bims-medebr 2024-05-12 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒05‒12
twenty papers selected by
Regina F. Fernández, Johns Hopkins University

Lipid droplets and neurodegeneration.
Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review.
The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects.
Unbiased Insights into the Multiplicity of the CYP46A1 Brain Effects in 5XFAD Mice Treated with Low Dose Efavirenz.
Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis.
Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis.
ORMDL MISLOCALIZATION BY IMPAIRED AUTOPHAGY IN NIEMANN-PICK TYPE C DISEASE LEADS TO INCREASED DE NOVO SPHINGOLIPID BIOSYNTHESIS.
Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System.
Human genetic defects of sphingolipid synthesis.
A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer's disease and aging research.
Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines.
Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.
Intestinal absorption of sphingosine: new insights on generated ceramide species using stable isotope tracing in vitro.
Lipidomic analysis of human TANGO2-deficient cells suggests a lipid imbalance as a cause of TANGO2 deficiency disease.
Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.
Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.
Functional regulation of microglia by vitamin B12 alleviates ischemic stroke-induced neuroinflammation in mice.
Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders.
Arachidonic acid in aging: New roles for old players.

Neuroscience. 2024 May 06. pii: S0306-4522(24)00173-8. [Epub ahead of print]

Lipid droplets and neurodegeneration.

Keya Mallick, Shuchismita Paul, Sayani Banerjee, Sugato Banerjee.

  Energy metabolism in the brain has been considered one of the critical research areas of neuroscience for ages. One of the most vital parts of brain metabolism cascades is lipid metabolism, and fatty acid plays a crucial role in this process. The fatty acid breakdown process in mitochondria undergoes through a conserved pathway known as β-oxidation where acetyl-CoA and shorter fatty acid chains are produced along with a significant amount of energy molecule. Further, the complete breakdown of fatty acids occurs when they enter the mitochondrial oxidative phosphorylation. Cells store energy as neutral lipids in organelles known as Lipid Droplets (LDs) to prepare for variations in the availability of nutrients. Fatty acids are liberated by lipid droplets and are transported to various cellular compartments for membrane biogenesis or as an energy source. Current research shows that LDs are important in inflammation, metabolic illness, and cellular communication. Lipid droplet biology in peripheral organs like the liver and heart has been well investigated, while the brain's LDs have received less attention. Recently, there has been increased awareness of the existence and role of these dynamic organelles in the central nervous system, mainly connected to neurodegeneration. In this review, we discussed the role of beta-oxidation and lipid droplet formation in the oxidative phosphorylation process, which directly affects neurodegeneration through various pathways.

Keywords:  Astrocyte; Lipids; Microglia; Mitochondria; Neurodegenerative disorders; Neuron

DOI:  https://doi.org/10.1016/j.neuroscience.2024.04.014
J Nutr Metab. 2024 ;2024 9672969

Medium-Chain Triglycerides (MCTs) for the Symptomatic Treatment of Dementia-Related Diseases: A Systematic Review.

Nike Meer, Tobias Fischer.

Pathomechanisms of dementias involve increasing damage to neuronal energy metabolism, resulting in degeneration-related insulin resistance and glucose hypometabolism. In this case, ketone bodies can provide an alternative energy source. Supplementation with medium-chain triglycerides (MCTs), which can induce ketogenesis, may alleviate brain energy deficits and improve neuronal function. This review aims to determine the effectiveness of MCT as a symptomatic treatment approach. The systematic literature search was conducted in April 2023 following the Cochrane Handbook and PRISMA guidelines. A total of 21 studies were included, comprising eight uncontrolled trials and 13 RCTs investigating the effects of MCT on Alzheimer's disease (AD) and mild cognitive impairment (MCI). A substantial increase in plasma ketone levels and brain metabolic rates was observed. Cognitive assessments showed only occasional or domain-specific performance improvements. The effects on functional abilities or psychological outcomes have been inadequately studied. Besides gastrointestinal side effects, no harmful effects were observed. However, the evidence was severely weakened by heterogeneous and poorly designed study protocols, bias, and conflicts of interest. In conclusion, the ketogenic properties of MCTs may have beneficial effects on brain metabolism in AD and MCI but do not always result in measurable clinical improvement. Current evidence is insufficient to recommend MCT as a comparable symptomatic treatment option.

DOI: https://doi.org/10.1155/2024/9672969
Heliyon. 2024 May 15. 10(9): e30523

The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects.

Li-Cheng Liu, Jun-Yi Liang, Yan-Hong Liu, Bin Liu, Xiao-Hong Dong, Wen-Hui Cai, Ning Zhang.

  Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly, the exact pathogenesis of which remains incompletely understood, and effective preventive and therapeutic drugs are currently lacking. Cholesterol plays a vital role in cell membrane formation and neurotransmitter synthesis, and its abnormal metabolism is associated with the onset of AD. With the continuous advancement of imaging techniques and molecular biology methods, researchers can more accurately explore the relationship between cholesterol metabolism and AD. Elevated cholesterol levels may lead to vascular dysfunction, thereby affecting neuronal function. Additionally, abnormal cholesterol metabolism may affect the metabolism of β-amyloid protein, thereby promoting the onset of AD. Brain cholesterol levels are regulated by multiple factors. This review aims to deepen the understanding of the subtle relationship between cholesterol homeostasis and AD, and to introduce the latest advances in cholesterol-regulating AD treatment strategies, thereby inspiring readers to contemplate deeply on this complex relationship. Although there are still many unresolved important issues regarding the risk of brain cholesterol and AD, and some studies may have opposite conclusions, further research is needed to enrich our understanding. However, these findings are expected to deepen our understanding of the pathogenesis of AD and provide important insights for the future development of AD treatment strategies targeting brain cholesterol homeostasis.

Keywords:  Alzheimer's disease; Amyloid β protein; Brain cholesterol; Cholesterol homeostasis; Cholesterol metabolism; Therapeutic pathway

DOI:  https://doi.org/10.1016/j.heliyon.2024.e30523
J Lipid Res. 2024 May 06. pii: S0022-2275(24)00060-9. [Epub ahead of print] 100555

Unbiased Insights into the Multiplicity of the CYP46A1 Brain Effects in 5XFAD Mice Treated with Low Dose Efavirenz.

Natalia Mast, Makaya Butts, Irina A Pikuleva.

  CYP46A1 is the CNS-specific cholesterol 24-hydroxylase that controls cholesterol elimination and turnover in the brain. In mouse models, pharmacologic CYP46A1 activation with low dose efavirenz (EFV) or by gene therapy mitigates the manifestations of various brain disorders, neurologic and non-neurologic, by affecting numerous, apparently unliked biological processes. Accordingly, CYP46A1 is emerging as a promising therapeutic target; however, the mechanisms underlying the multiplicity of the brain CYP46A1 activity effects are currently not understood. We proposed the chain reaction hypothesis, according to which CYP46A1 is important for the three primary (unifying) processes in the brain (sterol flux through the plasma membranes, acetyl-CoA and isoprenoid production), which in turn affect a variety of secondary processes. We already identified several processes secondary to changes in sterol flux and herein undertook a multiomics approach to compare the brain proteome, acetylproteome, and metabolome of 5XFAD mice (an Alzheimer's disease model), control and treated with low dose EFV. We found that the latter had increased production of phospholipids from the corresponding lysophospholipids and a globally increased protein acetylation (including histone acetylation). Apparently, these effects were secondary to increased acetyl-CoA production. Signaling of small GTPases due to their altered abundance or abundance of their regulators could be affected as well, potentially via isoprenoid biosynthesis. In addition, the omics data related differentially abundant molecules to other biological processes either reported previously or new. Thus, we obtained unbiased mechanistic insights and identified potential players mediating the multiplicity of the CYP46A1 brain effects and further detailed our chain reaction hypothesis.

Keywords:  brain lipids; cholesterol metabolism; glycerophospholipids; oxysterols; proteomics

DOI:  https://doi.org/10.1016/j.jlr.2024.100555
Neurobiol Dis. 2024 May 02. pii: S0969-9961(24)00119-0. [Epub ahead of print] 106520

Biomarkers of mitochondrial dysfunction in autism spectrum disorder: A systematic review and meta-analysis.

Richard E Frye, Nicole Rincon, Patrick J McCarty, Danielle Brister, Adrienne C Scheck, Daniel A Rossignol.

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting 1 in 36 children and is associated with physiological abnormalities, most notably mitochondrial dysfunction, at least in a subset of individuals. This systematic review and meta-analysis discovered 204 relevant articles which evaluated biomarkers of mitochondrial dysfunction in ASD individuals. Significant elevations (all p < 0.01) in the prevalence of lactate (17%), pyruvate (41%), alanine (15%) and creatine kinase (9%) were found in ASD. Individuals with ASD had significant differences (all p < 0.01) with moderate to large effect sizes (Cohen's d' ≥ 0.6) compared to controls in mean pyruvate, lactate-to-pyruvate ratio, ATP, and creatine kinase. Some studies found abnormal TCA cycle metabolites associated with ASD. Thirteen controlled studies reported mitochondrial DNA (mtDNA) deletions or variations in the ASD group in blood, peripheral blood mononuclear cells, lymphocytes, leucocytes, granulocytes, and brain. Meta-analyses discovered significant differences (p < 0.01) in copy number of mtDNA overall and in ND1, ND4 and CytB genes. Four studies linked specific mtDNA haplogroups to ASD. A series of studies found a subgroup of ASD with elevated mitochondrial respiration which was associated with increased sensitivity of the mitochondria to physiological stressors and neurodevelopmental regression. Lactate, pyruvate, lactate-to-pyruvate ratio, carnitine, and acyl-carnitines were associated with clinical features such as delays in language, social interaction, cognition, motor skills, and with repetitive behaviors and gastrointestinal symptoms, although not all studies found an association. Lactate, carnitine, acyl-carnitines, ATP, CoQ10, as well as mtDNA variants, heteroplasmy, haplogroups and copy number were associated with ASD severity. Variability was found across biomarker studies primarily due to differences in collection and processing techniques as well as the intrinsic heterogeneity of the ASD population. Several studies reported alterations in mitochondrial metabolism in mothers of children with ASD and in neonates who develop ASD. Treatments targeting mitochondria, particularly carnitine and ubiquinol, appear beneficial in ASD. The link between mitochondrial dysfunction in ASD and common physiological abnormalities in individuals with ASD including gastrointestinal disorders, oxidative stress, and immune dysfunction is outlined. Several subtypes of mitochondrial dysfunction in ASD are discussed, including one related to neurodevelopmental regression, another related to alterations in microbiome metabolites, and another related to elevations in acyl-carnitines. Mechanisms linking abnormal mitochondrial function with alterations in prenatal brain development and postnatal brain function are outlined. Given the multisystem complexity of some individuals with ASD, this review presents evidence for the mitochondria being central to ASD by contributing to abnormalities in brain development, cognition, and comorbidities such as immune and gastrointestinal dysfunction as well as neurodevelopmental regression. A diagnostic approach to identify mitochondrial dysfunction in ASD is outlined. From this evidence, it is clear that many individuals with ASD have alterations in mitochondrial function which may need to be addressed in order to achieve optimal clinical outcomes. The fact that alterations in mitochondrial metabolism may be found during pregnancy and early in the life of individuals who eventually develop ASD provides promise for early life predictive biomarkers of ASD. Further studies may improve the understanding of the role of the mitochondria in ASD by better defining subgroups and understanding the molecular mechanisms driving some of the unique changes found in mitochondrial function in those with ASD.

Keywords:  Autism Spectrum disorder; Biomarkers; Environmental genetic interactions; Meta-analysis; Mitochondrial DNA; Mitochondrial dysfunction; Mitochondrial respiration; Neurodevelopmental regression

DOI:  https://doi.org/10.1016/j.nbd.2024.106520
Life Sci Alliance. 2024 Jul;pii: e202302423. [Epub ahead of print]7(7):

Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis.

Takahiro Toshima, Mikako Yagi, Yura Do, Haruka Hirai, Yuya Kunisaki, Dongchon Kang, Takeshi Uchiumi.

Neurodegenerative diseases and other age-related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron-specific deficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer's disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation significantly reduced expression of the cholesterol synthase genes and degraded their sterol-regulated transcription factor, sterol regulatory element-binding protein 2 (Srebp2). Furthermore, the phosphorylation of Pyk2 and Gsk3β was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3β and that GSK3β inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2-Gsk3β axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3β inhibitors is a potential therapeutic strategy for leukoencephalopathy.

DOI: https://doi.org/10.26508/lsa.202302423
J Lipid Res. 2024 May 06. pii: S0022-2275(24)00061-0. [Epub ahead of print] 100556

ORMDL MISLOCALIZATION BY IMPAIRED AUTOPHAGY IN NIEMANN-PICK TYPE C DISEASE LEADS TO INCREASED DE NOVO SPHINGOLIPID BIOSYNTHESIS.

Ryan D R Brown, Usha Mahawar, Binks W Wattenberg, Sarah Spiegel.

  Niemann-Pick type C1 (NPC1) disease is rare neurodegenerative cholesterol and sphingolipid storage disorder primarily due to mutations in the cholesterol-trafficking protein NPC1. In addition to catabolic-derived sphingolipids, NPC1 dysfunction also leads to an increase in de novo sphingolipid biosynthesis, yet little is known of the cellular mechanism involved. Although deletion of NPC1 or inhibition of the NPC1 sterol binding domain enhanced de novo sphingolipid biosynthesis, surprisingly levels of the ORMDLs, the regulatory subunits of serine palmitoyltransferase (SPT), the rate-limiting step in sphingolipid biosynthesis, were also greatly increased. Nevertheless, less ORMDL was bound in the SPT-ORMDL complex despite elevated ceramide levels. Instead, ORMDL colocalized with p62, the selective autophagy receptor, and accumulated in stalled autophagosomes due to defective autophagy in NPC1 disease cells. Restoration of autophagic flux with N-acetyl-L-leucine in NPC1 deleted cells decreased ORMDL accumulation in autophagosomes and reduced de novo sphingolipid biosynthesis and their accumulation. This study revealed a previously unknown link between de novo sphingolipid biosynthesis, ORMDL and autophagic defects present in NCP1 disease. In addition, we provide further evidence and mechanistic insight for the beneficial role of N-acetyl-L-leucine treatment for NPC1 disease that is presently awaiting approval from the Food and Drug Administration and the European Medicines Agency.

Keywords:  NPC1; ORMDL; sphingolipid biosynthesis

DOI:  https://doi.org/10.1016/j.jlr.2024.100556
Cells. 2024 Apr 24. pii: 740. [Epub ahead of print]13(9):

Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System.

Maria Villa, Jingyun Wu, Stefanie Hansen, Jens Pahnke.

  ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders.

Keywords:  ABC transporter; ABCA1; ABCA7; ABCB1; ABCC1; Alzheimer’s disease; EAE; Huntington’s disease; MDR1; MRP1; P-gp; astrocyte; demyelination; glia; metabolic diseases; microglia; multiple sclerosis; neurodegeneration; neuroinflammation; oligodendrocyte; rare diseases; steroid hormones

DOI:  https://doi.org/10.3390/cells13090740
J Inherit Metab Dis. 2024 May 05.

Human genetic defects of sphingolipid synthesis.

Patricia Dubot, Frédérique Sabourdy, Thierry Levade.

  Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein. The resulting metabolic alterations lead to two major, non-exclusive types of clinical manifestations: a neurological disease, more or less rapidly progressive, associated or not with intellectual disability, and an ichthyotic-type skin disorder. These phenotypes highlight the critical importance of sphingolipids in brain and skin development and homeostasis. The present article reviews the clinical symptoms, genetic and biochemical alterations, pathophysiological mechanisms and therapeutic options of this relatively novel group of metabolic diseases.

Keywords:  ceramide; glycosphingolipid; ichthyosis; neurodevelopment; peripheral neuropathy; sphingomyelin

DOI:  https://doi.org/10.1002/jimd.12745
bioRxiv. 2024 Apr 23. pii: 2024.04.19.590328. [Epub ahead of print]

A disease similarity approach identifies short-lived Niemann-Pick type C disease mice with accelerated brain aging as a novel mouse model for Alzheimer's disease and aging research.

Vikas Anil Gujjala, Isaiah Klimek, Morteza Abyadeh, Alexander Tyshkovskiy, Naci Oz, José Pedro Castro, Vadim N Gladyshev, Jason Newton, Alaattin Kaya.

Since its first description in 1906 by Dr. Alois Alzheimer, Alzheimer's disease (AD) has been the most common type of dementia. Initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated AD with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of AD by using transcriptomic data from congenital diseases known to increase AD risk, namely Down Syndrome, Niemann Pick Disease Type C (NPC), and Mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of AD pathology, many of which have never been associated with AD. We then investigated common molecular alterations in brain samples from an NPC disease mouse model by juxtaposing them with brain samples of both human and mouse models of AD. Detailed phenotypic and molecular analyses revealed NPC mut mouse as a novel, short-lived in vivo model of AD characterized by accelerated brain aging, concluding that NPC mut mouse model can serve as a potential short-lived in vivo model for AD research and for understanding molecular factors affecting brain aging. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on AD research while highlighting shortcomings and lack of correlation in diverse in vitro models. Our findings provide a foundation for future animal and clinical studies and will lead to a better understanding of the molecular mechanisms underpinning the observed association between neurological congenital diseases and AD, thus has the potential to accelerate diagnostic and therapeutic applications against common types of dementia.

DOI: https://doi.org/10.1101/2024.04.19.590328
Cells. 2024 Apr 23. pii: 734. [Epub ahead of print]13(9):

Valproic Acid Treatment after Traumatic Brain Injury in Mice Alleviates Neuronal Death and Inflammation in Association with Increased Plasma Lysophosphatidylcholines.

Regina Hummel, Erika Dorochow, Sonja Zander, Katharina Ritter, Lisa Hahnefeld, Robert Gurke, Irmgard Tegeder, Michael K E Schäfer.

  The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have been partially attributed to the epigenetic disinhibition of the transcription repressor RE1-Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). Additionally, VPA changes post-traumatic brain injury (TBI) brain metabolism to create a neuroprotective environment. To address the interconnection of neuroprotection, metabolism, inflammation and REST/NRSF after TBI, we subjected C57BL/6N mice to experimental TBI and intraperitoneal VPA administration or vehicle solution at 15 min, 1, 2, and 3 days post-injury (dpi). At 7 dpi, TBI-induced an up-regulation of REST/NRSF gene expression and HDACi function of VPA on histone H3 acetylation were confirmed. Neurological deficits, brain lesion size, blood-brain barrier permeability, or astrogliosis were not affected, and REST/NRSF target genes were only marginally influenced by VPA. However, VPA attenuated structural damage in the hippocampus, microgliosis and expression of the pro-inflammatory marker genes. Analyses of plasma lipidomic and polar metabolomic patterns revealed that VPA treatment increased lysophosphatidylcholines (LPCs), which were inversely associated with interleukin 1 beta (Il1b) and tumor necrosis factor (Tnf) gene expression in the brain. The results show that VPA has mild neuroprotective and anti-inflammatory effects likely originating from favorable systemic metabolic changes resulting in increased plasma LPCs that are known to be actively taken up by the brain and function as carriers for neuroprotective polyunsaturated fatty acids.

Keywords:  lipidomic and metabolomic analyses; lysophoshatidylcholine; neuroinflammation; threonic acid; traumatic brain injury; valproic acid

DOI:  https://doi.org/10.3390/cells13090734
Ann Clin Transl Neurol. 2024 May 08.

Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.

Pamela J Yao, Apostolos Manolopoulos, Erden Eren, Susan Michelle Rivera, David R Hessl, Randi Hagerman, Veronica Martinez-Cerdeno, Flora Tassone, Dimitrios Kapogiannis.

OBJECTIVE: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum.METHODS: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls.
RESULTS: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity.
INTERPRETATION: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

DOI: https://doi.org/10.1002/acn3.52040
J Lipid Res. 2024 May 06. pii: S0022-2275(24)00062-2. [Epub ahead of print] 100557

Intestinal absorption of sphingosine: new insights on generated ceramide species using stable isotope tracing in vitro.

Catherine Calzada, David Cheillan, Nina Ritsch, Cécile Vors, Annie Durand, Sandra Pesenti, Magali Pettazzoni, Emmanuelle Meugnier, Marie-Caroline Michalski, Armelle Penhoat.

  Dietary sphingomyelin (SM) has been reported to favorably modulate postprandial lipemia. Mechanisms underlying these beneficial effects on cardiovascular risk markers are not fully elucidated. Rodent studies showed that tritiated SM was hydrolyzed in the intestinal lumen into ceramides (Cer), and further to sphingosine (SPH) and fatty acids (FA) that were absorbed by the intestine. Our objective was to investigate in Caco-2/TC7 cells cultured on semi-permeable inserts the uptake and metabolism of SPH and/or C23:0, the main FA of milk SM, as well as lipid secretion. Mixed micelles (MM) consisting of different digested lipids and taurocholate were prepared without or with SPH, SPH and C23:0 (SPH+C23:0) or C23:0. Triglycerides (TG) were quantified in the basolateral medium and sphingolipids were analyzed by tandem mass spectrometry. TG secretion increased 11-fold in all MM-incubated cells compared with lipid-free medium. Apical supply of SPH-enriched MM led to increased concentrations of total Cer in cells and co-addition of C23:0 in SPH-enriched MM led to a preferential increase of C23:0 Cer and C23:0 SM. Complementary experiments using deuterated SPH demonstrated that SPH-d9 was partly converted to sphingosine-1-phosphate-d9, Cer-d9 and SM-d9 within cells incubated with SPH-enriched MM. A few Cer-d9 (2% of added SPH-d9) was recovered in the basolateral medium of (MM+SPH)-incubated cells, especially C23:0 Cer-d9 in (MM+SPH+C23:0)-enriched cells. In conclusion, present results indicate that MM enriched with (SPH+C23:0), such as found in postprandial micelles formed after milk SM ingestion, impact directly sphingolipids endogenous metabolism in enterocytes, resulting in the secretion of TG-rich particles enriched with C23:0 Cer.

Keywords:  Chylomicrons; Dietary fat; Enterocytes; Lipidomics; Mass spectrometry; Milk; Polar lipids; Sphingolipids; Sphingomyelin,Triglycerides

DOI:  https://doi.org/10.1016/j.jlr.2024.100557
Biochem Biophys Res Commun. 2024 May 03. pii: S0006-291X(24)00583-7. [Epub ahead of print]717 150047

Lipidomic analysis of human TANGO2-deficient cells suggests a lipid imbalance as a cause of TANGO2 deficiency disease.

Mahsa Mehranfar, Paria Asadi, Rozmehr Shokohi, Miroslav P Milev, Chiara Gamberi, Michael Sacher.

TANGO2 deficiency disease (TDD) is a multisystem disease caused by variants in the TANGO2 gene. Symptoms include neurodevelopmental delays, seizures and potentially lethal metabolic crises and cardiac arrhythmias. While the function of TANGO2 remains elusive, vitamin B5/pantothenic acid supplementation has been shown to alleviate symptoms in a fruit fly model and has also been used with success to treat individuals suffering from TDD. Since vitamin B5 is the precursor to the lipid activator coenzyme A (CoA), we hypothesized that TANGO2-deficient cells would display changes in the lipid profile compared to control and that these changes would be rescued by vitamin B5 supplementation. In addition, the specific changes seen might point to a pathway in which TANGO2 functions. Indeed, we found profound changes in the lipid profile of human TANGO2-deficient cells as well as an increased pool of free fatty acids in both human cells devoid of TANGO2 and Drosophila harboring a previously described TANGO2 loss of function allele. All these changes were reversed upon vitamin B5 supplementation. Pathway analysis showed significant increases in triglyceride as well as in lysophospholipid levels as the top enriched pathways in the absence of TANGO2. Consistent with a defect in triglyceride metabolism, we found changes in lipid droplet numbers and sizes in the absence of TANGO2 compared to control. Our data will allow for comparison between other model systems of TDD and the homing in on critical lipid imbalances that lead to the disease state.

DOI: https://doi.org/10.1016/j.bbrc.2024.150047
Sci Rep. 2024 05 08. 14(1): 10573

Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Michael M Poon, Kym I Lorrain, Karin J Stebbins, Geraldine C Edu, Alexander R Broadhead, Ariana O Lorenzana, Bryanna E Paulson, Christopher S Baccei, Jeffrey R Roppe, Thomas O Schrader, Lino J Valdez, Yifeng Xiong, Austin C Chen, Daniel S Lorrain.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

DOI: https://doi.org/10.1038/s41598-024-61369-9
Proc Natl Acad Sci U S A. 2024 May 14. 121(20): e2318119121

Simultaneous targeting of peripheral and brain tumors with a therapeutic nanoparticle to disrupt metabolic adaptability at both sites.

Akash Ashokan, Shrita Sarkar, Mohammad Z Kamran, Bapurao Surnar, Akil A Kalathil, Alexis Spencer, Shanta Dhar.

  Brain metastasis of advanced breast cancer often results in deleterious consequences. Metastases to the brain lead to significant challenges in treatment options, as the blood-brain barrier (BBB) prevents conventional therapy. Thus, we hypothesized that creation of a nanoparticle (NP) that distributes to both primary tumor site and across the BBB for secondary brain tumor can be extremely beneficial. Here, we report a simple targeting strategy to attack both the primary breast and secondary brain tumors utilizing a single NP platform. The nature of these mitochondrion-targeted, BBB-penetrating NPs allow for simultaneous targeting and drug delivery to the hyperpolarized mitochondrial membrane of the extracranial primary tumor site in addition to tumors at the brain. By utilizing a combination of such dual anatomical distributing NPs loaded with therapeutics, we demonstrate a proof-of-concept idea to combat the increased metabolic plasticity of brain metastases by lowering two major energy sources, oxidative phosphorylation (OXPHOS) and glycolysis. By utilizing complementary studies and genomic analyses, we demonstrate the utility of a chemotherapeutic prodrug to decrease OXPHOS and glycolysis by pairing with a NP loaded with pyruvate dehydrogenase kinase 1 inhibitor. Decreasing glycolysis aims to combat the metabolic flexibility of both primary and secondary tumors for therapeutic outcome. We also address the in vivo safety parameters by addressing peripheral neuropathy and neurobehavior outcomes. Our results also demonstrate that this combination therapeutic approach utilizes mitochondrial genome targeting strategy to overcome DNA repair-based chemoresistance mechanisms.

Keywords:  Sirtuin 3; altered metabolism; chemoresistance; metabolic plasticity

DOI:  https://doi.org/10.1073/pnas.2318119121
iScience. 2024 Apr 19. 27(4): 109480

Functional regulation of microglia by vitamin B12 alleviates ischemic stroke-induced neuroinflammation in mice.

Yong Ge, Changjun Yang, Mojgan Zadeh, Shane M Sprague, Yang-Ding Lin, Heetanshi Sanjay Jain, Brenden Fitzgerald Determann, William H Roth, Juan Pablo Palavicini, Jonathan Larochelle, Eduardo Candelario-Jalil, Mansour Mohamadzadeh.

  Ischemic stroke is the second leading cause of death and disability worldwide, and efforts to prevent stroke, mitigate secondary neurological damage, and promote neurological recovery remain paramount. Recent findings highlight the critical importance of microbiome-related metabolites, including vitamin B12 (VB12), in alleviating toxic stroke-associated neuroinflammation. Here, we showed that VB12 tonically programmed genes supporting microglial cell division and activation and critically controlled cellular fatty acid metabolism in homeostasis. Intriguingly, VB12 promoted mitochondrial transcriptional and metabolic activities and significantly restricted stroke-associated gene alterations in microglia. Furthermore, VB12 differentially altered the functions of microglial subsets during the acute phase of ischemic stroke, resulting in reduced brain damage and improved neurological function. Pharmacological depletion of microglia before ischemic stroke abolished VB12-mediated neurological improvement. Thus, our preclinical studies highlight the relevance of VB12 in the functional programming of microglia to alleviate neuroinflammation, minimize ischemic injury, and improve host neurological recovery after ischemic stroke.

Keywords:  Immunology; Neuroscience; Omics; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2024.109480
Nat Metab. 2024 May 08.

Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.

Andrew Y Sung, Rachel M Guerra, Laura H Steenberge, Charlotte L Alston, Kei Murayama, Yasushi Okazaki, Masaru Shimura, Holger Prokisch, Daniele Ghezzi, Alessandra Torraco, Rosalba Carrozzo, Agnès Rötig, Robert W Taylor, James L Keck, David J Pagliarini.

Isolated complex I (CI) deficiencies are a major cause of primary mitochondrial disease. A substantial proportion of CI deficiencies are believed to arise from defects in CI assembly factors (CIAFs) that are not part of the CI holoenzyme. The biochemistry of these CIAFs is poorly defined, making their role in CI assembly unclear, and confounding interpretation of potential disease-causing genetic variants. To address these challenges, we devised a deep mutational scanning approach to systematically assess the function of thousands of NDUFAF6 genetic variants. Guided by these data, biochemical analyses and cross-linking mass spectrometry, we discovered that the CIAF NDUFAF6 facilitates incorporation of NDUFS8 into CI and reveal that NDUFS8 overexpression rectifies NDUFAF6 deficiency. Our data further provide experimental support of pathogenicity for seven novel NDUFAF6 variants associated with human pathology and introduce functional evidence for over 5,000 additional variants. Overall, our work defines the molecular function of NDUFAF6 and provides a clinical resource for aiding diagnosis of NDUFAF6-related diseases.

DOI: https://doi.org/10.1038/s42255-024-01039-2
J Neuroinflammation. 2024 May 07. 21(1): 118

Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders.

Hadley C Osman, Rachel Moreno, Destanie Rose, Megan E Rowland, Annie Vogel Ciernia, Paul Ashwood.

  Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.

Keywords:  Autism; Autism spectrum disorder (ASD); Cytokines; Development; Fetal brain; MIA; Maternal immune activation; Neurodevelopment; Placenta; Schizophrenia; Synapse

DOI:  https://doi.org/10.1186/s12974-024-03106-7
J Adv Res. 2024 May 04. pii: S2090-1232(24)00180-2. [Epub ahead of print]

Arachidonic acid in aging: New roles for old players.

Chen Qian, Qing Wang, Yusen Qiao, Ze Xu, Linlin Zhang, Haixiang Xiao, Zhixiang Lin, Mingzhou Wu, Wenyu Xia, Huilin Yang, Jiaxiang Bai, Dechun Geng.

  BACKGROUND: Arachidonic acid (AA), one of the most ubiquitous polyunsaturated fatty acids (PUFAs), provides fluidity to mammalian cell membranes. It is derived from linoleic acid (LA) and can be transformed into various bioactive metabolites, including prostaglandins (PGs), thromboxanes (TXs), lipoxins (LXs), hydroxy-eicosatetraenoic acids (HETEs), leukotrienes (LTs), and epoxyeicosatrienoic acids (EETs), by different pathways. All these processes are involved in AA metabolism. Currently, in the context of an increasingly visible aging world population, several scholars have revealed the essential role of AA metabolism in osteoporosis, chronic obstructive pulmonary disease, and many other aging diseases.AIM OF REVIEW: Although there are some reviews describing the role of AA in some specific diseases, there seems to be no or little information on the role of AA metabolism in aging tissues or organs. This review scrutinizes and highlights the role of AA metabolism in aging and provides a new idea for strategies for treating aging-related diseases.
KEY SCIENTIFIC CONCEPTS OF REVIEW: As a member of lipid metabolism, AA metabolism regulates the important lipids that interfere with the aging in several ways. We present a comprehensivereviewofthe role ofAA metabolism in aging, with the aim of relieving the extreme suffering of families and the heavy economic burden on society caused by age-related diseases. We also collected and summarized data on anti-aging therapies associated with AA metabolism, with the expectation of identifying a novel and efficient way to protect against aging.

Keywords:  Aging; Aging diseases; Arachidonic acid; Therapeutic strategies

DOI:  https://doi.org/10.1016/j.jare.2024.05.003