bims-medebr 2022-10-30 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–10–30
35 papers selected by
Regina F. Fernández, Johns Hopkins University

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy.
Potential mechanisms to modify impaired glucose metabolism in neurodegenerative disorders.
Metabolic Assessment of Human Induced Pluripotent Stem Cells-Derived Astrocytes and Fetal Primary Astrocytes: Lactate and Glucose Turnover.
Food Restriction Counteracts Dexamethasone-Induced Downregulation of Genes Involved in Cholesterol Homeostasis in Rat Brain during Aging.
SIRT3 alleviates mitochondrial dysfunction induced by recurrent low glucose and improves the supportive function of astrocytes to neurons.
Brain Effects of SC-Nanophytosomes on a Rotenone-Induced Rat Model of Parkinson's Disease-A Proof of Concept for a Mitochondria-Targeted Therapy.
Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice.
Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation.
ApoE isoform-dependent effects of xanthohumol on high fat diet-induced cognitive impairments and hippocampal metabolic pathways.
Acetoacetate and β-hydroxybutyrate reduce mouse embryo viability via differential metabolic and epigenetic mechanisms.
Ketogenic diet therapy in children with epilepsy caused by SLC2A1 mutations: a single-center single-arm retrospective study.
Metabolomic Signatures of Autism Spectrum Disorder.
Vitamin C Deficiency Reduces Neurogenesis and Proliferation in the SVZ and Lateral Ventricle Extensions of the Young Guinea Pig Brain.
A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer's Disease.
Beneficial effects of butyrate on brain functions: A view of epigenetic.
3-Acetylpyridine On-Tissue Paternò-Büchi Derivatization Enabling High Coverage Lipid C═C Location-Resolved MS Imaging in Biological Tissues.
Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil.
SIAH proteins regulate the degradation and intra-mitochondrial aggregation of PINK1: Implications for mitochondrial pathology in Parkinson's disease.
Design and optimization of Metformin-Loaded Solid Lipid Nanoparticles for Neuroprotective effects in a rat model of diffuse traumatic brain injury: A biochemical, behavioral, and histological study.
Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial.
Mitochondrial Redox Environments Predict Sensorimotor Brain-Behavior Dynamics in Adults with HIV.
Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency.
Maternal treatment with sodium butyrate reduces the development of autism-like traits in mice offspring.
Air Pollution Exposure Increases ABCB1 and ASCT1 Transporter Levels in Mouse Cortex.
Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?
Medium-chain Acyl-COA dehydrogenase deficiency: Pathogenesis, diagnosis, and treatment.
Endocannabinoid signaling in the central nervous system.
Quantitative NMR-Based Lipoprotein Analysis Identifies Elevated HDL-4 and Triglycerides in the Serum of Alzheimer's Disease Patients.
Insulin Diminishes Superoxide Increase in Cytosol and Mitochondria of Cultured Cortical Neurons Treated with Toxic Glutamate.
Aging is associated with lower neuroactive steroids and worsened outcomes following cerebral ischemia in male mice.
Chemical Probes to Control and Visualize Lipid Metabolism in the Brain.
PET imaging in animal models of Parkinson's disease.
The Hepatic Mitochondrial Alterations Exacerbate Meta-Inflammation in Autism Spectrum Disorders.

Int J Mol Sci. 2022 Oct 14. pii: 12302. [Epub ahead of print]23(20):

The Brain Protein Acylation System Responds to Seizures in the Rat Model of PTZ-Induced Epilepsy.

Lev G Zavileyskiy, Vasily A Aleshin, Thilo Kaehne, Irina S Karlina, Artem V Artiukhov, Maria V Maslova, Anastasia V Graf, Victoria I Bunik.

  Abnormal energy expenditure during seizures and metabolic regulation through post-translational protein acylation suggest acylation as a therapeutic target in epilepsy. Our goal is to characterize an interplay between the brain acylation system components and their changes after seizures. In a rat model of pentylenetetrazole (PTZ)-induced epilepsy, we quantify 43 acylations in 29 cerebral cortex proteins; levels of NAD+; expression of NAD+-dependent deacylases (SIRT2, SIRT3, SIRT5); activities of the acyl-CoA-producing/NAD+-utilizing complexes of 2-oxoacid dehydrogenases. Compared to the control group, acylations of 14 sites in 11 proteins are found to differ significantly after seizures, with six of the proteins involved in glycolysis and energy metabolism. Comparing the single and chronic seizures does not reveal significant differences in the acylations, pyruvate dehydrogenase activity, SIRT2 expression or NAD+. On the contrary, expression of SIRT3, SIRT5 and activity of 2-oxoglutarate dehydrogenase (OGDH) decrease in chronic seizures vs. a single seizure. Negative correlations between the protein succinylation/glutarylation and SIRT5 expression, and positive correlations between the protein acetylation and SIRT2 expression are shown. Our findings unravel involvement of SIRT5 and OGDH in metabolic adaptation to seizures through protein acylation, consistent with the known neuroprotective role of SIRT5 and contribution of OGDH to the Glu/GABA balance perturbed in epilepsy.

Keywords:  2-oxo acid dehydrogenase; PTZ-model of epilepsy; SIRT2; SIRT3; SIRT5; acylation of brain protein; brain energy metabolism

DOI:  https://doi.org/10.3390/ijms232012302
J Cereb Blood Flow Metab. 2022 Oct 24. 271678X221135061

Potential mechanisms to modify impaired glucose metabolism in neurodegenerative disorders.

Tanya S McDonald, Titaya Lerskiatiphanich, Trent M Woodruff, Pamela A McCombe, John D Lee.

  Neurodegeneration refers to the selective and progressive loss-of-function and atrophy of neurons, and is present in disorders such as Alzheimer's, Huntington's, and Parkinson's disease. Although each disease presents with a unique pattern of neurodegeneration, and subsequent disease phenotype, increasing evidence implicates alterations in energy usage as a shared and core feature in the onset and progression of these disorders. Indeed, disturbances in energy metabolism may contribute to the vulnerability of neurons to apoptosis. In this review we will outline these disturbances in glucose metabolism, and how fatty acids are able to compensate for this impairment in energy production in neurodegenerative disorders. We will also highlight underlying mechanisms that could contribute to these alterations in energy metabolism. A greater understanding of these metabolism-neurodegeneration processes could lead to improved treatment options for neurodegenerative disease patients.

Keywords:  Alzheimer’s disease; Energy metabolism; Huntington’s disease; Parkinson’s disease; insulin resistance

DOI:  https://doi.org/10.1177/0271678X221135061
Biosensors (Basel). 2022 Oct 08. pii: 839. [Epub ahead of print]12(10):

Metabolic Assessment of Human Induced Pluripotent Stem Cells-Derived Astrocytes and Fetal Primary Astrocytes: Lactate and Glucose Turnover.

Isabelle Matthiesen, Rohollah Nasiri, Alessandra Tamashiro Orrego, Thomas E Winkler, Anna Herland.

  Astrocytes represent one of the main cell types in the brain and play a crucial role in brain functions, including supplying the energy demand for neurons. Moreover, they are important regulators of metabolite levels. Glucose uptake and lactate production are some of the main observable metabolic actions of astrocytes. To gain insight into these processes, it is essential to establish scalable and functional sources for in vitro studies of astrocytes. In this study, we compared the metabolic turnover of glucose and lactate in astrocytes derived from human induced pluripotent stem cell (hiPSC)-derived Astrocytes (hiAstrocytes) as a scalable astrocyte source to human fetal astrocytes (HFAs). Using a user-friendly, commercial flow-based biosensor, we could verify that hiAstrocytes are as glycogenic as their fetal counterparts, but their normalized metabolic turnover is lower. Specifically, under identical culture conditions in a defined media, HFAs have 2.3 times higher levels of lactate production compared to hiAstrocytes. In terms of glucose, HFAs have 2.1 times higher consumption levels than hiAstrocytes at 24 h. Still, as we describe their glycogenic phenotype, our study demonstrates the use of hiAstrocytes and flow-based biosensors for metabolic studies of astrocyte function.

Keywords:  astrocytes; biosensor; brain metabolism; glucose; human fetal astrocytes (HFAs); human iPSC-derived astrocytes (hiAstrocytes); lactate

DOI:  https://doi.org/10.3390/bios12100839
Brain Sci. 2022 Sep 26. pii: 1297. [Epub ahead of print]12(10):

Food Restriction Counteracts Dexamethasone-Induced Downregulation of Genes Involved in Cholesterol Homeostasis in Rat Brain during Aging.

Jelena Ciric, Vesna Tesic, Nikola Milovanovic, Irena Jovanovic Macura, Sanja Ivkovic, Selma Kanazir, Milka Perovic.

  Glucocorticoids are the most potent anti-inflammatory agents known. Limited in vivo data are available to characterize the mechanism underlying their cognitive side effects and transient occurrence of steroid psychosis. Cholesterol is important for proper neurotransmission and brain plasticity, and disruption of its homeostasis in the brain has been closely associated with memory decline during aging and in age-related neurodegenerative disorders. In the present study, we assessed the direct effects of dexamethasone, a potent synthetic glucocorticoid, on the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), apolipoprotein E (ApoE) and cholesterol 24S-hydroxylase (CYP46A1), major enzymes involved in cholesterol synthesis, metabolism, and excretion, respectively. The effects of the dexamethasone were examined during aging, in the cortex and hippocampus of 6-, 12- and 18-month-old rats, and following long-term food restriction (FR). The most prominent change observed was the age-related decrease in ApoE mRNA regardless of the food regimen applied. In animals kept on FR, this decrease was accompanied by an increase in the mRNA expression of HMGCR and CYP46A1. The present study also demonstrates that food restriction reversed most of the dexamethasone-induced changes in the expression of genes involved in regulation of cholesterol homeostasis in aging rats, in a region-specific manner.

Keywords:  cortex; every-other-day feeding; hippocampus; intermittent fasting; lipid metabolism; serum glucose

DOI:  https://doi.org/10.3390/brainsci12101297
Free Radic Biol Med. 2022 Oct 25. pii: S0891-5849(22)00944-3. [Epub ahead of print]

SIRT3 alleviates mitochondrial dysfunction induced by recurrent low glucose and improves the supportive function of astrocytes to neurons.

Ruonan Gao, Zhou Chen, Yubin Wu, Ruiyu Chen, Wenrong Zheng, Liqin Qi, Xiaoying Liu, Xiaohong Liu, Libin Liu.

  Hypoglycemia is an independent risk factor of cognitive impairment in patients with diabetes. Our previous study indicated that dysfunction of astrocytic mitochondria induced by recurrent low glucose (RLG) may account for hypoglycemia-associated neuronal injury and cognitive decline. Sirtuin 3 (SIRT3) is a key deacetylase for mitochondrial proteins and has recently been demonstrated to be an important regulator of mitochondrial function. However, whether mitochondrial dysfunction due to hypoglycemia is associated with astrocytic SIRT3 remains unclear, and few studies have focused on the impact of astrocytic SIRT3 on neuronal survival. In the present work, primary mouse cortical astrocytes cultured in normal glucose (5.5 mM) and high glucose (16.5 mM) were treated with five rounds of RLG (0.1 mM). The results showed that RLG suppressed SIRT3 expression in a glucose-dependent manner. High-glucose culture considerably increased the vulnerability of SIRT3 to RLG, leading to disrupted mitochondrial morphology in astrocytes. Overexpression of SIRT3 markedly improved astrocytic mitochondrial function and reduced RLG-induced oxidative stress. Moreover, SIRT3 suppressed a shift towards a neuroinflammatory A1-like reactive phenotype of astrocytes in response to RLG with reduced IL-1β, IL-6, and TNFα levels. Furthermore, it elevated brain-derived neurotrophic factor (BDNF) levels and promoted neurite growth by activating BDNF/TrkB signaling in the co-cultured neurons. The present study reveals the probable crosstalk between neurons and astrocytes after hypoglycemic exposure and provides a potential target in treating hypoglycemia-associated neuronal injury.

Keywords:  Astrocyte; Diabetes; Mitochondrial functions; Recurrent low glucose; SIRT3

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.10.313
Int J Mol Sci. 2022 Oct 21. pii: 12699. [Epub ahead of print]23(20):

Brain Effects of SC-Nanophytosomes on a Rotenone-Induced Rat Model of Parkinson's Disease-A Proof of Concept for a Mitochondria-Targeted Therapy.

Daniela Mendes, Francisco Peixoto, Maria Manuel Oliveira, Paula Branquinho Andrade, Romeu António Videira.

  Mitochondria are an attractive target to fight neurodegenerative diseases due to their important functions for cells and the particularly close relationship between the functional connectivity among brain regions and mitochondrial performance. This work presents a mitochondria-targeted therapy designed to modulate the functionality of the mitochondrial respiratory chain and lipidome, parameters that are affected in neurodegeneration, including in Parkinson's disease (PD). This therapy is supported by SC-Nanophytosomes constructed with membrane polar lipids, from Codium tomentosum, and elderberry anthocyanin-enriched extract, from Sambucus nigra L. SC-Nanophytosomes are nanosized vesicles with a high negative surface charge that preserve their properties, including anthocyanins in the flavylium cation form, under conditions that mimic the gastrointestinal tract pH changes. SC-Nanophytosomes, 3 µM in phospholipid, and 2.5 mg/L of EAE-extract, delivered by drinking water to a rotenone-induced PD rat model, showed significant positive outcomes on disabling motor symptoms associated with the disease. Ex vivo assays were performed with two brain portions, one comprising the basal ganglia and cerebellum (BG-Cereb) and the other with the cerebral cortex (C-Cortex) regions. Results showed that rotenone-induced neurodegeneration increases the α-synuclein levels in the BG-Cereb portion and compromises mitochondrial respiratory chain functionality in both brain portions, well-evidenced by a 50% decrease in the respiratory control rate and up to 40% in complex I activity. Rotenone-induced PD phenotype is also associated with changes in superoxide dismutase and catalase activities that are dependent on the brain portion. Treatment with SC-Nanophytosomes reverted the α-synuclein levels and antioxidant enzymes activity to the values detected in control animals. Moreover, it mitigated mitochondrial dysfunction, with positive outcomes on the respiratory control rate, the activity of individual respiratory complexes, and the fatty acid profile of the membrane phospholipids. Therefore, SC-Nanophytosomes are a promising tool to support mitochondria-targeted therapy for neurodegenerative diseases.

Keywords:  algae lipids; anthocyanins; mitochondria; nanomedicine; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms232012699
Orphanet J Rare Dis. 2022 Oct 24. 17(1): 386

Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice.

Cheng Cheng, James Cleak, Lan Weiss, Heather Cater, Michelle Stewart, Sara Wells, Rod Carlo Columbres, Alyaa Shmara, C Alejandra Morato Torres, Faria Zafar, Birgitt Schüle, Jonathan Neumann, Eli Hatchwell, Virginia Kimonis.

   BACKGROUND: Variants in the mitochondrial complex I assembly factor, NUBPL are associated with a rare cause of complex I deficiency mitochondrial disease. Patients affected by complex I deficiency harboring homozygous NUBPL variants typically have neurological problems including seizures, intellectual disability, and ataxia associated with cerebellar hypoplasia. Thus far only 19 cases have been reported worldwide, and no treatment is available for this rare disease.
METHODS: To investigate the pathogenesis of NUBPL-associated complex I deficiency, and for translational studies, we generated a knock-in mouse harboring a patient-specific variant Nubpl c.311T>C; p. L104P reported in three families.
RESULTS: Similar to Nubpl global knockout mice, the Nubpl p. L104P homozygous mice are lethal at embryonic day E10.5, suggesting that the Nubpl p. L104P variant is likely a hypomorph allele. Given the recent link between Parkinson's disease and loss-of-function NUBPL variants, we also explored aging-related behaviors and immunocytochemical changes in Nubpl hemizygous mice and did not find significant behavioral and pathological changes for alpha-synuclein and oxidative stress markers .
CONCLUSION: Our data suggest that homozygotes with Nubpl variants, similar to the null mice, are lethal, and heterozygotes are phenotypically and neuropathologically normal. We propose that a tissue-specific knockout strategy is required to establish a mouse model of Nubpl-associated complex I deficiency disorder for future mechanistic and translational studies.

Keywords:  Complex I deficiency; Mitochondria; Mouse model; NUBPL; Parkinson’s disease

DOI:  https://doi.org/10.1186/s13023-022-02446-y
Int J Mol Sci. 2022 Oct 20. pii: 12603. [Epub ahead of print]23(20):

Mitochondrial Dysfunction and Neurodegenerative Disorders: Role of Nutritional Supplementation.

David Mantle, Iain Parry Hargreaves.

  Mitochondrial dysfunction has been implicated in the pathogenesis of a number of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multisystem atrophy, and progressive supranuclear palsy. This article is concerned specifically with mitochondrial dysfunction as defined by reduced capacity for ATP production, the role of depleted levels of key nutritionally related metabolites, and the potential benefit of supplementation with specific nutrients of relevance to normal mitochondrial function in the above neurodegenerative disorders. The article provides a rationale for a combination of CoQ10, B-vitamins/NADH, L-carnitine, vitamin D, and alpha-lipoic acid for the treatment of the above neurodegenerative disorders.

Keywords:  B-vitamins; alpha-lipoic acid; coenzyme Q10; l-carnitine; mitochondrial dysfunction; neurodegenerative disorders; selenium; vitamin D

DOI:  https://doi.org/10.3390/ijms232012603
Front Pharmacol. 2022 ;13 954980

ApoE isoform-dependent effects of xanthohumol on high fat diet-induced cognitive impairments and hippocampal metabolic pathways.

Payel Kundu, Sarah Holden, Ines L Paraiso, Reetesh Sudhakar, Chloe McQuesten, Jaewoo Choi, Cristobal L Miranda, Claudia S Maier, Gerd Bobe, Jan F Stevens, Jacob Raber.

  Consumption of a high fat diet (HFD) is linked to metabolic syndrome and cognitive impairments. This is exacerbated in age-related cognitive decline (ACD) and in individuals with a genetic risk for Alzheimer's disease (AD). Apolipoprotein E (apoE) is involved in cholesterol metabolism. In humans, there are three major isoforms, E2, E3, and E4. Compared to E3, E4 increases ACD and AD risk and vulnerability to the deleterious cognitive effects of a HFD. The plant compound Xanthohumol (XN) had beneficial effects on cognition and metabolism in C57BL/6J wild-type (WT) male mice put on a HFD at 9 weeks of age for 13 weeks. As the effects of XN in the context of a HFD in older WT, E3, and E4 female and male mice are not known, in the current study male and female WT, E3, and E4 mice were fed a HFD alone or a HFD containing 0.07% XN for 10 or 19 weeks, starting at 6 months of age, prior to the beginning of behavioral and cognitive testing. XN showed sex- and ApoE isoform-dependent effects on cognitive performance. XN-treated E4 and WT, but not E3, mice had higher glucose transporter protein levels in the hippocampus and cortex than HFD-treated mice. E3 and E4 mice had higher glucose transporter protein levels in the hippocampus and lower glucose transporter protein levels in the cortex than WT mice. In the standard experiment, regardless of XN treatment, E4 mice had nearly double as high ceramide and sphingomyelin levels than E3 mice and male mice had higher level of glycosylated ceramide than female mice. When the differential effects of HFD in E3 and E4 males were assessed, the arginine and proline metabolism pathway was affected. In the extended exposure experiment, in E3 males XN treatment affected the arginine and proline metabolism and the glycine, serine, and threonine metabolism. Myristic acid levels were decreased in XN-treated E3 males but not E3 females. These data support the therapeutic potential for XN to ameliorate HFD-induced cognitive impairments and highlight the importance of considering sex and ApoE isoform in determining who might most benefit from this dietary supplement.

Keywords:  APOE; cognition; glucose transporters; high-fat diet; hippocampus; metabolic syndrome; metabolomics; xanthohumol

DOI:  https://doi.org/10.3389/fphar.2022.954980
Reprod Biomed Online. 2022 Sep 25. pii: S1472-6483(22)00712-X. [Epub ahead of print]

Acetoacetate and β-hydroxybutyrate reduce mouse embryo viability via differential metabolic and epigenetic mechanisms.

Emma G Whatley, Thi T Truong, Alexandra J Harvey, David K Gardner.

   RESEARCH QUESTION: Does the ketone acetoacetate (AcAc) alone, or combined with β-hydroxybutyrate (βOHB), impact mouse embryo development, metabolism, histone acetylation and viability?
DESIGN: Pronucleate mouse oocytes were cultured in vitro in G1/G2 media supplemented with ketones (AcAc or AcAc + βOHB) at concentrations representing those in maternal serum during pregnancy (0.04 mmol/l AcAc, 0.1 mmol/l βOHB), standard diet consumption (0.1 mmol/l AcAc, 0.25 mmol/l βOHB), ketogenic diet consumption (0.8 mmol/l AcAc, 2 mmol/l βOHB) and diabetic ketoacidosis (2 mmol/l AcAc, 4 mmol/l βOHB). Day 5 blastocysts were assessed for cell allocation, glucose metabolism and histone acetylation. Day 4 blastocysts exposed to 0.8 mmol/l AcAc + 2 mmol/l βOHB were transferred to standard-fed recipient females, and E14.5 fetal and placental development assessed.
RESULTS: Exposure to 2 mmol/l AcAc or 0.8 mmol/l AcAc + 2 mmol/l βOHB did not impair blastocyst development, but significantly increased glucose consumption (P = 0.001 each), lowered glycolytic flux (P = 0.01, P < 0.001) and elevated trophectoderm (TE) histone 3 lysine 27 acetylation (H3K27ac; P < 0.001 each) compared with unexposed controls. Preimplantation AcAc + βOHB exposure reduced post-implantation fetal development by 25% (P = 0.037), and delayed female-specific fetal limb development (P = 0.019) and estimated fetal age (P = 0.019) compared with controls.
CONCLUSION: Preimplantation exposure to ketones affects underlying metabolism and histone acetylation in blastocysts that are associated with persistent, female-specific perturbations in fetal development. A periconceptional diet that elevates ketone concentrations may impair human embryonic viability.

Keywords:  Acetylation; Blastocyst; Development; Ketogenic diet; Ketone; Nutrient

DOI:  https://doi.org/10.1016/j.rbmo.2022.09.018
World J Pediatr. 2022 Oct 27.

Ketogenic diet therapy in children with epilepsy caused by SLC2A1 mutations: a single-center single-arm retrospective study.

Ying-Yan Wang, Yun-Qing Zhou, Li-Juan Luo, Cui-Jin Wang, Nan Shen, Hao Li, Ji-Wen Wang.

   BACKGROUND: This retrospective study assessed the efficacy and safety of ketogenic diet therapies in children with epilepsy caused by SLC2A1 genetic mutations and glucose transporter type 1 deficiency syndrome.
METHODS: Pediatric patients with epilepsy symptoms admitted to our medical center between January 2017 and October 2021 were included if they presented with an SLC2A1 genetic mutation on whole-exome sequencing. We analyzed the patients' convulsions and treatment with antiepileptic drugs. The patients were followed up at different time periods after ketogenic diet therapies.
RESULTS: Six patients with SLC2A1 mutations were included in this study. The patients had seizures of different types and frequencies, and they took antiepileptic drugs to relieve their symptoms. They were then treated with a ketogenic diet for at least four months. We analyzed epilepsy control rates at 1, 2, 3, 6, and 12 months after ketogenic diet treatment. All patients were seizure-free within a month of receiving the diet therapy. All patients were followed up for six months, three were followed up for 12 months after the treatment, and there was no recurrence of epilepsy during this period. After antiepileptic drug withdrawal, none of the patients experienced seizure relapse when receiving ketogenic diet treatment alone. No severe adverse events occurred during the therapy.
CONCLUSIONS: Ketogenic diet therapy is very effective and safe for the treatment of epilepsy caused by SLC2A1 mutations. Therefore, patients with glucose transporter type 1 deficiency syndrome caused by SLC2A1 mutations should begin ketogenic diet treatment as soon as possible.

Keywords:  Epilepsy; Glucose transporter type 1; Ketogenic diet; SLC2A1

DOI:  https://doi.org/10.1007/s12519-022-00620-7
J Pers Med. 2022 Oct 17. pii: 1727. [Epub ahead of print]12(10):

Metabolomic Signatures of Autism Spectrum Disorder.

Danielle Brister, Shannon Rose, Leanna Delhey, Marie Tippett, Yan Jin, Haiwei Gu, Richard E Frye.

  Autism Spectrum Disorder (ASD) is associated with many variations in metabolism, but the ex-act correlates of these metabolic disturbances with behavior and development and their links to other core metabolic disruptions are understudied. In this study, large-scale targeted LC-MS/MS metabolomic analysis was conducted on fasting morning plasma samples from 57 children with ASD (29 with neurodevelopmental regression, NDR) and 37 healthy controls of similar age and gender. Linear model determined the metabolic signatures of ASD with and without NDR, measures of behavior and neurodevelopment, as well as markers of oxidative stress, inflammation, redox, methylation, and mitochondrial metabolism. MetaboAnalyst ver 5.0 (the Wishart Research Group at the University of Alberta, Edmonton, Canada) identified the pathways associated with altered metabolic signatures. Differences in histidine and glutathione metabolism as well as aromatic amino acid (AAA) biosynthesis differentiated ASD from controls. NDR was associated with disruption in nicotinamide and energy metabolism. Sleep and neurodevelopment were associated with energy metabolism while neurodevelopment was also associated with purine metabolism and aminoacyl-tRNA biosynthesis. While behavior was as-sociated with some of the same pathways as neurodevelopment, it was also associated with alternations in neurotransmitter metabolism. Alterations in methylation was associated with aminoacyl-tRNA biosynthesis and branched chain amino acid (BCAA) and nicotinamide metabolism. Alterations in glutathione metabolism was associated with changes in glycine, serine and threonine, BCAA and AAA metabolism. Markers of oxidative stress and inflammation were as-sociated with energy metabolism and aminoacyl-tRNA biosynthesis. Alterations in mitochondrial metabolism was associated with alterations in energy metabolism and L-glutamine. Using behavioral and biochemical markers, this study finds convergent disturbances in specific metabolic pathways with ASD, particularly changes in energy, nicotinamide, neurotransmitters, and BCAA, as well as aminoacyl-tRNA biosynthesis.

Keywords:  amino acid metabolism; autism spectrum disorder; energy metabolism; mass spectrometry; metabolomics; mitochondria; redox metabolism

DOI:  https://doi.org/10.3390/jpm12101727
Antioxidants (Basel). 2022 Oct 14. pii: 2030. [Epub ahead of print]11(10):

Vitamin C Deficiency Reduces Neurogenesis and Proliferation in the SVZ and Lateral Ventricle Extensions of the Young Guinea Pig Brain.

Nery Jara, Manuel Cifuentes, Fernando Martínez, Iván González-Chavarría, Katterine Salazar, Lucas Ferrada, Francisco Nualart.

  Although scurvy, the severe form of vitamin C deficiency, has been almost eradicated, the prevalence of subclinical vitamin C deficiency is much higher than previously estimated and its impact on human health might not be fully understood. Vitamin C is an essential molecule, especially in the central nervous system where it performs numerous, varied and critical functions, including modulation of neurogenesis and neuronal differentiation. Although it was originally considered to occur only in the embryonic brain, it is now widely accepted that neurogenesis also takes place in the adult brain. The subventricular zone (SVZ) is the neurogenic niche where the largest number of new neurons are born; however, the effect of vitamin C deficiency on neurogenesis in this key region of the adult brain is unknown. Therefore, through BrdU labeling, immunohistochemistry, confocal microscopy and transmission electron microscopy, we analyzed the proliferation and cellular composition of the SVZ and the lateral ventricle (LVE) of adult guinea pigs exposed to a vitamin-C-deficient diet for 14 and 21 days. We found that neuroblasts in the SVZ and LVE were progressively and significantly decreased as the days under vitamin C deficiency elapsed. The neuroblasts in the SVZ and LVE decreased by about 50% in animals with 21 days of deficiency; this was correlated with a reduction in BrdU positive cells in the SVZ and LVE. In addition, the reduction in neuroblasts was not restricted to a particular rostro-caudal area, but was observed throughout the LVE. We also found that vitamin C deficiency altered cellular morphology at the ultrastructural level, especially the cellular and nuclear morphology of ependymal cells of the LVE. Therefore, vitamin C is essential for the maintenance of the SVZ cell populations required for normal activity of the SVZ neurogenic niche in the adult guinea pig brain. Based on our results from the guinea pig brain, we postulate that vitamin C deficiency could also affect neurogenesis in the human brain.

Keywords:  adult neurogenesis; ascorbic acid; lateral ventricle extensions; subventricular zone; vitamin C

DOI:  https://doi.org/10.3390/antiox11102030
HGG Adv. 2023 Jan 12. 4(1): 100148

A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.

Cameron Young, Dominyka Batkovskyte, Miyuki Kitamura, Maria Shvedova, Yutaro Mihara, Jun Akiba, Wen Zhou, Anna Hammarsjö, Gen Nishimura, Shuichi Yatsuga, Giedre Grigelioniene, Tatsuya Kobayashi.

  Mitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.

Keywords:  TOM; TOMM7; developmental delay; fatty liver; growth plate; lipoatrophy; mitochondria; mouse model; skeletal dysplasia; translocase

DOI:  https://doi.org/10.1016/j.xhgg.2022.100148
Int J Mol Sci. 2022 Oct 11. pii: 12092. [Epub ahead of print]23(20):

Amyloid β, Lipid Metabolism, Basal Cholinergic System, and Therapeutics in Alzheimer's Disease.

Victoria Campos-Peña, Pavel Pichardo-Rojas, Talía Sánchez-Barbosa, Emma Ortíz-Islas, Citlali Ekaterina Rodríguez-Pérez, Pedro Montes, Gerardo Ramos-Palacios, Daniela Silva-Adaya, Rafael Valencia-Quintana, Jorge Francisco Cerna-Cortes, Danira Toral-Rios.

  The presence of insoluble aggregates of amyloid β (Aβ) in the form of neuritic plaques (NPs) is one of the main features that define Alzheimer's disease. Studies have suggested that the accumulation of these peptides in the brain significantly contributes to extensive neuronal loss. Furthermore, the content and distribution of cholesterol in the membrane have been shown to have an important effect on the production and subsequent accumulation of Aβ peptides in the plasma membrane, contributing to dysfunction and neuronal death. The monomeric forms of these membrane-bound peptides undergo several conformational changes, ranging from oligomeric forms to beta-sheet structures, each presenting different levels of toxicity. Aβ peptides can be internalized by particular receptors and trigger changes from Tau phosphorylation to alterations in cognitive function, through dysfunction of the cholinergic system. The goal of this review is to summarize the current knowledge on the role of lipids in Alzheimer's disease and their relationship with the basal cholinergic system, as well as potential disease-modifying therapies.

Keywords:  Alzheimer’s disease; amyloid β; cholesterol; cholinergic system; lipid rafts

DOI:  https://doi.org/10.3390/ijms232012092
Crit Rev Food Sci Nutr. 2022 Oct 26. 1-10

Beneficial effects of butyrate on brain functions: A view of epigenetic.

Gabriela de Cássia Ávila Alpino, Gabriela Amorim Pereira-Sol, Mariana de Moura E Dias, Aline Silva de Aguiar, Maria do Carmo Gouveia Peluzio.

  Brain functions are influenced by the presence, activity, and metabolism of the gut microbiota through the gut-microbiota-brain (GMB) axis. The consumption of a fiber-rich diet increases the content of short-chain fatty acids (SCFAs) from bacterial fermentation in the colon. Among SCFAs, butyrate stands out because of its wide array of biological functions, such as ability to influence brain functions. Pharmacologically, sodium butyrate (NaB) regulates gene expression in the brain, where it has several beneficial effects ranging from neurodegenerative diseases to behavioral disorders through inhibitors of histone deacetylases (HDACis). In this context, we review the mechanisms of action of the two types of butyrate on brain functions, with an emphasis on the epigenetic approach. Both types of butyrate are potentially interesting for the prevention and adjuvant therapy of neurological and psychological disorders due to their neuroprotective functions. However, further studies are needed to investigate the possible neuroepigenetic effects of butyrate derived from bacterial fermentation.

Keywords:  Butyrate; brain disorders; epigenetics; gut-microbiota-brain axis; high-fiber diet

DOI:  https://doi.org/10.1080/10408398.2022.2137776
Anal Chem. 2022 Oct 26.

3-Acetylpyridine On-Tissue Paternò-Büchi Derivatization Enabling High Coverage Lipid C═C Location-Resolved MS Imaging in Biological Tissues.

Yanyan Chen, Chengyi Xie, Xiaoxiao Wang, Guodong Cao, Yi Ru, Yuanyuan Song, Ashok Iyaswamy, Min Li, Jianing Wang, Zongwei Cai.

Unsaturated lipids containing single or more carbon-carbon double bonds (C═C) within tissues are closely associated with various types of diseases. Mass spectrometry imaging (MSI) has been used to study the spatial distribution of lipid C═C location isomers in tissue sections. However, comprehensive characterization of lipid C═C location isomers using MSI remains challenging. Herein, we established an on-tissue charge-switching Paternò-Büchi (PB) derivatization method using 3-acetylpyridine (3-AP) as a reaction reagent, which can be used to detect and assign C═C location of glycerophospholipids (GPLs) as well as neutral lipids, such as fatty acids (FAs), under the same experimental workflow using matrix-assisted laser desorption/ionization (MALDI)-MSI. High coverage of mono- and poly-unsaturated C═C location isomers among various lipid classes including FA, phosphatidylcholine (PC), and sulfatide (SHexCer) in distinct regions of the mouse brain and kidney was visualized using MALDI-MS/MS imaging. This method has also been applied to map the spatial distribution of lipid C═C location isomers in the Alzheimer's disease (AD) mice model for the first time, which provides a new tool to study the relationships between the distribution of lipid structural diversity and neurodegenerative diseases.

DOI: https://doi.org/10.1021/acs.analchem.2c03089
Front Vet Sci. 2022 ;9 935430

Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil.

Benjamin Andreas Berk, Claudia Ottka, Tsz Hong Law, Rowena Mary Anne Packer, Annette Wessmann, Andrea Bathen-Nöthen, Tarja Susanna Jokinen, Anna Knebel, Andrea Tipold, Hannes Lohi, Holger Andreas Volk.

  Consumption of medium-chain triglycerides (MCT) has been shown to improve seizure control, reduce behavioural comorbidities and improve cognitive function in epileptic dogs. However, the exact metabolic pathways affected by dietary MCT remain poorly understood. In this study, we aimed to identify changes in the metabolome and neurotransmitters levels relevant to epilepsy and behavioural comorbidities associated with the consuming of an MCT supplement (MCT-DS) in dogs with idiopathic epilepsy (IE). Metabolic alterations induced by a commercial MCT-DS in a population of 28 dogs with IE were evaluated in a 6-month multi-centre, prospective, randomised, double-blinded, controlled cross-over trial design. A metabolic energy requirement-based amount of 9% MCT or control oil was supplemented to the dogs' stable base diet for 3 months, followed by the alternative oil for another 3 months. A validated, quantitative nuclear magnetic resonance (NMR) spectroscopy platform was applied to pre- and postprandially collected serum samples to compare the metabolic profile between both DS and baseline. Furthermore, alterations in urinary neurotransmitter levels were explored. Five dogs (30%) had an overall reduction in seizure frequency of ≥50%, and were classified as MCT-responders, while 23 dogs showed a ≤50% reduction, and were defined as MCT non-responders. Amino-acid metabolism was significantly influenced by MCT consumption compared to the control oil. While the serum concentrations of total fatty acids appeared similar during both supplements, the relative concentrations of individual fatty acids differed. During MCT supplementation, the concentrations of polyunsaturated fatty acids and arachidonic acid were significantly higher than under the control oil. β-Hydroxybutyric acid levels were significantly higher under MCT supplementation. In total, four out of nine neurotransmitters were significantly altered: a significantly increased γ-aminobutyric acid (GABA) concentration was detected during the MCT-phase accompanied by a significant shift of the GABA-glutamate balance. MCT-Responders had significantly lowered urinary concentrations of histamine, glutamate, and serotonin under MCT consumption. In conclusion, these novel data highlight metabolic changes in lipid, amino-acid and ketone metabolism due to MCT supplementation. Understanding the metabolic response to MCT provides new avenues to develop better nutritional management with improved anti-seizure and neuroprotective effects for dogs with epilepsy, and other behavioural disorders.

Keywords:  biomarker; canine; epilepsy; medium-chain triglyceride; metabolome; neurotransmitter

DOI:  https://doi.org/10.3389/fvets.2022.935430
Aging Cell. 2022 Oct 28. e13731

SIAH proteins regulate the degradation and intra-mitochondrial aggregation of PINK1: Implications for mitochondrial pathology in Parkinson's disease.

Fatimah Abd Elghani, Hazem Safory, Haya Hamza, Mor Savyon, Malik Farhoud, Michal Toren-Hershoviz, Zagorka Vitic, Kirsten Ebanks, Vered Shani, Sleman Bisharat, Lihi Shaulov, Claude Brodski, Zhiyin Song, Rina Bandopadhyay, Simone Engelender.

  Parkinson's disease (PD) is characterized by degeneration of neurons, particularly dopaminergic neurons in the substantia nigra. PD brains show accumulation of α-synuclein in Lewy bodies and accumulation of dysfunctional mitochondria. However, the mechanisms leading to mitochondrial pathology in sporadic PD are poorly understood. PINK1 is a key for mitophagy activation and recycling of unfit mitochondria. The activation of mitophagy depends on the accumulation of uncleaved PINK1 at the outer mitochondrial membrane and activation of a cascade of protein ubiquitination at the surface of the organelle. We have now found that SIAH3, a member of the SIAH proteins but lacking ubiquitin-ligase activity, is increased in PD brains and cerebrospinal fluid and in neurons treated with α-synuclein preformed fibrils (α-SynPFF). We also observed that SIAH3 is aggregated together with PINK1 in the mitochondria of PD brains. SIAH3 directly interacts with PINK1, leading to their intra-mitochondrial aggregation in cells and neurons and triggering a cascade of toxicity with PINK1 inactivation along with mitochondrial depolarization and neuronal death. We also found that SIAH1 interacts with PINK1 and promotes ubiquitination and proteasomal degradation of PINK1. Similar to the dimerization of SIAH1/SIAH2, SIAH3 interacts with SIAH1, promoting its translocation to mitochondria and preventing its ubiquitin-ligase activity toward PINK1. Our results support the notion that the increase in SIAH3 and intra-mitochondrial aggregation of SIAH3-PINK1 may mediate α-synuclein pathology by promoting proteotoxicity and preventing the elimination of dysfunctional mitochondria. We consider it possible that PINK1 activity is decreased in sporadic PD, which impedes proper mitochondrial renewal in the disease.

Keywords:  PINK1; Parkinson's disease; SIAH1; SIAH3; intra-mitochondrial protein aggregation; mitochondrial dysfunction; mitophagy; ubiquitin

DOI:  https://doi.org/10.1111/acel.13731
Eur J Pharm Biopharm. 2022 Oct 25. pii: S0939-6411(22)00244-2. [Epub ahead of print]

Design and optimization of Metformin-Loaded Solid Lipid Nanoparticles for Neuroprotective effects in a rat model of diffuse traumatic brain injury: A biochemical, behavioral, and histological study.

Hossein Ebrahimi, Sajjad Kazem Nezhad, Ali Farmoudeh, Amirhossein Babaei, Pedram Ebrahimnezhad, Esmaeil Akbari, Ali Siahposht-Khachaki.

   BACKGROUND AND PURPOSE: Following traumatic brain injury, inflammation, mitochondrial dysfunction, oxidative stress, ischemia, and energy crisis can cause mortality or long-term morbidity. As an activator of AMP-activated protein kinase, metformin reduces the secondary injuries of traumatic brain injury by compensating for the lack of energy in damaged cells. But the blood-brain barrier (BBB) prevents a hydrophilic drug such as metformin from penetrating the brain tissue. Solid lipid nanoparticles (SLN) with their lipid nature can cross the blood-brain barrier and solve this challenge.so This study aimed to investigate the effect of metformin-loaded lipid nanoparticles (NanoMet) for drug delivery to the brain and reduce complications from traumatic brain injury.
METHOD: Different formulations of NanoMet were designed by Box-Behnken, and after formulation, particle size, zeta potential, and entrapment efficiency were investigated. For in vivo study, Male rats were divided into eight groups, and except for the intact and sham groups, the other groups underwent brain trauma by the Marmarou method. After the intervention, the Veterinary Coma Scale, Vestibular Motor function, BBB integrity, cerebral edema, level of inflammatory cytokines, and histopathology of brain tissue were assessed.
RESULTS: The optimal formula had a size of 282.2 ± 9.05 nm, a zeta potential of -1.65 ± 0.33 mV, and entrapment efficiency of 60.61± 6.09% Which released the drug in 1400 minutes.Concentrations of 5 and 10 mg/kg of this formula improved the consequences of trauma .
CONCLUSION: This study showed that nanoparticles could help target drug delivery to the brain and apply the desired result.

Keywords:  Marmarou method; Metformin; SLN; Solid Lipid Nanoparticle; Traumatic Brain injury

DOI:  https://doi.org/10.1016/j.ejpb.2022.10.018
Mol Genet Metab. 2022 Oct 17. pii: S1096-7192(22)00419-X. [Epub ahead of print]137(4): 309-319

Intravenous 2-hydroxypropyl-β-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial.

Caroline Hastings, Benny Liu, Bryan Hurst, Gerald F Cox, Sharon Hrynkow.

   BACKGROUND: Niemann-Pick Disease Type C1 (NPC1) is a disorder of intracellular cholesterol and lipid trafficking that leads to the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment, resulting in systemic manifestations (including hepatosplenomegaly and lung infiltration) and neurodegeneration. Preclinical studies have demonstrated that systemically administered 2-hydroxypropyl-β-cyclodextrin (HPβCD; Trappsol® Cyclo™) restores cholesterol metabolism and homeostasis in peripheral organs and tissues and in the central nervous system (CNS). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of HPβCD in peripheral tissues and the CNS in adult subjects with NPC1.
METHODS: A Phase 1, randomized, double-blind, parallel group study enrolled 13 subjects with NPC1 who received either 1500 mg/kg or 2500 mg/kg HPβCD intravenously every 2 weeks for a total of 7 doses (14 weeks). Subjects were 18 years or older, with a confirmed diagnosis of NPC1 and evidence of systemic involvement on clinical assessment. Pharmacokinetic evaluations in plasma and cerebrospinal fluid (CSF) were performed at the first and seventh infusions. Pharmacodynamic assessments included biomarkers of systemic cholesterol synthesis (serum lathosterol) and degradation (serum 4β-hydroxycholesterol), secondary sphingomyelin storage (plasma lysosphingomyelin-509, now more accurately referred to as N-palmitoyl-O-phosphocholineserine [PPCS]), and CNS-specific biomarkers of neurodegeneration (CSF total Tau) and cholesterol metabolism (serum 24(S)-hydroxycholesterol [24(S)-HC]). Safety monitoring included assessments of liver and kidney function, infusion related adverse events, and hearing evaluations.
RESULTS: Ten subjects completed the study, with 6 at the 1500 mg/kg dose and 4 at the 2500 mg/kg dose. One subject withdrew following the first infusion after experiencing hypersensitivity pneumonitis, and 2 subjects withdrew after meeting a stopping rule related to hearing loss. Overall, HPβCD had an acceptable safety profile. The observed pharmacokinetic profile of HPβCD was similar following the first and seventh infusions, with a plasma half-life of 2 h, a maximum concentration reached at 6 to 8 h, and no evidence of accumulation. Serum biomarkers of cholesterol metabolism showed reduced synthesis and increased degradation. Compared to Baseline, filipin staining of liver tissue showed significant reductions of trapped unesterified cholesterol at both dose levels at Week 14. Plasma PPCS levels were also reduced. HPβCD was detected at low concentrations in the CSF (maximum, 33 μM) at both dose levels and persisted longer in CSF than in plasma. Total Tau levels in CSF decreased in most subjects. Serum levels of 24(S)-HC, a cholesterol metabolite from the CNS that is exported across the blood-brain barrier and into the circulation, decreased after both the first and seventh doses. Hence, pharmacodynamic assessments in both peripheral and CNS-related tissue show target engagement. While not the aim of the study, subjects reported favorable impacts on their quality of life.
CONCLUSIONS: The plasma pharmacokinetics and pharmacodynamics of HPβCD administered at two intravenous dose levels to subjects with NPC1 were comparable to those observed in preclinical models. HPβCD cleared cholesterol from the liver and improved peripheral biomarkers of cholesterol homeostasis. At low CSF concentrations, HPβCD appeared to be pharmacologically active in the CNS based on the increased efflux of 24(S)-HC and reduction in CSF total Tau, a biomarker of CNS neurodegeneration. These data support the initiation of longer-term clinical trials to evaluate the safety and efficacy of intravenous HPβCD in subjects with NPC1. (ClinicalTrials.gov numbers: present trial, NCT02939547; open-label extension of the present trial, NCT03893071; global pivotal trial, NCT04860960).

Keywords:  Cyclodextrin; Lysosome; Niemann-Pick Disease Type C; Pharmacodynamics; Pharmacokinetics

DOI:  https://doi.org/10.1016/j.ymgme.2022.10.004
Brain Behav Immun. 2022 Oct 19. pii: S0889-1591(22)00409-3. [Epub ahead of print]

Mitochondrial Redox Environments Predict Sensorimotor Brain-Behavior Dynamics in Adults with HIV.

Rachel K Spooner, Brittany K Taylor, Iman M Ahmad, Kelsey Dyball, Katy Emanuel, Jennifer O'Neill, Maureen Kubat, Susan Swindells, Howard S Fox, Sara H Bares, Kelly L Stauch, Matthew C Zimmerman, Tony W Wilson.

  Despite virologic suppression, people living with HIV (PLWH) remain at risk for developing cognitive impairment, with aberrations in motor control being a predominant symptom leading to functional dependencies in later life. While the neuroanatomical bases of motor dysfunction have recently been illuminated, the underlying molecular processes remain poorly understood. Herein, we evaluate the predictive capacity of the mitochondrial redox environment on sensorimotor brain-behavior dynamics in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art approaches, including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance spectroscopy to measure superoxide levels, antioxidant activity assays and dynamic magnetoencephalographic imaging to quantify sensorimotor oscillatory dynamics. We observed differential modulation of sensorimotor brain-behavior relationships by superoxide and hydrogen peroxide-sensitive features of the redox environment in PLWH, while only superoxide-sensitive features were related to optimal oscillatory response profiles and better motor performance in controls. Moreover, these divergent pathways may be attributable to immediate, separable mechanisms of action within the redox environment seen in PLWH, as evidenced by mediation analyses. These findings suggest that mitochondrial redox parameters are important modulators of healthy and pathological oscillations in motor systems and behavior, serving as potential targets for remedying HIV-related cognitive-motor dysfunction in the future.

Keywords:  EPR Spectroscopy; Hydrogen Peroxide; Magnetoencephalography; Motor Cortex; Neural Oscillations; Seahorse Analyzer; Superoxide

DOI:  https://doi.org/10.1016/j.bbi.2022.10.004
EMBO Mol Med. 2022 Oct 24. e15343

Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis.

Joris Guyon, Ignacio Fernandez-Moncada, Claire M Larrieu, Cyrielle L Bouchez, Antonio C Pagano Zottola, Johanna Galvis, Tiffanie Chouleur, Audrey Burban, Kevin Joseph, Vidhya M Ravi, Heidi Espedal, Gro Vatne Røsland, Boutaina Daher, Aurélien Barre, Benjamin Dartigues, Slim Karkar, Justine Rudewicz, Irati Romero-Garmendia, Barbara Klink, Konrad Grützmann, Marie-Alix Derieppe, Thibaut Molinié, Nina Obad, Céline Léon, Giorgio Seano, Hrvoje Miletic, Dieter Henrik Heiland, Giovanni Marsicano, Macha Nikolski, Rolf Bjerkvig, Andreas Bikfalvi, Thomas Daubon.

  Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy.

Keywords:  antiepileptic drug; energy metabolism; glioblastoma; invasion; lactate dehydrogenases

DOI:  https://doi.org/10.15252/emmm.202115343
Genes (Basel). 2022 Oct 13. pii: 1847. [Epub ahead of print]13(10):

ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency.

Matthias Christen, Jos Bongers, Déborah Mathis, Vidhya Jagannathan, Rodrigo Gutierrez Quintana, Tosso Leeb.

  A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain fatty acids and together with the clinical findings suggested a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. We sequenced the genome of the affected dog and compared the data to 923 control genomes of different dog breeds. The ACADM gene encoding MCAD was considered the top functional candidate gene. The genetic analysis revealed a single homozygous private protein-changing variant in ACADM in the affected dog. This variant, XM_038541645.1:c.444_445delinsGTTAATTCTCAATATTGTCTAAGAATTATG, introduces a premature stop codon and is predicted to result in truncation of ~63% of the wild type MCAD open reading frame, XP_038397573.1:p.(Thr150Ilefs*6). Targeted genotyping of the variant in 162 additional CKCS revealed a variant allele frequency of 23.5% and twelve additional homozygous mutant dogs. The acylcarnitine C8/C12 ratio was elevated ~43.3 fold in homozygous mutant dogs as compared to homozygous wild type dogs. Based on available clinical and biochemical data together with current knowledge in humans, we propose the ACADM frameshift variant as causative variant for the MCAD deficiency with likely contribution to the neurological phenotype in the index case. Testing the CKCS breeding population for the identified ACADM variant is recommended to prevent the unintentional breeding of dogs with MCAD deficiency. Further prospective studies are warranted to assess the clinical consequences of this enzyme defect.

Keywords:  Canis lupus familiaris; dog; fatty acid disorder; metabolism; neurology; precision medicine; seizure

DOI:  https://doi.org/10.3390/genes13101847
Biomed Pharmacother. 2022 Oct 21. pii: S0753-3322(22)01259-8. [Epub ahead of print]156 113870

Maternal treatment with sodium butyrate reduces the development of autism-like traits in mice offspring.

Claudia Cristiano, Eriola Hoxha, Pellegrino Lippiello, Ilaria Balbo, Roberto Russo, Filippo Tempia, Maria Concetta Miniaci.

  Several studies indicate a relationship between maternal gut microbiota alteration and increased risk of autism spectrum disorders (ASD) in offspring. The possibility of compensating for such metabolic dysfunction at a very early stage of disease via maternal treatment has not been enough explored. Here, we examined in BTBR mouse model of ASD the effect of maternal treatment with the gut microbial metabolite butyrate (BUT) on the behavioral and synaptic plasticity deficits in juvenile and adult offspring. We show that BUT treatment of BTBR dams rescues the social and partially the repetitive behavior deficits in the offspring. In addition, maternal BUT implementation prevents the cerebellar cortex hypertrophy as well as the Purkinje cells firing and long-term synaptic plasticity deficits in BTBR mice. Our results demonstrate, for the first time, that maternal BUT treatment can improve ASD-like symptoms in offspring thus providing new directions for the early treatment of neurodevelopmental disorders.

Keywords:  Autism spectrum disorder; Behavior; Cerebellum; Parallel fiber; Purkinje cells; Sodium butyrate

DOI:  https://doi.org/10.1016/j.biopha.2022.113870
Environ Toxicol Pharmacol. 2022 Oct 22. pii: S1382-6689(22)00196-X. [Epub ahead of print] 104003

Air Pollution Exposure Increases ABCB1 and ASCT1 Transporter Levels in Mouse Cortex.

Elena Puris, Liudmila Saveleva, Veronika Górová, Petra Vartiainen, Miika Kortelainen, Heikki Lamberg, Olli Sippula, Tarja Malm, Pasi I Jalava, Seppo Auriola, Gert Fricker, Katja M Kanninen.

  Membrane transporters are important for maintaining brain homeostasis by regulating the passage of solutes into, out of, and within the brain. Growing evidence suggests neurotoxic effects of air pollution exposure and its contribution to neurodegenerative disorders, including Alzheimer's disease (AD), yet limited knowledge is available on the exact cellular impacts of exposure. This study investigates how exposure to ubiquitous solid components of air pollution, ultrafine particles (UFPs), influence brain homeostasis by affecting protein levels of membrane transporters. Membrane transporters were quantified and compared in brain cortical samples of wild-type and the 5xFAD mouse model of AD in response to subacute exposure to inhaled UFPs. The cortical ASCT1 and ABCB1 transporter levels were elevated in wild-type and 5xFAD mice subjected to a 2-week UFP exposure paradigm, suggesting impairment of brain homeostatic mechanisms. This study provides new insight on the molecular mechanisms underlying adverse effects of air pollution on the brain.

Keywords:  5xFAD; air pollution; drug transporters; neurodegeneration; ultrafine particles (UFP)

DOI:  https://doi.org/10.1016/j.etap.2022.104003
Biomolecules. 2022 Oct 07. pii: 1434. [Epub ahead of print]12(10):

Aberrant Ganglioside Functions to Underpin Dysregulated Myelination, Insulin Signalling, and Cytokine Expression: Is There a Link and a Room for Therapy?

Evgeniy Svirin, Johannes de Munter, Aleksei Umriukhin, Elisaveta Sheveleva, Allan V Kalueff, Andrei Svistunov, Sergey Morozov, Susanne Walitza, Tatyana Strekalova.

  Gangliosides are molecules widely present in the plasma membranes of mammalian cells, participating in a variety of processes, including protein organization, transmembrane signalling and cell adhesion. Gangliosides are abundant in the grey matter of the brain, where they are critically involved in postnatal neural development and function. The common precursor of the majority of brain gangliosides, GM3, is formed by the sialylation of lactosylceramide, and four derivatives of its a- and b-series, GM1, GD1a, GD1b and GT1b, constitute 95% of all the brain gangliosides. Impairments in ganglioside metabolism due to genetic abnormalities of GM-synthases are associated with severe neurological disorders. Apart from that, the latest genome-wide association and translational studies suggest a role of genes involved in brain ganglioside synthesis in less pervasive psychiatric disorders. Remarkably, the most recent animal studies showed that abnormal ganglioside functions result in dysregulated neuroinflammation, aberrant myelination and altered insulin receptor signalling. At the same time, these molecular features are well established as accompanying developmental psychiatric disorders such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). This led us to hypothesize a role of deficient ganglioside function in developmental neuropsychiatric disorders and warrants further gene association clinical studies addressing this question. Here, we critically review the literature to discuss this hypothesis and focus on the recent studies on ST3GAL5-deficient mice. In addition, we elaborate on the therapeutic potential of various anti-inflammatory remedies for treatment of developmental neuropsychiatric conditions related to aberrant ganglioside functions.

Keywords:  insulin receptor signalling; major brain gangliosides; mice; myelination; neurodevelopmental disorders; neuroinflammation

DOI:  https://doi.org/10.3390/biom12101434
Endocrinol Diabetes Metab. 2022 Oct 27. e385

Medium-chain Acyl-COA dehydrogenase deficiency: Pathogenesis, diagnosis, and treatment.

Emily Mason, Charles C T Hindmarch, Kimberly J Dunham-Snary.

   INTRODUCTION: Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is the most common inherited metabolic disorder of β-oxidation. Patients with MCADD present with hypoketotic hypoglycemia, which may quickly progress to lethargy, coma, and death. Prognosis for MCADD patients is highly promising once a diagnosis has been established, though management strategies may vary depending on the severity of illness and the presence of comorbidities.
METHODS AND RESULTS: Given the rapid developments in the world of gene therapy and implementation of newborn screening for inherited metabolic disorders, the provision of concise and contemporary knowledge of MCADD is essential for clinicians to effectively manage patients. Thus, this review aims to consolidate current information for physicians on the pathogenesis, diagnostic tools, and treatment options for MCADD patients.
CONCLUSION: MCADD is a commonly inherited metabolic disease with serious implications for health outcomes, particularly in children, that may be successfully managed with proper intervention.

Keywords:  dietary management; fatty acids; medium-chain Acyl-CoA dehydrogenase; metabolic myopathy; β-Oxidation

DOI:  https://doi.org/10.1002/edm2.385
Glia. 2022 Oct 29.

Endocannabinoid signaling in the central nervous system.

César E Martinez Ramirez, Gonzalo Ruiz-Pérez, Todd M Stollenwerk, Christina Behlke, Ashley Doherty, Cecilia J Hillard.

  It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.

Keywords:  2-arachidonoylglycerol; N-arachidonoylethanolamine; astrocyte; cannabinoid receptor; microglia

DOI:  https://doi.org/10.1002/glia.24280
Int J Mol Sci. 2022 Oct 18. pii: 12472. [Epub ahead of print]23(20):

Quantitative NMR-Based Lipoprotein Analysis Identifies Elevated HDL-4 and Triglycerides in the Serum of Alzheimer's Disease Patients.

Georgy Berezhnoy, Christoph Laske, Christoph Trautwein.

  Alzheimer's disease (AD) is the most common form of dementia in the elderly and has been associated with changes in lipoprotein metabolism. We performed quantitative lipoprotein analysis in a local cohort of cognitively impaired elderly and control subjects using standardized nuclear magnetic resonance (NMR) spectroscopy. A commercially available quantitative NMR-based assay covering 112 lipoprotein main and subtype variables was used to investigate blood serum samples from a moderate cohort size of 161 persons (71 female, 90 male), including measures of quality control. Additionally, clinical metadata and cerebrospinal fluid AD biomarkers were collected and used for analysis. High-density lipoprotein (HDL) HDL-4 subfraction levels were mostly high in female individuals with mild cognitive impairment (MCI), followed by AD. Low-density lipoprotein (LDL) LDL-2 cholesterol was slightly elevated in male AD patients. HDL-2 apolipoprotein Apo-A1, HDL-2 phospholipids, and HDL-3 triglycerides were highly abundant in AD and MCI women compared to men. When considering clinical biomarkers (Aβ, tau), very low-density lipoprotein (VLDL) VLDL-1 and intermediate-density lipoprotein (IDL) triglycerides were substantially higher in AD compared to MCI. In addition, triglyceride levels correlated positively with dementia. Different lipoprotein serum patterns were identified for AD, MCI, and control subjects. Interestingly, HDL-4 and LDL-2 cholesterol parameters revealed strong gender-specific changes in the context of AD-driven dementia. As gender-based comparisons were based on smaller sub-groups with a low n-number, several statistical findings did not meet the significance threshold for multiple comparisons testing. Still, our finding suggests that serum HDL-4 parameters and various triglycerides correlate positively with AD pathology which could be a read-out of extended lipids traveling through the blood-brain barrier, supporting amyloid plaque formation processes. Thereof, we see herein a proof of concept that this quantitative NMR-based lipoprotein assay can generate important and highly interesting data for refined AD diagnosis and patient stratification, especially when larger cohorts are available.

Keywords:  1H-NMR; Alzheimer’s disease; beta-amyloid; lipoproteins; liquor; metabolism; metabolomics; neurodegeneration; plaques; serum; tau

DOI:  https://doi.org/10.3390/ijms232012472
Int J Mol Sci. 2022 Oct 20. pii: 12593. [Epub ahead of print]23(20):

Insulin Diminishes Superoxide Increase in Cytosol and Mitochondria of Cultured Cortical Neurons Treated with Toxic Glutamate.

Vsevolod Pinelis, Irina Krasilnikova, Zanda Bakaeva, Alexander Surin, Dmitrii Boyarkin, Andrei Fisenko, Olga Krasilnikova, Igor Pomytkin.

  Glutamate excitotoxicity is involved in the pathogenesis of many disorders, including stroke, traumatic brain injury, and Alzheimer's disease, for which central insulin resistance is a comorbid condition. Neurotoxicity of glutamate (Glu) is primarily associated with hyperactivation of the ionotropic N-methyl-D-aspartate receptors (NMDARs), causing a sustained increase in intracellular free calcium concentration ([Ca2+]i) and synchronous mitochondrial depolarization and an increase in intracellular superoxide anion radical (O2-•) production. Recently, we found that insulin protects neurons against excitotoxicity by decreasing the delayed calcium deregulation (DCD). However, the role of insulin in O2-• production in excitotoxicity still needs to be clarified. The present study aims to investigate insulin's effects on glutamate-evoked O2-• generation and DCD using the fluorescent indicators dihydroethidium, MitoSOX Red, and Fura-FF in cortical neurons. We found a linear correlation between [Ca2+]i and [O2-•] in primary cultures of the rat neuron exposed to Glu, with insulin significantly reducing the production of intracellular and mitochondrial O2-• in the primary cultures of the rat neuron. MK 801, an inhibitor of NMDAR-gated Ca2+ influx, completely abrogated the glutamate effects in both the presence and absence of insulin. In experiments in sister cultures, insulin diminished neuronal death and O2 consumption rate (OCR).

Keywords:  glutamate (Glu) excitotoxicity; insulin; intracellular free Ca2+ concentration ([Ca2+]i); intracellular superoxide (O2–•); mitochondrial superoxide production; primary cortical neurons

DOI:  https://doi.org/10.3390/ijms232012593
Endocrinology. 2022 Oct 28. pii: bqac183. [Epub ahead of print]

Aging is associated with lower neuroactive steroids and worsened outcomes following cerebral ischemia in male mice.

Neïké Fernandez, Anthony Petit, Antoine Pianos, Léna Haddad, Michael Schumacher, Philippe Liere, Rachida Guennoun.

  Ischemic stroke is a leading cause of disability and death and aging is the main non-modifiable risk factor. Following ischemia, neuroactive steroids have been shown to play a key role in cerebroprotection. Thus, brain steroid concentrations at the time of injury as well as their regulation after stroke are key factors to consider. Here, we investigated the effects of age and cerebral ischemia on steroid levels, behavioral outcomes and neuronal degeneration in 3-month-old and 18-month-old C57BL/6JRj male mice. Ischemia was induced by middle cerebral artery occlusion for 1 hour followed by reperfusion (MCAO/R) and analyzes were performed at 6 h post-MCAO. Extended steroid profiles established by gas chromatography coupled with tandem mass spectrometry revealed that: i) brain and plasma concentrations of the main 5α-reduced metabolites of progesterone, 11-deoxycorticosterone, and corticosterone were lower in old than in young mice ii) after MCAO/R, brain concentrations of progesterone, 5α-dihydroprogesterone, and corticosterone increased in young mice and iii) after MCAO/R, brain concentrations of 5α-reduced metabolites of progesterone, 3α5α-tetrahydrodeoxycorticosterone and 3β5α-tetrahydrodeoxycorticosterone were lower in old than in young mice. Following ischemia, old mice showed increased sensorimotor deficits and more degenerating neurons in the striatum than young mice. Altogether, these findings strongly suggest that the decreased capacity of old mice to metabolize steroids towards the 5α-reduction pathway comparatively to young mice may contribute to the worsening of their stroke outcomes.

Keywords:  5α-reduction; Age; MCAO/R; Stroke; neuroprotection; neurosteroids

DOI:  https://doi.org/10.1210/endocr/bqac183
Acc Chem Res. 2022 Oct 25.

Chemical Probes to Control and Visualize Lipid Metabolism in the Brain.

Jeroen M Punt, Daan van der Vliet, Mario van der Stelt.

ConspectusSignaling lipids, such as the endocannabinoids, play an important role in the brain. They regulate synaptic transmission and control various neurophysiological processes, including pain sensation, appetite, memory formation, stress, and anxiety. Unlike classical neurotransmitters, lipid messengers are produced on demand and degraded by metabolic enzymes to control their lifespan and signaling actions. Chemical biology approaches have become one of the main driving forces to study and unravel the physiological role of lipid messengers in the brain. Here, we review how the development and use of chemical probes has allowed one to study endocannabinoid signaling by (i) inhibiting the biosynthetic and metabolic enzymes; (ii) visualizing the activity of these enzymes; and (iii) controlling the release and transport of the endocannabinoids. Activity-based probes were instrumental to guide the discovery of highly selective and in vivo active inhibitors of the biosynthetic (DAGL, NAPE-PLD) and metabolic (MAGL, FAAH) enzymes of endocannabinoids. These inhibitors allowed one to study the role of these enzymes in animal models of disease. For instance, the DAGL-MAGL axis was shown to control neuroinflammation and the NAPE-PLD-FAAH axis to regulate emotional behavior. Activity-based protein profiling and chemical proteomics were essential to guide the drug discovery and development of compounds targeting MAGL and FAAH, such as ABX-1431 (Lu AG06466) and PF-04457845, respectively. These experimental drugs are now in clinical trials for multiple indications, including multiple sclerosis and post-traumatic stress disorders. Activity-based probes have also been used to visualize the activity of these lipid metabolizing enzymes with high spatial resolution in brain slices, thereby showing the cell type-specific activity of these lipid metabolizing enzymes. The transport, release, and uptake of signaling lipids themselves cannot, however, be captured by activity-based probes in a spatiotemporal controlled manner. Therefore, bio-orthogonal lipids equipped with photoreactive, photoswitchable groups or photocages have been developed. These chemical probes were employed to investigate the protein interaction partners of the endocannabinoids, such as putative membrane transporters, as well as to study the functional cellular responses within milliseconds upon irradiation. Finally, genetically encoded sensors have recently been developed to monitor the real-time release of endocannabinoids with high spatiotemporal resolution in cultured neurons, acute brain slices, and in vivo mouse models. It is anticipated that the combination of chemical probes, highly selective inhibitors, and sensors with advanced (super resolution) imaging modalities, such as PharmacoSTORM and correlative light-electron microscopy, will uncover the fundamental basis of lipid signaling at nanoscale resolution in the brain. Furthermore, chemical biology approaches enable the translation of these fundamental discoveries into clinical solutions for brain diseases with aberrant lipid signaling.

DOI: https://doi.org/10.1021/acs.accounts.2c00521
Behav Brain Res. 2022 Oct 22. pii: S0166-4328(22)00443-0. [Epub ahead of print] 114174

PET imaging in animal models of Parkinson's disease.

Ruiqing Ni.

  Alpha-synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, are characterized by aberrant accumulation of alpha-synuclein and synaptic dysfunction leading to motor and cognitive deficits. Animal models of alpha-synucleinopathy have greatly facilitated the mechanistic understanding of the disease and the development of therapeutics. Various transgenic, alpha-synuclein fibril-injected, and toxin-injected animal models of Parkinson's disease and multiple system atrophy that recapitulate the disease pathology have been developed and widely used. Recent advances in positron emission tomography have allowed the noninvasive visualization of molecular alterations, underpinning behavioral dysfunctions in the brains of animal models and the longitudinal monitoring of treatment effects. Imaging studies in these disease animal models have employed multi-tracer PET designs to reveal dopaminergic deficits together with other molecular alterations. This review focuses on the development of new positron emission tomography tracers and studies of alpha-synuclein, synaptic vesicle glycoprotein 2A, neurotransmitter receptor deficits such as dopaminergic receptor, dopaminergic transporter, serotonergic receptor, vesicular monoamine transporter 2, hypometabolism, neuroinflammation, mitochondrial dysfunction and leucine rich repeat kinase 2 in animal models of Parkinson's disease. The outstanding challenges and emerging applications are outlined, such as investigating the gut-brain-axis by using positron emission tomography in animal models, and provide a future outlook.

Keywords:  Parkinson’s disease; alpha-synuclein; animal models; hypometabolism; neuroinflammation; neurotransmitter receptors; positron emission tomography

DOI:  https://doi.org/10.1016/j.bbr.2022.114174
Antioxidants (Basel). 2022 Oct 07. pii: 1990. [Epub ahead of print]11(10):

The Hepatic Mitochondrial Alterations Exacerbate Meta-Inflammation in Autism Spectrum Disorders.

Giovanna Trinchese, Fabiano Cimmino, Gina Cavaliere, Angela Catapano, Chiara Fogliano, Adriano Lama, Claudio Pirozzi, Claudia Cristiano, Roberto Russo, Lidia Petrella, Rosaria Meli, Giuseppina Mattace Raso, Marianna Crispino, Bice Avallone, Maria Pina Mollica.

  The role of the liver in autism spectrum disorders (ASD), developmental disabilities characterized by impairments in social interactions and repetitive behavioral patterns, has been poorly investigated. In ASD, it has been shown a dysregulation of gut-brain crosstalk, a communication system able to influence metabolic homeostasis, as well as brain development, mood and cognitive functions. The liver, with its key role in inflammatory and metabolic states, represents the crucial metabolic organ in this crosstalk. Indeed, through the portal vein, the liver receives not only nutrients but also numerous factors derived from the gut and visceral adipose tissue, which modulate metabolism and hepatic mitochondrial functions. Here, we investigated, in an animal model of ASD (BTBR mice), the involvement of hepatic mitochondria in the regulation of inflammatory state and liver damage. We observed increased inflammation and oxidative stress linked to hepatic mitochondrial dysfunction, steatotic hepatocytes, and marked mitochondrial fission in BTBR mice. Our preliminary study provides a better understanding of the pathophysiology of ASD and could open the way to identifying hepatic mitochondria as targets for innovative therapeutic strategies for the disease.

Keywords:  autism spectrum disorders; inflammation; liver; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/antiox11101990