bims-medebr 2024-08-11 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–08–11
ten papers selected by
Regina F. Fernández, Johns Hopkins University

Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction.
Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease.
Desorption Electrospray Ionization Cyclic Ion Mobility-Mass Spectrometry Imaging for Traumatic Brain Injury Spatial Metabolomics.
Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.
Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.
Fasting induces metabolic switches and spatial redistributions of lipid processing and neuronal interactions in tanycytes.
Dichloroacetate attenuates brain injury through inhibiting neuroinflammation and mitochondrial fission in a rat model of sepsis-associated encephalopathy.
Mitochondrial plasticity and synaptic plasticity crosstalk; in health and Alzheimer's disease.
Brain metabolites are associated with sleep architecture and cognitive functioning in older adults.
Dietary gangliosides rescue GM3 synthase deficiency outcomes in mice accompanied by neurogenesis in the hippocampus.

Metab Brain Dis. 2024 Aug 09.

Modulation of brain energy metabolism in hepatic encephalopathy: impact of glucose metabolic dysfunction.

Shambhu Kumar Prasad, Arup Acharjee, Vishal Vikram Singh, Surendra Kumar Trigun, Papia Acharjee.

  Cerebral function is linked to a high level of metabolic activity and relies on glucose as its primary energy source. Glucose aids in the maintenance of physiological brain activities; as a result, a disruption in metabolism has a significant impact on brain function, launching a chain of events that leads to neuronal death. This metabolic insufficiency has been observed in a variety of brain diseases and neuroexcitotoxicity disorders, including hepatic encephalopathy. It is a significant neurological complication that develops in people with liver disease, ranging from asymptomatic abnormalities to coma. Hyperammonemia is the main neurotoxic villain in the development of hepatic encephalopathy and induces a wide range of complications in the brain. The neurotoxic effects of ammonia on brain function are thought to be mediated by impaired glucose metabolism. Accordingly, in this review, we provide an understanding of deranged brain energy metabolism, emphasizing the role of glucose metabolic dysfunction in the pathogenesis of hepatic encephalopathy. We also highlighted the differential metabolic profiles of brain cells and the status of metabolic cooperation between them. The major metabolic pathways that have been explored are glycolysis, glycogen metabolism, lactate metabolism, the pentose phosphate pathway, and the Krebs cycle. Furthermore, the lack of efficacy in current hepatic encephalopathy treatment methods highlights the need to investigate potential therapeutic targets for hepatic encephalopathy, with regulating deficient bioenergetics being a viable alternative in this case. This review also demonstrates the importance of the development of glucose metabolism-focused disease diagnostics and treatments, which are now being pursued for many ailments.

Keywords:  Glutamate; Glycolysis; Hepatic encephalopathy; Hyperammonemia; Lactate metabolism; Mitochondrial permeability transition

DOI:  https://doi.org/10.1007/s11011-024-01407-7
Neurobiol Dis. 2024 Aug 03. pii: S0969-9961(24)00223-7. [Epub ahead of print]200 106623

Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease.

Kelly Ceyzériat, Aurélien M Badina, Francesco Petrelli, Sylvie Montessuit, Alekos Nicolaides, Philippe Millet, Armand Savioz, Jean-Claude Martinou, Benjamin B Tournier.

  Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aβ) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel. Astrocytes rely on aerobic glycolysis to generate lactate by reducing pyruvate, the end product of glycolysis, through lactate dehydrogenase. Consequently, limited amounts of pyruvate enter astrocytic mitochondria through the Mitochondrial Pyruvate Carrier (MPC) to be oxidized. The MPC is a heterodimer composed of two subunits MPC1 and MPC2, the function of which in astrocytes has been poorly investigated. Here, we analyzed the role of the MPC in the pathogeny of AD, knowing that a reduction in overall glucose metabolism has been associated with a drop in cognitive performances and an accumulation of Aβ and Tau. We generated 3xTgAD mice in which MPC1 was knocked-out in astrocytes specifically and focused our study on the biochemical hallmarks of the disease, mainly Aβ and neurofibrillary tangle production. We show that inhibition of the MPC before the onset of the disease significantly reduces the quantity of Aβ and Tau aggregates in the brain of 3xTgAD mice, suggesting that acting on astrocytic glucose metabolism early on could hinder the progression of the disease.

Keywords:  3xTgAD; Amyloid; Astrocytes; MPC; Tau

DOI:  https://doi.org/10.1016/j.nbd.2024.106623
Anal Chem. 2024 Aug 06.

Desorption Electrospray Ionization Cyclic Ion Mobility-Mass Spectrometry Imaging for Traumatic Brain Injury Spatial Metabolomics.

Dmitry Leontyev, Hernando Olivos, Bindesh Shrestha, Pooja M Datta Roy, Michelle C LaPlaca, Facundo M Fernández.

Lipidomics focuses on investigating alterations in a wide variety of lipids that harness important information on metabolic processes and disease pathology. However, the vast structural diversity of lipids and the presence of isobaric and isomeric species creates serious challenges in feature identification, particularly in mass spectrometry imaging experiments that lack front-end separations. Ion mobility has emerged as a potential solution to address some of these challenges and is increasingly being utilized as part of mass spectrometry imaging platforms. Here, we present the results of a pilot mass spectrometry imaging study on rat brains subjected to traumatic brain injury (TBI) to evaluate the depth and quality of the information yielded by desorption electrospray ionization cyclic ion mobility mass spectrometry (DESI cIM MSI). Imaging data were collected with one and six passes through the cIM cell. Increasing the number of passes increased the ion mobility resolving power and the resolution of isobaric lipids, enabling the creation of more specific maps. Interestingly, drift time data enabled the recognition of multiply charged phosphoinositide species in the complex data set generated. These species have not been previously reported in TBI MSI studies and were found to decrease in the hippocampus region following injury. These changes were attributed to increased enzymatic activity after TBI, releasing arachidonic acid that is converted to eicosanoids to control inflammation. A substantial reduction in NAD and alterations in other adenine metabolites were also observed, supporting the hypothesis that energy metabolism in the brain is severely disrupted in TBI.

DOI: https://doi.org/10.1021/acs.analchem.4c02394
Mol Syndromol. 2024 Aug;15(4): 333-338

Leigh Syndrome due to MT-ATP6 Variants: A Case Presentation and the Review of the Literature.

Halil Tuna Akar, Esra Sayar, Özlem Sarıtaş Nakip, Esra Sönmez, Mehmet Burak Özkan, Asburçe Olgaç.

   Introduction: Leigh syndrome is a rare mitochondrial disorder characterized by subacute necrotizing encephalomyelopathy, resulting from defects in mitochondrial respiratory enzymes or pyruvate dehydrogenase complex. Symptoms can manifest in infancy, childhood, or adulthood. We present a case of a 7-month-old girl initially misdiagnosed with septic shock but was later found to have Leigh encephalomyelopathy due to MT-ATP6 deficiency.
Case Presentation: A 7-month-old girl was admitted with fever, drowsiness, and wheezing, initially diagnosed with septic shock. She had a history of parental consanguinity and hypotonia. Physical examination revealed unconsciousness, miotic pupils, and respiratory distress. Initial laboratory tests showed significant metabolic acidosis and elevated lactate, creatine kinase, and ammonia levels. The patient was treated for sepsis and shock, but her condition worsened with elevated lactate and liver transaminases, eventually leading to hypertrophic cardiomyopathy and multiorgan failure. Her basic metabolic scans showed extremely low citrulline levels, whole-exome sequencing analysis did not show any pathologic change in nuclear genome, and mitochondrial genome analysis revealed an MT-ATP homoplasmic variant. She passed away on the 22nd day of hospitalization.
Discussion/Conclusion: While mitochondrial disorders are broadly acknowledged for their phenotypic diversity, it is essential to note that specific disorders, such as Leigh syndrome, display distinctive presentations with varying degrees of severity. Factors such as the percentage of homoplasmy contribute to the variability in manifestations. Notably, MT-ATP6-associated Leigh syndrome is predominantly characterized by an early onset, typically occurring before the age of 2 years. Low citrulline levels have been observed in approximately 90% of patients with MT-ATP6-related disorders, distinguishing them from other mitochondrial disorders. The exact mechanisms underlying this specific metabolic alteration are not fully understood, but it could be linked to disruptions in the mitochondrial energy production process. The mitochondria are essential for various metabolic pathways, including the urea cycle, where citrulline is involved. The association between low citrulline levels and MT-ATP6-related disorders raises the possibility of using citrulline as a potential biomarker for disease identification. MT-ATP6 defects should be kept in mind in cases with mitochondrial disease and low plasma citrulline levels.

Keywords:  Inborn errors of metabolism; Leigh’s syndrome; Mitochondrial disorders

DOI:  https://doi.org/10.1159/000536676
Neurology. 2024 Aug 27. 103(4): e209728

Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.

Olivier Fortin, Kelsey Christoffel, Abdullah B Shoaib, Charu Venkatesan, Kate Cilli, Jason W Schroeder, Cesar Alves, Rebecca D Ganetzky, Jamie L Fraser.

BACKGROUND AND OBJECTIVES: Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings have been described, with a focus on malformative and encephaloclastic features. Fetal brain MRI in PDCD has not been comprehensively described. The aims of this study were (1) to further characterize the fetal brain MRI findings in PDCD using comprehensive fetal imaging and genetic testing and (2) to determine whether markers of diagnosis of PDCD could be identified on prenatal imaging.
METHODS: Fetuses with a diagnosis of PDCD related to a genetic etiology that had undergone fetal MRI were included. Fetuses were identified retrospectively from local databases of 4 fetal diagnostic clinics within tertiary pediatric health care centers. Electronic medical records were reviewed retrospectively: demographics, maternal and pregnancy history, fetal outcomes, and neonatal outcomes (if available) were reviewed and recorded. Fetal and neonatal imaging reports were reviewed; source fetal and neonatal brain MRI scans were reviewed by a single pediatric neuroradiologist (J.W.S.) for consistency. Genetic testing strategies and results including variant type, zygosity, inheritance pattern, and pathogenicity were recorded. Deidentified data were combined and reported descriptively.
RESULTS: A total of 10 fetuses with a diagnosis of PDCD were included. 8 fetuses had corpus callosum dysgenesis, 6 had an abnormal gyration pattern, 10 had reduced brain volumes, and 9 had cystic lesions. 1 fetus had intraventricular hemorrhages. 1 fetus had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. 6 fetuses imaged in the second trimester had cystic lesions involving the ganglionic eminences (GEs) while GE cysts were not present in the 4 fetuses imaged in the third trimester.
DISCUSSION: Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings are subtle early in pregnancy. Additional features, such as cystic lesions of the GEs, are noted in the second trimester in fetuses with PDCD. These may represent an early diagnostic marker of PDCD, although more data are needed to validate this association. Early diagnosis of PDCD using fetal MRI may inform genetic counseling, pregnancy decision making, and neonatal care planning.

DOI: https://doi.org/10.1212/WNL.0000000000209728
Nat Commun. 2024 Aug 04. 15(1): 6604

Fasting induces metabolic switches and spatial redistributions of lipid processing and neuronal interactions in tanycytes.

Maxime Brunner, David Lopez-Rodriguez, Judith Estrada-Meza, Rafik Dali, Antoine Rohrbach, Tamara Deglise, Andrea Messina, Bernard Thorens, Federico Santoni, Fanny Langlet.

The ependyma lining the third ventricle (3V) in the mediobasal hypothalamus plays a crucial role in energy balance and glucose homeostasis. It is characterized by a high functional heterogeneity and plasticity, but the underlying molecular mechanisms governing its features are not fully understood. Here, 5481 hypothalamic ependymocytes were cataloged using FACS-assisted scRNAseq from fed, 12h-fasted, and 24h-fasted adult male mice. With standard clustering analysis, typical ependymal cells and β2-tanycytes appear sharply defined, but other subpopulations, β1- and α-tanycytes, display fuzzy boundaries with few or no specific markers. Pseudospatial approaches, based on the 3V neuroanatomical distribution, enable the identification of specific versus shared tanycyte markers and subgroup-specific versus general tanycyte functions. We show that fasting dynamically shifts gene expression patterns along the 3V, leading to a spatial redistribution of cell type-specific responses. Altogether, we show that changes in energy status induce metabolic and functional switches in tanycyte subpopulations, providing insights into molecular and functional diversity and plasticity within the tanycyte population.

DOI: https://doi.org/10.1038/s41467-024-50913-w
Int Immunopharmacol. 2024 Aug 05. pii: S1567-5769(24)01361-4. [Epub ahead of print]140 112840

Dichloroacetate attenuates brain injury through inhibiting neuroinflammation and mitochondrial fission in a rat model of sepsis-associated encephalopathy.

Peng Wang, Lian Liang, Qiulin Ge, Siqi Liu, Zhengfei Yang, Longyuan Jiang.

  Sepsis-associated encephalopathy (SAE) is a severe complication of sepsis, characterized by neuroinflammation, mitochondrial dysfunction, and oxidative stress, leading to cognitive decline and high mortality. The effectiveness of dichloroacetate (DCA) in modulating mitochondrial function provides a novel therapeutic strategy for SAE. In this study, we evaluated the neuroprotective effects of DCA in a rat model of SAE induced by cecal ligation and puncture (CLP). Rats treated with DCA exhibited significant improvements in neurological function and survival, as evidenced by less neuron loss from histopathologic analysis, restored neurologic deficit scores, improved Y-maze alternation percentages, and enhanced recognition index performance. Biochemical analyses showed that DCA administration at 25 mg/kg and 100 mg/kg reduced astrocyte and microglial activation, indicating reduced neuroinflammation. Furthermore, DCA simultaneously reduced the production of circulating and cerebral inflammatory cytokines (including TNF-α, IL-1β, and IL-10), concomitant with mitigating oxidative stress through down-regulating expression of 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and reactive oxygen species (ROS) in the brain. Mechanistically, DCA modulated mitochondrial dynamics by suppressing Drp1 and pDrp1 expression, which are indicators of mitochondrial fission. This was corroborated by transmission electron microscopy, quantification of mitochondrial area, and Western blot analyses. Furthermore, DCA treatment improved ATP levels, mitochondrial complex I activity, and NAD+/NADH ratio, indicating a significant attenuation of brain mitochondrial dysfunction. In conclusion, our findings suggest that DCA confers neuroprotection in SAE by curtailing neuroinflammation and mitochondrial fission, outlining a promising therapeutic strategy for treating SAE in critically ill patients.

Keywords:  Cecal ligation and puncture; Dichloroacetate; Mitochondrial fission; Neuroinflammation; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.intimp.2024.112840
CNS Neurosci Ther. 2024 Aug;30(8): e14897

Mitochondrial plasticity and synaptic plasticity crosstalk; in health and Alzheimer's disease.

Fatemeh Sayehmiri, Fereshteh Motamedi, Zehra Batool, Nima Naderi, Fatima Shaerzadeh, Anahita Zoghi, Omidvar Rezaei, Fariba Khodagholi, Hamid Gholami Pourbadie.

  Synaptic plasticity is believed to underlie the cellular and molecular basis of memory formation. Mitochondria are one of the main organelles involved in metabolism and energy maintenance as plastic organelles that change morphologically and functionally in response to cellular needs and regulate synaptic function and plasticity through multiple mechanisms, including ATP generation, calcium homeostasis, and biogenesis. An increased neuronal activity enhances synaptic efficiency, during which mitochondria's spatial distribution and morphology change significantly. These organelles build up in the pre-and postsynaptic zones to produce ATP, which is necessary for several synaptic processes like neurotransmitter release and recycling. Mitochondria also regulate calcium homeostasis by buffering intracellular calcium, which ensures proper synaptic activity. Furthermore, mitochondria in the presynaptic terminal have distinct morphological properties compared to dendritic or postsynaptic mitochondria. This specialization enables precise control of synaptic activity and plasticity. Mitochondrial dysfunction has been linked to synaptic failure in many neurodegenerative disorders, like Alzheimer's disease (AD). In AD, malfunctioning mitochondria cause delays in synaptic vesicle release and recycling, ionic gradient imbalances, and mostly synaptic failure. This review emphasizes mitochondrial plasticity's contribution to synaptic function. It also explores the profound effect of mitochondrial malfunction on neurodegenerative disorders, focusing on AD, and provides an overview of how they sustain cellular health under normal conditions and how their malfunction contributes to neurodegenerative diseases, highlighting their potential as a therapeutic target for such conditions.

Keywords:  Alzheimer's disease; beta‐amyloid; mitochondria; synaptic plasticity

DOI:  https://doi.org/10.1111/cns.14897
Brain Commun. 2024 ;6(4): fcae245

Brain metabolites are associated with sleep architecture and cognitive functioning in older adults.

Christina Mueller, Rodolphe Nenert, Corina Catiul, Jennifer Pilkington, Jerzy P Szaflarski, Amy W Amara.

  Sleep deficits are a possible risk factor for development of cognitive decline and dementia in older age. Research suggests that neuroinflammation may be a link between the two. This observational, cross-sectional study evaluated relationships between sleep architecture, neuroinflammation and cognitive functioning in healthy older adults. Twenty-two adults aged ≥60 years underwent whole-brain magnetic resonance spectroscopic imaging (in vivo method of visualizing increased brain temperatures as a proxy for neuroinflammation), supervised laboratory-based polysomnography, and comprehensive neurocognitive testing. Multiple regressions were used to assess relationships between magnetic resonance spectroscopic imaging-derived brain temperature and metabolites related to inflammation (choline; myo-inositol; N-acetylaspartate), sleep efficiency, time and % N3 sleep and cognitive performance. Choline, myo-inositol and N-acetylaspartate were associated with sleep efficiency and cognitive performance. Higher choline and myo-inositol in the bilateral frontal lobes were associated with slower processing speed and lower sleep efficiency. Higher choline and myo-inositol in bilateral frontoparietal regions were associated with better cognitive performance. Higher N-acetylaspartate around the temporoparietal junction and adjacent white matter was associated with better visuospatial function. Brain temperature was not related to cognitive or sleep outcomes. Our findings are consistent with the limited literature regarding neuroinflammation and its relationships with sleep and cognition in older age, which has implicated ageing microglia and astrocytes in circadian dysregulation, impaired glymphatic clearance and increased blood-brain barrier integrity, with downstream effects of neurodegeneration and cognitive decline. Inflammatory processes remain difficult to measure in the clinical setting, but magnetic resonance spectroscopic imaging may serve as a marker of the relationship between neuroinflammation, sleep and cognitive decline in older adults.

Keywords:  brain metabolites; brain temperature; cognition; magnetic resonance spectroscopy; older adults

DOI:  https://doi.org/10.1093/braincomms/fcae245
Front Neurosci. 2024 ;18 1387221

Dietary gangliosides rescue GM3 synthase deficiency outcomes in mice accompanied by neurogenesis in the hippocampus.

Jin-Ichi Inokuchi, Shinji Go, Akemi Suzuki, Osamu Nakagawasai, Takayo Odaira-Satoh, Lucas Veillon, Takahiro Nitta, Paul McJarrow, Hirotaka Kanoh, Kei-Ichiro Inamori, Koichi Tan-No, Michael Collett.

  Ganglioside GM3 synthase is a key enzyme involved in the biosynthesis of gangliosides. GM3 synthase deficiency (GM3SD) causes an absence of GM3 and all downstream biosynthetic derivatives, including all the a-, b-, c-series gangliosides, commonly found in neural tissues. The affected individuals manifest with severe irritability, intractable seizures, hearing loss, blindness, and profound intellectual disability. It has been reported that oral ganglioside supplementation has achieved some significant improvements in clinical symptoms, growth parameters, and developmental and cognitive scores in GM3SD patients. To gain insight into the molecular mechanisms of this supplementation, we performed supplementation of oral bovine milk gangliosides to GM3 synthase-deficient mice from early weaning periods. The oral milk ganglioside preparations were dominated by GM3 and GD3 gangliosides. Oral milk ganglioside supplementation improved the decreased cognitive function observed in GM3 synthase-deficient mice. The improvement in cognitive function was accompanied by increased ganglioside levels and neurogenesis in the hippocampus in the supplemented animals.

Keywords:  GD3; GM3; GM3 synthase deficiency; cognitive function; hippocampus; milk gangliosides; neurogenesis; oral supplementation

DOI:  https://doi.org/10.3389/fnins.2024.1387221