced by Hypoxia in Naked Mole-Rat Brain and Liver.

Hang Cheng, Yiming Amy Qin, Rashpal Dhillon, James Dowell, John M Denu, Matthew E Pamenter.

  Hypoxia poses a major physiological challenge for mammals and has significant impacts on cellular and systemic metabolism. As with many other small rodents, naked mole-rats (NMRs; Heterocephalus glaber), who are among the most hypoxia-tolerant mammals, respond to hypoxia by supressing energy demand (i.e., through a reduction in metabolic rate mediated by a variety of cell- and tissue-level strategies), and altering metabolic fuel use to rely primarily on carbohydrates. However, little is known regarding specific metabolite changes that underlie these responses. We hypothesized that NMR tissues utilize multiple strategies in responding to acute hypoxia, including the modulation of signalling pathways to reduce anabolism and reprogram carbohydrate metabolism. To address this question, we evaluated changes of 64 metabolites in NMR brain and liver following in vivo hypoxia exposure (7% O2, 4 h). We also examined changes in matched tissues from similarly treated hypoxia-intolerant mice. We report that, following exposure to in vivo hypoxia: (1) phenylalanine, tyrosine and tryptophan anabolism are supressed both in NMR brain and liver; (2) carbohydrate metabolism is reprogramed in NMR brain and liver, but in a divergent manner; (3) redox state is significantly altered in NMR brain; and (4) the AMP/ATP ratio is elevated in liver. Overall, our results suggest that hypoxia induces significant metabolic remodelling in NMR brain and liver via alterations of multiple metabolic pathways.

Keywords:  AMP; aspartic acid; coenzyme; dopamine; glutamate; glutamine; glutathione; glycogen; pentose phosphate pathway

DOI:  https://doi.org/10.3390/metabo12010056
Cell Death Discov. 2022 Jan 17. 8(1): 28

Idebenone improves motor dysfunction, learning and memory by regulating mitophagy in MPTP-treated mice.

Junqiang Yan, Wenjie Sun, Mengmeng Shen, Yongjiang Zhang, Menghan Jiang, Anran Liu, Hongxia Ma, Xiaoyi Lai, Jiannan Wu.

The progression of Parkinson's disease (PD) is often accompanied by the loss of substantia nigra dopaminergic neurons, mitophagy damage, learning, and memory impairment. Idebenone is a therapeutic drug that targets the mitochondria of neurodegenerative diseases, but its role in Parkinson's disease and its pathological mechanism are still unclear. The purpose of this study was to investigate whether idebenone could improve behavioral disorders, especially motor, learning, and memory disorders, in mouse PD models and to explore its molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for five consecutive days. Then, a 200 mg/kg dose was given as a single daily gavage of idebenone dissolved in water for 21 days after the successful establishment of the subacute MPTP model. Motor, learning, and memory were measured by a water maze and a rotarod test. Our results showed that idebenone could reduce MPTP-induced dopaminergic neuron damage and improve movement disorders, memory, and learning ability, which may be associated with upregulating mitochondrial autophagy-related outer membrane proteins VDAC1 and BNIP3 and activating the Parkin/PINK1 mitochondrial autophagy pathway. To confirm whether idebenone promotes the smooth progression of autophagy, we used eGFP-mCherry-LC3 mice to construct a subacute model of Parkinson's disease and found that idebenone can increase autophagy in dopaminergic neurons in Parkinson's disease. In summary, our results confirm that idebenone can regulate the expression of the mitochondrial outer membrane proteins VDAC1 and BNIP3, activate Parkin/PINK1 mitophagy, promote the degradation of damaged mitochondria, reduce dopaminergic neuron damage, and improve behavioral disorders in Parkinson's disease mice.

DOI: https://doi.org/10.1038/s41420-022-00826-8
Antioxidants (Basel). 2021 Dec 24. pii: 41. [Epub ahead of print]11(1):

Insulin-like Growth Factor II Prevents MPP+ and Glucocorticoid Mitochondrial-Oxidative and Neuronal Damage in Dopaminergic Neurons.

Silvia Claros, Pablo Cabrera, Nadia Valverde, Silvana Y Romero-Zerbo, Manuel Víctor López-González, Kirill Shumilov, Alicia Rivera, Jose Pavia, Elisa Martín-Montañez, María Garcia-Fernandez.

  Stress seems to contribute to Parkinson's disease (PD) neuropathology, probably by dysregulation of the hypothalamic-pituitary-adrenal axis. Key factors in this pathophysiology are oxidative stress and mitochondrial dysfunction and neuronal glucocorticoid-induced toxicity. The insulin-like growth factor II (IGF-II), a pleiotropic hormone, has shown antioxidant and neuroprotective effects in some neurodegenerative disorders. Our aim was to examine the protective effect of IGF-II on a dopaminergic cellular combined model of PD and mild to moderate stress measuring oxidative stress parameters, mitochondrial and neuronal markers, and signalling pathways. IGF-II counteracts the mitochondrial-oxidative damage produced by the toxic synergistic effect of corticosterone and 1-methyl-4-phenylpyridinium, protecting dopaminergic neurons from death and neurodegeneration. IGF-II promotes PKC activation and nuclear factor (erythroid-derived 2)-like 2 antioxidant response in a glucocorticoid receptor-dependent pathway, preventing oxidative cell damage and maintaining mitochondrial function. Thus, IGF-II is a potential therapeutic tool for treatment and prevention of disease progression in PD patients suffering mild to moderate emotional stress.

Keywords:  Parkinson’s disease; hormonal stress; insulin-like growth factor II; mitochondria; neuroprotection; oxidative stress

DOI:  https://doi.org/10.3390/antiox11010041
Int J Mol Sci. 2022 Jan 16. pii: 961. [Epub ahead of print]23(2):

Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis.

Takayuki Kobayashi, Hiroyuki Uchino, Eskil Elmér, Yukihiko Ogihara, Hidetoshi Fujita, Shusuke Sekine, Yusuke Ishida, Iwao Saiki, Shoichiro Shibata, Aya Kawachi.

  Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Keywords:  cyclophilin D; encephalopathy; glutathione; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/ijms23020961
Molecules. 2022 Jan 14. pii: 514. [Epub ahead of print]27(2):

Design and Evaluation of a Lactate Microbiosensor: Toward Multianalyte Monitoring of Neurometabolic Markers In Vivo in the Brain.

Eliana Fernandes, Ana Ledo, Rui M Barbosa.

  Direct in vivo measurements of neurometabolic markers in the brain with high spatio-temporal resolution, sensitivity, and selectivity is highly important to understand neurometabolism. Electrochemical biosensors based on microelectrodes are very attractive analytical tools for continuous monitoring of neurometabolic markers, such as lactate and glucose in the brain extracellular space at resting and following neuronal activation. Here, we assess the merits of a platinized carbon fiber microelectrode (CFM/Pt) as a sensing platform for developing enzyme oxidase-based microbiosensors to measure extracellular lactate in the brain. Lactate oxidase was immobilized on the CFM/Pt surface by crosslinking with glutaraldehyde. The CFM/Pt-based lactate microbiosensor exhibited high sensitivity and selectivity, good operational stability, and low dependence on oxygen, temperature, and pH. An array consisting of a glucose and lactate microbiosensors, including a null sensor, was used for concurrent measurement of both neurometabolic substrates in vivo in the anesthetized rat brain. Rapid changes of lactate and glucose were observed in the cortex and hippocampus in response to local glucose and lactate application and upon insulin-induced fluctuations of systemic glucose. Overall, these results indicate that microbiosensors are a valuable tool to investigate neurometabolism and to better understand the role of major neurometabolic markers, such as lactate and glucose.

Keywords:  carbon fiber microelectrodes; electrochemical biosensors; in vivo brain monitoring; insulin; lactate and glucose

DOI:  https://doi.org/10.3390/molecules27020514
Cells. 2022 Jan 15. pii: 295. [Epub ahead of print]11(2):

Long-Term High-Fat Diet Consumption Depletes Glial Cells and Tyrosine Hydroxylase-Containing Neurons in the Brain of Middle-Aged Rats.

Mei-Chuan Chou, Hsiang-Chun Lee, Yen-Chin Liu, Patrick Szu-Ying Yen, Ching-Kuan Liu, Chu-Huang Chen, Tzu-Han Hsieh, Shiou-Lan Chen.

  Epidemiologic studies have indicated that dyslipidemia may facilitate the progression of neuronal degeneration. However, the effects of chronic dyslipidemia on brain function, especially in older individuals, remain unclear. In this study, middle-aged 37-week-old male Wistar-Kyoto rats were fed a normal diet (ND) or a 45% high-fat diet (HFD) for 30 weeks (i.e., until 67 weeks of age). To study the effects of chronic dyslipidemia on the brain, we analyzed spontaneous locomotor activity, cognitive function, and brain tissues in both groups of rats after 30 weeks. Compared with age-matched rats fed a ND, Wistar-Kyoto rats fed a HFD had dyslipidemia and showed decreased movement but normal recognition of a novel object. In our brain analyses, we observed a significant decrease in astrocytes and tyrosine hydroxylase-containing neurons in the substantia nigra and locus coeruleus of rats fed a HFD compared with rats fed a ND. However, hippocampal pyramidal neurons were not affected. Our findings indicate that the long-term consumption of a HFD may cause lipid metabolism overload in the brain and damage to glial cells. The decrease in astrocytes may lead to reduced protection of the brain and affect the survival of tyrosine hydroxylase-containing neurons but not pyramidal neurons of the hippocampus.

Keywords:  cognitive function; dopamine neuron; glial cell; lipids; locomotor activity

DOI:  https://doi.org/10.3390/cells11020295
Front Neurosci. 2021 ;15 732242

Voluntary Behavior and Training Conditions Modulate in vivo Extracellular Glucose and Lactate in the Mouse Primary Motor Cortex.

Alexandria Béland-Millar, Claude Messier.

  Learning or performing new behaviors requires significant neuronal signaling and is metabolically demanding. The metabolic cost of performing a behavior is mitigated by exposure and practice which result in diminished signaling and metabolic requirements. We examined the impact of novel and habituated wheel running, as well as effortful behaviors on the modulation of extracellular glucose and lactate using biosensors inserted in the primary motor cortex of mice. We found that motor behaviors produce increases in extracellular lactate and decreases in extracellular glucose in the primary motor cortex. These effects were modulated by experience, novelty and intensity of the behavior. The increase in extracellular lactate appears to be strongly associated with novelty of a behavior as well as the difficulty of performing a behavior. Our observations are consistent with the view that a main function of aerobic glycolysis is not to fuel the current neuronal activity but to sustain new bio-infrastructure as learning changes neural networks, chiefly through the shuttling of glucose derived carbons into the pentose phosphate pathway for the biosynthesis of nucleotides.

Keywords:  biosensor; glucose; lactate; primary motor cortex; running wheel

DOI:  https://doi.org/10.3389/fnins.2021.732242
Metabolites. 2021 Dec 27. pii: 21. [Epub ahead of print]12(1):

Regional Brain Analysis of Modified Amino Acids and Dipeptides during the Sleep/Wake Cycle.

Theodosia Vallianatou, Nicholas B Bèchet, Mario S P Correia, Iben Lundgaard, Daniel Globisch.

  Sleep is a state in which important restorative and anabolic processes occur. Understanding changes of these metabolic processes during the circadian rhythm in the brain is crucial to elucidate neurophysiological mechanisms important for sleep function. Investigation of amino acid modifications and dipeptides has recently emerged as a valuable approach in the metabolic profiling of the central nervous system. Nonetheless, very little is known about the effects of sleep on the brain levels of amino acid analogues. In the present study, we examined brain regional sleep-induced alterations selective for modified amino acids and dipeptides using Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) based metabolomics. Our approach enabled the detection and identification of numerous amino acid-containing metabolites in the cortex, the hippocampus, the midbrain, and the cerebellum. In particular, analogues of the aromatic amino acids phenylalanine, tyrosine and tryptophan were significantly altered during sleep in the investigated brain regions. Cortical levels of medium and long chain N-acyl glycines were higher during sleep. Regional specific changes were also detected, especially related to tyrosine analogues in the hippocampus and the cerebellum. Our findings demonstrate a strong correlation between circadian rhythms and amino acid metabolism specific for different brain regions that provide previously unknown insights in brain metabolism.

Keywords:  amino acids; brain regions; dipeptides; mass spectrometry; metabolomics; modifications; sleep/wake cycle

DOI:  https://doi.org/10.3390/metabo12010021