bims-medebr 2024-09-29 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024‒09‒29
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University

Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives.
White matter lipid alterations during aging in the rhesus monkey brain.
Setting the curve: the biophysical properties of lipids in mitochondrial form and function.
Protein kinase N1 deficiency results in upregulation of cerebral energy metabolism and is highly protective in in vivo and in vitro stroke models.
Recent advances on the physiological and pathophysiological roles of polyunsaturated fatty acids and their biosynthetic pathway.
In Vivo Glucose Transporter-2 Regulation of Dorsomedial Versus Ventrolateral VMN Astrocyte Metabolic Sensor and Glycogen Metabolic Enzyme Gene Expression in Female Rat.
New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease.
The role of ATP citrate lyase in myelin formation and maintenance.
Molecular Alterations in Core Subunits of Mitochondrial Complex I and Their Relation to Parkinson'S Disease.
Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability.
Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice.
Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets.
Chronic Corticosterone Treatment Decreases Extracellular pH and Increases Lactate Release via PDK4 Upregulation in Cultured Astrocytes.
Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.
A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.
Sphingolipids containing very long-chain fatty acids regulate Ypt7 function during the tethering stage of vacuole fusion.
Lipid Organization by the Caveolin-1 Complex.
Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow.
Animal Model of Autism Induced by Valproic Acid Combined with Maternal Deprivation: Sex-Specific Effects on Inflammation and Oxidative Stress.

Neurobiol Dis. 2024 Sep 19. pii: S0969-9961(24)00272-9. [Epub ahead of print]201 106672

Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives.

Ching-Pang Chang, Ching-Wen Wu, Yijuang Chern.

  Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutant huntingtin protein with an abnormal CAG/polyQ expansion in the N-terminus of HTT exon 1. HD is characterized by progressive neurodegeneration and metabolic abnormalities, particularly in the brain, which accounts for approximately 20 % of the body's resting metabolic rate. Dysregulation of energy homeostasis in HD includes impaired glucose transporters, abnormal functions of glycolytic enzymes, changes in tricarboxylic acid (TCA) cycle activity and enzyme expression in the basal ganglia and cortical regions of both HD mouse models and HD patients. However, current understanding of brain cell behavior during energy dysregulation and its impact on neuron-glia crosstalk in HD remains limited. This review provides a comprehensive summary of the current understanding of the differences in glucose metabolism between neurons and glial cells in HD and how these differences contribute to disease development compared with normal conditions. We also discuss the potential impact of metabolic shifts on neuron-glia communication in HD. A deeper understanding of these metabolic alterations may reveal potential therapeutic targets for future drug development.

Keywords:  Communication; Glial cells; Glucose metabolism; Huntington's disease

DOI:  https://doi.org/10.1016/j.nbd.2024.106672
Geroscience. 2024 Sep 23.

White matter lipid alterations during aging in the rhesus monkey brain.

Christina Dimovasili, Ana T Vitantonio, Bryce Conner, Kelli L Vaughan, Julie A Mattison, Douglas L Rosene.

  The brain of higher organisms, such as nonhuman primates, is particularly rich in lipids, with a gray to white matter ratio of approximately 40 to 60%. White matter primarily consists of lipids, and during normal aging, it undergoes significant degeneration due to myelin pathology, which includes structural abnormalities, like sheath splitting, and local inflammation. Cognitive decline in normal aging, without neurodegenerative diseases, is strongly linked to myelin pathology. Although the exact cause of myelin damage is unclear, older myelin differs from younger myelin, as shown by electron microscopy and altered expression of myelin-related RNAs. However, changes in lipid composition during brain aging remain poorly understood. This study assessed lipid profiles from the frontal lobe corpus callosum, an area where age-related myelin pathology is linked to cognitive decline. Results showed significant changes in lipids with age, revealing distinct age-related profiles. Some lipids that are enriched in myelin sheaths become more saturated, while important structural components, like ceramides, decrease. Disease-associated biomarkers such as cholesterol ester Che (22:6) and sulfatide ST (42:2) also change in older monkeys. Additionally, gene expression of lipid biosynthetic enzymes declines with age, while lipid peroxidation remains stable in the same brain region. This suggests that changes in lipid biosynthesis, rather than oxidative damage, likely account for the differences in lipid composition. Our findings indicate that myelin in the normal aging monkey brain shows diverse lipid changes, which may relate to age-related myelin pathology and could constitute targets for designing nutrient supplements or drugs to rejuvenate the brain's lipidome.

Keywords:  Brain aging; Lipidomics; Myelin pathology; Rhesus monkey

DOI:  https://doi.org/10.1007/s11357-024-01353-3
J Lipid Res. 2024 Sep 18. pii: S0022-2275(24)00148-2. [Epub ahead of print] 100643

Setting the curve: the biophysical properties of lipids in mitochondrial form and function.

Kailash Venkatraman, Christopher T Lee, Itay Budin.

  Mitochondrial membranes are defined by their diverse functions, complex geometries, and unique lipidomes. In the inner mitochondrial membrane (IMM), highly-curved membrane folds known as cristae house the electron transport chain and are the primary sites of cellular energy production. The outer mitochondrial membrane (OMM) is flat by contrast, but is critical for the initiation and mediation of processes key to mitochondrial physiology: mitophagy, inter-organelle contacts, fission and fusion dynamics and metabolite transport. While the lipid composition of both the IMM and OMM have been characterized across a variety of cell types, a mechanistic understanding for how individual lipid classes contribute to mitochondrial structure and function remains nebulous. In this review, we address the biophysical properties of mitochondrial lipids and their related functional roles. We highlight the intrinsic curvature of the bulk mitochondrial phospholipid pool, with an emphasis on the nuances surrounding the mitochondrially-synthesized cardiolipin. We also outline emerging questions about other lipid classes, ether lipids and sterols, with potential roles in mitochondrial physiology. We propose that further investigation is warranted to elucidate the specific properties of these lipids and their influence on mitochondrial architecture and function.

Keywords:  Cardiolipin; Curvature; Mitochondria; Phospholipids; Plasmalogens; Sterols

DOI:  https://doi.org/10.1016/j.jlr.2024.100643
Metabolism. 2024 Sep 25. pii: S0026-0495(24)00267-1. [Epub ahead of print] 156039

Protein kinase N1 deficiency results in upregulation of cerebral energy metabolism and is highly protective in in vivo and in vitro stroke models.

Stephanie Zur Nedden, Motahareh S Safari, Dido Weber, Louisa Kuenkel, Carolin Garmsiri, Luisa Lang, Cyrille Orset, Tom Freret, Benoît Haelewyn, Madlen Hotze, Marcel Kwiatkowski, Bettina Sarg, Klaus Faserl, Dragana Savic, Ira-Ida Skvortsova, Anne Krogsdam, Sandro Carollo, Zlatko Trajanoski, Herbert Oberacher, Dominik Zlotek, Florian Ostermaier, Angus Cameron, Gottfried Baier, Gabriele Baier-Bitterlich.

  BACKGROUND AND AIM: We recently identified protein kinase N1 (PKN1) as a master regulator of brain development. However, its function in the adult brain has not been clearly established. In this study, we assessed the cerebral energetic phenotype of wildtype (WT) and global Pkn1 knockout (Pkn1-/-) animals under physiological and pathophysiological conditions.METHODS: Cerebral energy metabolism was analyzed by 13C6-glucose tracing in vivo and real time seahorse analysis of extracellular acidification rates as well as mitochondrial oxygen consumption rates (OCR) of brain slice punches in vitro. Isolated WT and Pkn1-/- brain mitochondria were tested for differences in OCR with different substrates. Metabolite levels were determined by mass spectrometric analysis in brain slices under control and energetic stress conditions, induced by oxygen-glucose deprivation and reperfusion, an in vitro model of ischemic stroke. Differences in enzyme activities were assessed by enzymatic assays, western blotting and bulk RNA sequencing. A middle cerebral artery occlusion stroke model was used to analyze lesion volumes and functional recovery in WT and Pkn1-/- mice.
RESULTS: Pkn1 deficiency resulted in a remarkable upregulation of cerebral energy metabolism, in vivo and in vitro. This was due to two separate mechanisms involving an enhanced glycolytic flux and higher pyruvate-induced mitochondrial OCR. Mechanistically we show that Pkn1-/- brain tissue exhibits an increased activity of the glycolysis rate-limiting enzyme phosphofructokinase. Additionally, glucose-1,6-bisphosphate levels, a metabolite that increases mitochondrial pyruvate uptake, were elevated upon Pkn1 deficiency. Consequently, Pkn1-/- brain slices had more ATP and a greater accumulation of ATP degradation metabolites during energetic stress. This translated into increased phosphorylation and activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) during in vitro stroke. Accordingly, Pkn1-/- brain slices showed a post-ischemic transcriptional upregulation of energy metabolism pathways and Pkn1 deficiency was strongly protective in in vitro and in vivo stroke models. While inhibition of mitochondrial pyruvate uptake only moderately affected the protective phenotype, inhibition of AMPK in Pkn1-/- slices increased post-ischemic cell death in vitro.
CONCLUSION: This is the first study to comprehensively demonstrate an essential and unique role of PKN1 in cerebral energy metabolism, regulating both glycolysis and mitochondrial pyruvate-induced respiration. We further uncovered a highly protective phenotype of Pkn1 deficiency in both, in vitro and in vivo stroke models, validating inhibition of PKN1 as a promising new therapeutic target for the development of novel stroke therapies.

Keywords:  AMPK; Cerebral energy metabolism; PFK; PGM2L1; Protein kinase N1; Stroke

DOI:  https://doi.org/10.1016/j.metabol.2024.156039
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Sep 24. pii: S1388-1981(24)00114-8. [Epub ahead of print]1870(1): 159564

Recent advances on the physiological and pathophysiological roles of polyunsaturated fatty acids and their biosynthetic pathway.

Hyeon-Cheol Lee-Okada, Chengxuan Xue, Takehiko Yokomizo.

  Polyunsaturated fatty acids (PUFAs)-fatty acids containing multiple double bonds within their carbon chain-are an indispensable component of the cell membrane. PUFAs, including the omega-6 PUFA arachidonic acid (ARA; C20:4n-6) and the omega-3 PUFAs eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), have been implicated in various (patho)physiological events. These PUFAs are either obtained from the diet or biosynthesized from the essential fatty acids linoleic acid (LA; C18:2n-6) and α-linolenic acid (ALA; C18:3n-3) via enzymatic reactions that are catalyzed by fatty acid elongases (ELOVL2 and ELOVL5) and fatty acid desaturases (FADS1 and FADS2). In this review, we summarize the recent literature studying the role of PUFAs, placing a special emphasis on the newly discovered functions of PUFAs and their biosynthetic pathway as revealed by studies using animal models targeting the PUFA biosynthetic pathway and genetic approaches including genome-wide association studies.

Keywords:  Bipolar disorder; DHA; FADS1; FADS2; Polyunsaturated fatty acids (PUFAs); Steroid hormones

DOI:  https://doi.org/10.1016/j.bbalip.2024.159564
Neurochem Res. 2024 Sep 21.

In Vivo Glucose Transporter-2 Regulation of Dorsomedial Versus Ventrolateral VMN Astrocyte Metabolic Sensor and Glycogen Metabolic Enzyme Gene Expression in Female Rat.

Sagor C Roy, Subash Sapkota, Madhu Babu Pasula, Karen P Briski.

  Astrocyte glycogenolysis shapes ventromedial hypothalamic nucleus (VMN) regulation of glucostasis in vivo. Glucose transporter-2 (GLUT2), a plasma membrane glucose sensor, controls hypothalamic primary astrocyte culture glycogen metabolism in vitro. In vivo gene silencing tools and single-cell laser-catapult-microdissection/multiplex qPCR techniques were used here to examine whether GLUT2 governs dorsomedial (VMNdm) and/or ventrolateral (VMNvl) VMN astrocyte metabolic sensor and glycogen metabolic enzyme gene profiles. GLUT2 gene knockdown diminished astrocyte GLUT2 mRNA in both VMN divisions. Hypoglycemia caused GLUT2 siRNA-reversible up-regulation of this gene profile in the VMNdm, but down-regulated VMNvl astrocyte GLUT2 transcription. GLUT2 augmented baseline VMNdm and VMNvl astrocyte glucokinase (GCK) gene expression, but increased (VMNdm) or reduced (VMNvl) GCK transcription during hypoglycemia. GLUT2 imposed opposite control, namely stimulation versus inhibition of VMNdm or VMNvl astrocyte 5'-AMP-activated protein kinase-alpha 1 and -alpha 2 gene expression, respectively. GLUT2 stimulated astrocyte glycogen synthase (GS) gene expression in each VMN division. GLUT2 inhibited transcription of the AMP-sensitive glycogen phosphorylase (GP) isoform GP-brain type (GPbb) in each site, yet diminished (VMNdm) or augmented (VMNvl) astrocyte GP-muscle type (GPmm) mRNA. GLUT2 enhanced VMNdm and VMNvl glycogen accumulation during euglycemia, and curbed hypoglycemia-associated VMNdm glycogen depletion. Results show that VMN astrocytes exhibit opposite, division-specific GLUT2 transcriptional responsiveness to hypoglycemia. Data document divergent GLUT2 control of GCK, AMPK catalytic subunit, and GPmm gene profiles in VMNdm versus VMNvl astrocytes. Ongoing studies seek to determine how differential GLUT2 regulation of glucose and energy sensor function and glycogenolysis in each VMN location may affect local neuron responses to hypoglycemia.

Keywords:  AMPK; GLUT2 siRNA; Glucokinase; Glycogen; Glycogen phosphorylase-brain type; LC–ESI–MS

DOI:  https://doi.org/10.1007/s11064-024-04246-1
Front Neurosci. 2024 ;18 1430465

New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease.

Yuan Cao, Lin-Wei Zhao, Zi-Xin Chen, Shao-Hua Li.

  Alzheimer's disease (AD) is increasingly recognized as being intertwined with the dysregulation of lipid metabolism. Lipids are a significant class of nutrients vital to all organisms, playing crucial roles in cellular structure, energy storage, and signaling. Alterations in the levels of various lipids in AD brains and dysregulation of lipid pathways and transportation have been implicated in AD pathogenesis. Clinically, evidence for a high-fat diet firmly links disrupted lipid metabolism to the pathogenesis and progression of AD, although contradictory findings warrant further exploration. In view of the significance of various lipids in brain physiology, the discovery of complex and diverse mechanisms that connect lipid metabolism with AD-related pathophysiology will bring new hope for patients with AD, underscoring the importance of lipid metabolism in AD pathophysiology, and promising targets for therapeutic intervention. Specifically, cholesterol, sphingolipids, and fatty acids have been shown to influence amyloid-beta (Aβ) accumulation and tau hyperphosphorylation, which are hallmarks of AD pathology. Recent studies have highlighted the potential therapeutic targets within lipid metabolism, such as enhancing apolipoprotein E lipidation, activating liver X receptors and retinoid X receptors, and modulating peroxisome proliferator-activated receptors. Ongoing clinical trials are investigating the efficacy of these strategies, including the use of ketogenic diets, statin therapy, and novel compounds like NE3107. The implications of these findings suggest that targeting lipid metabolism could offer new avenues for the treatment and management of AD. By concentrating on alterations in lipid metabolism within the central nervous system and their contribution to AD development, this review aims to shed light on novel research directions and treatment approaches for combating AD, offering hope for the development of more effective management strategies.

Keywords:  Alzheimer’s disease; diet; lipid; lipid metabolism; therapy strategies

DOI:  https://doi.org/10.3389/fnins.2024.1430465
Glia. 2024 Sep 25.

The role of ATP citrate lyase in myelin formation and maintenance.

Andrew Schneider, Seongsik Won, Eric A Armstrong, Aaron J Cooper, Amulya Suresh, Rachell Rivera, Gregory Barrett-Wilt, John M Denu, Judith A Simcox, John Svaren.

  Formation of myelin by Schwann cells is tightly coupled to peripheral nervous system development and is important for neuronal function and long-term maintenance. Perturbation of myelin causes a number of specific disorders that are among the most prevalent diseases affecting the nervous system. Schwann cells synthesize myelin lipids de novo rather than relying on uptake of circulating lipids, yet one unresolved matter is how acetyl CoA, a central metabolite in lipid formation is generated during myelin formation and maintenance. Recent studies have shown that glucose-derived acetyl CoA itself is not required for myelination. However, the importance of mitochondrially-derived acetyl CoA has never been tested for myelination in vivo. Therefore, we have developed a Schwann cell-specific knockout of the ATP citrate lyase (Acly) gene to determine the importance of mitochondrial metabolism to supply acetyl CoA in nerve development. Intriguingly, the ACLY pathway is important for myelin maintenance rather than myelin formation. In addition, ACLY is required to maintain expression of a myelin-associated gene program and to inhibit activation of the latent Schwann cell injury program.

Keywords:  Schwann; acetyl CoA; lipid; lipidomic; myelin

DOI:  https://doi.org/10.1002/glia.24620
Mol Neurobiol. 2024 Sep 27.

Molecular Alterations in Core Subunits of Mitochondrial Complex I and Their Relation to Parkinson'S Disease.

Matheus Caetano Epifane-de-Assunção, Ana Gabrielle Bispo, Ândrea Ribeiro-Dos-Santos, Giovanna C Cavalcante.

  Among the myriad of neurodegenerative diseases, mitochondrial dysfunction represents a nexus regarding their pathogenic processes, in which Parkinson's disease (PD) is notable for inherent vulnerability of the dopaminergic pathway to energy deficits and oxidative stress. Underlying this dysfunction, the occurrence of defects in complex I (CI) derived from molecular alterations in its subunits has been described in the literature. However, the mechanistic understanding of the processes mediating the occurrence of mitochondrial dysfunction mediated by CI deficiency in PD remains uncertain and subject to some inconsistencies. Therefore, this review analyzed existing evidence that may explain the relationship between molecular alterations in the core subunits of CI, recognized for their direct contribution to its enzymatic performance, and the pathogenesis of PD. As a result, we discussed 47 genetic variants in the 14 core subunits of CI, which, despite some discordant results, were predominantly associated with varying degrees of deficiency in complex enzymatic activity, as well as defects in supercomplex biogenesis and CI itself. Finally, we hypothesized about the relationship of the described alterations with the pathogenesis of PD and offered some suggestions that may aid in the design of future studies aimed at elucidating the relationship between such alterations and PD.

Keywords:  Complex I; Mitochondria; NADH ubiquinone oxidoreductase; Oxidative phosphorylation; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-024-04526-5
Front Pharmacol. 2024 ;15 1469053

Unraveling the nexus of age, epilepsy, and mitochondria: exploring the dynamics of cellular energy and excitability.

Wen Xie, Sushruta Koppula, Mayur B Kale, Lashin S Ali, Nitu L Wankhede, Mohit D Umare, Aman B Upaganlawar, Ahmed Abdeen, Elturabi E Ebrahim, Mohamed El-Sherbiny, Tapan Behl, Bairong Shen, Rajeev K Singla.

  Epilepsy, a complex neurological condition marked by recurring seizures, is increasingly recognized for its intricate relationship with mitochondria, the cellular powerhouses responsible for energy production and calcium regulation. This review offers an in-depth examination of the interplay between epilepsy, mitochondrial function, and aging. Many factors might account for the correlation between epilepsy and aging. Mitochondria, integral to cellular energy dynamics and neuronal excitability, perform a critical role in the pathophysiology of epilepsy. The mechanisms linking epilepsy and mitochondria are multifaceted, involving mitochondrial dysfunction, reactive oxygen species (ROS), and mitochondrial dynamics. Mitochondrial dysfunction can trigger seizures by compromising ATP production, increasing glutamate release, and altering ion channel function. ROS, natural byproducts of mitochondrial respiration, contribute to oxidative stress and neuroinflammation, critical factors in epileptogenesis. Mitochondrial dynamics govern fusion and fission processes, influence seizure threshold and calcium buffering, and impact seizure propagation. Energy demands during seizures highlight the critical role of mitochondrial ATP generation in maintaining neuronal membrane potential. Mitochondrial calcium handling dynamically modulates neuronal excitability, affecting synaptic transmission and action potential generation. Dysregulated mitochondrial calcium handling is a hallmark of epilepsy, contributing to excitotoxicity. Epigenetic modifications in epilepsy influence mitochondrial function through histone modifications, DNA methylation, and non-coding RNA expression. Potential therapeutic avenues targeting mitochondria in epilepsy include mitochondria-targeted antioxidants, ketogenic diets, and metabolic therapies. The review concludes by outlining future directions in epilepsy research, emphasizing integrative approaches, advancements in mitochondrial research, and ethical considerations. Mitochondria emerge as central players in the complex narrative of epilepsy, offering profound insights and therapeutic potential for this challenging neurological disorder.

Keywords:  ageing; epigenetic modification; epilepsy; ketogenic diet; mitochondria targeted therapy

DOI:  https://doi.org/10.3389/fphar.2024.1469053
Neuroimage. 2024 Sep 25. pii: S1053-8119(24)00357-4. [Epub ahead of print] 120860

Astroglial glucose uptake determines brain FDG-PET alterations and metabolic connectivity during healthy aging in mice.

Laura M Bartos, Sebastian T Kunte, Stephan Wagner, Philipp Beumers, Rebecca Schaefer, Artem Zatcepin, Yunlei Li, Maria Griessl, Leonie Hoermann, Karin Wind-Mark, Peter Bartenstein, Sabina Tahirovic, Sibylle Ziegler, Matthias Brendel, Johannes Gnörich.

  PURPOSE: 2-Fluorodeoxyglucose-PET (FDG-PET) is a powerful tool to study glucose metabolism in mammalian brains, but cellular sources of glucose uptake and metabolic connectivity during aging are not yet understood.METHODS: Healthy wild-type mice of both sexes (2-21 months of age) received FDG-PET and cell sorting after in vivo tracer injection (scRadiotracing). FDG uptake per cell was quantified in isolated microglia, astrocytes and neurons. Cerebral FDG uptake and metabolic connectivity were determined by PET. A subset of mice received measurement of blood glucose levels to study associations with cellular FDG uptake during aging.
RESULTS: Cerebral FDG-PET signals in healthy mice increased linearly with age. Cellular FDG uptake of neurons increased between 2 and 12 months of age, followed by a strong decrease towards late ages. Contrarily, FDG uptake in microglia and astrocytes exhibited a U-shaped function with respect to age, comprising the predominant cellular source of higher cerebral FDG uptake in the later stages. Metabolic connectivity was closely associated with the ratio of glucose uptake in astroglial cells relative to neurons. Cellular FDG uptake was not associated with blood glucose levels and increasing FDG brain uptake as a function of age was still observed after adjusting for blood glucose levels.
CONCLUSION: Trajectories of astroglial glucose uptake drive brain FDG-PET alterations and metabolic connectivity during aging.

Keywords:  FDG-PET; aging; astroglia; metabolic connectivity; scRadiotracing

DOI:  https://doi.org/10.1016/j.neuroimage.2024.120860
Neurobiol Dis. 2024 Sep 25. pii: S0969-9961(24)00282-1. [Epub ahead of print] 106682

Signaling roles of sphingolipids in the ischemic brain and their potential utility as therapeutic targets.

Ayan Mohamud Yusuf, Xiaoni Zhang, Erich Gulbins, Ying Peng, Nina Hagemann, Dirk M Hermann.

  Sphingolipids comprise a class of lipids, which are composed of a sphingoid base backbone and are essential structural components of cell membranes. Beyond their role in maintaining cellular integrity, several sphingolipids are pivotally involved in signaling pathways controlling cell proliferation, differentiation, and death. The brain exhibits a particularly high concentration of sphingolipids and dysregulation of the sphingolipid metabolism due to ischemic injury is implicated in consecutive pathological events. Experimental stroke studies revealed that the stress sphingolipid ceramide accumulates in the ischemic brain post-stroke. Specifically, counteracting ceramide accumulation protects against ischemic damage and promotes brain remodeling, which translates into improved behavioral outcome. Sphingomyelin substantially influences cell membrane fluidity and thereby controls the release of extracellular vesicles, which are important vehicles in cellular communication. By modulating sphingomyelin content, these vesicles were shown to contribute to behavioral recovery in experimental stroke studies. Another important sphingolipid that influences stroke pathology is sphingosine-1-phosphate, which has been attributed a pro-angiogenic function, that is presumably mediated by its effect on endothelial function and/or immune cell trafficking. In experimental and clinical studies, sphingosine-1-phosphate receptor modulators allowed to modify clinically significant stroke recovery. Due to their pivotal roles in cell signaling, pharmacological compounds modulating sphingolipids, their enzymes or receptors hold promise as therapeutics in human stroke patients.

Keywords:  Ceramide; Ischemic stroke; Sphingomyelin; Sphingosine-1-phosphate

DOI:  https://doi.org/10.1016/j.nbd.2024.106682
Biol Pharm Bull. 2024 ;47(9): 1542-1549

Chronic Corticosterone Treatment Decreases Extracellular pH and Increases Lactate Release via PDK4 Upregulation in Cultured Astrocytes.

Ayami Kita, Ryota Araki, Takeshi Yabe.

  The pathogenesis of stress-related disorders involves aberrant glucocorticoid secretion, and decreased pH and increased lactate in the brain are common phenotypes in several psychiatric disorders. Mice treated with glucocorticoids develop these phenotypes, but it is unclear how glucocorticoids affect brain pH. Therefore, we investigated the effect of corticosterone (CORT), the main glucocorticoid in rodents, on extracellular pH and lactate release in cultured astrocytes, which are the main glial cells that produce lactate in the brain. CORT treatment for one week decreased the extracellular pH and increased the extracellular lactate level via glucocorticoid receptors. CORT also increased the intracellular pyruvate level and upregulated pyruvate dehydrogenase kinase 4 (PDK4), while PDK4 overexpression increased extracellular lactate and decreased the extracellular pH. Furthermore, PDK4 inhibition suppressed the increase in extracellular lactate and the decrease in extracellular pH induced by CORT. These results suggest that increased lactate release via accumulation of intracellular pyruvate in astrocytes by chronic glucocorticoid exposure contributes to decreased brain pH.

Keywords:  astrocyte; corticosterone; extracellular pH; lactate

DOI:  https://doi.org/10.1248/bpb.b24-00396
Genet Med. 2024 Sep 19. pii: S1098-3600(24)00207-7. [Epub ahead of print] 101273

Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a severe developmental disorder spectrum.

Daniel G Calame, Jovi Huixin Wong, Puravi Panda, Dat Tuan Nguyen, Nancy C P Leong, Riccardo Sangermano, Sohil G Patankar, Mohamed S Abdel-Hamid, Lama AlAbdi, Sylvia Safwat, Kyle P Flannery, Zain Dardas, Jawid M Fatih, Chaya Murali, Varun Kannan, Timothy E Lotze, Isabella Herman, Farah Ammouri, Brianna Rezich, Stephanie Efthymiou, Shahryar Alavi, David Murphy, Zahra Firoozfar, Mahya Ebrahimi Nasab, Amir Bahreini, Majid Ghasemi, Nourelhoda A Haridy, Hamid Reza Goldouzi, Fatemeh Eghbal, Ehsan Ghayoor Karimiani, Amber Begtrup, Houda Elloumi, Varunvenkat M Srinivasan, Vykuntaraju K Gowda, Haowei Du, Shalini N Jhangiani, Zeynep Coban-Akdemir, Dana Marafi, Lance Rodan, Sedat Isikay, Jill A Rosenfeld, Subhadra Ramanathan, Michael Staton, Kerby C Oberg, Robin D Clark, Catharina Wenman, Sam Loughlin, Ramy Saad, Tazeen Ashraf, Alison Male, Shereen Tadros, Reza Boostani, Ghada M H Abdel-Salam, Maha Zaki, Ali Mardi, Farzad Hashemi-Gorji, Ebtesam Abdalla, M Chiara Manzini, Davut Pehlivan, Jennifer E Posey, Richard A Gibbs, Henry Houlden, Fowzan S Alkuraya, Kinga Bujakowska, Reza Maroofian, James R Lupski, Long Nam Nguyen.

  PURPOSE: FLVCR1 encodes a solute carrier (SLC) protein implicated in heme, choline, and ethanolamine transport. While Flvcr1-/- mice exhibit skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia (DBA), biallelic FLVCR1 variants in humans have previously only been linked to childhood or adult-onset ataxia, sensory neuropathy, and retinitis pigmentosa.METHODS: We identified individuals with undiagnosed neurodevelopmental disorders and biallelic FLVCR1 variants through international data sharing and characterized the functional consequences of their FLVCR1 variants.
RESULTS: We ascertained 30 patients from 23 unrelated families with biallelic FLVCR1 variants and characterized a novel FLVCR1-related phenotype: severe developmental disorders with profound developmental delay, microcephaly (Z-score -2.5 to -10.5), brain malformations, epilepsy, spasticity, and premature death. Brain malformations ranged from mild brain volume reduction to hydranencephaly. Severely affected patients share traits including macrocytic anemia and skeletal malformations with Flvcr1-/- mice and DBA. FLVCR1 variants significantly reduce choline and ethanolamine transport and/or disrupt mRNA splicing.
CONCLUSION: These data demonstrate a broad FLVCR1-related phenotypic spectrum ranging from severe multiorgan developmental disorders resembling DBA to adult-onset neurodegeneration. Our study expands our understanding of Mendelian choline and ethanolamine disorders and illustrates the importance of anticipating a wide phenotypic spectrum for known disease genes and incorporating model organism data into genome analysis to maximize genetic testing yield.

Keywords:  Diamond-Blackfan anemia; FLVCR1; choline; neurodegeneration; neurodevelopmental disorders

DOI:  https://doi.org/10.1016/j.gim.2024.101273
bioRxiv. 2024 Sep 09. pii: 2024.09.09.612087. [Epub ahead of print]

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine Ward, Lichao Liu, Katrin J Svensson, Emily L Goldberg, Christopher D Gardner, Jonathan P Little, Steven M Banik, Yong Xu, Jonathan Z Long.

β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.

DOI: https://doi.org/10.1101/2024.09.09.612087
J Biol Chem. 2024 Sep 20. pii: S0021-9258(24)02309-3. [Epub ahead of print] 107808

Sphingolipids containing very long-chain fatty acids regulate Ypt7 function during the tethering stage of vacuole fusion.

Chi Zhang, Jorge D Calderin, Logan R Hurst, Zeynep D Gokbayrak, Michael R Hrabak, Adam Balutowski, David A Rivera-Kohr, Thomas D D Kazmirchuk, Christopher L Brett, Rutilio A Fratti.

  Sphingolipids are essential in membrane trafficking and cellular homeostasis. Here, we show that sphingolipids containing very long-chain fatty acids (VLCFAs) promote homotypic vacuolar fusion in Saccharomyces cerevisiae. The elongase Elo3 adds the last two carbons to VLCFAs that are incorporated into sphingolipids. Cells lacking Elo3 have fragmented vacuoles, which is also seen when WT cells are treated with the sphingolipid synthesis inhibitor Aureobasidin-A. Isolated elo3Δ vacuoles show acidification defects and increased membrane fluidity, and this correlates with deficient fusion. Fusion arrest occurs at the tethering stage as elo3Δ vacuoles fail to cluster efficiently in vitro. Unlike HOPS and fusogenic lipids, GFP-Ypt7 does not enrich at elo3Δ vertex microdomains, a hallmark of vacuole docking prior to fusion. Pulldown assays using bacterially expressed GST-Ypt7 showed that HOPS from elo3Δ vacuole extracts failed to bind GST-Ypt7 while HOPS from WT extracts interacted strongly with GST-Ypt7. Treatment of WT vacuoles with the fluidizing anesthetic dibucaine recapitulates the elo3Δ phenotype and shows increased membrane fluidity, mislocalized GFP-Ypt7, inhibited fusion, and attenuated acidification. Together these data suggest that sphingolipids contribute to Rab-mediated tethering and docking required for vacuole fusion.

Keywords:  Elo3; HOPS; SNARE; Vps33; Ypt7

DOI:  https://doi.org/10.1016/j.jbc.2024.107808
Biophys J. 2024 Sep 20. pii: S0006-3495(24)00630-1. [Epub ahead of print]

Lipid Organization by the Caveolin-1 Complex.

Korbinian Liebl, Gregory A Voth.

  Caveolins are lipid-binding proteins that can organize membrane remodeling and oligomerize into the 8S-complex. The CAV1 8S-complex comprises a disk-like structure, about 15nm in diameter, with a central beta barrel. Further oligomerization of 8S-complexes remodels the membrane into caveolae vessels, with a dependence on cholesterol concentration. However, the molecular mechanisms behind membrane remodeling and cholesterol filtering are still not understood. Performing atomistic Molecular Dynamics simulations in combination with advanced sampling techniques, we describe how the CAV1-8S complex bends the membrane and accumulates cholesterol. Here, our simulations show an enhancing effect by the palmitoylations of CAV1, and we predict that the CAV1-8S complex can extract cholesterol molecules from the lipid bilayer and accommodate them in its beta barrel. Through backmapping to the all-atom level we also conclude that the Martini v2 coarse-grained forcefield overestimates membrane bending, as the atomistic simulations exhibit only very localized bending.

Keywords:  Caveolin-1; Martini CG simulation; Metadynamics simulations; cholesterol accumulation; palmitoylation

DOI:  https://doi.org/10.1016/j.bpj.2024.09.018
bioRxiv. 2024 Sep 10. pii: 2024.09.05.611035. [Epub ahead of print]

Hyperglycemia selectively increases cerebral non-oxidative glucose consumption without affecting blood flow.

Tyler Blazey, John J Lee, Abraham Z Snyder, Manu S Goyal, Tamara Hershey, Ana Maria Arbeláez, Marcus E Raichle.

  Multiple studies have shown that hyperglycemia increases the cerebral metabolic rate of glucose (CMRglc) in subcortical white matter. This observation remains unexplained. Using positron emission tomography (PET) and euinsulinaemic glucose clamps, we found, for the first time, that acute hyperglycemia increases non-oxidative CMRglc (i.e., aerobic glycolysis (AG)) in subcortical white mater as well as in medial temporal lobe structures, cerebellum and brainstem, all areas with low euglycemic CMRglc. Surprisingly, hyperglycemia did not change regional cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2), or the blood-oxygen-level-dependent (BOLD) response. Regional gene expression data reveal that brain regions where CMRglc increased have greater expression of hexokinase 2 (HK2). Simulations of glucose transport revealed that, unlike hexokinase 1, HK2 is not saturated at euglycemia, thus accommodating increased AG during hyperglycemia.

Keywords:  Diabetes; Energy metabolism; Glucose; Hyperglycemia; Positron Emission Tomography; White matter / oligodendrocytes

DOI:  https://doi.org/10.1101/2024.09.05.611035
Mol Neurobiol. 2024 Sep 24.

Animal Model of Autism Induced by Valproic Acid Combined with Maternal Deprivation: Sex-Specific Effects on Inflammation and Oxidative Stress.

José Marcelo Botancin Campos, Maiara de Aguiar da Costa, Victória Linden de Rezende, Rosiane Ronchi Nascimento Costa, Maria Fernanda Pedro Ebs, João Paulo Behenck, Laura de Roch Casagrande, Ligia Milanez Venturini, Paulo Cesar Lock Silveira, Gislaine Zilli Réus, Cinara Ludvig Gonçalves.

  Autism spectrum disorder (ASD) etiology probably involves a complex interplay of both genetic and environmental risk factors, which includes pre- and perinatal exposure to environmental stressors. Thus, this study evaluated the effects of prenatal exposure to valproic acid (VPA) combined with maternal deprivation (MD) on behavior, oxidative stress parameters, and inflammatory state at a central and systemic level in male and female rats. Pregnant Wistar rats were exposed to VPA during gestation, and the offspring were submitted to MD. Offspring were tested for locomotor and social behavior; rats were euthanized, where the cerebellum, posterior cortex, prefrontal cortex, and peripheric blood were collected for oxidative stress and inflammatory analysis. It was observed that young rats (25-30 days old) exposed only to VPA presented a lower social approach when compared to the control group. VPA + MD rats did not present the same deficit. Female rats exposed to VPA + MD presented oxidative stress in all brain areas analyzed. Male rats in the VPA and VPA + MD groups presented oxidative stress only in the cerebellum. Regarding inflammatory parameters, male rats exposed only to MD exhibited an increase in pro-inflammatory cytokines in the blood and in the cortex total. The same was observed in females exposed only to VPA. Animals exposed to VPA + MD showed no alterations in the cytokines analyzed. In summary, gestational (VPA) and perinatal (MD) insults can affect molecular mechanisms such as oxidative stress and inflammation differently depending on the sex and brain area analyzed. Combined exposition to VPA and MD triggers oxidative stress especially in female brains without evoking an inflammatory response.

Keywords:  Brain; Cytokines; Multi-hit; Neuroinflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s12035-024-04491-z