bims-medebr 2024-09-22 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–09–22
23 papers selected by
Regina F. Fernández, Johns Hopkins University

CoA synthase plays a critical role in neurodevelopment and neurodegeneration.
Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome.
Altered fatty acid distribution in lysosome-associated membrane protein-2 deficient mice.
iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.
Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.
18F-FDG brain PET: a metabolic predictive factor for gait improvement after cerebrospinal fluid shunting in normal pressure hydrocephalus?
LDL Exposure Disrupts Mitochondrial Function and Dynamics in a Hippocampal Neuronal Cell Line.
Therapeutic ketogenic diet as treatment for anorexia nervosa.
Clinical-grade intranasal NGF fuels neurological and metabolic functions of Mecp2-deficient mice.
The Unconventional Effects of the Ketogenic Diet (KD) in Preclinical Epilepsy.
Cholesterol dynamics in rabbit liver: High-fat diet, olive oil, and synergistic dietary effects.
Early brain neuroinflammatory and metabolic changes identified by dual tracer microPET imaging in mice with acute liver injury.
Deciphering the role of sphingosine 1-phosphate in central nervous system myelination and repair.
Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
Infantile Fructose-1,6-Bisphosphatase Deficiency Masquerading as Mitochondriopathy.
Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function.
Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis.
Spatiotemporal Mapping of the Oxytocin Receptor at Single-Cell Resolution in the Postnatally Developing Mouse Brain.
A new perspective on the regulation of glucose and cholesterol transport by mitochondria-lysosome contact sites.
Spatiotemporal relationships between neuronal, metabolic, and hemodynamic signals in the awake and anesthetized mouse brain.
Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.
The partitioning of fatty acids between membrane and storage lipids controls ER membrane expansion.
Acetyl-CoA carboxylase Inhibition increases retinal pigment epithelial cell fatty acid flux and restricts apolipoprotein efflux.

Front Cell Neurosci. 2024 ;18 1458475

CoA synthase plays a critical role in neurodevelopment and neurodegeneration.

Chiara Cavestro, Marco D'Amato, Maria Nicol Colombo, Floriana Cascone, Andrea Stefano Moro, Sonia Levi, Valeria Tiranti, Ivano Di Meo.

  Coenzyme A (CoA), which is widely distributed and vital for cellular metabolism, is a critical molecule essential in both synthesizing and breaking down key energy sources in the body. Inborn errors of metabolism in the cellular de novo biosynthetic pathway of CoA have been linked to human genetic disorders, emphasizing the importance of this pathway. The COASY gene encodes the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of the CoA biosynthetic pathway and serves as one of the rate-limiting components of the pathway. Recessive variants of this gene cause an exceptionally rare and devastating disease called COASY protein-associated neurodegeneration (CoPAN) while complete loss-of-function variants in COASY have been identified in fetuses/neonates with Pontocerebellar Hypoplasia type 12 (PCH 12). Understanding why the different symptoms emerge in these disorders and what determines the development of one syndrome over the other is still not achieved. To shed light on the pathogenesis, we generated a new conditional animal model in which Coasy was deleted under the control of the human GFAP promoter. We used this mouse model to investigate how defects in the CoA biosynthetic pathway affect brain development. This model showed a broad spectrum of severity of the in vivo phenotype, ranging from very short survival (less than 2 weeks) to normal life expectancy in some animals. Surviving mice displayed a behavioral phenotype with sensorimotor defects. Ex vivo histological analysis revealed variable but consistent cerebral and cerebellar cortical hypoplasia, in parallel with a broad astrocytic hyper-proliferation in the cerebral cortex. In addition, primary astrocytes derived from this model exhibited lipid peroxidation, iron dyshomeostasis, and impaired mitochondrial respiration. Notably, Coasy ablation in radial glia and astrocytic lineage triggers abnormal neuronal development and chronic neuroinflammation, offering new insights into disease mechanisms.

Keywords:  COASY protein-associated neurodegeneration; CoA synthase; animal models; neurodegeneration; neurodevelopment; pontocerebellar hypoplasia type 12

DOI:  https://doi.org/10.3389/fncel.2024.1458475
Mol Autism. 2024 Sep 19. 15(1): 39

Pharmacological inhibition of the CB1 cannabinoid receptor restores abnormal brain mitochondrial CB1 receptor expression and rescues bioenergetic and cognitive defects in a female mouse model of Rett syndrome.

Livia Cosentino, Chiara Urbinati, Chiara Lanzillotta, Domenico De Rasmo, Daniela Valenti, Mattia Pellas, Maria Cristina Quattrini, Fabiana Piscitelli, Magdalena Kostrzewa, Fabio Di Domenico, Donatella Pietraforte, Tiziana Bisogno, Anna Signorile, Rosa Anna Vacca, Bianca De Filippis.

   BACKGROUND: Defective mitochondria and aberrant brain mitochondrial bioenergetics are consistent features in syndromic intellectual disability disorders, such as Rett syndrome (RTT), a rare neurologic disorder that severely affects mainly females carrying mutations in the X-linked MECP2 gene. A pool of CB1 cannabinoid receptors (CB1R), the primary receptor subtype of the endocannabinoid system in the brain, is located on brain mitochondrial membranes (mtCB1R), where it can locally regulate energy production, synaptic transmission and memory abilities through the inhibition of the intra-mitochondrial protein kinase A (mtPKA). In the present study, we asked whether an overactive mtCB1R-mtPKA signaling might underlie the brain mitochondrial alterations in RTT and whether its modulation by systemic administration of the CB1R inverse agonist rimonabant might improve bioenergetics and cognitive defects in mice modeling RTT.
METHODS: Rimonabant (0.3 mg/kg/day, intraperitoneal injections) was administered daily to symptomatic female mice carrying a truncating mutation of the Mecp2 gene and its effects on brain mitochondria functionality, systemic oxidative status, and memory function were assessed.
RESULTS: mtCB1R is overexpressed in the RTT mouse brain. Subchronic treatment with rimonabant normalizes mtCB1R expression in RTT mouse brains, boosts mtPKA signaling, and restores the defective brain mitochondrial bioenergetics, abnormal peripheral redox homeostasis, and impaired cognitive abilities in RTT mice.
LIMITATIONS: The lack of selectivity of the rimonabant treatment towards mtCB1R does not allow us to exclude that the beneficial effects exerted by the treatment in the RTT mouse model may be ascribed more broadly to the modulation of CB1R activity and distribution among intracellular compartments, rather than to a selective effect on mtCB1R-mediated signaling. The low sample size of few experiments is a further limitation that has been addressed replicating the main findings under different experimental conditions.
CONCLUSIONS: The present data identify mtCB1R overexpression as a novel molecular alteration in the RTT mouse brain that may underlie defective brain mitochondrial bioenergetics and cognitive dysfunction.

Keywords:  Brain mitochondria; CB1 cannabinoid receptor; Energy metabolism; Intellectual disability; Mouse model; PKA; Rett syndrome

DOI:  https://doi.org/10.1186/s13229-024-00617-1
Biochem Biophys Rep. 2024 Dec;40 101822

Altered fatty acid distribution in lysosome-associated membrane protein-2 deficient mice.

Ziming Xu, Shoji Notomi, Guannan Wu, Yosuke Fukuda, Yusuke Maehara, Masatoshi Fukushima, Yusuke Murakami, Masatomo Takahashi, Yoshihiro Izumi, Koh-Hei Sonoda.

  Lysosome-associated membrane protein-2 (LAMP2) deficiency causes the human Danon disease and represents a lysosomal dysfunction because of its pivotal role in regulating autophagy and lysosome biogenesis. LAMP2-deficient mice exhibit a spectrum of phenotypes, including cardioskeletal myopathy, mental retardation, and retinopathy, similar to those observed in patients with Danon disease. Its pathology is thought to involve altered energy metabolism and lipid dysregulation; however, the lipidomic profiles of LAMP2-deficient animals have not been investigated. In this study, we investigated lipid alterations in LAMP2 KO mice tissues, including those of the liver, plasma, and retina, using liquid chromatography-mass spectrometry. Our results revealed significantly increased free fatty acid (FFA) levels and decreased in triglyceride (TG) levels in LAMP2 KO liver tissues at three and six months. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species significantly decreased in LAMP2 KO mice livers at six months. Similarly, plasma TG and PC/PE levels decreased in LAMP2 KO mice. In contrast, plasma FFA levels were significantly lower in LAMP2 KO mice. Retina FFA levels were elevated in LAMP2 KO mice, accompanied by a partial decrease in PC/PE at six months. In summary, FFA levels increased in several tissues but not in the LAMP2 KO mice plasma, suggesting the potential consumption of FFA as an energy source in the peripheral tissues. The depletion of TG and PC/PE accelerated with age, suggesting an underlying age-dependent energy crisis condition. Our findings underscore the dysregulated distribution of fatty acids in LAMP2-deficient animals and provide new mechanistic insights into the pathology of Danon disease.

Keywords:  Fatty acid metabolism; LC-MS; Lipidomics; PC; PUFA; TGs

DOI:  https://doi.org/10.1016/j.bbrep.2024.101822
J Neuroinflammation. 2024 Sep 18. 21(1): 228

iPLA2β loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.

Li Jiao, Wenxin Shao, Wenqi Quan, Longjiang Xu, Penghui Liu, Jinling Yang, Xiaozhong Peng.

BACKGROUND: During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2β are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2β deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation. We hypothesized that iPLA2β contributes to age-related cognitive decline by disrupting neuronal mitophagy.
METHODOLOGY: We used aged wild-type (WT) mice and iPLA2β-/- mice as natural aging models to assess cognitive performance, iPLA2β expression in the cortex, levels of chemokines and inflammatory cytokines, and mitochondrial dysfunction, with a specific focus on mitophagy and the mitochondrial phospholipid profile. To further elucidate the role of iPLA2β, we employed adeno-associated virus (AAV)-mediated iPLA2β overexpression in aged mice and re-evaluated these parameters.
RESULTS: Our findings revealed a significant reduction in iPLA2β levels in the prefrontal cortex of aged brains. Notably, iPLA2β-deficient mice exhibited impaired learning and memory. Loss of iPLA2β in the PFC of aged mice led to increased levels of chemokines and inflammatory cytokines. This damage was associated with altered mitochondrial morphology, reduced ATP levels due to dysregulation of the parkin-independent mitophagy pathway, and changes in the mitochondrial phospholipid profile. AAV-mediated overexpression of iPLA2β alleviated age-related parkin-independent mitophagy pathway dysregulation in primary neurons and the PFC of aged mice, reduced inflammation, and improved cognitive function.
CONCLUSIONS: Our study suggests that age-related iPLA2β loss in the PFC leads to cognitive decline through the disruption of mitophagy. These findings highlight the potential of targeting iPLA2β to ameliorate age-related neurocognitive disorders.

DOI: https://doi.org/10.1186/s12974-024-03219-z
Brain. 2024 Aug 30. pii: awae268. [Epub ahead of print]

Biallelic PTPMT1 variants disrupt cardiolipin metabolism and lead to a neurodevelopmental syndrome.

Micol Falabella, Chiara Pizzamiglio, Luis Carlos Tabara, Benjamin Munro, Mohamed S Abdel-Hamid, Ece Sonmezler, William L Macken, Shanti Lu, Lisa Tilokani, Padraig J Flannery, Nina Patel, Simon A S Pope, Simon J R Heales, Dania B H Hammadi, Charlotte L Alston, Robert W Taylor, Hanns Lochmuller, Cathy E Woodward, Robyn Labrum, Jana Vandrovcova, Henry Houlden, Efstathia Chronopoulou, Germaine Pierre, Reza Maroofian, Michael G Hanna, Jan-Willem Taanman, Semra Hiz, Yavuz Oktay, Maha S Zaki, Rita Horvath, Julien Prudent, Robert D S Pitceathly.

  Primary mitochondrial diseases (PMDs) are among the most common inherited neurological disorders. They are caused by pathogenic variants in mitochondrial or nuclear DNA that disrupt mitochondrial structure and/or function, leading to impaired oxidative phosphorylation (OXPHOS). One emerging subcategory of PMDs involves defective phospholipid (PL) metabolism. Cardiolipin (CL), the signature PL of mitochondria, resides primarily in the inner mitochondrial membrane, where it is biosynthesised and remodelled via multiple enzymes and is fundamental to several aspects of mitochondrial biology. Genes that contribute to CL biosynthesis have recently been linked with PMD. However, the pathophysiological mechanisms that underpin human CL-related PMDs are not fully characterised. Here, we report six individuals, from three independent families, harbouring biallelic variants in PTPMT1, a mitochondrial tyrosine phosphatase required for de novo CL biosynthesis. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome comprising developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy, and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy, and white matter changes. Using patient-derived fibroblasts and skeletal muscle tissue, combined with cellular rescue experiments, we characterise the molecular defects associated with mutant PTPMT1 and confirm the downstream pathogenic effects that loss of PTPMT1 has on mitochondrial structure and function. To further characterise the functional role of PTPMT1 in CL homeostasis, we established a zebrafish ptpmt1 knockout model associated with abnormalities in body size, developmental alterations, decreased total CL levels, and OXPHOS deficiency. Together, these data indicate that loss of PTPMT1 function is associated with a new autosomal recessive PMD caused by impaired CL metabolism, highlight the contribution of aberrant CL metabolism towards human disease, and emphasise the importance of normal CL homeostasis during neurodevelopment.

Keywords:  cardiolipin; mitochondria; mitochondrial dynamics; neurodevelopmental syndrome; primary mitochondrial disease

DOI:  https://doi.org/10.1093/brain/awae268
Q J Nucl Med Mol Imaging. 2024 Sep 18.

18F-FDG brain PET: a metabolic predictive factor for gait improvement after cerebrospinal fluid shunting in normal pressure hydrocephalus?

Tatiana Horowitz, Stephan Grimaldi, Henri Dufour, Thomas Graillon, Jean-Philippe Azulay, Eric Guedj.

BACKGROUND: The pathophysiology of normal pressure hydrocephalus (NPH) has not been fully elucidated. Treating NPH with cerebrospinal fluid shunts to improve gait disturbances may have some risks and inconsistent benefits. No clear predictive factor has been identified thus far. This preliminary study aimed to evaluate the predictive value of preoperative brain 18F-FDG positron emission tomography (PET) on overall gait response in patients with NPH.
METHODS: Sixteen patients with NPH who underwent 18F-FDG PET before shunt surgery between 2012 and 2022 were included retrospectively and separated into two groups based on their gait response one year after surgery: responders (R) or nonresponders (NR). Brain glucose metabolism was assessed using visual and semiquantitative analyses using SPM8 software (Welcome Department of Cognitive Neurology, University College, London, UK). Five regions of interest were selected: global cortex, cerebellum, thalamus, striatum, and midbrain.
RESULTS: Visual interpretation showed more frequent hypometabolism of the striatum, thalamus and global cortex in NR. None of the patients showing hypometabolism of these regions were R. Based on these results, the visual interpretation allowed us to identify 3/8 NR and 8/8 R. Semiquantitative analysis confirmed significantly lower thalamic metabolism in the NR group (P=0.037) and a trend towards lower metabolism of the striatum (P=0.075) with an area under the curve of 0.77 for thalamic metabolism to discriminate between R and NR.
CONCLUSIONS: This preliminary study using brain 18F-FDG PET suggests that reduced brain metabolism in the thalamus and striatum along with cortical hypometabolism may be associated with poorer gait response to CSF shunting in normal pressure hydrocephalus (NPH). Although these findings suggest that preoperative brain 18F-FDG PET could potentially aid in selecting appropriate candidates for shunt surgery, further research with larger sample sizes is needed to confirm these results.

DOI: https://doi.org/10.23736/S1824-4785.24.03582-9
Mol Neurobiol. 2024 Sep 20.

LDL Exposure Disrupts Mitochondrial Function and Dynamics in a Hippocampal Neuronal Cell Line.

Hémelin Resende Farias, Jessica Marques Obelar Ramos, Caroline Tainá Griesang, Lucas Santos, Osmar Vieira Ramires Junior, Debora Guerini Souza, Fernanda Silva Ferreira, Sabrina Somacal, Leo Anderson Meira Martins, Diogo Onofre Gomes de Souza, José Cláudio Fonseca Moreira, Angela T S Wyse, Fátima Theresinha Costa Rodrigues Guma, Jade de Oliveira.

  Hypercholesterolemia has been associated with cognitive dysfunction and neurodegenerative diseases. Moreover, this metabolic condition disrupts the blood-brain barrier, allowing low-density lipoprotein (LDL) to enter the central nervous system. Thus, we investigated the effects of LDL exposure on mitochondrial function in a mouse hippocampal neuronal cell line (HT-22). HT-22 cells were exposed to human LDL (50 and 300 μg/mL) for 24 h. After this, intracellular lipid droplet (LD) content, cell viability, cell death, and mitochondrial parameters were assessed. We found that the higher LDL concentration increases LD content compared with control. Both concentrations increased the number of Annexin V-positive cells, indicating apoptosis. Moreover, in mitochondrial parameters, the LDL exposure on hippocampal neuronal cell line leads to a decrease in mitochondrial complexes I and II activities in both concentrations tested and a reduction in Mitotracker™ Red fluorescence and Mitotracker™ Red and Mitotracker™ Green ratio in the higher concentration, indicating mitochondrial impairment. The LDL incubation induces mitochondrial superoxide production and decreases superoxide dismutase activity in the lower concentration in HT-22 cells. Finally, LDL exposure increases the expression of genes associated with mitochondrial fusion (OPA1 and mitofusin 2) in the lower concentration. In conclusion, our findings suggest that LDL exposure induces mitochondrial dysfunction and modulates mitochondrial dynamics in the hippocampal neuronal cells.

Keywords:  Brain dysfunction; HT-22 cells; Hypercholesterolemia; LDL cholesterol; Mitochondria

DOI:  https://doi.org/10.1007/s12035-024-04476-y
Front Nutr. 2024 ;11 1392135

Therapeutic ketogenic diet as treatment for anorexia nervosa.

Guido K W Frank, Barbara Scolnick.

  Anorexia nervosa (AN) is a severe psychiatric disorder. However, we lack neurobiological models and interventions to explain and treat the core characteristics of food restriction, feeling fat, and body size overestimation. Research has made progress in understanding brain function involved in the pathophysiology of AN, but translating those results into biological therapies has been challenging. Studies have suggested that metabolic factors could contribute to developing and maintaining AN pathophysiology. Here, we describe a neurobiological model for why using a therapeutic ketogenic diet could address key alterations in brain function in AN and prevent the desire for weight loss and associated eating disorder-specific symptoms. This translational model is based on animal studies and human data and integrates behavioral traits, brain neural energy metabolism, and neurotransmitter function. Pilot data indicate that the intervention can dramatically reduce eating and body-related fears, although larger studies across illness stages still need to be conducted.

Keywords:  anorexia nervosa; behavior; brain; ketogenic; metabolism; treatment

DOI:  https://doi.org/10.3389/fnut.2024.1392135
Brain. 2024 Sep 20. pii: awae291. [Epub ahead of print]

Clinical-grade intranasal NGF fuels neurological and metabolic functions of Mecp2-deficient mice.

Diego Pozzer, Marzia Indrigo, Martina Breccia, Elena Florio, Camilla Aurora Franchino, Giuseppina De Rocco, Francesca Maltecca, Antonio Fadda, Marzia Rossato, Andrea Aramini, Marcello Allegretti, Angelisa Frasca, Lidia De Filippis, Nicoletta Landsberger.

  MECP2 deficiency causes a broad spectrum of neuropsychiatric disorders that can affect both genders. Rett syndrome is the most common and is characterized by an apparently normal growth period followed by a regression phase in which patients lose most of their previously acquired skills. After this dramatic period, various symptoms progressively appear, including severe intellectual disability, epilepsy, apraxia, breathing abnormalities and motor deterioration. MECP2 encodes for an epigenetic transcription factor that is particularly abundant in the brain; consequently, several transcriptional defects characterize the Rett syndrome brain. The well-known deficiency of several neurotrophins and growth factors, together with the positive effects exerted by Trofinetide, a synthetic analogue of insulin-like growth factor 1, in Rett patients and in mouse models of Mecp2 deficiency, prompted us to investigate the therapeutic potential of nerve growth factor. Initial in vitro studies demonstrated a healing effect of rhNGF on neuronal maturation and activity in cultured Mecp2-null neurons. Subsequently, we designed in vivo studies with clear translational potential using intranasally administered recombinant human GMP-grade NGF (rhNGF) already used in the clinic. Efficacy of rhNGF in vivo in Mecp2-null hemizygous male mice and heterozygous female mice was assessed. General well-being was evaluated by a conventional phenotypic score and motor performance through the Pole and Beam Walking tests, while cognitive function and interaction with the environment were measured by the Novel Object Recognition Test and the Marble Burying test, respectively. At the end of the treatment, mouse cortices were dissected and bulk RNA sequencing was performed to identify the molecular pathways involved in the protective effects of rhNGF. rhNGF exerted positive effects on cognitive and motor functions in both male and female mouse models of Rett syndrome. In male hemizygous mice, which suffer from significantly more severe and rapidly advancing symptoms, the drug's ability to slow the disease's progression was more pronounced. The unbiased research for the molecular mechanisms triggering the observed benefits revealed a strong positive effect on gene sets related to oxidative phosphorylation, mitochondrial structure and function. These results were validated by demonstrating the drug's ability to improve mitochondrial structure and respiration in Mecp2-null cerebral cortices. Furthermore, GO analyses indicated that NGF exerted the expected improvement in neuronal maturation. We conclude that intranasal administration of rhNGF is a non-invasive and effective route of administration for the treatment of Rett syndrome and possibly for other neurometabolic disorders with overt mitochondrial dysfunction.

Keywords:   Mecp2 null mice; Rett syndrome; animal behavior; cognitive function; mitochondrial dysfunction; rhNGF

DOI:  https://doi.org/10.1093/brain/awae291
Epilepsy Curr. 2024 Mar-Apr;24(2):24(2): 117-122

The Unconventional Effects of the Ketogenic Diet (KD) in Preclinical Epilepsy.

Timothy Simeone, Kristina Simeone.

  The integration of metabolic therapeutics in the available clinical armory is becoming more commonplace in health care as our understanding about the dependence of disease on metabolism continues to deepen and evolve. In the epilepsy field, we often think about the ketogenic diet (KD, high fat: carbohydrate ratio) in terms of its anti-seizure efficacy. The aim of this article is to review what we've learned from preclinical studies about the KD's more unconventional effects, including its neuroprotective effects, anti-epileptogenic and disease-modifying effects, and how the KD influences comorbidities associated with epilepsy. As time moves us into the future and metabolic therapies become more common place, the effects of the KD considered unconventional herein, may end up being referred to as traditional.

Keywords:  anxiety; autism; cognitive dysfunction; comorbidity; depression; epilepsy; ketogenic diet; metabolic therapy; preclinical; sleep problems

DOI:  https://doi.org/10.1177/15357597231216916
Biochem Biophys Res Commun. 2024 Sep 12. pii: S0006-291X(24)01211-7. [Epub ahead of print]733 150675

Cholesterol dynamics in rabbit liver: High-fat diet, olive oil, and synergistic dietary effects.

Abi K Funes, Virginia Avena, Paola V Boarelli, María A Monclus, Dario Fernández Zoppino, Tania E Saez-Lancellotti, Miguel W Fornes.

   BACKGROUND & AIMS: Lipid metabolism disorders contribute to a range of human diseases, including liver-related pathologies. Rabbits, highly sensitive to dietary cholesterol, provide a model for understanding the development of liver disorders. Sterol regulatory element-binding protein isoform 2 (SREBP2) crucially regulates intracellular cholesterol pathways. Extra-virgin olive oil (EVOO) has shown reducing cholesterol levels and restoring liver parameters affected by HFD. The aim was to investigate the molecular impact of an HFD and supplemented with EVOO on rabbit liver cholesterol metabolism.
APPROACH & RESULTS: Male rabbits were assigned to dietary cohorts, including control, acute/chronic HFD, sequential HFD with EVOO, and EVOO. Parameters such as serum lipid profiles, hepatic enzymes, body weight, and molecular analyses. After 6 months of HFD, plasma and hepatic cholesterol increased with decreased SREBP2 and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) expression. Prolonged HFD increased cholesterol levels, upregulating SREBP2 mRNA and HMGCR protein. Combining this with EVOO lowered cholesterol, increased SREBP2 mRNA, and upregulated low-density lipoprotein receptor (LDLR) expression. HFD-induced metabolic dysfunction-associated fatty liver disease was mitigated by EVOO. In conclusion, the SREBP2 system responds to dietary changes.
CONCLUSIONS: In rabbits, the SREBP2 system responds to dietary changes. Acute HFD hinders cholesterol synthesis, while prolonged HFD disrupts regulation, causing SREBP2 upregulation. EVOO intake prompts LDLR upregulation, potentially enhancing cholesterol clearance and restoring hepatic alterations.

Keywords:  HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase); LDL receptor (LDLR); Lipid metabolism; MAFLD (metabolic dysfunction-associated fatty liver disease); Sterol regulatory element-binding protein 2 (SREBP2)

DOI:  https://doi.org/10.1016/j.bbrc.2024.150675
bioRxiv. 2024 Sep 03. pii: 2024.09.02.610840. [Epub ahead of print]

Early brain neuroinflammatory and metabolic changes identified by dual tracer microPET imaging in mice with acute liver injury.

Santhoshi P Palandira, Aidan Falvey, Joseph Carrion, Qiong Zeng, Saher Chaudhry, Kira Grossman, Lauren Turecki, Nha Nguyen, Michael Brines, Sangeeta S Chavan, Christine N Metz, Yousef Al-Abed, Eric H Chang, Yilong Ma, David Eidelberg, An Vo, Kevin J Tracey, Valentin A Pavlov.

Background: Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is one of the main diagnostic criteria for ALF. While neuroinflammation and brain metabolic alterations significantly contribute to hepatic encephalopathy, their evaluation at early stages of ALI remained challenging. To provide insights, we utilized post-mortem analysis and non-invasive brain micro positron emission tomography (microPET) imaging of mice with APAP-induced ALI.
Methods: Male C57BL/6 mice were treated with vehicle or APAP (600 mg/kg, i.p.). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver damage (using H&E staining), hepatic and serum IL-6 levels, and hippocampal IBA1 (using immunolabeling) were evaluated at 24h and 48h. Vehicle and APAP treated animals also underwent microPET imaging utilizing a dual tracer approach, including [ 11 C]-peripheral benzodiazepine receptor ([ 11 C]PBR28) to assess microglia/astrocyte activation and [ 18 F]-fluoro-2-deoxy-2-D-glucose ([ 18 F]FDG) to assess energy metabolism. Brain images were pre-processed and evaluated using conjunction and individual tracer uptake analysis.
Results: APAP-induced ALI and hepatic and systemic inflammation were detected at 24h and 48h by significantly elevated serum ALT and AST levels, hepatocellular damage, and increased hepatic and serum IL-6 levels. In parallel, increased microglial numbers, indicative for neuroinflammation were observed in the hippocampus of APAP-treated mice. MicroPET imaging revealed overlapping increases in [ 11 C]PBR28 and [ 18 F]FDG uptake in the hippocampus, thalamus, and habenular nucleus indicating microglial/astroglial activation and increased energy metabolism in APAP-treated mice (vs. vehicle-treated mice) at 24h. Similar significant increases were also found in the hypothalamus, thalamus, and cerebellum at 48h. The individual tracer uptake analyses (APAP vs vehicle) at 24h and 48h confirmed increases in these brain areas and indicated additional tracer- and region-specific effects including hippocampal alterations.
Conclusion: Peripheral manifestations of APAP-induced ALI in mice are associated with brain neuroinflammatory and metabolic alterations at relatively early stages of disease progression, which can be non-invasively evaluated using microPET imaging and conjunction analysis. These findings support further PET-based investigations of brain function in ALI/ALF that may inform timely therapeutic interventions.

DOI: https://doi.org/10.1101/2024.09.02.610840
J Neurochem. 2024 Sep 17.

Deciphering the role of sphingosine 1-phosphate in central nervous system myelination and repair.

Fatima Binish, Junhua Xiao.

  Sphingosine 1-phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1-phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein-coupled S1P receptors 1-5 (S1PR1-5). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P-S1PR signalling protects myelin-forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P-S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation.

Keywords:  S1P; SPL; multiple sclerosis; myelination; oligodendrocyte; remyelination

DOI:  https://doi.org/10.1111/jnc.16228
Elife. 2024 Sep 17. pii: RP98834. [Epub ahead of print]13

Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.

Stefan Passlick, Ghanim Ullah, Christian Henneberger.

  Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modeled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the mouse hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed unexpected differences in the vulnerability of the investigated cellular mechanisms. Axonal action potential firing and glutamate uptake were surprisingly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.

Keywords:  glutamate release; glutamate uptake; ischemia; metabolic failure; mouse; neuroscience; stroke; synaptic transmission

DOI:  https://doi.org/10.7554/eLife.98834
Cureus. 2024 Aug;16(8): e67291

Infantile Fructose-1,6-Bisphosphatase Deficiency Masquerading as Mitochondriopathy.

Varshini Chandrasekhar, Pallavi Yelkur, Vidhyasagar K.

  Fructose-1,6-bisphosphatase 1 (FBP1) deficiency is a rare autosomal recessive disorder of gluconeogenesis. Affected children present with severe hypoglycemia and lactic acidosis in infancy. We report a case of a female child, aged one year and six months, born out of a third-degree consanguineous marriage, who initially presented with sudden-onset vomiting episodes and failure to thrive. Despite a clinical suspicion of mitochondrial disorder, biochemical investigations revealed elevated levels of alanine, glycine, lactic acid, pyruvic acid, 3-hydroxy isovaleric acid, fumaric acid, and 4-hydroxy phenylacetic acid. Clinical exome sequencing confirmed homozygous inheritance of a mutated FBP1 gene, establishing the diagnosis of FBP1 deficiency. Differential diagnoses included mitochondrial disorders and transaldolase deficiency, but comprehensive genetic testing excluded these conditions. Management focused on dietary adjustments to avoid simple sugars and increase complex carbohydrates during illness. This case underscores the complexity of diagnosing rare metabolic disorders and highlights the pivotal role of genetic testing in accurate diagnosis and management.

Keywords:  fructose; genetic testing; hypoglycemia; metabolic acidosis; mitochondriopathy

DOI:  https://doi.org/10.7759/cureus.67291
J Comp Neurol. 2024 Sep;532(9): e25669

Invariance of Mitochondria and Synapses in the Primary Visual Cortex of Mammals Provides Insight Into Energetics and Function.

Molly T Karl, Young Do Kim, Kavita Rajendran, Paul R Manger, Chet C Sherwood.

  The cerebral cortex accounts for substantial energy expenditure, primarily driven by the metabolic demands of synaptic signaling. Mitochondria, the organelles responsible for generating cellular energy, play a crucial role in this process. We investigated ultrastructural characteristics of the primary visual cortex in 18 phylogenetically diverse mammals, spanning a broad range of brain sizes from mouse to elephant. Our findings reveal remarkable uniformity in synapse density, postsynaptic density (PSD) length, and mitochondria density, indicating functional and metabolic constraints that maintain these fundamental features. Notably, we observed an average of 1.9 mitochondria per synapse across mammalian species. When considered together with the trend of decreasing neuron density with larger brain size, we find that brain enlargement in mammals is characterized by increasing proportions of synapses and mitochondria per cortical neuron. These results shed light on the adaptive mechanisms and metabolic dynamics that govern cortical ultrastructure across mammals.

Keywords:  RRID:SCR_008515; RRID:SCR_021162; brain evolution; energy; mammals; mitochondria; neocortex; synapse

DOI:  https://doi.org/10.1002/cne.25669
Proc Natl Acad Sci U S A. 2024 Sep 24. 121(39): e2320611121

Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis.

Peter Rodriguez, Vrinda Kalia, Cristina Fenollar-Ferrer, Chelsea L Gibson, Zayna Gichi, Andre Rajoo, Carson D Matier, Aidan T Pezacki, Tong Xiao, Lucia Carvelli, Christopher J Chang, Gary W Miller, Andy V Khamoui, Jana Boerner, Randy D Blakely.

  Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson's disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10, the putative Caenorhabditis elegans ortholog of MBLAC1, establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10. Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases.

Keywords:  C. elegans; copper; glia; neurodegeneration; swip-10

DOI:  https://doi.org/10.1073/pnas.2320611121
Neurosci Bull. 2024 Sep 15.

Spatiotemporal Mapping of the Oxytocin Receptor at Single-Cell Resolution in the Postnatally Developing Mouse Brain.

Hao Li, Ying Li, Ting Wang, Shen Li, Heli Liu, Shuyi Ning, Wei Shen, Zhe Zhao, Haitao Wu.

  The oxytocin receptor (OXTR) has garnered increasing attention for its role in regulating both mature behaviors and brain development. It has been established that OXTR mediates a range of effects that are region-specific or period-specific. However, the current studies of OXTR expression patterns in mice only provide limited help due to limitations in resolution. Therefore, our objective was to generate a comprehensive, high-resolution spatiotemporal expression map of Oxtr mRNA across the entire developing mouse brain. We applied RNAscope in situ hybridization to investigate the spatiotemporal expression pattern of Oxtr in the brains of male mice at six distinct postnatal developmental stages (P7, P14, P21, P28, P42, P56). We provide detailed descriptions of Oxtr expression patterns in key brain regions, including the cortex, basal forebrain, hippocampus, and amygdaloid complex, with a focus on the precise localization of Oxtr+ cells and the variance of expression between different neurons. Furthermore, we identified some neuronal populations with high Oxtr expression levels that have been little studied, including glutamatergic neurons in the ventral dentate gyrus, Vgat+Oxtr+ cells in the basal forebrain, and GABAergic neurons in layers 4/5 of the cortex. Our study provides a novel perspective for understanding the distribution of Oxtr and encourages further investigations into its functions.

Keywords:  Expression pattern; Oxytocin receptor; Postnatal development; RNAscope

DOI:  https://doi.org/10.1007/s12264-024-01296-x
Front Physiol. 2024 ;15 1431030

A new perspective on the regulation of glucose and cholesterol transport by mitochondria-lysosome contact sites.

Xiaolong Chen, Chun Guang Li, Xian Zhou, Minghua Zhu, Jing Jin, Ping Wang.

  Mitochondria and lysosomes play a very important role in maintaining cellular homeostasis, and the dysfunction of these organelles is closely related to many diseases. Recent studies have revealed direct interactions between mitochondria and lysosomes, forming mitochondria-lysosome contact sites that regulate organelle network dynamics and mediate the transport of metabolites between them. Impaired function of these contact sites is not only linked to physiological processes such as glucose and cholesterol transport but also closely related to the pathological processes of metabolic diseases. Here, we highlight the recent progress in understanding the mitochondria-lysosome contact sites, elucidate their role in regulating metabolic homeostasis, and explore the potential implications of this pathway in metabolic disorders.

Keywords:  cholesterol transport; glucose transport; insulin resistance; mitochondria-lysosome contact sites; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.3389/fphys.2024.1431030
Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01074-X. [Epub ahead of print]43(9): 114723

Spatiotemporal relationships between neuronal, metabolic, and hemodynamic signals in the awake and anesthetized mouse brain.

Xiaodan Wang, Jonah A Padawer-Curry, Annie R Bice, Byungchan Kim, Zachary P Rosenthal, Jin-Moo Lee, Manu S Goyal, Shannon L Macauley, Adam Q Bauer.

  Neurovascular coupling (NVC) and neurometabolic coupling (NMC) provide the basis for functional magnetic resonance imaging and positron emission tomography to map brain neurophysiology. While increases in neuronal activity are often accompanied by increases in blood oxygen delivery and oxidative metabolism, these observations are not the rule. This decoupling is important when interpreting brain network organization (e.g., resting-state functional connectivity [RSFC]) because it is unclear whether changes in NMC/NVC affect RSFC measures. We leverage wide-field optical imaging in Thy1-jRGECO1a mice to map cortical calcium activity in pyramidal neurons, flavoprotein autofluorescence (representing oxidative metabolism), and hemodynamic activity during wake and ketamine/xylazine anesthesia. Spontaneous dynamics of all contrasts exhibit patterns consistent with RSFC. NMC/NVC relative to excitatory activity varies over the cortex. Ketamine/xylazine profoundly alters NVC but not NMC. Compared to awake RSFC, ketamine/xylazine affects metabolic-based connectomes moreso than hemodynamic-based measures of RSFC. Anesthesia-related differences in NMC/NVC timing do not appreciably alter RSFC structure.

Keywords:  CP: Neuroscience; calcium imaging; functional connectivity; neurometabolic coupling; neurovascular coupling; oxidative metabolism

DOI:  https://doi.org/10.1016/j.celrep.2024.114723
Mitochondrion. 2024 Sep 12. pii: S1567-7249(24)00124-7. [Epub ahead of print] 101966

Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line.

Moris Sangineto, Martina Ciarnelli, Archana Moola, Vidyasagar Naik Bukke, Tommaso Cassano, Rosanna Villani, Antonino D Romano, Giuseppe Di Gioia, Carlo Avolio, Gaetano Serviddio.

  Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.

Keywords:  Dimethyl fumarate; Immunometabolism; Itaconate; Krebs cycle; Microglia; Mitochondria

DOI:  https://doi.org/10.1016/j.mito.2024.101966
bioRxiv. 2024 Sep 05. pii: 2024.09.05.611378. [Epub ahead of print]

The partitioning of fatty acids between membrane and storage lipids controls ER membrane expansion.

Pawel K Lysyganicz, Antonio D Barbosa, Shoily Khondker, Nicholas A Stewart, George M Carman, Phillip J Stansfeld, Marcus K Dymond, Symeon Siniossoglou.

The biogenesis of membrane-bound organelles involves the synthesis, remodelling and degradation of their constituent phospholipids. How these pathways regulate organelle size, remains still poorly understood. Here we demonstrate that a lipid degradation pathway inhibits the expansion of the endoplasmic reticulum (ER) membrane. Phospholipid diacylglycerol acyltransferases (PDATs) use endogenous phospholipids as fatty acyl donors to generate triglyceride stored in lipid droplets. The significance of this non-canonical triglyceride biosynthetic pathway has remained elusive. We find that the activity of the yeast PDAT Lro1 is regulated by a membrane- proximal domain facing the luminal side of the ER bilayer. To reveal the biological roles of PDATs, we engineered an Lro1 variant with derepressed activity. We show that active Lro1 mediates the retraction of ER membrane expansion driven by phospholipid synthesis. Furthermore, the subcellular distribution and membrane turnover activity of Lro1 are controlled by diacylglycerol, produced by the activity of Pah1, a conserved member of the lipin family. Collectively, our findings reveal a lipid metabolic network that regulates endoplasmic reticulum biogenesis by converting phospholipids into storage lipids.

DOI: https://doi.org/10.1101/2024.09.05.611378
J Biol Chem. 2024 Sep 12. pii: S0021-9258(24)02273-7. [Epub ahead of print] 107772

Acetyl-CoA carboxylase Inhibition increases retinal pigment epithelial cell fatty acid flux and restricts apolipoprotein efflux.

Daniel T Hass, Kriti Pandey, Abbi Engel, Noah Horton, Cameron D Haydinger, Brian M Robbings, Rayne R Lim, Martin Sadilek, Qitao Zhang, Gillian A Gulette, Amy Li, Libin Xu, Jason M L Miller, Jennifer R Chao, James B Hurley.

  Lipid-rich deposits called drusen accumulate under the retinal pigment epithelium (RPE) in the eyes of patients with age-related macular degeneration (AMD) and Sorsby's fundus dystrophy (SFD). Drusen may contribute to photoreceptor and RPE degeneration in these blinding diseases. We hypothesize that stimulating β-oxidation of fatty acids could decrease the availability of lipid with which RPE cells can generate drusen. Inhibitors of acetyl-CoA carboxylase (ACC) stimulate β-oxidation and diminish lipid accumulation in fatty liver disease. In this report we test the hypothesis that an ACC inhibitor, Firsocostat, can diminish lipid deposition by RPE cells. We probed metabolism and cellular function in mouse RPE-choroid tissue and in cultured human RPE cells. We used 13C6-glucose, 13C16-palmitate, and gas chromatography-linked mass spectrometry to monitor effects of Firsocostat on glycolytic, Krebs cycle, and fatty acid metabolism. We quantified lipid abundance, apolipoprotein E (ApoE) and vascular endothelial growth factor (VEGF) release using liquid chromatography-mass spectrometry, enzyme-linked immunosorbent assays and localized ApoE deposits by immunostaining. RPE barrier function was assessed by trans-epithelial electrical resistance (TEER). Firsocostat-mediated ACC inhibition increases β-oxidation, decreases intracellular lipid levels, diminishes lipoprotein release, and increases TEER. When human serum or outer segments are used to stimulate lipoprotein release, fewer lipoproteins are released in the presence of either lipid source and Firsocostat. In a culture model of SFD, Firsocostat stimulates fatty acid oxidation, increases TEER, and decreases ApoE release. We conclude that Firsocostat remodels RPE metabolism and can limit lipid deposition. This suggests that ACC inhibition could be an effective strategy for diminishing pathologic drusen in the eyes of patients with AMD or SFD.

Keywords:  Retinal pigment epithelium; age-related macular degeneration; apolipoprotein E (ApoE); beta‐oxidation; energy metabolism; fatty acid; retinal degeneration

DOI:  https://doi.org/10.1016/j.jbc.2024.107772