bims-medebr 2024-04-21 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–04–21
35 papers selected by
Regina F. Fernández, Johns Hopkins University

Focusing on mitochondria in the brain: from biology to therapeutics.
Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy.
Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.
Seasonality in regional brain glucose metabolism.
Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.
Neuronal control of microglia through the mitochondria.
Mitochondrial energy state controls AMPK-mediated foraging behavior in C. elegans.
APOE regulates the transport of GM1.
DHCR7 links cholesterol synthesis with neuronal development and axonal integrity.
The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism.
Dodecyl creatine ester therapy: from promise to reality.
The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats.
Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial β-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.
Bisphenol S impairs mitochondrial function by targeting Myo19/oxidative phosphorylation pathway contributing to axonal and dendritic injury.
Membrane specificity of the human cholesterol transfer protein STARD4.
Hypothalamic GABAergic neurons expressing Cellular Retinoic Acid Binding Protein 1 (CRABP1) are sensitive to metabolic status and liraglutide in male mice.
Metabolite Study and Structural Authentication for the First-in-Human Use Sphingosine-1-phosphate Receptor 1 Radiotracer.
Murine Alox8 versus the human ALOX15B ortholog: differences and similarities.
Dehydration of Lipid Membranes Drives Redistribution of Cholesterol Between Lateral Domains.
Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity.
Editorial: Emerging aspects of ketone metabolism in health & disease.
AAV-mediated upregulation of VDAC1 rescues the mitochondrial respiration and sirtuins expression in a SOD1 mouse model of inherited ALS.
Ldl-stimulated microglial activation exacerbates ischemic white matter damage.
Butyrate as a potential therapeutic agent for neurodegenerative disorders.
Tanycytes release glucose using the glucose-6-phosphatase system during hypoglycemia to control hypothalamic energy balance.
The Role of Vitamin K in the Development of Neurodegenerative Diseases.
A crazy trio in Parkinson's disease: metabolism alteration, α-synuclein aggregation, and oxidative stress.
LXR agonism for CNS diseases: promises and challenges.
Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.
Approach to the Neonate with Hypoglycemia.
Restoring retinal polyunsaturated fatty acid balance and retina function by targeting ceramide in AdipoR1 deficient mice.
Relationship between Neonatal Cerebral Fuels and Neurosensory Outcomes at 3 Years in Well Babies: Follow-Up of the Glucose in Well Babies (GLOW) Study.
Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.
Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.
Lipid scrambling is a general feature of protein insertases.

Transl Neurodegener. 2024 Apr 17. 13(1): 23

Focusing on mitochondria in the brain: from biology to therapeutics.

Nanshan Song, Shuyuan Mei, Xiangxu Wang, Gang Hu, Ming Lu.

  Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.

Keywords:  Brain; Mitochondria; Mitochondrial transfer; Neurological disorders

DOI:  https://doi.org/10.1186/s40035-024-00409-w
Cancer Res. 2024 Apr 18.

Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy.

Jacob Chen Ming Low, Jianbo Cao, Friederike Hesse, Alan J Wright, Anastasia Tsyben, Islam Alshamleh, Richard Mair, Kevin M Brindle.

Metabolic subtypes of glioblastoma have different prognoses and responses to treatment. Deuterium metabolic imaging with 2H-labeled substrates is a potential approach to stratify patients into metabolic subtypes for targeted treatment. Here, we used 2H magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) measurements of [6,6'-2H2]glucose metabolism to identify metabolic subtypes and their responses to chemoradiotherapy in patient-derived glioblastoma xenografts in vivo. The metabolism of patient-derived cells was first characterized in vitro by measuring the oxygen consumption rate, a marker of mitochondrial TCA cycle activity, as well as the extracellular acidification rate and 2H-labeled lactate production from [6,6'-2H2]glucose, which are markers of glycolytic activity. Two cell lines representative of a glycolytic subtype and two representative of a mitochondrial subtype were identified. 2H MRS and MRSI measurements showed similar concentrations of 2H-labeled glucose from [6,6'-2H2]glucose in all four tumor models when implanted orthotopically in mice. The glycolytic subtypes showed higher concentrations of 2H-labeled lactate than the mitochondrial subtypes and normal-appearing brain tissue, whereas the mitochondrial subtypes showed more glutamate/glutamine labeling, a surrogate for TCA cycle activity, than the glycolytic subtypes and normal-appearing brain tissue. The response of the tumors to chemoradiation could be detected within 24 hours of treatment completion, with the mitochondrial subtypes showing a decrease in both 2H-labeled glutamate/glutamine and lactate concentrations and glycolytic tumors showing a decrease in 2H-labeled lactate concentration. This technique has the potential to be used clinically for treatment selection and early detection of treatment response.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2552
JCI Insight. 2024 Apr 16. pii: e168594. [Epub ahead of print]

Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.

Yijing Zhou, Vanessa B Sanchez, Peining Xu, Thomas Roule, Marco Flores-Mendez, Brianna Ciesielski, Donna Yoo, Hiab Teshome, Teresa Jimenez, Shibo Liu, Mike Henne, Tim O'Brien, Ye He, Clementina Mesaros, Naiara Akizu.

  Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an inter-organelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14 deficient mice. However, pre-degenerating SNX14 deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in pre-degenerating PCs, suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.

Keywords:  Lysosomes; Monogenic diseases; Neurodegeneration; Neuroscience

DOI:  https://doi.org/10.1172/jci.insight.168594
Psychol Med. 2024 Apr 18. 1-9

Seasonality in regional brain glucose metabolism.

Rui Zhang, Dardo Tomasi, Ehsan Shokri-Kojori, Peter Manza, Sukru Baris Demiral, Gene-Jack Wang, Nora D Volkow.

   BACKGROUND: Daylength and the rates of changes in daylength have been associated with seasonal fluctuations in psychiatric symptoms and in cognition and mood in healthy adults. However, variations in human brain glucose metabolism in concordance with seasonal changes remain under explored.
METHODS: In this cross-sectional study, we examined seasonal effects on brain glucose metabolism, which we measured using 18F-fluorodeoxyglucose-PET in 97 healthy participants. To maximize the sensitivity of regional effects, we computed relative metabolic measures by normalizing the regional measures to white matter metabolism. Additionally, we explored the role of rest-activity rhythms/sleep-wake activity measured with actigraphy in the seasonal variations of regional brain metabolic activity.
RESULTS: We found that seasonal variations of cerebral glucose metabolism differed across brain regions. Glucose metabolism in prefrontal regions increased with longer daylength and with greater day-to-day increases in daylength. The cuneus and olfactory bulb had the maximum and minimum metabolic values around the summer and winter solstice respectively (positively associated with daylength), whereas the temporal lobe, brainstem, and postcentral cortex showed maximum and minimum metabolic values around the spring and autumn equinoxes, respectively (positively associated with faster daylength gain). Longer daylength was associated with greater amplitude and robustness of diurnal activity rhythms suggesting circadian involvement.
CONCLUSIONS: The current findings advance our knowledge of seasonal patterns in a key indicator of brain function relevant for mood and cognition. These data could inform treatment interventions for psychiatric symptoms that peak at specific times of the year.

Keywords:  cerebral glucose metabolism; circadian rhythms; daylength; seasonal effects

DOI:  https://doi.org/10.1017/S0033291724000436
Biosci Trends. 2024 Apr 17.

Association between abnormal lipid metabolism and Alzheimer's disease: New research has revealed significant findings on the APOE4 genotype in microglia.

Xiqi Hu, Ya-Nan Ma, Ying Xia.

  APOE4 is widely recognized as a genetic risk factor for Alzheimer's disease (AD), implicated in 60-80% of all AD cases. Recent research suggests that microglia carrying the APOE4 genotype display abnormal lipid metabolism and accumulate lipid droplets, which may exacerbate the pathology of AD. Microglia play a critical role in immune surveillance within the central nervous system and are responsible for removing harmful particles and preserving neuronal function. The APOE4 genotype causes abnormal lipid metabolism in microglia, resulting in excessive accumulation of lipid droplets. This accumulation not only impairs the phagocytic and clearance capabilities of microglia but also disrupts their interactions with neurons, resulting in disorganization and neurodegenerative alterations at the neuronal network level. In addition, the presence of APOE4 modifies the metabolic landscape of microglia, particularly affecting purinergic signaling and lipid metabolism, thereby exacerbating the pathological processes of AD. In conclusion, the accumulation of lipid droplets and abnormal lipid metabolism may be critical mechanisms in the progression of AD in microglia carrying the APOE4 genotype.

Keywords:  APOE4; Alzheimer's disease; apolipoprotein E; lipid metabolism; microglia

DOI:  https://doi.org/10.5582/bst.2024.01092
Biochim Biophys Acta Mol Basis Dis. 2024 Apr 16. pii: S0925-4439(24)00156-X. [Epub ahead of print]1870(5): 167167

Neuronal control of microglia through the mitochondria.

A R Pereira-Santos, Emanuel Candeias, J D Magalhães, Nuno Empadinhas, A Raquel Esteves, Sandra M Cardoso.

  The microbial toxin β-N-methylamino-L-alanine (BMAA), which is derived from cyanobacteria, targets neuronal mitochondria, leading to the activation of neuronal innate immunity and, consequently, neurodegeneration. Although known to modulate brain inflammation, the precise role of aberrant microglial function in the neurodegenerative process remains elusive. To determine if neurons signal microglial cells, we treated primary cortical neurons with BMAA and then co-cultured them with the N9 microglial cell line. Our observations indicate that microglial cell activation requires initial neuronal priming. Contrary to what was observed in cortical neurons, BMAA was not able to activate inflammatory pathways in N9 cells. We observed that microglial activation is dependent on mitochondrial dysfunction signaled by BMAA-treated neurons. In this scenario, the NLRP3 pro-inflammatory pathway is activated due to mitochondrial impairment in N9 cells. These results demonstrate that microglia activation in the presence of BMAA is dependent on neuronal signaling. This study provides evidence that neurons may trigger microglia activation and subsequent neuroinflammation. In addition, we demonstrate that microglial activation may have a protective role in ameliorating neuronal innate immune activation, at least in the initial phase. This work challenges the current understanding of neuroinflammation by assigning the primary role to neurons.

Keywords:  Microglia; Mitochondrial dysfunction; Neuronal innate immunity; Neurons; β-N-methylamino-L-alanine

DOI:  https://doi.org/10.1016/j.bbadis.2024.167167
Sci Adv. 2024 Apr 19. 10(16): eadm8815

Mitochondrial energy state controls AMPK-mediated foraging behavior in C. elegans.

Anežka Vodičková, Annika Müller-Eigner, Chidozie N Okoye, Andrew P Bischer, Jacob Horn, Shon A Koren, Nada Ahmed Selim, Andrew P Wojtovich.

Organisms surveil and respond to their environment using behaviors entrained by metabolic cues that reflect food availability. Mitochondria act as metabolic hubs and at the center of mitochondrial energy production is the protonmotive force (PMF), an electrochemical gradient generated by metabolite consumption. The PMF serves as a central integrator of mitochondrial status, but its role in governing metabolic signaling is poorly understood. We used optogenetics to dissipate the PMF in Caenorhabditis elegans tissues to test its role in food-related behaviors. Our data demonstrate that PMF reduction in the intestine is sufficient to initiate locomotor responses to acute food deprivation. This behavioral adaptation requires the cellular energy regulator AMP-activated protein kinase (AMPK) in neurons, not in the intestine, and relies on mitochondrial dynamics and axonal trafficking. Our results highlight a role for intestinal PMF as an internal metabolic cue, and we identify a bottom-up signaling axis through which changes in the PMF trigger AMPK activity in neurons to promote foraging behavior.

DOI: https://doi.org/10.1126/sciadv.adm8815
bioRxiv. 2024 Apr 02. pii: 2024.04.02.587789. [Epub ahead of print]

APOE regulates the transport of GM1.

Dong Yan Zhang, Jian Wang, Gangtong Huang, Sara Langberg, Feng Ding, Nikolay V Dokholyan.

Apolipoprotein E (APOE) is responsible for lipid transport, including cholesterol transport and clearance. While the ε4 allele of APOE (APOE4) is associated with a significant genetic risk factor for late-onset Alzheimer's disease (AD), no mechanistic understanding of its contribution to AD etiology has been established yet. In addition to cholesterol, monosialotetrahexosylganglioside (GM1) is a crucial lipid component in cell membranes and has been implicated in promoting the aggregation of amyloid beta protein (Aβ), a key protein associated with AD. Here, we ask whether there are direct interactions between APOE and GM1 that further impact AD pathology. We find that both APOE3 and APOE4 exhibit superior binding affinity to GM1 compared to cholesterol and have an enhanced cellular uptake to GM1 lipid structures than cholesterol lipid structures. APOE regulates the transport process of GM1 depending on the cell type, which is influenced by the expression of APOE receptors in different cell lines and alters GM1 contents in cell membranes. We also find that the presence of GM1 alters the secondary structure of APOE3 and APOE4 and enhances the binding affinity between APOE and its receptor low-density lipoprotein receptor (LDLR), consequently promoting the cellular uptake of lipid structures in the presence of APOE. To understand the enhanced cellular uptake observed in lipid structures containing 20% GM1, we determined the distribution of GM1 on the membrane and found that GM1 clustering in lipid rafts, thereby supporting the physiological interaction between APOE and GM1. Overall, we find that APOE plays a regulatory role in GM1 transport, and the presence of GM1 on the lipid structures influences this transport process. Our studies introduce a plausible direct link between APOE and AD etiology, wherein APOE regulates GM1, which, in turn, promotes Aβ oligomerization and aggregation.

DOI: https://doi.org/10.1101/2024.04.02.587789
Biochem Biophys Res Commun. 2024 Apr 12. pii: S0006-291X(24)00468-6. [Epub ahead of print]712-713 149932

DHCR7 links cholesterol synthesis with neuronal development and axonal integrity.

Shuya Miyazaki, Nobuyuki Shimizu, Hiroaki Miyahara, Hitoshi Teranishi, Ryohei Umeda, Shinji Yano, Tatsuo Shimada, Hiroshi Shiraishi, Kosaku Komiya, Akira Katoh, Akihiko Yoshimura, Reiko Hanada, Toshikatsu Hanada.

  The DHCR7 enzyme converts 7-DHC into cholesterol. Mutations in DHCR7 can block cholesterol production, leading to abnormal accumulation of 7-DHC and causing Smith-Lemli-Opitz syndrome (SLOS). SLOS is an autosomal recessive disorder characterized by multiple malformations, including microcephaly, intellectual disability, behavior reminiscent of autism, sleep disturbances, and attention-deficit/hyperactivity disorder (ADHD)-like hyperactivity. Although 7-DHC affects neuronal differentiation in ex vivo experiments, the precise mechanism of SLOS remains unclear. We generated Dhcr7 deficient (dhcr7-/-) zebrafish that exhibited key features of SLOS, including microcephaly, decreased neural stem cell pools, and behavioral phenotypes similar to those of ADHD-like hyperactivity. These zebrafish demonstrated compromised myelination, synaptic anomalies, and neurotransmitter imbalances. The axons of the dhcr7-/- zebrafish showed increased lysosomes and attenuated autophagy, suggesting that autophagy-related neuronal homeostasis is disrupted.

Keywords:  Brain; Cholesterol; DHCR7; SLOS; Zebrafish

DOI:  https://doi.org/10.1016/j.bbrc.2024.149932
Redox Biol. 2024 Apr 10. pii: S2213-2317(24)00131-9. [Epub ahead of print]72 103155

The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism.

Ryan J Mailloux.

The α-keto acid dehydrogenase complex (KDHc) class of mitochondrial enzymes is composed of four members: pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (KGDHc), branched-chain keto acid dehydrogenase (BCKDHc), and 2-oxoadipate dehydrogenase (OADHc). These enzyme complexes occupy critical metabolic intersections that connect monosaccharide, amino acid, and fatty acid metabolism to Krebs cycle flux and oxidative phosphorylation (OxPhos). This feature also imbues KDHc enzymes with the heightened capacity to serve as platforms for propagation of intracellular and intercellular signaling. KDHc enzymes serve as a source and sink for mitochondrial hydrogen peroxide (mtH2O2), a vital second messenger used to trigger oxidative eustress pathways. Notably, deactivation of KDHc enzymes through reversible oxidation by mtH2O2 and other electrophiles modulates the availability of several Krebs cycle intermediates and related metabolites which serve as powerful intracellular and intercellular messengers. The KDHc enzymes also play important roles in the modulation of mitochondrial metabolism and epigenetic programming in the nucleus through the provision of various acyl-CoAs, which are used to acylate proteinaceous lysine residues. Intriguingly, nucleosomal control by acylation is also achieved through PDHc and KGDHc localization to the nuclear lumen. In this review, I discuss emerging concepts in the signaling roles fulfilled by the KDHc complexes. I highlight their vital function in serving as mitochondrial redox sensors and how this function can be used by cells to regulate the availability of critical metabolites required in cell signaling. Coupled with this, I describe in detail how defects in KDHc function can cause disease states through the disruption of cell redox homeodynamics and the deregulation of metabolic signaling. Finally, I propose that the intracellular and intercellular signaling functions of the KDHc enzymes are controlled through the reversible redox modification of the vicinal lipoic acid thiols in the E2 subunit of the complexes.

DOI: https://doi.org/10.1016/j.redox.2024.103155
Cell Mol Life Sci. 2024 Apr 17. 81(1): 186

Dodecyl creatine ester therapy: from promise to reality.

Aloïse Mabondzo, Jiddeke van de Kamp, Saadet Mercimek-Andrews.

  Pathogenic variants in SLC6A8, the gene which encodes creatine transporter SLC6A8, prevent creatine uptake in the brain and result in a variable degree of intellectual disability, behavioral disorders (e.g., autism spectrum disorder), epilepsy, and severe speech and language delay. There are no treatments to improve neurodevelopmental outcomes for creatine transporter deficiency (CTD). In this spotlight, we summarize recent advances in innovative molecules to treat CTD, with a focus on dodecyl creatine ester, the most promising drug candidate.

Keywords:  Biomarkers; Blood–brain barrier; Clinical trial; Cognitive functions; Creatine transporter deficiency; Nose-to-brain drug delivery; Proton MRS

DOI:  https://doi.org/10.1007/s00018-024-05218-y
Aging (Albany NY). 2024 Apr 12. 16

The impact of continuous and intermittent ketogenic diets on cognitive behavior, motor function, and blood lipids in TgF344-AD rats.

Jennifer M Rutkowsky, Zabrisky Roland, Anthony Valenzuela, An B Nguyen, Heui Hye Park, Natalie Six, Ilknur Dursun, Kyoungmi Kim, Pamela J Lein, Jon J Ramsey.

  Studies suggest that ketogenic diets (KD) may improve memory in mouse models of aging and Alzheimer's disease (AD). This study determined whether a continuous or intermittent KD (IKD) enhanced cognitive behavior in the TgF344-AD rat model of AD. At 6 months-old, TgF344-AD and wild-type (WT) littermates were placed on a control (CD), KD, or IKD (morning CD and afternoon KD) provided as two meals per day for 2 or 6 months. Cognitive and motor behavior and circulating β-hydroxybutyrate (BHB), AD biomarkers and blood lipids were assessed. Animals on a KD diet had elevated circulating BHB, with IKD levels intermediate to CD and KD. TgF344-AD rats displayed impaired spatial learning memory in the Barnes maze at 8 and 12 months of age and impaired motor coordination at 12 months of age. Neither KD nor IKD improved performance compared to CD. At 12 months of age, TgF344-AD animals had elevated blood lipids. IKD reduced lipids to WT levels with KD further reducing cholesterol below WT levels. This study shows that at 8 or 12 months of age, KD or IKD intervention did not improve measures of cognitive or motor behavior in TgF344-AD rats; however, both IKD and KD positively impacted circulating lipids.

Keywords:  Alzheimer’s disease; cognitive behavior; ketogenic diet; lipids; motor function

DOI:  https://doi.org/10.18632/aging.205741
Br J Pharmacol. 2024 Apr 19.

Hydroxymethylglutaryl-CoA reductase activity is essential for mitochondrial β-oxidation of fatty acids to prevent lethal accumulation of long-chain acylcarnitines in the mouse liver.

Edgars Liepinsh, Liga Zvejniece, Laura Clemensson, Melita Ozola, Edijs Vavers, Helena Cirule, Stanislava Korzh, Sandra Skuja, Valerija Groma, Monta Briviba, Solveiga Grinberga, Wen Liu, Paweł Olszewski, Mélissa Gentreau, Robert Fredriksson, Maija Dambrova, Helgi B Schiöth.

   BACKGROUND AND PURPOSE: Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen-induced Hmgcr-knockout (KO) mouse model, a multi-omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways.
EXPERIMENTAL APPROACH: We established a new mouse strain using the Cre/loxP system, which enabled whole-body deletion of Hmgcr expression. These mice were crossed with Rosa26Cre mice and treated with tamoxifen to delete Hmgcr in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time-dependent changes in metabolic functions to identify the pathways leading to cell death in Hmgcr-KO mice.
KEY RESULTS: Lack of Hmgcr expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid β-oxidation and very high accumulation of long-chain (LC) acylcarnitines in both male and female mice. Gene expression and KO-related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole-body hypoglycaemia.
CONCLUSION AND IMPLICATIONS: Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial β-oxidation. Moreover, statin-induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation.

Keywords:  HMG‐CoA reductase; Rosa26Cre mice; mitochondria; statins; tamoxifen‐induced knockout mouse model

DOI:  https://doi.org/10.1111/bph.16363
Environ Int. 2024 Apr 13. pii: S0160-4120(24)00229-0. [Epub ahead of print]186 108643

Bisphenol S impairs mitochondrial function by targeting Myo19/oxidative phosphorylation pathway contributing to axonal and dendritic injury.

Xing Zhang, Hongyang Gong, Ying Zhao, Yangna Wu, Jihan Cheng, Yuanyuan Song, Binquan Wang, Yufeng Qin, Mingkuan Sun.

  Exposure to bisphenol S (BPS) is known to adversely affect neuronal development. As pivotal components of neuronal polarization, axons and dendrites are indispensable structures within neurons, crucial for the maintenance of nervous system function. Here, we investigated the impact of BPS exposure on axonal and dendritic development both in vivo and in vitro. Our results revealed that exposure to BPS during pregnancy and lactation led to a reduction in the complexity, density, and length of axons and dendrites in the prefrontal cortex (PFC) of offspring. Employing RNA sequencing technology to elucidate the underlying mechanisms of axonal and dendritic damage induced by BPS, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted a significant alteration in the oxidative phosphorylation (OXPHOS) pathway, essential for mitochondrial function. Subsequent experiments demonstrate BPS-induced impairment in mitochondrial function, including damaged morphology, decreased adenosine triphosphate (ATP) and superoxide dismutase (SOD) levels, and increased reactive oxygen species and malondialdehyde (MDA). These alterations coincided with the downregulated expression of OXPHOS pathway-related genes (ATP6V1B1, ATP5K, NDUFC1, NDUFC2, NDUFA3, COX6B1) and Myosin 19 (Myo19). Notably, Myo19 overexpression restored the BPS-induced mitochondrial dysfunction by alleviating the inhibition of OXPHOS pathway. Consequently, this amelioration was associated with a reduction in BPS-induced axonal and dendritic injury observed in cultured neurons of the PFC.

Keywords:  Axon and dendrite; Bisphenol S; Mitochondrial function; Myosin 19; Oxidative phosphorylation pathway

DOI:  https://doi.org/10.1016/j.envint.2024.108643
J Mol Biol. 2024 Apr 12. pii: S0022-2836(24)00167-0. [Epub ahead of print] 168572

Membrane specificity of the human cholesterol transfer protein STARD4.

Reza Talandashti, Larissa van Ek, Charlotte Gehin, Dandan Xue, Mahmoud Moqadam, Anne-Claude Gavin, Nathalie Reuter.

  STARD4 regulates cholesterol homeostasis by transferring cholesterol between the plasma membrane and endoplasmic reticulum. The STARD4 structure features a helix-grip fold surrounding a large hydrophobic cavity holding the sterol. Its access is controlled by a gate formed by the Ω1 and Ω4 loops and the C-terminal α-helix. Little is known about the mechanisms by which STARD4 binds to membranes and extracts/releases cholesterol. All available structures of STARD4 are without a bound sterol and display the same closed conformation of the gate. The cholesterol transfer activity of the mouse STARD4 is enhanced in the presence of anionic lipids, and in particular of phosphatidylinositol biphosphates (PIP2) for which two binding sites were proposed on the mouse STARD4 surface. Yet only one of these sites is conserved in human STARD4. We here report the results of a liposome microarray-based assay and microseconds-long molecular dynamics simulations of human STARD4 with complex lipid bilayers mimicking the composition of the donor and acceptor membranes. We show that the binding of apo form of human STARD4 is sensitive to the presence of PIP2 through two specific binding sites, one of which was not identified on mouse STARD4. We report two novel conformations of the gate in holo-STARD4: a yet-unobserved close conformation and an open conformation of Ω4 shedding light on the opening/closure mechanism needed for cholesterol uptake/release. Overall, the modulation of human STARD4 membrane-binding by lipid composition, and by the presence of the cargo supports the capacity of human STARD4 to achieve directed transfer between specific organelle membranes.

Keywords:  STARD4; StART domain; cholesterol; liposome microarray-based assay; molecular simulations

DOI:  https://doi.org/10.1016/j.jmb.2024.168572
Neuroendocrinology. 2024 Apr 17.

Hypothalamic GABAergic neurons expressing Cellular Retinoic Acid Binding Protein 1 (CRABP1) are sensitive to metabolic status and liraglutide in male mice.

Olivier Lavoie, Audrey Turmel, Paige Mattoon, William James Desrosiers, Julie Plamondon, Natalie Jane Michael, Alexandre Caron.

INTRODUCTION: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing Cellular retinoic acid binding protein 1 (Crabp1).
METHODS: Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of Crabp1 across the mouse brain and characterized the molecular identity of Crabp1ARC neurons. We also determined whether Crabp1ARC neurons are sensitive to fasting, leptin and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity.
RESULTS: Crabp1ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and distinct from the prototypical melanocortin neurons. Crabp1ARC neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing Htr3b, Tbx19 and Tmem215, respectively. Notably, Crabp1ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism.
CONCLUSION: Crabp1ARC neurons represent a novel heterogenous population of GABAergic neurons sensitive to metabolic status.

DOI: https://doi.org/10.1159/000538716
ACS Chem Neurosci. 2024 Apr 18.

Metabolite Study and Structural Authentication for the First-in-Human Use Sphingosine-1-phosphate Receptor 1 Radiotracer.

Lin Qiu, Hao Jiang, Kevin Cho, Yanbo Yu, Lynne A Jones, Tianyu Huang, Joel S Perlmutter, Robert J Gropler, Matthew R Brier, Gary J Patti, Tammie L S Benzinger, Zhude Tu.

  The sphingosine-1-phosphate receptor 1 (S1PR1) radiotracer [11C]CS1P1 has shown promise in proof-of-concept PET imaging of neuroinflammation in multiple sclerosis (MS). Our HPLC radiometabolite analysis of human plasma samples collected during PET scans with [11C]CS1P1 detected a radiometabolite peak that is more lipophilic than [11C]CS1P1. Radiolabeled metabolites that cross the blood-brain barrier complicate quantitative modeling of neuroimaging tracers; thus, characterizing such radiometabolites is important. Here, we report our detailed investigation of the metabolite profile of [11C]CS1P1 in rats, nonhuman primates, and humans. CS1P1 is a fluorine-containing ligand that we labeled with C-11 or F-18 for preclinical studies; the brain uptake was similar for both radiotracers. The same lipophilic radiometabolite found in human studies also was observed in plasma samples of rats and NHPs for CS1P1 labeled with either C-11 or F-18. We characterized the metabolite in detail using rats after injection of the nonradioactive CS1P1. To authenticate the molecular structure of this radiometabolite, we injected rats with 8 mg/kg of CS1P1 to collect plasma for solvent extraction and HPLC injection, followed by LC/MS analysis of the same metabolite. The LC/MS data indicated in vivo mono-oxidation of CS1P1 produces the metabolite. Subsequently, we synthesized three different mono-oxidized derivatives of CS1P1 for further investigation. Comparing the retention times of the mono-oxidized derivatives with the metabolite observed in rats injected with CS1P1 identified the metabolite as N-oxide 1, also named TZ82121. The MS fragmentation pattern of N-oxide 1 also matched that of the major metabolite in rat plasma. To confirm that metabolite TZ82121 does not enter the brain, we radiosynthesized [18F]TZ82121 by the oxidation of [18F]FS1P1. Radio-HPLC analysis confirmed that [18F]TZ82121 matched the radiometabolite observed in rat plasma post injection of [18F]FS1P1. Furthermore, the acute biodistribution study in SD rats and PET brain imaging in a nonhuman primate showed that [18F]TZ82121 does not enter the rat or nonhuman primate brain. Consequently, we concluded that the major lipophilic radiometabolite N-oxide [11C]TZ82121, detected in human plasma post injection of [11C]CS1P1, does not enter the brain to confound quantitative PET data analysis. [11C]CS1P1 is a promising S1PR1 radiotracer for detecting S1PR1 expression in the CNS.

Keywords:  N-oxide; S1PR1; [11C]CS1P1; [18F]FS1P1; [18F]TZ82121; human clinical study; radiometabolite; radiosynthesis

DOI:  https://doi.org/10.1021/acschemneuro.4c00077
Pflugers Arch. 2024 Apr 19.

Murine Alox8 versus the human ALOX15B ortholog: differences and similarities.

Megan A Palmer, Yvonne Benatzy, Bernhard Brüne.

  Human arachidonate 15-lipoxygenase type B is a lipoxygenase that catalyzes the peroxidation of arachidonic acid at carbon-15. The corresponding murine ortholog however has 8-lipoxygenase activity. Both enzymes oxygenate polyunsaturated fatty acids in S-chirality with singular reaction specificity, although they generate a different product pattern. Furthermore, while both enzymes utilize both esterified fatty acids and fatty acid hydro(pero)xides as substrates, they differ with respect to the orientation of the fatty acid in their substrate-binding pocket. While ALOX15B accepts the fatty acid "tail-first," Alox8 oxygenates the free fatty acid with its "head-first." These differences in substrate orientation and thus in regio- and stereospecificity are thought to be determined by distinct amino acid residues. Towards their biological function, both enzymes share a commonality in regulating cholesterol homeostasis in macrophages, and Alox8 knockdown is associated with reduced atherosclerosis in mice. Additional roles have been linked to lung inflammation along with tumor suppressor activity. This review focuses on the current knowledge of the enzymatic activity of human ALOX15B and murine Alox8, along with their association with diseases.

Keywords:  Cholesterol; Lipid peroxidation; Lipoxygenase; Oxylipins; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1007/s00424-024-02961-w
J Phys Chem Lett. 2024 Apr 18. 4515-4522

Dehydration of Lipid Membranes Drives Redistribution of Cholesterol Between Lateral Domains.

Hanna Orlikowska-Rzeznik, Emilia Krok, Maria Domanska, Piotr Setny, Anna Lągowska, Madhurima Chattopadhyay, Lukasz Piatkowski.

Cholesterol-rich lipid rafts are found to facilitate membrane fusion, central to processes like viral entry, fertilization, and neurotransmitter release. While the fusion process involves local, transient membrane dehydration, the impact of reduced hydration on cholesterol's structural organization in biological membranes remains unclear. Here, we employ confocal fluorescence microscopy and atomistic molecular dynamics simulations to investigate cholesterol behavior in phase-separated lipid bilayers under controlled hydration. We unveiled that dehydration prompts cholesterol release from raft-like domains into the surrounding fluid phase. Unsaturated phospholipids undergo more significant dehydration-induced structural changes and lose more hydrogen bonds with water than sphingomyelin. The results suggest that cholesterol redistribution is driven by the equalization of biophysical properties between phases and the need to satisfy lipid hydrogen bonds. This underscores the role of cholesterol-phospholipid-water interplay in governing cholesterol affinity for a specific lipid type, providing a new perspective on the regulatory role of cell membrane heterogeneity during membrane fusion.

DOI: https://doi.org/10.1021/acs.jpclett.4c00332
Mol Neurodegener. 2024 Apr 14. 19(1): 34

Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity.

Pasquale D'Acunzo, Elentina K Argyrousi, Jonathan M Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N Goulbourne, Ottavio Arancio, Efrat Levy.

   BACKGROUND: Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer's disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved.
METHODS: Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices.
RESULTS: Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP.
CONCLUSIONS: Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Down syndrome; Exosome; Extracellular vesicle; Long-term potentiation; MAO-B; Microvesicle; Mitochondria; Mitovesicle; Neurodegenerative disease

DOI:  https://doi.org/10.1186/s13024-024-00721-z
Front Physiol. 2024 ;15 1404454

Editorial: Emerging aspects of ketone metabolism in health & disease.

Brianna Jane Stubbs, Kenneth M Ford, Jeff Volek.



Keywords:  butanediol; exogenous ketone; ketogenic diet; ketone ester; ketone infusion; ketosis

DOI:  https://doi.org/10.3389/fphys.2024.1404454
Cell Death Discov. 2024 Apr 16. 10(1): 178

AAV-mediated upregulation of VDAC1 rescues the mitochondrial respiration and sirtuins expression in a SOD1 mouse model of inherited ALS.

Andrea Magrì, Cristiana Lucia Rita Lipari, Antonella Caccamo, Giuseppe Battiato, Stefano Conti Nibali, Vito De Pinto, Francesca Guarino, Angela Messina.

Mitochondrial dysfunction represents one of the most common molecular hallmarks of both sporadic and familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder caused by the selective degeneration and death of motor neurons. The accumulation of misfolded proteins on and within mitochondria, as observed for SOD1 G93A mutant, correlates with a drastic reduction of mitochondrial respiration and the inhibition of metabolites exchanges, including ADP/ATP and NAD+/NADH, across the Voltage-Dependent Anion-selective Channel 1 (VDAC1), the most abundant channel protein of the outer mitochondrial membrane. Here, we show that the AAV-mediated upregulation of VDAC1 in the spinal cord of transgenic mice expressing SOD1 G93A completely rescues the mitochondrial respiratory profile. This correlates with the increased activity and levels of key regulators of mitochondrial functions and maintenance, namely the respiratory chain Complex I and the sirtuins (Sirt), especially Sirt3. Furthermore, the selective increase of these mitochondrial proteins is associated with an increase in Tom20 levels, the receptor subunit of the TOM complex. Overall, our results indicate that the overexpression of VDAC1 has beneficial effects on ALS-affected tissue by stabilizing the Complex I-Sirt3 axis.

DOI: https://doi.org/10.1038/s41420-024-01949-w
Brain Behav Immun. 2024 Apr 16. pii: S0889-1591(24)00360-X. [Epub ahead of print]

Ldl-stimulated microglial activation exacerbates ischemic white matter damage.

Luo-Qi Zhou, Yun-Hui Chu, Ming-Hao Dong, Sheng Yang, Man Chen, Yue Tang, Xiao-Wei Pang, Yun-Fan You, Long-Jun Wu, Wei Wang, Chuan Qin, Dai-Shi Tian.

  The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

Keywords:  Lipid metabolism; Low-density lipoprotein; Microglia; White matter ischemia

DOI:  https://doi.org/10.1016/j.bbi.2024.04.014
Neurochem Int. 2024 Apr 17. pii: S0197-0186(24)00072-X. [Epub ahead of print] 105745

Butyrate as a potential therapeutic agent for neurodegenerative disorders.

Prapti Chakraborty, Hasinika K A H Gamage, Angela S Laird.

  Maintaining an optimum microbial community within the gastrointestinal tract is intricately linked to human metabolic, immune and brain health. Disturbance to these microbial populations perturbs the production of vital bioactive compounds synthesised by the gut microbiome, such as short-chain fatty acids (SCFAs). Of the SCFAs, butyrate is known to be a major source of energy for colonocytes and has valuable effects on the maintenance of intestinal epithelium and blood brain barrier integrity, gut motility and transit, anti-inflammatory effects, and autophagy induction. Inducing endogenous butyrate production is likely to be beneficial for gut-brain homeostasis and for optimal neuronal function. For these reasons, butyrate has gained interest as a potential therapy for not only metabolic and immunological disorders, but also conditions related to the brain, including neurodegenerative diseases. While direct and indirect sources of butyrate, including prebiotics, probiotics, butyrate pro-drugs and glucosidase inhibitors, offer a promising therapeutic avenue, their efficacy and dosage in neurodegenerative conditions remain largely unknown. Here, we review current literature on effects of butyrate relevant to neuronal function, the impact of butyrate in a range of neurodegenerative diseases and related treatments that may have potential for the treatment of neurodegenerative diseases.

Keywords:  butyrate; gut microbiome; neurodegenerative disease; prebiotic; probiotic; short-chain fatty acids

DOI:  https://doi.org/10.1016/j.neuint.2024.105745
Mol Metab. 2024 Apr 17. pii: S2212-8778(24)00071-1. [Epub ahead of print] 101940

Tanycytes release glucose using the glucose-6-phosphatase system during hypoglycemia to control hypothalamic energy balance.

M J Barahona, L Ferrada, M Vera, F Nualart.

   OBJECTIVE: The liver releases glucose into the blood using the glucose-6-phosphatase (G6Pase) system, a multiprotein complex located in the endoplasmic reticulum (ER). Here, we show for the first time that the G6Pase system is also expressed in hypothalamic tanycytes, and t is required to regulate energy balance.
METHODS: Using automatized qRT-PCR and immunohistochemical analyses, we evaluated the expression of the G6Pase system. Fluorescent glucose analogue (2-NBDG) uptake was evaluated by 4D live-cell microscopy. Glucose release was tested using a glucose detection kit and high-content live-cell analysis instrument, Incucyte s3. In vivo G6pt knockdown in tanycytes was performed by AAV1-shG6PT-mCherry intracerebroventricular injection. Body weight gain, adipose tissue weight, food intake, glucose metabolism, c-Fos, and neuropeptide expression were evaluated at 4 weeks post-transduction.
RESULTS: Tanycytes sequester glucose-6-phosphate (G6P) into the ER through the G6Pase system and release glucose in hypoglycaemia via facilitative glucose transporters (GLUTs). Strikingly, in vivo tanycytic G6pt knockdown has a powerful peripheral anabolic effect observed through decreased body weight, white adipose tissue (WAT) tissue mass, and strong downregulation of lipogenesis genes. Selective deletion of G6pt in tanycytes also decreases food intake, c-Fos expression in the arcuate nucleus (ARC), and Npy mRNA expression in fasted mice.
CONCLUSION: The tanycyte-associated G6Pase system is a central mechanism involved in controlling metabolism and energy balance.

Keywords:  G6Pase system; Tanycytes; energy balance; hypoglycaemia

DOI:  https://doi.org/10.1016/j.molmet.2024.101940
Biochemistry (Mosc). 2024 Jan;89(Suppl 1): S57-S70

The Role of Vitamin K in the Development of Neurodegenerative Diseases.

Anna I Diachenko, Igor A Rodin, Tatiana N Krasnova, Oleg I Klychnikov, Lidia N Nefedova.

  Neurodegenerative diseases are a growing global health problem with enormous consequences for individuals and society. The most common neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, can be caused by both genetic factors (mutations) and epigenetic changes caused by the environment, in particular, oxidative stress. One of the factors contributing to the development of oxidative stress that has an important effect on the nervous system is vitamin K, which is involved in redox processes. However, its role in cells is ambiguous: accumulation of high concentrations of vitamin K increases the content of reactive oxygen species increases, while small amounts of vitamin K have a protective effect and activate the antioxidant defense systems. The main function of vitamin K is its involvement in the gamma carboxylation of the so-called Gla proteins. Some Gla proteins are expressed in the nervous system and participate in its development. Vitamin K deficiency can lead to a decrease or loss of function of Gla proteins in the nervous system. It is assumed that the level of vitamin K in the body is associated with specific changes involved in the development of dementia and cognitive abilities. Vitamin K also influences the sphingolipid profile in the brain, which also affects cognitive function. The role of vitamin K in the regulation of biochemical processes at the cellular and whole-organism levels has been studied insufficiently. Further research can lead to the discovery of new targets for vitamin K and development of personalized diets and therapies.

Keywords:  Alzheimer’s disease; Parkinson’s disease; neurodegenerative diseases; vitamin K

DOI:  https://doi.org/10.1134/S0006297924140049
Mol Cell Biochem. 2024 Apr 16.

A crazy trio in Parkinson's disease: metabolism alteration, α-synuclein aggregation, and oxidative stress.

Sheng Li, Yanbing Liu, Sen Lu, Jiayi Xu, Xiaokun Liu, Di Yang, Yuxuan Yang, Lin Hou, Ning Li.

  Parkinson's disease (PD) is an aging-associated neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies containing α-synuclein within these neurons. Oligomeric α-synuclein exerts neurotoxic effects through mitochondrial dysfunction, glial cell inflammatory response, lysosomal dysfunction and so on. α-synuclein aggregation, often accompanied by oxidative stress, is generally considered to be a key factor in PD pathology. At present, emerging evidences suggest that metabolism alteration is closely associated with α-synuclein aggregation and PD progression, and improvement of key molecules in metabolism might be potentially beneficial in PD treatment. In this review, we highlight the tripartite relationship among metabolic changes, α-synuclein aggregation, and oxidative stress in PD, and offer updated insights into the treatments of PD, aiming to deepen our understanding of PD pathogenesis and explore new therapeutic strategies for the disease.

Keywords:  Amino acid; Glycolysis; Lipid; Metabolism; Oxidative stress; Parkinson's disease; α-Synuclein

DOI:  https://doi.org/10.1007/s11010-024-04985-3
J Neuroinflammation. 2024 Apr 16. 21(1): 97

LXR agonism for CNS diseases: promises and challenges.

Ruiyi Zhang, Emily Wuerch, V Wee Yong, Mengzhou Xue.

  The unfavorable prognosis of many neurological conditions could be attributed to limited tissue regeneration in central nervous system (CNS) and overwhelming inflammation, while liver X receptor (LXR) may regulate both processes due to its pivotal role in cholesterol metabolism and inflammatory response, and thus receives increasing attentions from neuroscientists and clinicians. Here, we summarize the signal transduction of LXR pathway, discuss the therapeutic potentials of LXR agonists based on preclinical data using different disease models, and analyze the dilemma and possible resolutions for clinical translation to encourage further investigations of LXR related therapies in CNS disorders.

Keywords:  Cholesterol metabolism; Clinical translation; Liver X receptor; Neuroinflammation; Neurological diseases; Tissue regeneration

DOI:  https://doi.org/10.1186/s12974-024-03056-0
J Biomed Sci. 2024 Apr 17. 31(1): 38

Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.

Vicki Wang, Kuan-Yin Tseng, Tung-Tai Kuo, Eagle Yi-Kung Huang, Kuo-Lun Lan, Zi-Rong Chen, Kuo-Hsing Ma, Nigel H Greig, Jin Jung, Ho-Ii Choi, Lars Olson, Barry J Hoffer, Yuan-Hao Chen.

   BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood.
METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse.
RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae.
CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.

Keywords:  Exenatide; Glucagon-like peptide-1 receptor agonist; MitoPark mouse; Mitochondria; PT320; Parkinson’s disease

DOI:  https://doi.org/10.1186/s12929-024-01025-6
J Clin Endocrinol Metab. 2024 Apr 17. pii: dgae267. [Epub ahead of print]

Approach to the Neonate with Hypoglycemia.

Katherine Lord, Diva D De León.

  After birth, healthy neonates undergo a period of altered glucose metabolism, known as "transitional hypoglycemia". During the first 0-4 hours of life, the mean plasma glucose concentration decreases to 57 mg/dL, then by 72-96 hours of life increases to 82 mg/dL, well within the normal adult range. Recent data suggests that transitional hypoglycemia is due to persistence of the fetal beta cell's lower threshold for insulin release, resulting in a transient hyperinsulinemic state. While hypoglycemia is an expected part of the transition to postnatal life, it makes the identification of infants with persistent hypoglycemia disorders challenging. Given the risk of neurologic injury from hypoglycemia, identifying these infants is critical. Hyperinsulinism is the most common cause of persistent hypoglycemia in neonates and infants and carries a high risk of neurocognitive dysfunction given the severity of the hypoglycemia and the inability to generate ketones, a critical alternative cerebral fuel. Screening neonates at risk for persistent hypoglycemia disorders and completing evaluations prior to hospital discharge is essential to prevent delayed diagnoses and neurologic damage.

Keywords:  Glucose; Hyperinsulinism; Hypoglycemia; Ketones; Neonate

DOI:  https://doi.org/10.1210/clinem/dgae267
J Biol Chem. 2024 Apr 16. pii: S0021-9258(24)01792-7. [Epub ahead of print] 107291

Restoring retinal polyunsaturated fatty acid balance and retina function by targeting ceramide in AdipoR1 deficient mice.

Dominik Lewandowski, Fangyuan Gao, Sanae Imanishi, Aleksander Tworak, Marco Bassetto, Zhiqian Dong, Antonio F M Pinto, Marcin Tabaka, Philip D Kiser, Yoshikazu Imanishi, Dorota Skowronska-Krawczyk, Krzysztof Palczewski.

Mutations in the adiponectin receptor 1 gene (AdipoR1) lead to retinitis pigmentosa and are associated with age-related macular degeneration (AMD). This study explores the effects of AdipoR1 gene deficiency in mice, revealing a striking decline in ω3 polyunsaturated fatty acids (PUFA), an increase in ω6 FAs, and elevated ceramides in the retina. The AdipoR1 deficiency impairs peroxisome proliferator-activated receptor α (PPARα) signaling, which is crucial for FA metabolism, particularly affecting proteins associated with FA transport and oxidation in the retina and retinal pigmented epithelium (RPE). Our lipidomic and proteomic analyses indicate changes that could affect membrane composition and viscosity through altered ω3 PUFA transport and synthesis, suggesting a potential influence of AdipoR1 on these properties. Furthermore, we noted a reduction in the Bardet-Biedl syndrome (BBS) proteins, which are crucial for forming and maintaining photoreceptor outer segments that are PUFA-enriched ciliary structures. Diminution in BBS-proteins content combined with our electron microscopic observations raises the possibility that AdipoR1 deficiency might impair ciliary function. Treatment with inhibitors of ceramide synthesis led to substantial elevation of ω3 LC-PUFAs, alleviating photoreceptor degeneration and improving retinal function. These results serve as the proof of concept for a ceramide-targeted strategy to treat retinopathies linked to PUFA deficiency, including AMD.

DOI: https://doi.org/10.1016/j.jbc.2024.107291
Neonatology. 2024 Apr 17. 1-9

Relationship between Neonatal Cerebral Fuels and Neurosensory Outcomes at 3 Years in Well Babies: Follow-Up of the Glucose in Well Babies (GLOW) Study.

Deborah L Harris, Philip J Weston, Greg D Gamble, Jane E Harding.

   INTRODUCTION: We sought to investigate if the availability of cerebral fuels soon after birth in healthy term babies was associated with developmental progress at 3 years of age.
METHODS: Healthy term babies had plasma glucose, lactate, and beta-hydroxybutyrate concentrations measured over the first 5 days. At 3 years, parents completed Ages and Stages (ASQ-3) questionnaires between December 2018 and August 2022. Developmental progress, analysed using structural equation modelling, was compared between children whose median fuel concentrations were above and below the mean neonatal concentrations of glucose (3.3 mmol/L) and total ATP-equivalents (140 mmol/L) in the first 48 h and over the first 5 days.
RESULTS: Sixty-four (96%) families returned completed questionnaires. We found no differences between developmental progress in children who had median neonatal plasma glucose concentrations <3.3 or ≥3.3 mmol/L in the first 48 h (estimated mean difference in ASQ scores -1.0, 95% confidence interval: -5.8, 3.7, p = 0.66) or 120 h (-3.7, -12.0, 4.6, p = 0.39]). There were also no differences for any other measures of cerebral fuels including total ATP above and below the median over 48 and 120 h, any plasma or interstitial glucose concentration <2.6 mmol/L, or cumulative duration of interstitial glucose concentration <2.6 mmol/L.
CONCLUSIONS: There was no detectable relationship between plasma concentrations of glucose, lactate, and beta-hydroxybutyrate soon after birth in healthy term babies and developmental progress at 3 years of age.

Keywords:  Ages and Stages questionnaire; Alternative cerebral fuels; Developmental assessment; Neonatal hypoglycaemia; Preschool

DOI:  https://doi.org/10.1159/000538377
J Lipids. 2024 ;2024 4530255

Gangliosides as Therapeutic Targets for Neurodegenerative Diseases.

Orhan Kerim Inci, Hande Basırlı, Melike Can, Selman Yanbul, Volkan Seyrantepe.

Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.

DOI: https://doi.org/10.1155/2024/4530255
Nat Commun. 2024 Apr 18. 15(1): 3326

Cdk8/CDK19 promotes mitochondrial fission through Drp1 phosphorylation and can phenotypically suppress pink1 deficiency in Drosophila.

Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen.

Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. We show that Cdk8 promotes the phosphorylation of Drp1 at S616, a protein required for mitochondrial fission. Interestingly, Pink1, a mitochondrial kinase implicated in Parkinson's disease, also phosphorylates Drp1 at the same residue. Indeed, overexpression of Cdk8 significantly suppresses the phenotypes observed in flies with low levels of Pink1, including elevated levels of ROS, mitochondrial dysmorphology, and behavioral defects. In summary, we propose that Pink1 and Cdk8 perform similar functions to promote Drp1-mediated fission.

DOI: https://doi.org/10.1038/s41467-024-47623-8
Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2319476121

Lipid scrambling is a general feature of protein insertases.

Dazhi Li, Cristian Rocha-Roa, Matthew A Schilling, Karin M Reinisch, Stefano Vanni.

  Glycerophospholipids are synthesized primarily in the cytosolic leaflet of the endoplasmic reticulum (ER) membrane and must be equilibrated between bilayer leaflets to allow the ER and membranes derived from it to grow. Lipid equilibration is facilitated by integral membrane proteins called "scramblases." These proteins feature a hydrophilic groove allowing the polar heads of lipids to traverse the hydrophobic membrane interior, similar to a credit card moving through a reader. Nevertheless, despite their fundamental role in membrane expansion and dynamics, the identity of most scramblases has remained elusive. Here, combining biochemical reconstitution and molecular dynamics simulations, we show that lipid scrambling is a general feature of protein insertases, integral membrane proteins which insert polypeptide chains into membranes of the ER and organelles disconnected from vesicle trafficking. Our data indicate that lipid scrambling occurs in the same hydrophilic channel through which protein insertion takes place and that scrambling is abolished in the presence of nascent polypeptide chains. We propose that protein insertases could have a so-far-overlooked role in membrane dynamics as scramblases.

Keywords:  cellular organelles; lipid transport; membrane biology; membrane proteins; molecular dynamics

DOI:  https://doi.org/10.1073/pnas.2319476121