bims-medebr 2022-04-03 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022‒04‒03
twenty papers selected by
Regina F. Fernández
Johns Hopkins University

Dietary Phospholipid-Bound Conjugated Linoleic Acid and Docosahexaenoic Acid Incorporation Into Fetal Liver and Brain Modulates Fatty Acid and N-Acylethanolamine Profiles.
MAnGLed astrocytes in traumatic brain injury: astrocytic 2-AG metabolism as a new therapeutic target.
The metabolic basis of epilepsy.
Hyperphosphorylated Human Tau Accumulates at the Synapse, Localizing on Synaptic Mitochondrial Outer Membranes and Disrupting Respiration in a Mouse Model of Tauopathy.
Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.
Hyperandrogenism diminishes maternal-fetal fatty acid transport by increasing FABP 4-mediated placental lipid accumulation.
Pharmacological Targeting of Mitochondrial Fission and Fusion Alleviates Cognitive Impairment and Brain Pathologies in Pre-diabetic Rats.
Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.
Alteration in glucose metabolism in the brain associated with tamoxifen treatment: Study in postmenopausal animal model.
Glycolytic metabolism and activation of Na+ pumping contribute to extracellular acidification in the central clock of the suprachiasmatic nucleus: Differential glucose sensitivity and utilization between oxidative and non-oxidative glycolytic pathways.
Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice.
[Applications and perspectives of ketone body D-β-hydroxybutyrate in the medical fields].
Influence of Cerebral Glucose Metabolism by Chronic Pain-Mediated Cognitive Impairment in Adolescent Rats.
Of axons struggling making ends meet: Linking axonal bioenergetic failure to programmed axon degeneration.
Label-free in vivo assessment of brain mitochondrial redox states during the development of diabetic cognitive impairment using Raman spectroscopy.
The intracellular cholesterol pool in steroidogenic cells plays a role in basal steroidogenesis.
Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice.
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice.
Sirtuin 3 and mitochondrial permeability transition pore (mPTP): a systematic review.
Decreased rates of cerebral protein synthesis in conscious young adults with fragile X syndrome demonstrated by L-[1-11C]leucine PET.

Front Nutr. 2022 ;9 834066

Dietary Phospholipid-Bound Conjugated Linoleic Acid and Docosahexaenoic Acid Incorporation Into Fetal Liver and Brain Modulates Fatty Acid and N-Acylethanolamine Profiles.

Elisabetta Murru, Gianfranca Carta, Claudia Manca, Asgeir Saebo, Michele Santoni, Rafaela Mostallino, Marco Pistis, Sebastiano Banni.

  We evaluated whether maternal intake of conjugated linoleic acid (CLA) and docosahexaenoic acid (DHA) in the phospholipid (PL) form (CLA-DHA PL) affects maternal and fetal brain and liver fatty acids (FAs) profile and the biosynthesis of FA-derived bioactive lipid mediators N-acylethanolamines (NAEs) involved in several neurophysiological functions. We fed rat dams during the first 2/3 of their pregnancy a CLA-DHA PL diet containing PL-bound 0.5% CLA and 0.2% DHA. FA and NAE profiles were analyzed in maternal and fetal liver and brain by Liquid Chromatography diode array detector (LC-DAD) and MS/MS in line. We found that CLA and DHA crossed the placenta and were readily incorporated into the fetal liver and brain. CLA metabolites were also found abundantly in fetal tissues. Changes in the FA profile induced by the CLA-DHA PL diet influenced the biosynthesis of NAE derived from arachidonic acid (ARA; N-arachidonoylethanolamine, AEA) and from DHA (N-docosahexaenoylethanolamine, DHEA). The latter has been previously shown to promote synaptogenesis and neuritogenesis. The reduced tissue n6/n3 ratio was associated to a significant decrease of AEA levels in the fetal and maternal liver and an increase of DHEA in the fetal and maternal liver and in the fetal brain. Maternal dietary CLA-DHA PL by promptly modifying fetal brain FA metabolism, and thereby, increasing DHEA, might represent an effective nutritional strategy to promote neurite growth and synaptogenesis and protect the offspring from neurological and psychiatric disorders with neuroinflammatory and neurodegenerative basis during the critical prenatal period.

Keywords:  N-acylethanolamines (NAEs); conjugated linoleic acid (CLA); docosahexaenoic acid (DHA); fetal brain; maternal nutrition

DOI:  https://doi.org/10.3389/fnut.2022.834066
Brain. 2022 Mar 29. 145(1): 7-10

MAnGLed astrocytes in traumatic brain injury: astrocytic 2-AG metabolism as a new therapeutic target.

David J Loane.

DOI: https://doi.org/10.1093/brain/awac014
Nat Rev Neurol. 2022 Mar 31.

The metabolic basis of epilepsy.

Jong M Rho, Detlev Boison.

The brain is a highly energy-demanding organ and requires bioenergetic adaptability to balance normal activity with pathophysiological fuelling of spontaneous recurrent seizures, the hallmark feature of the epilepsies. Recurrent or prolonged seizures have long been known to permanently alter neuronal circuitry and to cause excitotoxic injury and aberrant inflammation. Furthermore, pathological changes in bioenergetics and metabolism are considered downstream consequences of epileptic seizures that begin at the synaptic level. However, as we highlight in this Review, evidence is also emerging that primary derangements in cellular or mitochondrial metabolism can result in seizure genesis and lead to spontaneous recurrent seizures. Basic and translational research indicates that the relationships between brain metabolism and epileptic seizures are complex and bidirectional, producing a vicious cycle that compounds the deleterious consequences of seizures. Metabolism-based treatments such as the high-fat, antiseizure ketogenic diet have become mainstream, and metabolic substrates and enzymes have become attractive molecular targets for seizure prevention and recovery. Moreover, given that metabolism is crucial for epigenetic as well as inflammatory changes, the idea that epileptogenesis can be both negatively and positively influenced by metabolic changes is rapidly gaining ground. Here, we review evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy.

DOI: https://doi.org/10.1038/s41582-022-00651-8
Front Mol Neurosci. 2022 ;15 852368

Hyperphosphorylated Human Tau Accumulates at the Synapse, Localizing on Synaptic Mitochondrial Outer Membranes and Disrupting Respiration in a Mouse Model of Tauopathy.

Andrew J Trease, Joseph W George, Nashanthea J Roland, Eliezer Z Lichter, Katy Emanuel, Steven Totusek, Howard S Fox, Kelly L Stauch.

  Neurogenerative disorders, such as Alzheimer's disease (AD), represent a growing public health challenge in aging societies. Tauopathies, a subset of neurodegenerative disorders that includes AD, are characterized by accumulation of fibrillar and hyperphosphorylated forms of microtubule-associated protein tau with coincident mitochondrial abnormalities and neuronal dysfunction. Although, in vitro, tau impairs axonal transport altering mitochondrial distribution, clear in vivo mechanisms associating tau and mitochondrial dysfunction remain obscure. Herein, we investigated the effects of human tau on brain mitochondria in vivo using transgenic htau mice at ages preceding and coinciding with onset of tauopathy. Subcellular proteomics combined with bioenergetic assessment revealed pathologic forms of tau preferentially associate with synaptic over non-synaptic mitochondria coinciding with changes in bioenergetics, reminiscent of an aged synaptic mitochondrial phenotype in wild-type mice. While mitochondrial content was unaltered, mitochondrial maximal respiration was impaired in synaptosomes from htau mice. Further, mitochondria-associated tau was determined to be outer membrane-associated using the trypsin protection assay and carbonate extraction. These findings reveal non-mutant human tau accumulation at the synapse has deleterious effects on mitochondria, which likely contributes to synaptic dysfunction observed in the context of tauopathy.

Keywords:  Alzheimer’s disease; aging; bioenergetics; phosphorylation; proteomics; synaptic mitochondria; tau; tauopathy

DOI:  https://doi.org/10.3389/fnmol.2022.852368
Autophagy. 2022 Mar 29. 1-3

Proteomic profiling shows mitochondrial nucleoids are autophagy cargo in neurons: implications for neuron maintenance and neurodegenerative disease.

Juliet Goldsmith, Erika L F Holzbaur.

  Neurons depend on macroautophagy/autophagy to maintain cellular homeostasis, and loss of autophagy leads to neurodegeneration. To better understand the role of basal autophagy in neurons, we enriched autophagic vesicles from healthy adult mouse brain and performed mass spectrometry to identify cargos cleared by autophagy. We found that synaptic and mitochondrial proteins comprise nearly half of the unique AV cargos identified in brain. Similarly, synaptic and mitochondrial proteins are major cargos for basal autophagy in neurons. Strikingly, we noted a specific enrichment of mitochondrial nucleoids within neuronal autophagosomes, which occurs through a mechanism distinct from damage-associated mitophagy. Here, we discuss the implications of these findings for our understanding of homeostatic mechanisms in neurons and how the age-dependent decline of autophagy in neurons may contribute to the onset or progression of neurodegenerative disease.

Keywords:  DNM1L; SYN1; TFAM; macroautophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1080/15548627.2022.2056865
Biol Reprod. 2022 Mar 31. pii: ioac059. [Epub ahead of print]

Hyperandrogenism diminishes maternal-fetal fatty acid transport by increasing FABP 4-mediated placental lipid accumulation.

Kathirvel Gopalakrishnan, Jay S Mishra, Jordan R Ross, David H Abbott, Sathish Kumar.

  Long-chain polyunsaturated fatty acids (LCPUFAs) are critical for fetal brain development. Infants born to preeclamptic mothers or those born growth restricted due to placental insufficiency have reduced LCPUFA, and are at higher risk for developing neurodevelopmental disorders. Since plasma levels of testosterone (T) and fatty acid-binding protein 4 (FABP4) are elevated in preeclampsia, we hypothesized that elevated T induces the expression of FABP4 in the placenta leading to compromised transplacental transport of LCPUFAs. Increased maternal T in pregnant rats significantly decreased n-3 and n-6 LCPUFA levels in maternal and fetal circulation, but increased their placental accumulation. Dietary LCPUFAs supplementation in T dams increased LCPUFA levels in the maternal circulation and further augmented placental storage, while failing to increase fetal levels. The placenta in T dams exhibited increased FABP4 mRNA and protein levels. In vitro, T dose-dependently upregulated FABP4 transcription in trophoblasts. T stimulated androgen receptor (AR) recruitment to the androgen response element and trans-activated FABP4 promoter activity, both of which were abolished by AR antagonist. T in pregnant rats and cultured trophoblasts significantly reduced transplacental transport of C14-docosahexaenoic acid (DHA) and increased C14-DHA accumulation in the placenta. Importantly, FABP4-overexpression by itself in pregnant rats and trophoblasts increased transplacental transport of C14-DHA with no significant placental accumulation. T exposure, in contrast, inhibited this FABP4-mediated effect by promoting C14-DHA placental accumulation. In summary, our studies show that maternal hyperandrogenism increases placental FABP4 expression via transcriptional upregulation and preferentially routes LCPUFAs toward cellular storage in the placenta leading to offspring lipid deficiency.

Keywords:  Androgens; FABP4; Fatty acids; Fetal growth; Placenta; Preeclampsia; Pregnancy

DOI:  https://doi.org/10.1093/biolre/ioac059
Mol Neurobiol. 2022 Apr 02.

Pharmacological Targeting of Mitochondrial Fission and Fusion Alleviates Cognitive Impairment and Brain Pathologies in Pre-diabetic Rats.

Chayodom Maneechote, Titikorn Chunchai, Nattayaporn Apaijai, Nipon Chattipakorn, Siriporn C Chattipakorn.

  It has recently been accepted that long-term high-fat diet (HFD) intake is a significant possible cause for prediabetes and cognitive and brain dysfunction through the disruption of brain mitochondrial function and dynamic balance. Although modulation of mitochondrial dynamics by inhibiting fission and promoting fusion has been shown to reduce the morbidity and mortality associated with a variety of chronic diseases, the impact of either pharmacological inhibition of mitochondrial fission (Mdivi-1) or stimulation of fusion (M1) on brain function in HFD-induced prediabetic models has never been studied. Thirty-two male Wistar rats were separated into 2 groups and fed either a normal diet (ND, n = 8) or HFD (n = 24) for 14 weeks. At week 12, HFD-fed rats were divided into 3 subgroups (n = 8/subgroup) and given an intraperitoneal injection of either saline, Mdivi-1 (1.2 mg/kg/day), or M1 (2 mg/kg/day) for 2 weeks. Cognitive function and metabolic parameters were determined toward the end of the protocol. The rats then were euthanized, and the brain was immediately removed in order to evaluate brain mitochondrial function and mitochondrial dynamics. HFD-fed rats experienced prediabetes, evidenced by elevated plasma insulin and the HOMA index, impaired mitochondrial function in the brain, altered dynamic regulation, and cognitive impairment were also found. Mdivi-1 and M1 treatment exerted neuroprotection to a similar extent by improving metabolic parameters, balancing mitochondrial dynamics, and reducing mitochondrial dysfunction, resulting in a gradual increase in cognitive function. Therefore, pharmacological targeting of mitochondrial fission and fusion protected the brain against chronic HFD-induced prediabetes.

Keywords:  Brain; Cognition; Mitochondria; Mitochondrial dynamics; Obesity; Prediabetes

DOI:  https://doi.org/10.1007/s12035-022-02813-7
Methods Mol Biol. 2022 Mar 29.

Analysis of Mitochondrial Dysfunction by Microplate Reader in hiPSC-Derived Neuronal Cell Models of Neurodegenerative Disorders.

Tatiana R Rosenstock, Congxin Sun, Georgina Wynne Hughes, Katherine Winter, Sovan Sarkar.

  Mitochondria are responsible for many vital pathways governing cellular homeostasis, including cellular energy management, heme biosynthesis, lipid metabolism, cellular proliferation and differentiation, cell cycle regulation, and cellular viability. Electron transport and ADP phosphorylation coupled with proton pumping through the mitochondrial complexes contribute to the preservation of mitochondrial membrane potential (ΔΨm). Importantly, mitochondrial polarization is essential for reactive oxygen species (ROS) production and cytosolic calcium (Ca2+) handling. Thus, changes in mitochondrial oxidative phosphorylation (OXPHOS), ΔΨm, and ATP/ADP may occur in parallel or stimulate each other. Brain cells like neurons are heavily reliant on mitochondrial OXPHOS for its high-energy demands, and hence improper mitochondrial function is detrimental for neuronal survival. Indeed, several neurodegenerative disorders are associated with mitochondrial dysfunction. Modeling this disease-relevant phenotype in neuronal cells differentiated from patient-derived human induced pluripotent stem cells (hiPSCs) provide an appropriate cellular platform for studying the disease pathology and drug discovery. In this review, we describe high-throughput analysis of crucial parameters related to mitochondrial function in hiPSC-derived neurons. These methodologies include measurement of ΔΨm, intracellular Ca2+, oxidative stress, and ATP/ADP levels using fluorescence probes via a microplate reader. Benefits of such an approach include analysis of mitochondrial parameters on a large population of cells, simultaneous analysis of different cell lines and experimental conditions, and for drug screening to identify compounds restoring mitochondrial function.

Keywords:  Fluorescent dyes; Human induced pluripotent stem cells; Microplate reader; Mitochondria; Mitochondrial calcium; Mitochondrial dysfunction; Mitochondrial membrane potential; Mitochondrial superoxide; Neurodegenerative disease; Neuronal differentiation; Reactive oxygen species; hiPSC-derived neurons

DOI:  https://doi.org/10.1007/7651_2021_451
Toxicol Appl Pharmacol. 2022 Mar 27. pii: S0041-008X(22)00147-8. [Epub ahead of print] 116002

Alteration in glucose metabolism in the brain associated with tamoxifen treatment: Study in postmenopausal animal model.

Suélyn Koerich, Fernanda Coleraus Silva, Ana Maria Itinose, Paula Maria Quaglio Bellozi, Fabiano Sandrini, Sara Cristina Sagae Schneider, Carla Brugin Marek.

  Tamoxifen is an effective breast cancer therapy in postmenopausal women. However, it can induce hyperglycemia through different mechanisms, such as the impairment of mitochondrial metabolism. Quercetin, a flavonoid with antioxidant potential, has beneficial effects on tamoxifen-induced adverse effects. Therefore, this study aimed to (1) investigate glucose concentration in blood, cerebrospinal fluid, cerebellum, cortex, and hippocampus of tamoxifen-treated ovariectomized female rats, non-treated and treated with quercetin; and (2) establish the metabolic profile of these regions. For that purpose, ovariectomized female rats were divided into four groups: canola oil 1 mL/kg (CONT); tamoxifen 5 mg/kg (TAM); quercetin 22.5 mg/kg (QUER); and tamoxifen 5 mg/kg + quercetin 22.5 mg/kg (TAM + Q); and were treated for 14 days orally. Subsequently, glucose levels were measured in blood, cerebrospinal fluid, cerebellum, cortex, and hippocampus. Pyruvate and lactate concentrations were analyzed in the three brain regions. Tamoxifen-induced hyperglycemia significantly increased glucose concentrations in the cerebrospinal fluid, cortex, and hippocampus, as well as lactate production in the hippocampus. Quercetin significantly prevented the tamoxifen-induced increase in glucose concentrations in all analyzed samples. Besides, quercetin decreased cortical pyruvate production. The copper content decreased only in the hippocampus of group TAM + Q animals. In addition, it is important to highlight that this study also observed that fourteen days of tamoxifen treatment strongly affects brain glucose metabolism, potentially disrupting normal brain functions. Therefore, this drug might represent a risk factor for postmenopausal women undergoing chemoprevention. Meanwhile, quercetin represents a potential intervention to promote metabolic regulation of glucose in tamoxifen-treated women.

Keywords:  Flavonoids; Hyperglycemia; Neurodegeneration; Postmenopausal women; Quercetin; Tamoxifen

DOI:  https://doi.org/10.1016/j.taap.2022.116002
Biomed J. 2021 Feb 12. pii: S2319-4170(21)00010-X. [Epub ahead of print]

Glycolytic metabolism and activation of Na+ pumping contribute to extracellular acidification in the central clock of the suprachiasmatic nucleus: Differential glucose sensitivity and utilization between oxidative and non-oxidative glycolytic pathways.

Hsin-Yi Lin, Rong-Chi Huang.

  BACKGROUND: The central clock of the suprachiasmatic nucleus (SCN) controls the metabolism of glucose and is sensitive to glucose shortage. However, it is only beginning to be understood how metabolic signals such as glucose availability regulate the SCN physiology. We previously showed that the ATP-sensitive K+ channel plays a glucose-sensing role in regulating SCN neuronal firing at times of glucose shortage. Nevertheless, it is unknown whether the energy-demanding Na+/K+-ATPase (NKA) is also sensitive to glucose availability. Furthermore, we recently showed that the metabolically active SCN constantly extrudes H+ to acidify extracellular pH (pHe). This study investigated whether the standing acidification is associated with Na+ pumping activity, energy metabolism, and glucose utilization, and whether glycolysis- and mitochondria-fueled NKAs may be differentially sensitive to glucose shortage.METHODS: Double-barreled pH-selective microelectrodes were used to determine the pHe in the SCN in hypothalamic slices.
RESULTS: NKA inhibition with K+-free (0-K+) solution rapidly and reversibly alkalinized the pHe, an effect abolished by ouabain. Mitochondrial inhibition with cyanide acidified the pHe but did not inhibit 0-K+-induced alkalinization. Glycolytic inhibition with iodoacetate alkalinized the pHe, completely blocked cyanide-induced acidification, and nearly completely blocked 0-K+-induced alkalinization. The results indicate that glycolytic metabolism and activation of Na+ pumping contribute to the standing acidification. Glucoprivation also alkalinized the pHe, nearly completely eliminated cyanide-induced acidification, but only partially reduced 0-K+-induced alkalinization. In contrast, hypoglycemia preferentially and partially blocked cyanide-induced acidification. The result indicates sensitivity to glucose shortage for the mitochondria-associated oxidative glycolytic pathway.
CONCLUSION: Glycolytic metabolism and activation of glycolysis-fueled NKA Na+ pumping activity contribute to the standing acidification in the SCN. Furthermore, the oxidative and non-oxidative glycolytic pathways differ in their glucose sensitivity and utilization, with the oxidative glycolytic pathway susceptible to glucose shortage, and the non-oxidative glycolytic pathway able to maintain Na+ pumping even in glucoprivation.

Keywords:  Glycolysis; Metabolism; Na(+)/K(+)-ATPase; Suprachiasmatic nucleus; pH

DOI:  https://doi.org/10.1016/j.bj.2021.02.004
Lipids Health Dis. 2022 Mar 27. 21(1): 32

Lipidomic analysis identifies age-disease-related changes and potential new biomarkers in brain-derived extracellular vesicles from metachromatic leukodystrophy mice.

Melissa R Pergande, Christina Kang, Diann George, Pearl A Sutter, Stephen J Crocker, Stephanie M Cologna, Maria I Givogri.

  BACKGROUND: Recent findings show that extracellular vesicle constituents can exert short- and long-range biological effects on neighboring cells in the brain, opening an exciting avenue for investigation in the field of neurodegenerative diseases. Although it is well documented that extracellular vesicles contain many lipids and are enriched in sphingomyelin, cholesterol, phosphatidylserines and phosphatidylinositols, no reports have addressed the lipidomic profile of brain derived EVs in the context of Metachromatic Leukodystrophy, a lysosomal storage disease with established metabolic alterations in sulfatides.METHODS: In this study, we isolated and characterized the lipid content of brain-derived EVs using the arylsulfatase A knockout mouse as a model of the human condition.
RESULTS: Our results suggest that biogenesis of brain-derived EVs is a tightly regulated process in terms of size and protein concentration during postnatal life. Our lipidomic analysis demonstrated that sulfatides and their precursors (ceramides) as well as other lipids including fatty acids are altered in an age-dependent manner in EVs isolated from the brain of the knockout mouse.
CONCLUSIONS: In addition to the possible involvement of EVs in the pathology of Metachromatic Leukodystrophy, our study underlines that measuring lipid signatures in EVs may be useful as biomarkers of disease, with potential application to other genetic lipidoses.

Keywords:  Extracellular vesicles; Lipidomic; Mass spectrometry; Metachromatic leukodystrophy

DOI:  https://doi.org/10.1186/s12944-022-01644-8
Sheng Wu Gong Cheng Xue Bao. 2022 Mar 25. 38(3): 976-989

[Applications and perspectives of ketone body D-β-hydroxybutyrate in the medical fields].

Liya A, Zihua Li, Jinyan Lü, Liusong Yu, Wei Situ, Lingyun Xue, Hui Wang, Guoqiang Chen.

  Human body can obtain energy from either carbohydrate or fat digestion. Although glucose metabolism derived from carbohydrate-based diets has long been utilized for energy supply, it has been recently discovered that shifting from glucose to fatty acid metabolism may become a novel way for improving human health especially when carbohydrate is deprived. In recent years, intermittent fasting and ketogenic diets have received a lot of attention in respect to favoring fatty acid metabolism. In all cases, fatty acid metabolism produces D-β-hydroxybutyrate (D3HB), which is a natural ketone body, as well as, a monomer of microbial poly-D-β-hydroxybutyrate (PHB). D3HB can be utilized by different cells of the body as an alternative energy fuel or an intracellular signaling molecule with multiple downstream signaling pathways. Usually, the serum level of D3HB is increased during ketogenic diets, however, requires a very long period of adaptation (over 3-months) and exhibits unwanted adverse effects. Hence, exogenous ketone supplements using D3HB have become a more effective approach to induce and maintain nutritional ketosis for subsequent functional effects. This review describes how D3HB is produced and metabolized within the body, the functional roles played by D3HB, and a detailed summary of the different applications of exogenous ketones that have been explored to date in both nutritional and therapeutical context.

Keywords:  D-β-hydroxybutyrate; D3HB; PHB; biosynthesis; exogenous ketones; ketone metabolism; nutritional ketosis

DOI:  https://doi.org/10.13345/j.cjb.210343
Mol Neurobiol. 2022 Mar 31.

Influence of Cerebral Glucose Metabolism by Chronic Pain-Mediated Cognitive Impairment in Adolescent Rats.

Yuanyuan Fang, Chang Chen, Qi Zhong, Lirong Wang, Zhu Gui, Jinpiao Zhu, Anne Manyande, Fuqiang Xu, Jie Wang, Zongze Zhang.

  Chronic pain during adolescence can lead to mental health disorders in adulthood, but the underlying mechanism is still unclear. Furthermore, the homeostasis of cerebral glucose metabolism and neurotransmitter metabolic kinetics are closely associated with cognitive development and pain progression. The present study investigated changes in cognitive function and glucose metabolism in adult rats, which had experienced chronic pain during their adolescence. Here, spared nerve injury (SNI) surgery was conducted in 4-week-old male rats. Mechanical nociceptive reflex thresholds were analyzed, and SNI chronic pain (SNI-CP) animals were screened. Based on animal behavioral tests (open field, three-chambered social, novel object recognition and the Y maze), the SNI-CP animals showed learning and memory impairment and anxiety-like behaviors, compared to SNI no chronic pain (SNI-NCP) animals. The cerebral glucose metabolism in the prefrontal cortex and hippocampus of adult SNI-CP animals was decreased with positron emission tomography/computed tomography. GABA2 and Glu4 levels in the metabolic kinetics study were significantly decreased in the hippocampus, frontal cortex, and temporal cortex, and the expression of GLUT3 and GLUT4 was also significantly downregulated in the prefrontal cortex and hippocampus of adult rats in the SNI-CP group. These findings suggest that the rats which suffered chronic pain during adolescence have lower cerebral glucose metabolism in the cortex and hippocampus, which could be related to cognitive function during the development of the central nervous system.

Keywords:  Cognitive impairment; Cortex; Glucose metabolism; Hippocampus; Metabolic kinetics; Neuropathic pain

DOI:  https://doi.org/10.1007/s12035-022-02816-4
Biochim Biophys Acta Bioenerg. 2022 Mar 23. pii: S0005-2728(22)00014-7. [Epub ahead of print] 148545

Of axons struggling making ends meet: Linking axonal bioenergetic failure to programmed axon degeneration.

Elisabetta Babetto, Bogdan Beirowski.

  Axons are the long, fragile, and energy hungry projections of neurons challenging to sustain. Together with their associated glia they form the bulk of the neuronal network. Pathological axon degeneration (pAxD) is a driver of irreversible neurological disability in a host of neurodegenerative conditions. Halting pAxD is therefore an attractive therapeutic strategy. Here we review recent work demonstrating that pAxD is regulated by an auto-destruction program that revolves around axonal bioenergetics. We then focus on the emerging concept that axonal and glial energy metabolism are intertwined. We anticipate these discoveries will encourage the pursuit of new treatment strategies for neurodegeneration.

Keywords:  ATP; Axon degeneration; Glia; Monocarboxylate transporter; Schwann cells; Wallerian degeneration

DOI:  https://doi.org/10.1016/j.bbabio.2022.148545
Free Radic Biol Med. 2022 Mar 23. pii: S0891-5849(22)00100-9. [Epub ahead of print]

Label-free in vivo assessment of brain mitochondrial redox states during the development of diabetic cognitive impairment using Raman spectroscopy.

Meiyan Wu, Kairui Pu, Nan Wang, Yubo Wang, Yansong Li, Yue Wang, Na Duan, Qian Zhai, Qiang Wang.

  Mitochondrial redox imbalance has been recognized as a unifying cause for diabetic cognitive impairment. Currently, a robust method for the in vivo assessment of brain mitochondrial redox imbalance is still lacking. Here, we conducted a spectral study to assess brain mitochondrial redox imbalance in the process of diabetic cognitive impairment by using label-free resonance Raman spectroscopy (RRS). Our findings showed that mitochondrial redox imbalance in cultured neurons and organotypic cortical slices exposed to high glucose were quantified by the reduction of Raman peak area at 750 cm-1 and 1128 cm-1, which were also associated with synaptic injury and neuron apoptosis. Raman peak area at 750 cm-1 and 1128 cm-1 were also decreased in db/db mice at the age of 8, 16 and 24 weeks, and had a high correlation with the mitochondrial NAD+/NADH redox couple. Of note, this mitochondrial redox imbalance occurred before measurable cognitive decline in 8-week-old diabetic mice, and might signal impending diabetic cognitive impairment. In summary, RRS-based mitochondrial redox states assay enabled the in vivo assessment of brain mitochondrial redox imbalance, and might provide an early indicator to enhance the prediction of diabetic cognitive impairment and inform on the response to therapies targeting mitochondrial redox imbalance.

Keywords:  Cognitive impairment; Diabetes; Label-free; Mitochondrial redox states; Resonance Raman spectroscopy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.03.005
J Steroid Biochem Mol Biol. 2022 Mar 24. pii: S0960-0760(22)00050-4. [Epub ahead of print]220 106099

The intracellular cholesterol pool in steroidogenic cells plays a role in basal steroidogenesis.

Geetika Bassi, Simarjit Kaur Sidhu, Suresh Mishra.

  The framework of steroidogenesis across steroidogenic cells is constructed around cholesterol - the precursor substrate molecule for all steroid hormones - including its cellular uptake, storage in intracellular lipid droplets, mobilization upon steroidogenic stimulation, and finally, its transport to the mitochondria, where steroidogenesis begins. Thus, cholesterol and the mitochondria are highly interconnected in steroidogenic cells. Moreover, accruing evidence suggests that autophagy and mitochondrial dynamics are important cellular events in the regulation of trophic hormone-induced cholesterol homeostasis and steroidogenesis. However, a potential role of cholesterol in itself in the regulation of steroidogenic factors and events remain largely unexplored. We tested the hypothesis that cholesterol plays a role in the regulation of cell-intrinsic factors and events involving steroidogenesis. Here, we show that depleting the intracellular cholesterol pool in steroidogenic cells induces autophagy, affects mitochondrial dynamics, and upregulates steroidogenic factors and basal steroidogenesis in three different steroidogenic cell types producing different steroid hormones. Notably, the cholesterol insufficiency-induced changes in different steroidogenic cell types occur independent of pertinent hormone stimulation and work in a dynamic and temporal manner with or without hormonal stimulation. Such effects of cholesterol deprivation on autophagy and mitochondrial dynamics were not observed in the non-steroidogenic cells, indicating that cholesterol insufficiency-induced changes in steroidogenic cells are specific to steroidogenesis. Thus, our data suggests a role of cholesterol in steroidogenesis beyond being a mere substrate for steroid hormones. The implications of our findings are broad and offer new insights into trophic hormone-dependent and hormone-independent steroidogenesis during development, as well as in health and disease.

Keywords:  Autophagy; Lipophagy; Mitochondria; Mitochondrial dynamics; Steroid hormone

DOI:  https://doi.org/10.1016/j.jsbmb.2022.106099
Cell Death Discov. 2022 Mar 28. 8(1): 138

Attenuated succinate accumulation relieves neuronal injury induced by hypoxia in neonatal mice.

Mengdi Zhang, Yao Cheng, Yujie Zhai, Yaru Cui, Wenshen Zhang, Hongwei Sun, Wenyu Xin, Ling Zhou, Xue Gao, Shucui Li, Hongliu Sun.

Hypoxia causes neonatal neuronal damage. However, the underlying mechanism remains unclear. This study aimed to explore the changes in succinate levels and identify the mechanisms underlying their contribution to hypoxia-induced damage in newborn mice. The neonatal C57BL/6J mouse hypoxia model was used in our study. We evaluated the levels of succinate, iron, reactive oxygen species (ROS), and mitochondrial ROS, and assessed mitophagy, neuronal damage, and learning and memory function, after hypoxia treatment. The neonatal mice showed increased succinate levels in the early hypoxia stage, followed by increased levels of oxidative stress, iron stress, neuronal damage, and cognitive deficits. Succinate levels were significantly reduced following treatment with inhibitors of succinate dehydrogenase (SDH), purine nucleotide cycle (PNC), and malate/aspartate shuttle (MAS), with the corresponding attenuation of oxidative stress, iron stress, neuronal damage, and cognitive impairment. Reversal catalysis of SDH through fumarate from the PNC and MAS pathways might be involved in hypoxia-induced succinate accumulation. Succinate accumulation in the early period after hypoxia may crucially contribute to oxidative and iron stress. Relieving succinate accumulation at the early hypoxia stage could prevent neuronal damage and cognitive impairment in neonatal hypoxia.

DOI: https://doi.org/10.1038/s41420-022-00940-7
Transl Psychiatry. 2022 03 29. 12(1): 129

Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice.

André Miguel Miranda, Archana Ashok, Robin Barry Chan, Bowen Zhou, Yimeng Xu, Laura Beth McIntire, Estela Area-Gomez, Gilbert Di Paolo, Karen E Duff, Tiago Gil Oliveira, Tal Nuriel.

Apolipoprotein E ε4 (APOE4) is the primary genetic risk factor for the late-onset form of Alzheimer's disease (AD). Although the reason for this association is not completely understood, researchers have uncovered numerous effects of APOE4 expression on AD-relevant brain processes, including amyloid beta (Aβ) accumulation, lipid metabolism, endosomal-lysosomal trafficking, and bioenergetics. In this study, we aimed to determine the effect of APOE4 allelic dosage on regional brain lipid composition in aged mice, as well as in cultured neurons. We performed a targeted lipidomic analysis on an AD-vulnerable brain region (entorhinal cortex; EC) and an AD-resistant brain region (primary visual cortex; PVC) from 14-15 month-old APOE3/3, APOE3/4, and APOE4/4 targeted replacement mice, as well as on neurons cultured with conditioned media from APOE3/3 or APOE4/4 astrocytes. Our results reveal that the EC possesses increased susceptibility to APOE4-associated lipid alterations compared to the PVC. In the EC, APOE4 expression showed a dominant effect in decreasing diacylglycerol (DAG) levels, and a semi-dominant, additive effect in the upregulation of multiple ceramide, glycosylated sphingolipid, and bis(monoacylglycerol)phosphate (BMP) species, lipids known to accumulate as a result of endosomal-lysosomal dysfunction. Neurons treated with conditioned media from APOE4/4 vs. APOE3/3 astrocytes showed similar alterations of DAG and BMP species to those observed in the mouse EC. Our results suggest that APOE4 expression differentially modulates regional neuronal lipid signatures, which may underlie the increased susceptibility of EC-localized neurons to AD pathology.

DOI: https://doi.org/10.1038/s41398-022-01881-6
Mitochondrion. 2022 Mar 25. pii: S1567-7249(22)00024-1. [Epub ahead of print]

Sirtuin 3 and mitochondrial permeability transition pore (mPTP): a systematic review.

Yaping Yang, Weiping Wang, Ye Tian, Jiong Shi.

  Mitochondrial permeability transition pore (mPTP) is a channel that opens at the inner mitochondrial membrane under conditions of stress. Sirtuin 3 (Sirt3) is a mitochondrial deacetylase known to play a major role in stress resistance and a regulatory role in cell death. This systematic review aims to elucidate the role of Sirt3 in mPTP inhibition. Electronic databases, including PubMed, EMBASE, Web of Science and Cochrane Library were searched up to May 2020. Original studies that investigated the relationship between Sirt3 and mPTP were included. Two reviewers independently extracted data on study characteristics, methods and outcomes. A total of 194 articles were found. Twenty-nine articles, which met criteria were included in the systematic review. Twenty-three studies provided evidence of the inhibitory effect of Sirt3 on the mPTP aperture. This review summarizes up-to-date evidence of the protective and inhibitory role of Sirt3 through deacetylating Cyclophilin D (CypD) on the mPTP aperture. Furthermore, we discuss the implications of this effect in disease.

Keywords:  Cyclophilin D; Sirtuin3; deacetylase; mPTP; mitochondria

DOI:  https://doi.org/10.1016/j.mito.2022.03.004
J Cereb Blood Flow Metab. 2022 Mar 29. 271678X221090997

Decreased rates of cerebral protein synthesis in conscious young adults with fragile X syndrome demonstrated by L-[1-11C]leucine PET.

Kathleen C Schmidt, Inna Loutaev, Thomas V Burlin, Audrey Thurm, Carrie Sheeler, Carolyn Beebe Smith.

  Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Fragile X mental retardation protein, a putative translation suppressor, is significantly reduced in FXS. The prevailing hypothesis is that rates of cerebral protein synthesis (rCPS) are increased by the absence of this regulatory protein. We have previously reported increased rCPS in the Fmr1 knockout mouse model of FXS. To address the hypothesis in human subjects, we measured rCPS in young men with FXS with L-[1-11C]leucine PET. In previous studies we had used sedation during imaging, and we did not find increases in rCPS as had been seen in the mouse model. Since mouse measurements were conducted in awake animals, we considered the possibility that sedation may have confounded our results. In the present study we used a modified and validated PET protocol that made it easier for participants with FXS to undergo the study awake. We compared rCPS in 10 fragile X participants and 16 healthy controls all studied while awake. Contrary to the prevailing hypothesis and findings in Fmr1 knockout mice, results indicate that rCPS in awake participants with FXS are decreased in whole brain and most brain regions by 13-21% compared to healthy controls.

Keywords:  FMRP; Fragile X syndrome; PET; protein synthesis; translation

DOI:  https://doi.org/10.1177/0271678X221090997