bims-medebr 2024-02-18 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–02–18
eightteen papers selected by
Regina F. Fernández, Johns Hopkins University

Exogenous Substrates Prevent the Decline in the Cellular ATP Content of Primary Rat Astrocytes During Glucose Deprivation.
A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.
Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP SAA knock-in mouse model of Alzheimer's disease.
Plasma lipidomics analysis reveals altered profile of triglycerides and phospholipids in children with Medium-Chain Acyl-CoA dehydrogenase deficiency.
Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
PARP-1 inhibitor alleviates cerebral ischemia/reperfusion injury by reducing PARylation of HK-1 and LDH in mice.
MUFA synthesis and stearoyl-CoA desaturase as a new pharmacological target for modulation of lipid and alpha-synuclein interaction against Parkinson's disease synucleinopathy.
Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.
Hereditary spastic paraplegia type 35 in a Turkish girl with fatty acid hydroxylase-associated neurodegeneration.
Mechanisms and functions of protein S-acylation.
Hypothalamic AMP-Activated Protein Kinase as a Whole-Body Energy Sensor and Regulator.
Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.
Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease.
Loss of function and reduced levels of sphingolipid desaturase DEGS1 variants are both relevant in disease mechanism.
Metabolic Reprogramming in Gliocyte Post-cerebral Ischemia/ Reperfusion: From Pathophysiology to Therapeutic Potential.
Potential for a cerebellar role in moderate-late preterm associated behavioural disorders.
NADH: the redox sensor in aging-related disorders.
Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.

Neurochem Res. 2024 Feb 11.

Exogenous Substrates Prevent the Decline in the Cellular ATP Content of Primary Rat Astrocytes During Glucose Deprivation.

Antonia Regina Harders, Paul Spellerberg, Ralf Dringen.

  Brain astrocytes are well known for their broad metabolic potential. After glucose deprivation, cultured primary astrocytes maintain a high cellular ATP content for many hours by mobilizing endogenous substrates, but within 24 h the specific cellular ATP content was lowered to around 30% of the initial ATP content. This experimental setting was used to test for the potential of various exogenous substrates to prevent a loss in cellular ATP in glucose deprived astrocytes. The presence of various extracellular monocarboxylates, purine nucleosides or fatty acids prevented the loss of ATP from glucose-deprived astrocytes. Of the 20 proteinogenic amino acids, only alanine, aspartate, glutamate, glutamine, lysine or proline maintained high ATP levels in starved astrocytes. Among these amino acids, proline was found to be the most potent one to prevent the ATP loss. The astrocytic consumption of proline as well as the ability of proline to maintain a high cellular ATP content was prevented in a concentration-dependent manner by the proline dehydrogenase inhibitor tetrahydro-2-furoic acid. Analysis of the concentration-dependencies obtained by considering the different carbon content of the applied substrates revealed that fatty acids and proline are more potent than glucose and monocarboxylates as exogenous substrates to prevent ATP depletion in glucose-deprived astrocytes. These data demonstrate that cultured astrocytes can utilise a wide range of extracellular substrates as fuels to support mitochondrial ATP regeneration and identify proline as potent exogenous substrate for the energy metabolism of starved astrocytes.

Keywords:  ATP; Amino acids; Fatty acids; Metabolism; Mitochondria; Nucleosides; Proline

DOI:  https://doi.org/10.1007/s11064-024-04104-0
Nat Neurosci. 2024 Feb 15.

A neuron-glia lipid metabolic cycle couples daily sleep to mitochondrial homeostasis.

Paula R Haynes, Elana S Pyfrom, Yongjun Li, Carly Stein, Vishnu Anand Cuddapah, Jack A Jacobs, Zhifeng Yue, Amita Sehgal.

Sleep is thought to be restorative to brain energy homeostasis, but it is not clear how this is achieved. We show here that Drosophila glia exhibit a daily cycle of glial mitochondrial oxidation and lipid accumulation that is dependent on prior wake and requires the Drosophila APOE orthologs NLaz and GLaz, which mediate neuron-glia lipid transfer. In turn, a full night of sleep is required for glial lipid clearance, mitochondrial oxidative recovery and maximal neuronal mitophagy. Knockdown of neuronal NLaz causes oxidative stress to accumulate in neurons, and the neuronal mitochondrial integrity protein, Drp1, is required for daily glial lipid accumulation. These data suggest that neurons avoid accumulation of oxidative mitochondrial damage during wake by using mitophagy and passing damage to glia in the form of lipids. We propose that a mitochondrial lipid metabolic cycle between neurons and glia reflects a fundamental function of sleep relevant for brain energy homeostasis.

DOI: https://doi.org/10.1038/s41593-023-01568-1
bioRxiv. 2024 Feb 04. pii: 2024.02.02.578668. [Epub ahead of print]

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP SAA knock-in mouse model of Alzheimer's disease.

Andrés Norambuena, Vijay Kumar Sagar, Zhuoying Wang, Prakash Raut, Ziang Feng, Horst Wallrabe, Evelyn Pardo, Taylor Kim, Shagufta Rehman Alam, Song Hu, Ammasi Periasamy, George S Bloom.

Introduction: Reduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-β oligomer (xcAβO) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit N utrient-induced M itochondrial A ctivity (NiMA) in cultured neurons. We now report NiMA disruption in vivo .
Methods: Brain energy metabolism and oxygen consumption were recorded in APP SAA/+ mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.
Results: NiMA is inhibited in APP SAA/+ mice before other defects are detected in these amyloid-β-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3β signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP SAA mice.
Conclusion: NiMA disruption in vivo occurs before histopathological changes and cognitive decline in APP SAA mice, and may represent an early stage in human AD.

DOI: https://doi.org/10.1101/2024.02.02.578668
J Inherit Metab Dis. 2024 Feb 14.

Plasma lipidomics analysis reveals altered profile of triglycerides and phospholipids in children with Medium-Chain Acyl-CoA dehydrogenase deficiency.

Inês M S Guerra, Helena B Ferreira, Tatiana Maurício, Marisa Pinho, Luísa Diogo, Sónia Moreira, Laura Goracci, Stefano Bonciarelli, Tânia Melo, Pedro Domingues, M Rosário Domingues, Ana S P Moreira.

  Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most prevalent mitochondrial fatty acid β-oxidation disorder. In this study, we assessed the variability of the lipid profile in MCADD by analysing plasma samples obtained from 25 children with metabolically controlled MCADD (following a normal diet with frequent feeding and under l-carnitine supplementation) and 21 paediatric control subjects (CT). Gas chromatography-mass spectrometry was employed for the analysis of esterified fatty acids, while high-resolution C18-liquid chromatography-mass spectrometry was used to analyse lipid species. We identified a total of 251 lipid species belonging to 15 distinct lipid classes. Principal component analysis revealed a clear distinction between the MCADD and CT groups. Univariate analysis demonstrated that 126 lipid species exhibited significant differences between the two groups. The lipid species that displayed the most pronounced variations included triacylglycerols and phosphatidylcholines containing saturated and monounsaturated fatty acids, specifically C14:0 and C16:0, which were found to be more abundant in MCADD. The observed changes in the plasma lipidome of children with non-decompensated MCADD suggest an underlying alteration in lipid metabolism. Therefore, longitudinal monitoring and further in-depth investigations are warranted to better understand whether such alterations are specific to MCADD children and their potential long-term impacts.

Keywords:  Lipid profile; Lipidomics; Mass spectrometry; Medium-chain acyl-CoA dehydrogenase deficiency (MCADD); Phospholipids (PL); Plasma analysis; Triacylglycerols (TG)

DOI:  https://doi.org/10.1002/jimd.12718
Cell. 2024 Feb 08. pii: S0092-8674(24)00067-9. [Epub ahead of print]

Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.

Baiyu Qiu, Fereshteh Zandkarimi, Carla T Bezjian, Eduard Reznik, Rajesh Kumar Soni, Wei Gu, Xuejun Jiang, Brent R Stockwell.

  Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.

Keywords:  PUFA; ROS; complex I; diacyl-PUFA phosphatidylcholine; electron transport chain; ferroptosis; lipids; mitochondria; phospholipid; polyunsaturated fatty acid

DOI:  https://doi.org/10.1016/j.cell.2024.01.030
Eur J Pharmacol. 2024 Feb 10. pii: S0014-2999(24)00065-7. [Epub ahead of print]967 176377

PARP-1 inhibitor alleviates cerebral ischemia/reperfusion injury by reducing PARylation of HK-1 and LDH in mice.

Ya-Ling Chen, Yi Wang, Qiu-Yu Fang, Tong Wang, Cong Chen, Tong-Yao Gao, Ming Wu, Wei-Ping Zhang, Yun-Bi Lu.

  Poly (ADP-ribose) polymerase-1 (PARP-1) activity significantly increases during cerebral ischemia/reperfusion. PARP-1 is an NAD+-consumption enzyme. PARP-1 hyperactivity causes intracellular NAD+ deficiency and bioenergetic collapse, contributing to neuronal death. Besides, the powerful trigger of PARP-1 causes the catalyzation of poly (ADP-ribosyl)ation (PARylation), a posttranslational modification of proteins. Here, we found that PARP-1 was activated in the ischemic brain tissue during middle-cerebral-artery occlusion and reperfusion (MCAO/R) for 24 h, and PAR accumulated in the neurons in mice. Using immunoprecipitation, Western blotting, liquid chromatography-mass spectrometry, and 3D-modeling analysis, we revealed that the activation of PARP-1 caused PARylation of hexokinase-1 and lactate dehydrogenase-B, which, therefore, caused the inhibition of these enzyme activities and the resulting cell energy metabolism collapse. PARP-1 inhibition significantly reversed the activity of hexokinase and lactate dehydrogenase, decreased infarct volume, and improved neuronal deficiency. PARP-1 inhibitor combined with pyruvate further alleviated MCAO/R-induced ischemic brain injury in mice. As such, we conclude that PARP-1 inhibitor alleviates neuronal death partly by inhibiting the PARylation of metabolic-related enzymes and reversing metabolism reprogramming during cerebral ischemia/reperfusion injury in mice. PARP-1 inhibitor combined with pyruvate might be a promising therapeutic approach against brain ischemia/reperfusion injury.

Keywords:  Cerebral ischemia/reperfusion; Hexokinase (HK); Lactate dehydrogenase (LDH); Poly (ADP-ribose) polymerase 1 (PARP-1); Poly(ADP-ribosyl)ation (PARylation)

DOI:  https://doi.org/10.1016/j.ejphar.2024.176377
Neuropharmacology. 2024 Feb 09. pii: S0028-3908(24)00032-7. [Epub ahead of print] 109865

MUFA synthesis and stearoyl-CoA desaturase as a new pharmacological target for modulation of lipid and alpha-synuclein interaction against Parkinson's disease synucleinopathy.

Joanna Kula, Katarzyna Z Kuter.

  Protein pathology spreading within the nervous system, accompanies neurodegeneration and a spectrum of motor and cognitive dysfunctions. Currently available therapies against Parkinson's disease and other synucleinopathies are mostly symptomatic and fail to slow the disease progression in the long term. Modification of α synuclein (αS) aggregation and toxicity of its pathogenic forms is one of the main goals in neuroprotective approach. Since the discovery of lipid component of Lewy bodies fatty acids became a crucial, yet little explored target for research. MUFAs (monounsaturated fatty acids) are substrates for lipids, such as phospholipids, triglycerides and cholesteryl esters. They regulate membrane fluidity, take part in signal transduction, cellular differentiation and other fundamental processes. αS and MUFA interactions are essential for Lewy body pathology. αS increases level of MUFAs, mainly oleic acid, which in turn can enhance αS toxicity and aggregation. Thus, reduction of MUFAs synthesis by inhibition of stearoyl-CoA desaturase (SCD) activity could be the new way to prevent aggravation of αS pathology. Due to the limited distribution in peripheral tissues, SCD5 is a potential target in novel therapies and therefore could be an important starting point in search for disease-modifying neuroprotective therapy. Here we summarize facts about physiology and pathology of αS, explain recently discovered lipid-αS interactions, review SCD function and involved mechanisms, present available SCD inhibitors and discuss their pharmacological potential in disease management. Modulation of MUFA synthesis, decreasing αS and lipid toxicity is clearly essential, but unexplored avenue in pharmacotherapy in Parkinson's disease and synucleinopathies.

Keywords:  Alpha-synuclein; Fatty acids; Lewy bodies; Monounsaturated fatty acids; New pharmacotherapies; Saturated fatty acid metabolism

DOI:  https://doi.org/10.1016/j.neuropharm.2024.109865
Glia. 2024 Feb 16.

Transient demyelination causes long-term cognitive impairment, myelin alteration and network synchrony defects.

Océane Mercier, Pascale P Quilichini, Karine Magalon, Florian Gil, Antoine Ghestem, Fabrice Richard, Thomas Boudier, Myriam Cayre, Pascale Durbec.

  In the adult brain, activity-dependent myelin plasticity is required for proper learning and memory consolidation. Myelin loss, alteration, or even subtle structural modifications can therefore compromise the network activity, leading to functional impairment. In multiple sclerosis, spontaneous myelin repair process is possible, but it is heterogeneous among patients, sometimes leading to functional recovery, often more visible at the motor level than at the cognitive level. In cuprizone-treated mouse model, massive brain demyelination is followed by spontaneous and robust remyelination. However, reformed myelin, although functional, may not exhibit the same morphological characteristics as developmental myelin, which can have an impact on the activity of neural networks. In this context, we used the cuprizone-treated mouse model to analyze the structural, functional, and cognitive long-term effects of transient demyelination. Our results show that an episode of demyelination induces despite remyelination long-term cognitive impairment, such as deficits in spatial working memory, social memory, cognitive flexibility, and hyperactivity. These deficits were associated with a reduction in myelin content in the medial prefrontal cortex (mPFC) and hippocampus (HPC), as well as structural myelin modifications, suggesting that the remyelination process may be imperfect in these structures. In vivo electrophysiological recordings showed that the demyelination episode altered the synchronization of HPC-mPFC activity, which is crucial for memory processes. Altogether, our data indicate that the myelin repair process following transient demyelination does not allow the complete recovery of the initial myelin properties in cortical structures. These subtle modifications alter network features, leading to prolonged cognitive deficits in mice.

Keywords:  Cognition; Mouse model of multiple sclerosis; Myelin regeneration; Network activity

DOI:  https://doi.org/10.1002/glia.24513
J Pediatr Endocrinol Metab. 2024 Feb 06.

Hereditary spastic paraplegia type 35 in a Turkish girl with fatty acid hydroxylase-associated neurodegeneration.

Ayşenur Engin Erdal, Burak Yürek, Oya Kıreker Köylü, Ahmet Cevdet Ceylan, Ayşegül Neşe Çıtak Kurt, Çiğdem Seher Kasapkara.

   OBJECTIVES: The fatty acid 2-hydroxylase gene (FA2H) compound heterozygous or homozygous variants that cause spastic paraplegia type 35 (SPG35) (OMIM # 612319) are autosomal recessive HSPs. FA2H gene variants in humans have been shown to be associated with not only SPG35 but also leukodystrophy and neurodegeneration with brain iron accumulation.
CASE PRESENTATION: A patient with a spastic gait since age seven was admitted to the paediatric metabolism department. She was born to consanguineous, healthy Turkish parents and had no family history of neurological disease. She had normal developmental milestones and was able to walk at 11 months. At age seven, she developed a progressive gait disorder with increased muscle tone in her lower limbs, bilateral ankle clonus and dysdiadochokinesis. She had frequent falls and deteriorating school performance. Despite physiotherapy, her spastic paraplegia was progressive. Whole exome sequencing (WES) identified a homozygous NM_024306.5:c.460C>T missense variant in the FA2H gene, of which her parents were heterozygous carriers. A brain MRI showed a slight reduction in the cerebellar volume with no iron deposits.
CONCLUSIONS: Pathogenic variants of the FA2H gene have been linked to neurodegeneration with iron accumulation in the brain, leukodystrophy and SPG35. When patients developed progressive gait deterioration since early childhood even if not exhibited hypointensity in the basal ganglia detected by neuroimaging, FA2H-related neurodegeneration with brain iron accumulation should be ruled out. FA2H/SPG35 disease is characterised by notable clinical and imaging variability, as well as phenotypic diversity.

Keywords:   FA2H ; SPG35; brain iron accumulation; pontocerebellar atrophy

DOI:  https://doi.org/10.1515/jpem-2023-0481
Nat Rev Mol Cell Biol. 2024 Feb 14.

Mechanisms and functions of protein S-acylation.

Francisco S Mesquita, Laurence Abrami, Maurine E Linder, Shernaz X Bamji, Bryan C Dickinson, F Gisou van der Goot.

Over the past two decades, protein S-acylation (often referred to as S-palmitoylation) has emerged as an important regulator of vital signalling pathways. S-Acylation is a reversible post-translational modification that involves the attachment of a fatty acid to a protein. Maintenance of the equilibrium between protein S-acylation and deacylation has demonstrated profound effects on various cellular processes, including innate immunity, inflammation, glucose metabolism and fat metabolism, as well as on brain and heart function. This Review provides an overview of current understanding of S-acylation and deacylation enzymes, their spatiotemporal regulation by sophisticated multilayered mechanisms, and their influence on protein function, cellular processes and physiological pathways. Furthermore, we examine how disruptions in protein S-acylation are associated with a broad spectrum of diseases from cancer to autoinflammatory disorders and neurological conditions.

DOI: https://doi.org/10.1038/s41580-024-00700-8
Endocrinol Metab (Seoul). 2024 Feb 14.

Hypothalamic AMP-Activated Protein Kinase as a Whole-Body Energy Sensor and Regulator.

Se Hee Min, Do Kyeong Song, Chan Hee Lee, Eun Roh, Min-Seon Kim.

  5´-Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a cellular energy sensor, is an essential enzyme that helps cells maintain stable energy levels during metabolic stress. The hypothalamus is pivotal in regulating energy balance within the body. Certain neurons in the hypothalamus are sensitive to fluctuations in food availability and energy stores, triggering adaptive responses to preserve systemic energy equilibrium. AMPK, expressed in these hypothalamic neurons, is instrumental in these regulatory processes. Hypothalamic AMPK activity is modulated by key metabolic hormones. Anorexigenic hormones, including leptin, insulin, and glucagon-like peptide 1, suppress hypothalamic AMPK activity, whereas the hunger hormone ghrelin activates it. These hormonal influences on hypothalamic AMPK activity are central to their roles in controlling food consumption and energy expenditure. Additionally, hypothalamic AMPK activity responds to variations in glucose concentrations. It becomes active during hypoglycemia but is deactivated when glucose is introduced directly into the hypothalamus. These shifts in AMPK activity within hypothalamic neurons are critical for maintaining glucose balance. Considering the vital function of hypothalamic AMPK in the regulation of overall energy and glucose balance, developing chemical agents that target the hypothalamus to modulate AMPK activity presents a promising therapeutic approach for metabolic conditions such as obesity and type 2 diabetes mellitus.

Keywords:  AMP-activated protein kinases; Energy metabolism; Glucose metabolism; Hormones; Hypothalamus

DOI:  https://doi.org/10.3803/EnM.2024.1922
Metab Brain Dis. 2024 Feb 16.

Molecular and in silico investigation of a novel ECHS1 gene mutation in a consanguine family with short-chain enoyl-CoA hydratase deficiency and Mt-DNA depletion: effect on trimer assembly and catalytic activity.

Marwa Maalej, Lamia Sfaihi, Olfa-Alila Fersi, Boudour Khabou, Marwa Ammar, Rahma Felhi, Marwa Kharrat, Jihen Chouchen, Thouraya Kammoun, Abdelaziz Tlili, Faiza Fakhfakh.

  Short-chain enoyl-CoA hydratase deficiency (ECHS1D) is a rare congenital metabolic disorder that follows an autosomal recessive inheritance pattern. It is caused by mutations in the ECHS1 gene, which encodes a mitochondrial enzyme involved in the second step of mitochondrial β-oxidation of fatty acids. The main characteristics of the disease are severe developmental delay, regression, seizures, neurodegeneration, high blood lactate, and a brain MRI pattern consistent with Leigh syndrome. Here, we report three patients belonging to a consanguineous family who presented with mitochondrial encephalomyopathy. Whole-exome sequencing revealed a new homozygous mutation c.619G > A (p.Gly207Ser) at the last nucleotide position in exon 5 of the ECHS1 gene. Experimental analysis showed that normal ECHS1 pre-mRNA splicing occurred in all patients compared to controls. Furthermore, three-dimensional models of wild-type and mutant echs1 proteins revealed changes in catalytic site interactions, conformational changes, and intramolecular interactions, potentially disrupting echs1 protein trimerization and affecting its function. Additionally, the quantification of mtDNA copy number variation in blood leukocytes showed severe mtDNA depletion in all probands.

Keywords:  ECHS1; Short-chain enoyl-CoA hydratase deficiency; mtDNA depletion

DOI:  https://doi.org/10.1007/s11011-024-01343-6
Sci Rep. 2024 Feb 16. 14(1): 3896

Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease.

Hannah Compton, Madeleine L Smith, Caroline Bull, Roxanna Korologou-Linden, Yoav Ben-Shlomo, Joshua A Bell, Dylan M Williams, Emma L Anderson.

  Mechanisms through which most known Alzheimer's disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically.

Keywords:  ALSPAC; APOE; Alzheimer’s disease; Epidemiology; Mendelian randomization; Metabolism; NMR; Polygenic risk score; UK Biobank

DOI:  https://doi.org/10.1038/s41598-024-54569-w
J Lipid Res. 2024 Feb 09. pii: S0022-2275(24)00022-1. [Epub ahead of print] 100517

Loss of function and reduced levels of sphingolipid desaturase DEGS1 variants are both relevant in disease mechanism.

Michele Dei Cas, Linda Montavoci, Claudia Pasini, Anna Caretti, Sara Penati, Carla Martinelli, Umberto Gianelli, Sara Casati, Francesca Nardecchia, Annalaura Torella, Nicola Brunetti-Pierri, Marco Trinchera.

  The last step of ex novo ceramide biosynthesis consists of the conversion of dihydroceramide into ceramide catalyzed by sphingolipid Δ4-desaturase DEGS1. DEGS1 variants were found to be responsible for heterogeneous clinical pictures belonging to the family of hypomyelinating leukodystrophies. To investigate the mechanisms making such variants pathogenic, we designed a procedure for the efficient detection of desaturase activity in vitro using LC-MS/MS and prepared a suitable cell model knocking-out DEGS1 in HEK-293T cells through CRISPR-Cas9 genome editing (KO-DES-HEK). Transfecting KO-DES-HEK cells with DEGS1 variants, we found that their transcripts were all overexpressed as much as the WT transcript, while the levels of cognate protein were 40-80% lower. In vitro desaturase activity was lost by many variants except L175Q and N255S, which maintain a catalytic efficiency close to 12% of the WT enzyme. Metabolic labeling of KO-DES-HEK with deuterated palmitate followed by LC-MS/MS analysis of the formed sphingolipids revealed that the ceramide/dihydroceramide and sphingomyelin/dihydrosphingomyelin ratios were low and could be reverted by the overexpression of WT DEGS1 as well as of L175Q and N255S variants, but not by the overexpression of all other variants. Similar analyses performed on fibroblasts from a patient heterozygous for the N255S variant showed very low variant DEGS1 levels and a low ratio between the same unsaturated and saturated sphingolipids formed upon metabolic labeling, notwithstanding the residual activity measured at high substrate and homogenate protein concentrations. We conclude that loss of function and reduced protein levels are both relevant in disease pathogenesis.

Keywords:  brain lipids; ceramides; dihydroceramide; glycolipids; hypomyelinating leukodystrophy 18; lipidomics; mass spectrometry; sphingolipid biosynthesis; sphingolipids

DOI:  https://doi.org/10.1016/j.jlr.2024.100517
Curr Neuropharmacol. 2024 Feb 16.

Metabolic Reprogramming in Gliocyte Post-cerebral Ischemia/ Reperfusion: From Pathophysiology to Therapeutic Potential.

Lipeng Gong, Junjie Liang, Letian Xie, Zhanwei Zhang, Zhigang Mei, Wenli Zhang.

  Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/ reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes to be reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.

Keywords:  Ischemic stroke; cerebral ischemia/reperfusion injury; gliocyte; metabolic reprogramming; oxidative stress.; pathophysiology

DOI:  https://doi.org/10.2174/1570159X22666240131121032
Front Pediatr. 2024 ;12 1336137

Potential for a cerebellar role in moderate-late preterm associated behavioural disorders.

Carlton L Pavy, Julia C Shaw, Roisin A Moloney, Hannah K Palliser, Jonathon J Hirst.

  Preterm birth is known to cause impaired cerebellar development, and this is associated with the development of neurobehavioral disorders. This review aims to identify the mechanisms through which preterm birth impairs cerebellar development and consequently, increases the risk of developing neurobehavioral disorders. The severity of these disorders is directly related to the degree of prematurity, but it is also evident that even late preterm births are at significantly increased risk of developing serious neurobehavioral disorders. Preterm birth is associated with hypoxic events and increased glutamatergic tone within the neonatal brain which contribute to excitotoxic damage. The cerebellum is a dense glutamatergic region which undergoes relatively late neurodevelopment up to and beyond birth. Evidence indicates that the cerebellum forms reciprocal connections to regions important in behaviour regulation such as the limbic system and frontal cortex. Studies using fMRI (functional magnetic resonance Imaging), BOLD (blood oxygen level dependent) response and morphology studies in humans show the cerebellum is often involved in disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. The vulnerability of the cerebellum to preterm birth insult and its connections to behaviour associated brain regions implicates it in the development of neurobehavioral disorders. Protection against preterm associated insults on the cerebellum may provide a novel avenue through which ADHD and anxiety can be reduced in children born preterm.

Keywords:  cerebellum; hypoxia; myelination; neurodevelopment; neurosteroids; preterm birth

DOI:  https://doi.org/10.3389/fped.2024.1336137
Antioxid Redox Signal. 2024 Feb 17.

NADH: the redox sensor in aging-related disorders.

Giovanna Schiuma, Djidjell Lara, James Clement, Marco Narducci, Roberta Rizzo.

SIGNIFICANCE: NADH represents the reduced form of NAD+, and together they constitute the two forms of the Nicotinamide adenine dinucleotide whose balance is named as the NAD+/NADH ratio. NAD+/NADH ratio is mainly involved in redox reactions since both the molecules are responsible for carrying electrons to maintain redox homeostasis. NADH acts as a reducing agent and one of the most known processes exploiting NADH function is energy metabolism. The two main pathways generating energy and involving NADH are Glycolysis and Oxidative phosphorylation, occurring in cell cytosol and in the mitochondrial matrix, respectively.
RECENT ADVANCES: Although NADH is primarily produced through the reduction of NAD+ and consumed by its own oxidation, several are the biosynthetic and consumption pathways, reflecting the NADH role in multiple cellular processes.
CRITICAL ISSUES: This review gathers all the main current data referring to NADH in correlation with metabolic and cellular pathways, such as its coenzyme activity, effect in cell death and on modulating redox and calcium homeostasis. Data were selected following eligibility criteria accordingly to the reviewed topic. A set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) have been used for a systematic search until January 2024 using MeSH keywords/terms (i.e., NADH, NAD+/NADH and NADH/NAD+ ratio, redox homeostasis, energy metabolism, aging, aging-related disorders, therapies).
FUTURE DIRECTION: Gene expression control, as well as to the potential impact on neurodegenerative, cardiac disorders and infections suggest NADH application in clinical settings.

DOI: https://doi.org/10.1089/ars.2023.0375
Nat Commun. 2024 Feb 13. 15(1): 1328

Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.

Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.

Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

DOI: https://doi.org/10.1038/s41467-024-45524-4