bims-medebr 2024-07-07 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒07‒07
thirty papers selected by
Regina F. Fernández, Johns Hopkins University

Adenosine signalling to astrocytes coordinates brain metabolism and function.
Ex-Vivo 13C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites.
Intraperitoneally injected d11-11(12)-epoxyeicosatrienoic acid is rapidly incorporated and esterified within rat plasma and peripheral tissues but not the brain.
Sex-dependent susceptibility to brain metabolic dysfunction and memory impairment in response to pre- and postnatal high-fat diet.
Fatty acid preference for beta-oxidation in mitochondria of murine cultured astrocytes.
Capturing alterations of intracellular-extracellular lactate distribution in the brain using diffusion-weighted MR spectroscopy in vivo.
Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model.
Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer's Disease.
The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.
Bridging lipid metabolism and mitochondrial genome maintenance.
Omega-3 Attenuates Disrupted Neurotransmission and Partially Protects Metabolic Dysfunction Caused by Obesity in Wistar Rats.
SLC25A19 is required for NADH homeostasis and mitochondrial respiration.
The diagnostic and prognostic role of cerebrospinal fluid biomarkers in glucose transporter 1 deficiency: a systematic review.
Sex-dependent differences in macaque brain mitochondria.
Deuterium MRI of serine metabolism in mouse models of glioblastoma.
Inborn errors of the malate aspartate shuttle - Update on patients and cellular models.
X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.
The immune and metabolic milieu of the choroid plexus as a potential target in brain protection.
Multiomics to Characterize the Molecular Events Underlying Impaired Glucose Tolerance in FXR-Knockout Mice.
Pericytes: Unsung heroes in myelin repair after neonatal brain hypoxia.
Physiology of malate dehydrogenase and how dysregulation leads to disease.
Illuminating the dark space of neutral glycosphingolipidome by selective enrichment and profiling at multi-structural levels.
MRI in LARS1 deficiency-Spectrum, patterns, and correlation with acute neurological deterioration.
Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation.
Delineation of the role of G6PD in Alzheimer's disease and potential enhancement through microfluidic and nanoparticle approaches.
Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.
Rate of abnormalities in quantitative MR neuroimaging of persons with chronic traumatic brain injury.
Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.
A review on polyamines as promising next-generation neuroprotective and anti-aging therapy.
[Clinical, imaging, and pathological characteristics of 35 cases of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome].

Nature. 2024 Jul 03.

Adenosine signalling to astrocytes coordinates brain metabolism and function.

Shefeeq M Theparambil, Olga Kopach, Alice Braga, Shereen Nizari, Patrick S Hosford, Virag Sagi-Kiss, Anna Hadjihambi, Christos Konstantinou, Noemi Esteras, Ana Gutierrez Del Arroyo, Gareth L Ackland, Anja G Teschemacher, Nicholas Dale, Tobias Eckle, Petros Andrikopoulos, Dmitri A Rusakov, Sergey Kasparov, Alexander V Gourine.

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply1,2. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism3,4, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood5,6. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory.

DOI: https://doi.org/10.1038/s41586-024-07611-w
J Proteome Res. 2024 Jun 29.

Ex-Vivo 13C NMR Spectroscopy of Rodent Brain: TNF Restricts Neuronal Utilization of Astrocyte-Derived Metabolites.

Daniel Radford-Smith, Tang T Ng, Abi G Yates, Isobel Dunstan, Timothy D W Claridge, Daniel C Anthony, Fay Probert.

  Tumor necrosis factor (TNF) has well-established roles in neuroinflammatory disorders, but the effect of TNF on the biochemistry of brain cells remains poorly understood. Here, we microinjected TNF into the brain to study its impact on glial and neuronal metabolism (glycolysis, pentose phosphate pathway, citric acid cycle, pyruvate dehydrogenase, and pyruvate carboxylase pathways) using 13C NMR spectroscopy on brain extracts following intravenous [1,2-13C]-glucose (to probe glia and neuron metabolism), [2-13C]-acetate (probing astrocyte-specific metabolites), or [3-13C]-lactate. An increase in [4,5-13C]-glutamine and [2,3-13C]-lactate coupled with a decrease in [4,5-13C]-glutamate was observed in the [1,2-13C]-glucose-infused animals treated with TNF. As glutamine is produced from glutamate by astrocyte-specific glutamine synthetase the increase in [4,5-13C]-glutamine reflects increased production of glutamine by astrocytes. This was confirmed by infusion with astrocyte substrate [2-13C]-acetate. As lactate is metabolized in the brain to produce glutamate, the simultaneous increase in [2,3-13C]-lactate and decrease in [4,5-13C]-glutamate suggests decreased lactate utilization, which was confirmed using [3-13C]-lactate as a metabolic precursor. These results suggest that TNF rearranges the metabolic network, disrupting the energy supply chain perturbing the glutamine-glutamate shuttle between astrocytes and the neurons. These insights pave the way for developing astrocyte-targeted therapeutic strategies aimed at modulating effects of TNF to restore metabolic homeostasis in neuroinflammatory disorders.

Keywords:  astrocyte; ex-vivo NMR; metabolomics; neuroinflammation; stable isotope tracing; tumor necrosis factor

DOI:  https://doi.org/10.1021/acs.jproteome.4c00035
Prostaglandins Leukot Essent Fatty Acids. 2024 May 15. pii: S0952-3278(24)00016-4. [Epub ahead of print]202 102622

Intraperitoneally injected d11-11(12)-epoxyeicosatrienoic acid is rapidly incorporated and esterified within rat plasma and peripheral tissues but not the brain.

Sho Watanabe, Felipe Da Costa Souza, Ibuki Kusumoto, Qing Shen, Nitin Nitin, Pamela J Lein, Ameer Y Taha.

  Epoxyeicosatrienoic acids (EpETrEs) are bioactive lipid mediators of arachidonic acid cytochrome P450 oxidation. In vivo, the free (unbound) form of EpETrEs regulate multiple processes including blood flow, angiogenesis and inflammation resolution. Free EpETrEs are thought to rapidly degrade via soluble epoxide hydrolase (sEH); yet, in many tissues, the majority of EpETrEs are esterified to complex lipids (e.g. phospholipids) suggesting that esterification may play a major role in regulating free, bioactive EpETrE levels. This hypothesis was tested by quantifying the metabolism of intraperitoneally injected free d11-11(12)-Epoxyeicosatrienoic acid (d11-11(12)-EpETrE) in male and female rats. Plasma and tissues (liver, adipose and brain) were obtained 3 to 4 min later and assayed for d11-11(12)-EpETrE and its sEH metabolite, d11-11,12-dihydroxyeicosatrienoic acid (d11-11,12-diHETrE) in both the free and esterified lipid fractions. In both males and females, the majority of injected tracer was recovered in liver followed by plasma and adipose. No tracer was detected in the brain, indicating that brain levels are maintained by endogenous synthesis from precursor fatty acids. In plasma, liver, and adipose, the majority (>54 %) of d11-11(12)-EpETrE was found esterified to phospholipids or neutral lipids (triglycerides and cholesteryl esters). sEH-derived d11-11,12-diHETrE was not detected in plasma or tissues, suggesting negligible conversion within the 3-4 min period post tracer injection. This study shows that esterification is the main pathway regulating free 11(12)-EpETrE levels in vivo.

Keywords:  Acyl-CoA synthetase; Acyltransferase; Esterification; Fatty acid epoxide; Mass spectrometry (MS); Metabolic tracer; Rodents

DOI:  https://doi.org/10.1016/j.plefa.2024.102622
J Nutr Biochem. 2024 Jun 28. pii: S0955-2863(24)00108-6. [Epub ahead of print] 109675

Sex-dependent susceptibility to brain metabolic dysfunction and memory impairment in response to pre- and postnatal high-fat diet.

Azam Abedi, Tahereh Foroutan, Leila Mohaghegh Shalmani, Leila Dargahi.

  The developing brain is sensitive to the impacts of early-life nutritional intake. This study investigates whether maternal high fat diet (HFD) causes glucose metabolism impairment, neuroinflammation, and memory impairment in immature and adult offspring, and whether it may be affected by postweaning diets in a sex-dependent manner in adult offspring. After weaning, female rats were fed HFD (55.9% fat) or normal chow diet (NCD; 10% fat) for 8 weeks before mating, during pregnancy, and lactation. On postnatal day 21 (PND21), the male and female offspring of both groups were split into two new groups, and NCD or HFD feeding was maintained until PND180. On PND21 and PND180, brain glucose metabolism-, inflammation-, and Alzheimer's pathology-related markers were by qPCR. In adult offspring, peripheral insulin resistance parameters, spatial memory performance, and brain glucose metabolism (18F-FDG-PET scan and protein levels of IDE and GLUT3) were assessed. Histological analysis was also performed on PND21 and adult offspring. On PND21, we found that maternal HFD affected transcript levels of glucose metabolism markers in both sexes. In adult offspring, more profoundly in males, postweaning HFD in combination with maternal HFD induced peripheral and brain metabolic disturbances, impaired memory performance and elevated inflammation, dementia risk markers, and neuronal loss. Our results suggest that maternal HFD affects brain glucose metabolism in the early ages of both sexes. Postweaning HFD sex-dependently causes brain metabolic dysfunction and memory impairment in later-life offspring; effects that can be worsened in combination with maternal HFD.

Keywords:  High fat diet; brain glucose metabolism; cognitive impairment; male and female offspring

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109675
Genes Cells. 2024 Jul 04.

Fatty acid preference for beta-oxidation in mitochondria of murine cultured astrocytes.

Laarni Grace Corales, Hitoshi Inada, Yuji Owada, Noriko Osumi.

  The brain utilizes glucose as a primary energy substrate but also fatty acids for the β-oxidation in mitochondria. The β-oxidation is reported to occur mainly in astrocytes, but its capacity and efficacy against different fatty acids remain unknown. Here, we show the fatty acid preference for the β-oxidation in mitochondria of murine cultured astrocytes. Fatty acid oxidation assay using an extracellular flux analyzer showed that saturated or monosaturated fatty acids, palmitic acid and oleic acid, are preferred substrates over polyunsaturated fatty acids like arachidonic acid and docosahexaenoic acid. We also report that fatty acid binding proteins expressed in the astrocytes contribute less to fatty acid transport to mitochondria for β-oxidation. Our results could give insight into understanding energy metabolism through fatty acid consumption in the brain.

Keywords:  astrocyte; fatty acid binding proteins; mitochondria; palmitic acid; polyunsaturated fatty acids; β‐oxidation

DOI:  https://doi.org/10.1111/gtc.13144
Proc Natl Acad Sci U S A. 2024 Jul 09. 121(28): e2403635121

Capturing alterations of intracellular-extracellular lactate distribution in the brain using diffusion-weighted MR spectroscopy in vivo.

Sophie Malaquin, Rodrigo Lerchundi, Eloïse Mougel, Julien Valette.

  While the intracellular-extracellular distribution of lactate has been suggested to play a critical role in the healthy and diseased brain, tools are lacking to noninvasively probe lactate in intracellular and extracellular spaces. Here, we show that, by measuring the diffusion of lactate with diffusion-weighted magnetic resonance (MR) spectroscopy in vivo and comparing it to the diffusion of purely intracellular metabolites, noninvasive quantification of extracellular and intracellular lactate fractions becomes possible. More specifically, we detect alterations of lactate diffusion in the APP/PS1 mouse model of Alzheimer's disease. Data modeling allows quantifying decreased extracellular lactate fraction in APP/PS1 mice as compared to controls, which is quantitatively confirmed with implanted enzyme-microelectrodes. The capability of diffusion-weighted MR spectroscopy to quantify extracellular-intracellular lactate fractions opens a window into brain metabolism, including in Alzheimer's disease.

Keywords:  NMR spectroscopy; brain metabolism; compartmentation; lactate; metabolite diffusion

DOI:  https://doi.org/10.1073/pnas.2403635121
bioRxiv. 2024 Jun 20. pii: 2024.06.19.599741. [Epub ahead of print]

Role of ACSBG1 in brain lipid metabolism and X-linked adrenoleukodystrophy pathogenesis: Insights from a knockout mouse model.

Xiaoli Ye, Yuanyuan Li, Domingo González-Lamuño, Zhengtong Pei, Ann B Moser, Kirby D Smith, Paul A Watkins.

The "bubblegum" acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during the development of the mouse brain, facilitating the activation of long-chain fatty acids (LCFAs) and their integration into essential lipid species crucial for brain function. Through its enzymatic activity, ACSBG1 converts LCFAs into acyl-CoA derivatives, supporting vital processes like membrane formation, myelination, and energy production. Its regulatory role significantly influences neuronal growth, synaptic plasticity, and overall brain development, highlighting its importance in maintaining lipid homeostasis and proper brain function. Originally discovered in the fruit fly brain, ACSBG1 attracted attention for its potential implication in X-linked adrenoleukodystrophy (XALD) pathogenesis. Studies using Drosophila melanogaster lacking the ACSBG1 homolog, bubblegum, revealed adult neurodegeneration with elevated levels of very long-chain fatty acids (VLCFA). To explore ACSBG1's role in fatty acid (FA) metabolism and its relevance to XALD, we created an ACSBG1 knockout (Acsbg1-/-) mouse model and examined its impact on lipid metabolism during mouse brain development. Phenotypically, Acsbg1-/- mice resembled wild type (w.t.) mice. Despite its primary expression in tissues affected by XALD, brain, adrenal gland and testis, ACSBG1 depletion did not significantly reduce total ACS enzyme activity in these tissues when using LCFA or VLCFA as substrates. However, analysis unveiled intriguing developmental and compositional changes in FA levels associated with ACSBG1 deficiency. In the adult mouse brain, ACSBG1 expression peaked in the cerebellum, with lower levels observed in other brain regions. Developmentally, ACSBG1 expression in the cerebellum was initially low during the first week of life but increased dramatically thereafter. Cerebellar FA levels were assessed in both w.t. and Acsbg1-/- mouse brains throughout development, revealing notable differences. While saturated VLCFA levels were typically high in XALD tissues and in fruit flies lacking ACSBG1, cerebella from Acsbg1-/- mice displayed lower saturated VLCFA levels, especially after about 8 days of age. Additionally, monounsaturated ω9 FA levels exhibited a similar trend as saturated VLCFA, while ω3 polyunsaturated FA levels were elevated in Acsbg1-/- mice. Further analysis of specific FA levels provided additional insights into potential roles for ACSBG1. Notably, the decreased VLCFA levels in Acsbg1-/- mice primarily stemmed from changes in C24:0 and C26:0, while reduced ω9 FA levels were mainly observed in C18:1 and C24:1. ACSBG1 depletion had minimal effects on saturated long-chain FA or ω6 polyunsaturated FA levels but led to significant increases in specific ω3 FA, such as C20:5 and C22:5. Moreover, the impact of ACSBG1 deficiency on the developmental expression of several cerebellar FA metabolism enzymes, including those required for synthesis of ω3 polyunsaturated FA, was assessed; these FA can potentially be converted into bioactive signaling molecules like eicosanoids and docosanoids. In conclusion, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated.

DOI: https://doi.org/10.1101/2024.06.19.599741
J Mol Neurosci. 2024 Jul 03. 74(3): 62

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer's Disease.

Parisa Faraji, Hartmut Kühn, Shahin Ahmadian.

  Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.

Keywords:  Free radicals; Glutathione peroxidase 4; Iron homeostasis; Lipid peroxidation; Neurodegeneration; Proteostasis

DOI:  https://doi.org/10.1007/s12031-024-02224-4
bioRxiv. 2024 Jun 17. pii: 2024.06.17.599406. [Epub ahead of print]

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

Peter A Barbuti, Cristina Guardia-Laguarta, Taekyung Yun, Zena K Chatila, Xena Flowers, Bruno Fr Santos, Simone B Larsen, Nobutaka Hattori, Elizabeth Bradshaw, Ulf Dettmer, Saranna Fanning, Manon Vilas, Hasini Reddy, Andrew F Teich, Rejko Krüger, Estela Area-Gomez, Serge Przedborski.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show region-and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.Significance Statement: Synucleinopathy is a complex group of neurodegenerative disorders whose causes and underlying mechanisms remain unknown. In this work, we examined synucleinopathy postmortem brain samples and patient-derived neuron models and identified the functional impairment of the mitochondrial-associated endoplasmic reticulum membrane (MAM) domain, which facilitates lipid regulation. The protein alpha-synuclein is associated with synucleinopathy and increasing levels result in the mislocalization of this protein and the disruption of MAM domains, which, in turn, results in lipid and membrane composition alterations. Specifically, we report that increased alpha-synuclein expression impairs the regulation of phosphatidylserine synthase 2 and the levels of phosphatidylserine in cellular membranes from affected cells. Our study offers mechanistic insight tying alpha-synuclein pathology and lipid dysregulation as seminal factors in synucleinopathy, which may have pathogenic and therapeutic implications.

DOI: https://doi.org/10.1101/2024.06.17.599406
J Biol Chem. 2024 Jun 27. pii: S0021-9258(24)01999-9. [Epub ahead of print] 107498

Bridging lipid metabolism and mitochondrial genome maintenance.

Casadora Boone, Samantha C Lewis.

  Mitochondria are the nexus of cellular energy metabolism and major signaling hubs that integrate information from within and without the cell to implement cell function. Mitochondria harbor a distinct polyploid genome, mitochondrial DNA (mtDNA), that encodes respiratory chain components required for energy production. MtDNA mutation and depletion have been linked to obesity and metabolic syndrome in humans. At the cellular and subcellular levels, mtDNA synthesis is coordinated by membrane contact sites implicated in lipid transfer from the endoplasmic reticulum, tying genome maintenance to lipid storage and homeostasis. Here, we examine the relationship between mtDNA and lipid trafficking, the influence of lipotoxicity on mtDNA integrity, and how lipid metabolism may be disrupted in primary mtDNA disease.

Keywords:  Mitochondria; lipid metabolism; lipotoxicity; mitochondrial DNA (mtDNA); mitochondrial metabolism

DOI:  https://doi.org/10.1016/j.jbc.2024.107498
Neurochem Res. 2024 Jul 03.

Omega-3 Attenuates Disrupted Neurotransmission and Partially Protects Metabolic Dysfunction Caused by Obesity in Wistar Rats.

Gabriel de Farias Fraga, Fernanda da Silva Rodrigues, Jeferson Jantsch, Victor Silva Dias, Vitória Milczarski, Fernanda Wickert, Camila Pereira Medeiros, Sarah Eller, Alethéa Gatto Barschak, Marcia Giovenardi, Renata Padilha Guedes.

  Omega-3 (n3) is a polyunsaturated fatty acid well known for its anti-inflammatory and neuroprotective properties. Obesity is linked to chronic inflammation that disrupts metabolism, the intestine physiology and the central nervous system functioning. This study aims to determine if n3 supplementation can interfere with the effects of obesity on the mitochondrial activity, intestinal barrier, and neurotransmitter levels in the brain of Wistar rats that received cafeteria diet (CAF). We examined adipose tissue, skeletal muscle, plasma, intestine, and the cerebral cortex of four groups: CT (control diet), CTn3 (control diet with n3 supplementation), CAF, and CAFn3 (CAF and n3). Diets were offered for 13 weeks, with n3 supplementation in the final 5 weeks. Adipose tissue Electron Transport Chain complexes I, II, and III showed higher activity in CAF groups, as did complexes III and IV in skeletal muscle. Acetate levels in plasma were reduced in CAF groups, and Lipopolysaccharide (LPS) was higher in the CAF group but reduced in CAFn3 group. Claudin-5 in the intestine was lower in CAF groups, with no n3 supplementation effect. In the cerebral cortex, dopamine levels were decreased with CAF, which was reversed by n3. DOPAC, a dopamine metabolite, also showed a supplementation effect, and HVA, a diet effect. Serotonin levels increased in the CAF group that received supplementation. Therefore, we demonstrate disturbances in mitochondria, plasma, intestine and brain of rats submitted to CAF and the potential benefit of n3 supplementation in endotoxemia and neurotransmitter levels.

Keywords:  Cafeteria diet; Claudin-5; Electron transport chain; LPS; Neurotransmitters; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1007/s11064-024-04201-0
Free Radic Biol Med. 2024 Jun 27. pii: S0891-5849(24)00536-7. [Epub ahead of print]222 317-330

SLC25A19 is required for NADH homeostasis and mitochondrial respiration.

Zongsheng Jiang.

  Mitochondrial transporters facilitate the translocation of metabolites between the cytoplasm and mitochondria and are critical for mitochondrial functional integrity. Although many mitochondrial transporters are associated with metabolic diseases, how they regulate mitochondrial function and their metabolic contributions at the cellular level are largely unknown. Here, we show that mitochondrial thiamine pyrophosphate (TPP) transporter SLC25A19 is required for mitochondrial respiration. SLC25A19 deficiency leads to reduced cell viability, increased integrated stress response (ISR), enhanced glycolysis and elevated cell sensitivity to 2-deoxyglucose (2-DG) treatment. Through a series of biochemical assays, we found that the depletion of mitochondrial NADH is the primary cause of the impaired mitochondrial respiration in SLC25A19 deficient cells. We also showed involvement of SLC25A19 in regulating the enzymatic activities of complexes I and III, the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle and amino acid metabolism. Consistently, addition of idebenone, an analog of coenzyme Q10, restores mitochondrial respiration and cell viability in SLC25A19 deficient cells. Together, our findings provide new insight into the functions of SLC25A19 in mitochondrial and cellular physiology, and suggest that restoring mitochondrial respiration could be a novel strategy for treating SLC25A19-associated disorders.

Keywords:  Electron transport chain; Idebenone; Mitochondrial respiration; Mitochondrial transporter; NADH; SLC25A19; TPP

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.019
Eur J Pediatr. 2024 Jul 02.

The diagnostic and prognostic role of cerebrospinal fluid biomarkers in glucose transporter 1 deficiency: a systematic review.

Mario Mastrangelo, Filippo Manti, Giacomina Ricciardi, Elisa Maria Colacino Cinnante, Noemi Cameli, Annachiara Beatrice, Manuela Tolve, Francesco Pisani.

  The purpose of this study is to investigate the diagnostic and prognostic role of cerebrospinal fluid (CSF) biomarkers in the diagnostic work-up of glucose transporter 1 (GLUT1) deficiency. Reported here is a systematic review according to PRISMA guidelines collecting clinical and biochemical data about all published patients who underwent CSF analysis. Clinical phenotypes were compared between groups defined by the levels of CSF glucose (≤ 2.2 mmol/L versus > 2.2 mmol/L), CSF/blood glucose ratio (≤ 0.45 versus > 0.45), and CSF lactate (≤ 1 mmol/L versus > 1 mmol/L). Five hundred sixty-two patients fulfilled the inclusion criteria with a mean age at the diagnosis of 8.6 ± 6.7 years. Patients with CSF glucose ≤ 2.2 mmol/L and CSF/blood glucose ratio ≤ 0.45 presented with an earlier onset of symptoms (16.4 ± 22.0 versus 54.4 ± 45.9 months, p < 0.01; 15.7 ± 23.8 versus 40.9 ± 38.0 months, p < 0.01) and received an earlier molecular genetic confirmation (92.1 ± 72.8 versus 157.1 ± 106.2 months, p < 0.01). CSF glucose ≤ 2.2 mmol/L was consistently associated with response to ketogenic diet (p = 0.018) and antiseizure medications (p = 0.025). CSF/blood glucose ratio ≤ 0.45 was significantly associated with absence seizures (p = 0.048), paroxysmal exercise-induced dyskinesia (p = 0.046), and intellectual disability (p = 0.016) while CSF lactate > 1 mmol/L was associated with a response to antiseizure medications (p = 0.026) but not to ketogenic diet.Conclusions:This systematic review supported the diagnostic usefulness of lumbar puncture for the early identification of patients with GLUT1 deficiency responsive to treatments especially if they present with co-occurring epilepsy, movement, and neurodevelopmental disorders. What is Known: • Phenotypes of GLUT1 deficiency syndrome range between early epileptic and developmental encephalopathy to paroxysmal movement disorders and developmental impairment What is New: • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with early onset absences • CSF blood/glucose ratio may predict better than CSF glucose the diagnosis in children presenting with paroxysmal exercise induced dyskinesia and intellectual disability. • CSF glucose may predict better than CSF blood/glucose and lactate the response to ketogenic diet and antiseizure medications.

Keywords:  Children; Epilepsy; Genetic epilepsies; Movement disorders; Neurodevelopmental disorders

DOI:  https://doi.org/10.1007/s00431-024-05657-6
Biochim Biophys Acta Bioenerg. 2024 Jul 01. pii: S0005-2728(24)00464-X. [Epub ahead of print] 149494

Sex-dependent differences in macaque brain mitochondria.

Ivan Guerrero, Belem Yoval-Sánchez, Csaba Konrad, Giovanni Manfredi, Ilka Wittig, Alexander Galkin.

  Mitochondrial bioenergetics in females and males is different. Whether mitochondria from male and female brains display differences in mitochondrial enzymes is unknown. We measured the function of mitochondrial complexes from the brains of male and female macaques (Macaca mulatta). Cerebral tissue of macaques males exhibit elevated content and activity of mitochondrial complex I (NADH:ubiquinone oxidoreductase) and activity of complex II compared to females. No significant differences between sexes were found in the content of α-ketoglutarate dehydrogenase and activities of cytochrome c oxidase and F1Fo ATPase. Our results, underscore the need for further investigations to elucidate sex-related mitochondrial distinctions in humans.

Keywords:  ATPase; Mitochondria; Mitochondrial complex I; Primates; Sex; Succinate dehydrogenase; TCA cycle; α-Ketoglutarate dehydrogenase

DOI:  https://doi.org/10.1016/j.bbabio.2024.149494
Magn Reson Med. 2024 Jun 30.

Deuterium MRI of serine metabolism in mouse models of glioblastoma.

Friederike Hesse, Jacob Low, Jianbo Cao, Flaviu Bulat, Felix Kreis, Alan J Wright, Kevin M Brindle.

  PURPOSE: Serine is a major source of one-carbon units needed for the synthesis of nucleotides and the production of intramitochondrial nicotinamide adenine dinucleotide phosphate (NADPH), and it plays an important role in cancer cell proliferation. The aim of this study was to develop a deuterium (2H) MRS imaging method for imaging tumor serine metabolism.METHODS: Sequential (2H) spectra and spectroscopic images were used to monitor the metabolism of [2,3,3-2H3]serine in patient-derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain.
RESULTS: [14,14-2H2] 5,10-methylene-tetrahydrofolate, [2H]glycine, [2H]formate, and labeled water were detected in cell suspensions and water labeling in spectroscopic images of tumors. Studies in cells and tumors with variable mitochondrial content and inhibitor studies in cells demonstrated that most of the labeled serine was metabolized in the mitochondria. Water labeling in the cell suspensions was correlated with formate labeling; therefore, water labeling observed in tumors could be used to provide a surrogate measure of flux in the pathway of one-carbon metabolism in vivo.
CONCLUSION: The method has the potential to be used clinically to select patients for treatment with inhibitors of one-carbon metabolism and subsequently to detect their early responses to such treatment.

Keywords:  folate cycle; one‐carbon metabolism; serine; tumor

DOI:  https://doi.org/10.1002/mrm.30198
Mol Genet Metab. 2024 Jun 24. pii: S1096-7192(24)00404-9. [Epub ahead of print]142(4): 108520

Inborn errors of the malate aspartate shuttle - Update on patients and cellular models.

Jasmine Koch, Melissa H Broeks, Matthias Gautschi, Judith Jans, Alexander Laemmle.

The malate aspartate shuttle (MAS) plays a pivotal role in transporting cytosolic reducing equivalents - electrons - into the mitochondria for energy conversion at the electron transport chain (ETC) and in the process of oxidative phosphorylation. The MAS consists of two pairs of cytosolic and mitochondrial isoenzymes (malate dehydrogenases 1 and 2; and glutamate oxaloacetate transaminases 1 and 2) and two transporters (malate-2-oxoglutarate carrier and aspartate glutamate carrier (AGC), the latter of which has two tissue-dependent isoforms AGC1 and AGC2). While the inner mitochondrial membrane is impermeable to NADH, the MAS forms one of the main routes for mitochondrial electron uptake by promoting uptake of malate. Inherited bi-allelic pathogenic variants in five of the seven components of the MAS have been described hitherto and cause a wide spectrum of symptoms including early-onset epileptic encephalopathy. This review provides an overview of reported patients suffering from MAS deficiencies. In addition, we give an overview of diagnostic procedures and research performed on patient-derived cellular models and tissues. Current cellular models are briefly discussed and novel ways to achieve a better understanding of MAS deficiencies are highlighted.

DOI: https://doi.org/10.1016/j.ymgme.2024.108520
Nat Commun. 2024 Jul 02. 15(1): 5571

X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction.

Peixiang Zhang, Joseph J Munier, Carrie B Wiese, Laurent Vergnes, Jenny C Link, Fahim Abbasi, Emilio Ronquillo, Katherine Scheker, Antonio Muñoz, Yu-Lin Kuang, Elizabeth Theusch, Meng Lu, Gabriela Sanchez, Akinyemi Oni-Orisan, Carlos Iribarren, Michael J McPhaul, Daniel K Nomura, Joshua W Knowles, Ronald M Krauss, Marisa W Medina, Karen Reue.

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

DOI: https://doi.org/10.1038/s41467-024-49764-2
Trends Neurosci. 2024 Jun 29. pii: S0166-2236(24)00090-0. [Epub ahead of print]

The immune and metabolic milieu of the choroid plexus as a potential target in brain protection.

Afroditi Tsitsou-Kampeli, Stefano Suzzi, Michal Schwartz.

  The brain's choroid plexus (CP), which operates as an anatomical and functional 'checkpoint', regulates the communication between brain and periphery and contributes to the maintenance of healthy brain homeostasis throughout life. Evidence from mouse models and humans reveals a link between loss of CP checkpoint properties and dysregulation of the CP immune milieu as a conserved feature across diverse neurological conditions. In particular, we suggest that an imbalance between different immune signals at the CP, including CD4+ T cell-derived cytokines, type-I interferon, and complement components, can perpetuate brain inflammation and cognitive deterioration in aging and neurodegeneration. Furthermore, we highlight the role of CP metabolism in controlling CP inflammation, and propose that targeting molecules that regulate CP metabolism could be effective in safeguarding brain function.

Keywords:  T cells; aging; checkpoint; inflammation; interferon; metabolism; neurodegeneration

DOI:  https://doi.org/10.1016/j.tins.2024.05.010
J Proteome Res. 2024 Jul 05.

Multiomics to Characterize the Molecular Events Underlying Impaired Glucose Tolerance in FXR-Knockout Mice.

Yun-Chung Hsiao, Yifei Yang, Chih-Wei Liu, Jingya Peng, Jiahao Feng, Haoduo Zhao, Taylor Teitelbaum, Kun Lu.

  The prevalence of different metabolic syndromes has grown globally, and the farnesoid X receptor (FXR), a metabolic homeostat for glucose, lipid, and bile acid metabolisms, may serve an important role in the progression of metabolic disorders. Glucose intolerance by FXR deficiency was previously reported and observed in our study, but the underlying biology remained unclear. To investigate the ambiguity, we collected the nontargeted profiles of the fecal metaproteome, serum metabolome, and liver proteome in Fxr-null (Fxr-/-) and wild-type (WT) mice with LC-HRMS. FXR deficiency showed a global impact on the different molecular levels we monitored, suggesting its serious disruption in the gut microbiota, hepatic metabolism, and circulating biomolecules. The network and enrichment analyses of the dysregulated metabolites and proteins suggested the perturbation of carbohydrate and lipid metabolism by FXR deficiency. Fxr-/- mice presented lower levels of hepatic proteins involved in glycogenesis. The impairment of glycogenesis by an FXR deficiency may leave glucose to accumulate in the circulation, which may deteriorate glucose tolerance. Lipid metabolism was dysregulated by FXR deficiency in a structural-dependent manner. Fatty acid β-oxidations were alleviated, but cholesterol metabolism was promoted by an FXR deficiency. Together, we explored the molecular events associated with glucose intolerance by impaired FXR with integrated novel multiomic data.

Keywords:  FXR; glucose tolerance; metabolic syndrome; metabolomic; metaproteomic; proteomic

DOI:  https://doi.org/10.1021/acs.jproteome.3c00475
Neuron. 2024 Jul 03. pii: S0896-6273(24)00407-0. [Epub ahead of print]112(13): 2081-2083

Pericytes: Unsung heroes in myelin repair after neonatal brain hypoxia.

Vanessa Coelho-Santos, Andy Y Shih.

Preterm infants can face lasting neurodevelopmental challenges due to hypoxia-induced injury of the cerebral white matter. In this issue of Neuron, Ren et al.1 identify microvascular pericytes as unexpected targets for growth hormone signaling, which enhances angiogenesis and remyelination after hypoxic injury in the developing mouse brain.

DOI: https://doi.org/10.1016/j.neuron.2024.05.030
Essays Biochem. 2024 Jul 04. pii: EBC20230085. [Epub ahead of print]

Physiology of malate dehydrogenase and how dysregulation leads to disease.

Amy D Parente, Danielle E Bolland, Kathryn L Huisinga, Joseph J Provost.

  Malate dehydrogenase (MDH) is pivotal in mammalian tissue metabolism, participating in various pathways beyond its classical roles and highlighting its adaptability to cellular demands. This enzyme is involved in maintaining redox balance, lipid synthesis, and glutamine metabolism and supports rapidly proliferating cells' energetic and biosynthetic needs. The involvement of MDH in glutamine metabolism underlines its significance in cell physiology. In contrast, its contribution to lipid metabolism highlights its role in essential biosynthetic processes necessary for cell maintenance and proliferation. The enzyme's regulatory mechanisms, such as post-translational modifications, underscore its complexity and importance in metabolic regulation, positioning MDH as a potential target in metabolic dysregulation. Furthermore, the association of MDH with various pathologies, including cancer and neurological disorders, suggests its involvement in disease progression. The overexpression of MDH isoforms MDH1 and MDH2 in cancers like breast, prostate, and pancreatic ductal adenocarcinoma, alongside structural modifications, implies their critical role in the metabolic adaptation of tumor cells. Additionally, mutations in MDH2 linked to pheochromocytomas, paragangliomas, and other metabolic diseases emphasize MDH's role in metabolic homeostasis. This review spotlights MDH's potential as a biomarker and therapeutic target, advocating for further research into its multifunctional roles and regulatory mechanisms in health and disease.

Keywords:  MDH; OAA; TCA; disease; malate dehydrogenase; metabolism

DOI:  https://doi.org/10.1042/EBC20230085
Nat Commun. 2024 Jul 04. 15(1): 5627

Illuminating the dark space of neutral glycosphingolipidome by selective enrichment and profiling at multi-structural levels.

Zidan Wang, Donghui Zhang, Junhan Wu, Wenpeng Zhang, Yu Xia.

Glycosphingolipids (GSLs) are essential components of cell membranes, particularly enriched in the nervous system. Altered molecular distributions of GSLs are increasingly associated with human diseases, emphasizing the significance of lipidomic profiling. Traditional GSL analysis methods are hampered by matrix effect from phospholipids and the difficulty in distinguishing structural isomers. Herein, we introduce a highly sensitive workflow that harnesses magnetic TiO2 nanoparticle-based selective enrichment, charge-tagging Paternò-Büchi reaction, and liquid chromatography-tandem mass spectrometry. This approach enables mapping over 300 distinct GSLs in brain tissues by defining sugar types, long chain bases, N-acyl chains, and the locations of desaturation and hydroxylation. Relative quantitation of GSLs across multiple structural levels provides evidence of dysregulated gene and protein expressions of FA2H and CerS2 in human glioma tissue. Based on the structural features of GSLs, our method accurately differentiates human glioma with/without isocitrate dehydrogenase genetic mutation, and normal brain tissue.

DOI: https://doi.org/10.1038/s41467-024-50014-8
J Inherit Metab Dis. 2024 Jul 01.

MRI in LARS1 deficiency-Spectrum, patterns, and correlation with acute neurological deterioration.

Nicole Hammann, Dominic Lenz, Alyssa Bianzano, Ralf A Husain, Eva Forman, Jonathan A Bernstein, Tal Dattner, Marc Engelen, Andrea K Hanson-Kahn, Bertrand Isidor, Urania Kotzaeridou, Anna Tietze, Regina Trollmann, Claudia Weiß, Bruce H R Wolffenbuttel, Stefan Kölker, Georg F Hoffmann, Ellen Crushell, Christian Staufner, Alexander Mohr, Inga Harting.

  Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.

Keywords:  ILFS1; LARS1; MRI; acute liver failure; aminoacyl‐tRNA synthetase deficiencies; cerebellar watershed; encephalopathy; metabolic stroke; thalamus

DOI:  https://doi.org/10.1002/jimd.12764
Natl Sci Rev. 2024 Jun;11(6): nwae182

Lysophosphatidylcholine binds α-synuclein and prevents its pathological aggregation.

Chunyu Zhao, Jia Tu, Chuchu Wang, Wenbin Liu, Jinge Gu, Yandong Yin, Shengnan Zhang, Dan Li, Jiajie Diao, Zheng-Jiang Zhu, Cong Liu.

  Accumulation of aggregated α-synuclein (α-syn) in Lewy bodies is the pathological hallmark of Parkinson's disease (PD). Genetic mutations in lipid metabolism are causative for a subset of patients with Parkinsonism. The role of α-syn's lipid interactions in its function and aggregation is recognized, yet the specific lipids involved and how lipid metabolism issues trigger α-syn aggregation and neurodegeneration remain unclear. Here, we found that α-syn shows a preference for binding to lysophospholipids (LPLs), particularly targeting lysophosphatidylcholine (LPC) without relying on electrostatic interactions. LPC is capable of maintaining α-syn in a compact conformation, significantly reducing its propensity to aggregate both in vitro and within cellular environments. Conversely, a reduction in the production of cellular LPLs is associated with an increase in α-syn accumulation. Our work underscores the critical role of LPLs in preserving the natural conformation of α-syn to inhibit improper aggregation, and establishes a potential connection between lipid metabolic dysfunction and α-syn aggregation in PD.

Keywords:  Parkinson's disease; lysophosphatidylcholine, aggregation; α-synuclein

DOI:  https://doi.org/10.1093/nsr/nwae182
Ageing Res Rev. 2024 Jun 29. pii: S1568-1637(24)00212-5. [Epub ahead of print]99 102394

Delineation of the role of G6PD in Alzheimer's disease and potential enhancement through microfluidic and nanoparticle approaches.

Omnya A Sharallah, Nitesh Kumar Poddar, Omnia A Alwadan.

  Alzheimer's disease (AD) is a neurodegenerative pathologic entity characterized by the abnormal presence of tau and macromolecular Aβ deposition that leads to the degeneration or death of neurons. In addition to that, glucose-6-phosphate dehydrogenase (G6PD) has a multifaceted role in the process of AD development, where it can be used as both a marker and a target. G6PD activity is dysregulated due to its contribution to oxidative stress, neuroinflammation, and neuronal death. In this context, the current review presents a vivid depiction of recent findings on the relationship between AD progression and changes in the expression or activity of G6PD. The efficacy of the proposed G6PD-based therapeutics has been demonstrated in multiple studies using AD mouse models as representative animal model systems for cognitive decline and neurodegeneration associated with this disease. Innovative therapeutic insights are made for the boosting of G6PD activity via novel innovative nanotechnology and microfluidics tools in drug administration technology. Such approaches provide innovative methods of surpassing the blood-brain barrier, targeting step-by-step specific neural pathways, and overcoming biochemical disturbances that accompany AD. Using different nanoparticles loaded with G6DP to target specific organs, e.g., G6DP-loaded liposomes, enhances BBB penetration and brain distribution of G6DP. Many nanoparticles, which are used for different purposes, are briefly discussed in the paper. Such methods to mimic BBB on organs on-chip offer precise disease modeling and drug testing using microfluidic chips, requiring lower sample amounts and producing faster findings compared to conventional techniques. There are other contributions to microfluid in AD that are discussed briefly. However, there are some limitations accompanying microfluidics that need to be worked on to be used for AD. This study aims to bridge the gap in understanding AD with the synergistic use of promising technologies; microfluid and nanotechnology for future advancements.

Keywords:  Alzheimer's disease (AD); Aβ (Abeta) peptide; Blood-Brain Barrier (BBB); Glucose-6-phosphate dehydrogenase (G6PD); Gold nanoparticles (AuNPs); Microfluidics

DOI:  https://doi.org/10.1016/j.arr.2024.102394
Dev Med Child Neurol. 2024 Jul 04.

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

DOI: https://doi.org/10.1111/dmcn.16032
BMC Neurol. 2024 Jul 05. 24(1): 235

Rate of abnormalities in quantitative MR neuroimaging of persons with chronic traumatic brain injury.

Farzaneh Rahmani, Richard D Batson, Alexandra Zimmerman, Samir Reddigari, Erin D Bigler, Shawn C Lanning, Eveline Ilasa, Jordan H Grafman, Hanzhang Lu, Alexander P Lin, Cyrus A Raji.

  BACKGROUND: Mild traumatic brain injury (mTBI) can result in lasting brain damage that is often too subtle to detect by qualitative visual inspection on conventional MR imaging. Although a number of FDA-cleared MR neuroimaging tools have demonstrated changes associated with mTBI, they are still under-utilized in clinical practice.METHODS: We investigated a group of 65 individuals with predominantly mTBI (60 mTBI, 48 due to motor-vehicle collision, mean age 47 ± 13 years, 27 men and 38 women) with MR neuroimaging performed in a median of 37 months post-injury. We evaluated abnormalities in brain volumetry including analysis of left-right asymmetry by quantitative volumetric analysis, cerebral perfusion by pseudo-continuous arterial spin labeling (PCASL), white matter microstructure by diffusion tensor imaging (DTI), and neurometabolites via magnetic resonance spectroscopy (MRS).
RESULTS: All participants demonstrated atrophy in at least one lobar structure or increased lateral ventricular volume. The globus pallidi and cerebellar grey matter were most likely to demonstrate atrophy and asymmetry. Perfusion imaging revealed significant reductions of cerebral blood flow in both occipital and right frontoparietal regions. Diffusion abnormalities were relatively less common though a subset analysis of participants with higher resolution DTI demonstrated additional abnormalities. All participants showed abnormal levels on at least one brain metabolite, most commonly in choline and N-acetylaspartate.
CONCLUSION: We demonstrate the presence of coup-contrecoup perfusion injury patterns, widespread atrophy, regional brain volume asymmetry, and metabolic aberrations as sensitive markers of chronic mTBI sequelae. Our findings expand the historic focus on quantitative imaging of mTBI with DTI by highlighting the complementary importance of volumetry, arterial spin labeling perfusion and magnetic resonance spectroscopy neurometabolite analyses in the evaluation of chronic mTBI.

Keywords:  Diffusion Tensor Imaging; Magnetic resonance spectroscopy; Pseudocontinuous arterial spin labeling; Traumatic brain Injury

DOI:  https://doi.org/10.1186/s12883-024-03745-6
J Clin Invest. 2024 Jul 01. pii: e175560. [Epub ahead of print]134(13):

Primary cilia formation requires the Leigh syndrome-associated mitochondrial protein NDUFAF2.

Chien-Hui Lo, Zhiquan Liu, Siyu Chen, Frank Lin, Andrew R Berneshawi, Charles Q Yu, Euna B Koo, Tia J Kowal, Ke Ning, Yang Hu, Won-Jing Wang, Y Joyce Liao, Yang Sun.

  Mitochondria-related neurodegenerative diseases have been implicated in the disruption of primary cilia function. Mutation in an intrinsic mitochondrial complex I component NDUFAF2 has been identified in Leigh syndrome, a severe inherited mitochondriopathy. Mutations in ARMC9, which encodes a basal body protein, cause Joubert syndrome, a ciliopathy with defects in the brain, kidney, and eye. Here, we report a mechanistic link between mitochondria metabolism and primary cilia signaling. We discovered that loss of NDUFAF2 caused both mitochondrial and ciliary defects in vitro and in vivo and identified NDUFAF2 as a binding partner for ARMC9. We also found that NDUFAF2 was both necessary and sufficient for cilia formation and that exogenous expression of NDUFAF2 rescued the ciliary and mitochondrial defects observed in cells from patients with known ARMC9 deficiency. NAD+ supplementation restored mitochondrial and ciliary dysfunction in ARMC9-deficient cells and zebrafish and ameliorated the ocular motility and motor deficits of a patient with ARMC9 deficiency. The present results provide a compelling mechanistic link, supported by evidence from human studies, between primary cilia and mitochondrial signaling. Importantly, our findings have significant implications for the development of therapeutic approaches targeting ciliopathies.

Keywords:  Cell biology; Neurodegeneration; Neurological disorders; Ophthalmology; Retinopathy

DOI:  https://doi.org/10.1172/JCI175560
Eur J Pharmacol. 2024 Jun 29. pii: S0014-2999(24)00492-8. [Epub ahead of print]978 176804

A review on polyamines as promising next-generation neuroprotective and anti-aging therapy.

Richmond Arthur, Sumit Jamwal, Puneet Kumar.

  Neurodegenerative disorders are diseases characterized by progressive degeneration of neurons and associated structures and are a major global issue growing more widespread as the global population's average age increases. Despite several investigations on their etiology, the specific cause of these disorders remains unknown. However, there are few symptomatic therapies to treat these disorders. Polyamines (PAs) (putrescine, spermidine, and spermine) are being studied for their role in neuroprotection, aging and cognitive impairment. They are ubiquitous polycations which have relatively higher concentrations in the brain and possess pleiotropic biochemical activities, including regulation of gene expression, ion channels, mitochondria Ca2+ transport, autophagy induction, programmed cell death, and many more. Their cellular content is tightly regulated, and substantial evidence indicates that their altered levels and metabolism are strongly implicated in aging, stress, cognitive dysfunction, and neurodegenerative disorders. In addition, dietary polyamine supplementation has been reported to induce anti-aging effects, anti-oxidant effects, and improve locomotor abnormalities, and cognitive dysfunction. Thus, restoring the polyamine level is considered a promising pharmacological strategy to counteract neurodegeneration. This review highlights PAs' physiological role and the molecular mechanism underpinning their proposed neuroprotective effect in aging and neurodegenerative disorders.

Keywords:  Autophagy; Mitochondrial dysfunction; Neurodegeneration; Neuroprotection; Oxidative stress; Polyamines

DOI:  https://doi.org/10.1016/j.ejphar.2024.176804
Zhonghua Nei Ke Za Zhi. 2024 Jul 01. 63(7): 674-679

[Clinical, imaging, and pathological characteristics of 35 cases of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome].

S Xu, L J Qu, X Chen, X L Zhu, F N Niu.

Objective: To summarize the clinical, imaging, and pathological characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) to improve the diagnosis of this rare disease. Methods: A retrospective case series was conducted to collect the clinical data and results of genetic testing, muscle biopsy, and imaging studies including computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) of 35 patients with MELAS admitted to the Nanjing Drum Tower Hospital from 2012 to 2021. Descriptive statistical analysis including mean, standard deviation, and frequency percentage were carried out. Results: The average age of onset of the patients was 30.2±2.3 years; the prevalence of family history was 20%. The two main initial symptoms were limb weakness and convulsions. The clinical manifestations of the neuromuscular system were proximal muscle weakness and exercise intolerance. The endocrine system is the most affected outside the neuromuscular system, with diabetes being the most common condition. Among the five patients who underwent brain CT, four showed hypodense lesions and two had calcified lesions. Brain MRI in 26 patients showed that the lesions more often affected the parietal lobe, basal ganglia, temporal lobe, occipital lobe, and frontal lobe than the infratentorial areas. Twelve of these individuals exhibited different levels of brain atrophy. Among the 10 patients who underwent 1H-MRS, nine showed a decrease in N-acetylaspartate (NAA) levels, eight exhibited abnormal lactate elevation (Lac peaks), whereas six had both reduced NAA levels and the presence of Lac peaks. Thirty-one patients underwent genetic testing; among them, 25 were found to have the mt.3243A>G mutation, while the remaining six exhibited rare gene alterations. Muscle biopsies were performed in 21 patients, and 15 showed abnormal mitochondrial proliferation manifested by ragged red fibers and defective oxidative phosphorylation manifested by cytochrome C oxidase (COX) enzyme-deficient muscle fibers. Conclusion: The clinical manifestations of MELAS syndrome are variable and complex, and early atypical symptoms could be missed or misdiagnosed. A detailed clinical history, imaging MRS analysis, muscle biopsy, and genetic testing are necessary to confirm the accurate diagnosis of MELAS.

DOI: https://doi.org/10.3760/cma.j.cn112138-20231227-00411