bims-medebr 2023-05-07 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–05–07
twenty-two papers selected by
Regina F. Fernández, Johns Hopkins University

Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer's Disease.
Exploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders.
Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct ( 2 H) and indirect ( 1 H) detection of deuterium labeled compounds at 7T and clinical 3T.
Accelerated hypometabolism with disease progression associated with faster cognitive decline among amyloid positive patients.
Energy metabolism disturbance in migraine: From a mitochondrial point of view.
Liver acts as a metabolic gate for the traumatic brain injury pathology: Protective action of thyroid hormone.
Ellagic acid and its metabolites urolithins A/B ameliorate most common disease phenotypes in cellular and mouse models for lysosomal storage disorders by enhancing extracellular vesicle secretion.
Correction to: Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.
Porcine blood cell and brain tissue energy metabolism: Effects of "early life stress".
Serum short chain fatty acids mediate hippocampal BDNF and correlate with decreasing neuroinflammation following high pectin fiber diet in mice.
Sex differences in the progression of glucose metabolism dysfunction in Alzheimer's disease.
Modulation of sleep by trafficking of lipids through the Drosophila blood brain barrier.
Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.
AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.
Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia.
Kinetic data for modeling the dynamics of the enzymes involved in animal fatty acid synthesis.
Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species.
Metabolomics in acromegaly: a systematic review.
Intermittent fasting alleviates type 1 diabetes-induced cognitive dysfunction by improving the frontal cortical metabolic disorder.
Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.
A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes.
The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.

J Alzheimers Dis. 2023 Apr 21.

Insulin Resistance and Impaired Branched-Chain Amino Acid Metabolism in Alzheimer's Disease.

Rui Liu, Lei Zhang, Hao You.

  The pathogenesis of Alzheimer's disease (AD) is complicated and involves multiple contributing factors. Mounting evidence supports the concept that AD is an age-related metabolic neurodegenerative disease mediated in part by brain insulin resistance, and sharing similar metabolic dysfunctions and brain pathological characteristics that occur in type 2 diabetes mellitus (T2DM) and other insulin resistance disorders. Brain insulin signal pathway is a major regulator of branched-chain amino acid (BCAA) metabolism. In the past several years, impaired BCAA metabolism has been described in several insulin resistant states such as obesity, T2DM and cardiovascular disease. Disrupted BCAA metabolism leading to elevation in circulating BCAAs and related metabolites is an early metabolic phenotype of insulin resistance and correlated with future onset of T2DM. Brain is a major site for BCAA metabolism. BCAAs play pivotal roles in normal brain function, especially in signal transduction, nitrogen homeostasis, and neurotransmitter cycling. Evidence from animal models and patients support the involvement of BCAA dysmetabolism in neurodegenerative diseases including Huntington's disease, Parkinson's disease, and maple syrup urine disease. More recently, growing studies have revealed altered BCAA metabolism in AD, but the relationship between them is poorly understood. This review is focused on the recent findings regarding BCAA metabolism and its role in AD. Moreover, we will explore how impaired BCAA metabolism influences brain function and participates in the pathogenesis of AD.

Keywords:  Alzheimer’s disease; branched-chain amino acids; insulin resistance; metabolic neurodegenerative disease; metabolism

DOI:  https://doi.org/10.3233/JAD-221147
Front Psychiatry. 2023 ;14 1142682

Exploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders.

Naomi Elyse Omori, Mantas Kazimieras Malys, Geoffrey Woo, Latt Mansor.

  In recent times, advances in the field of metabolomics have shed greater light on the role of metabolic disturbances in neuropsychiatric conditions. The following review explores the role of ketone bodies and ketosis in both the diagnosis and treatment of three major psychiatric disorders: major depressive disorder, anxiety disorders, and schizophrenia. Distinction is made between the potential therapeutic effects of the ketogenic diet and exogenous ketone preparations, as exogenous ketones in particular offer a standardized, reproducible manner for inducing ketosis. Compelling associations between symptoms of mental distress and dysregulation in central nervous system ketone metabolism have been demonstrated in preclinical studies with putative neuroprotective effects of ketone bodies being elucidated, including effects on inflammasomes and the promotion of neurogenesis in the central nervous system. Despite emerging pre-clinical data, clinical research on ketone body effectiveness as a treatment option for psychiatric disorders remains lacking. This gap in understanding warrants further investigating, especially considering that safe and acceptable ways of inducing ketosis are readily available.

Keywords:  BHB; anxiety; depression; diagnosis; ketone; schizophrenia; treatment; β-hydroxybutyric acid

DOI:  https://doi.org/10.3389/fpsyt.2023.1142682
medRxiv. 2023 Apr 17. pii: 2023.04.17.23288672. [Epub ahead of print]

Reproducibility of 3D MRSI for imaging human brain glucose metabolism using direct ( 2 H) and indirect ( 1 H) detection of deuterium labeled compounds at 7T and clinical 3T.

Fabian Niess, Bernhard Strasser, Lukas Hingerl, Eva Niess, Stanislav Motyka, Gilbert Hangel, Martin Krššák, Stephan Gruber, Benjamin Spurny-Dworak, Siegfried Trattnig, Thomas Scherer, Rupert Lanzenberger, Wolfgang Bogner.

Introduction: Deuterium metabolic imaging (DMI) and quantitative exchange label turnover (QELT) are novel MR spectroscopy techniques for non-invasive imaging of human brain glucose and neurotransmitter metabolism with high clinical potential. Following oral or intravenous administration of non-ionizing [6,6'- 2 H 2 ]-glucose, its uptake and synthesis of downstream metabolites can be mapped via direct or indirect detection of deuterium resonances using 2 H MRSI (DMI) and 1 H MRSI (QELT), respectively. The purpose of this study was to compare the dynamics of spatially resolved brain glucose metabolism, i.e., estimated concentration enrichment of deuterium labeled Glx (glutamate+glutamine) and Glc (glucose) acquired repeatedly in the same cohort of subjects using DMI at 7T and QELT at clinical 3T.
Methods: Five volunteers (4m/1f) were scanned in repeated sessions for 60 min after overnight fasting and 0.8g/kg oral [6,6'- 2 H 2 ]-glucose administration using time-resolved 3D 2 H FID-MRSI with elliptical phase encoding at 7T and 3D 1 H FID-MRSI with a non-Cartesian concentric ring trajectory readout at clinical 3T.
Results: One hour after oral tracer administration regionally averaged deuterium labeled Glx 4 concentrations and the dynamics were not significantly different over all participants between 7T 2 H DMI and 3T 1 H QELT data for GM (1.29±0.15 vs. 1.38±0.26 mM, p=0.65 & 21±3 vs. 26±3 µM/min, p=0.22) and WM (1.10±0.13 vs. 0.91±0.24 mM, p=0.34 & 19±2 vs. 17±3 µM/min, p=0.48). Also, the observed time constants of dynamic Glc 6 data in GM (24±14 vs. 19±7 min, p=0.65) and WM (28±19 vs. 18±9 min, p=0.43) dominated regions showed no significant differences. Between individual 2 H and 1 H data points a weak to moderate negative correlation was observed for Glx 4 concentrations in GM (r=-0.52, p<0.001), and WM (r=-0.3, p<0.001) dominated regions, while a strong negative correlation was observed for Glc 6 data GM (r=- 0.61, p<0.001) and WM (r=-0.70, p<0.001).
Conclusion: This study demonstrates that indirect detection of deuterium labeled compounds using 1 H QELT MRSI at widely available clinical 3T without additional hardware is able to reproduce absolute concentration estimates of downstream glucose metabolites and the dynamics of glucose uptake compared to 2 H DMI data acquired at 7T. This suggests significant potential for widespread application in clinical settings especially in environments with limited access to ultra-high field scanners and dedicated RF hardware.

DOI: https://doi.org/10.1101/2023.04.17.23288672
Front Neurosci. 2023 ;17 1151820

Accelerated hypometabolism with disease progression associated with faster cognitive decline among amyloid positive patients.

Alzheimer’s Disease Neuroimaging Initiative

   Objective: To evaluate the progression of brain glucose metabolism among participants with biological signature of Alzheimer's disease (AD) and its relevance to cognitive decline.
Method: We studied 602 amyloid positive individuals who underwent 18F-fluorodeoxyglucose PET (FDG-PET) scan, 18F-AV-45 amyloid PET (AV45-PET) scan, structural MRI scan and neuropsychological examination, including 116 cognitively normal (CN) participants, 314 participants diagnosed as mild cognitive impairment (MCI), and 172 participants diagnosed as AD dementia. The first FDG-PET scan satisfying the inclusion criteria was considered as the baseline scan. Cross-sectional analysis were conducted with the baseline FDG-PET data to compare the regional differences between diagnostic groups after adjusting confounding factors. Among these participants, 229 participants (55 CN, 139 MCI, and 35 AD dementia) had two-year follow-up FDG-PET data available. Regional glucose metabolism was computed and the progression rates of regional glucose metabolism were derived from longitudinal FDG-PET scans. Then the group differences of regional progression rates were examined to assess whether glucose metabolism deficit accelerates or becomes stable with disease progression. The association of cognitive decline rate with baseline regional glucose metabolism, and progression rate in longitudinal data, were evaluated.
Results: Participants with AD dementia showed substantial glucose metabolism deficit than CN and MCI at left hippocampus, in addition to the traditionally reported frontal and parietal-temporal lobe. More substantial metabolic change was observed with the contrast AD - MCI than the contrast MCI - CN, even after adjusting time duration since cognitive symptom onset. With the longitudinal data, glucose metabolism was observed to decline the most rapidly in the AD dementia group and at a slower rate in MCI. Lower regional glucose metabolism was correlated to faster cognitive decline rate with mild-moderate correlations, and the progression rate was correlated to cognitive decline rate with moderate-large correlations.
Discussion and conclusion: Hippocampus was identified to experience hypometabolism in AD pathology. Hypometabolism accelerates with disease progression toward AD dementia. FDG-PET, particularly longitudinal scans, could potentially help predict how fast cognition declines and assess the impact of treatment in interventional trials.

Keywords:  AD; Alzheimer’s continuum; FDG-PET; brain metabolism; cognitive decline

DOI:  https://doi.org/10.3389/fnins.2023.1151820
Front Physiol. 2023 ;14 1133528

Energy metabolism disturbance in migraine: From a mitochondrial point of view.

Yicheng Wang, Yongli Wang, Guangxin Yue, Yonglie Zhao.

  Migraine is a serious central nervous system disease with a high incidence rate. Its pathogenesis is very complex, which brings great difficulties for clinical treatment. Recently, many studies have revealed that mitochondrial dysfunction may play a key role in migraine, which affects the hyperosmotic of Ca2+, the excessive production of free radicals, the decrease of mitochondrial membrane potential, the imbalance of mPTP opening and closing, and the decrease of oxidative phosphorylation level, which leads to neuronal energy exhaustion and apoptosis, and finally lessens the pain threshold and migraine attack. This article mainly introduces cortical spreading depression, a pathogenesis of migraine, and then damages the related function of mitochondria, which leads to migraine. Oxidative phosphorylation and the tricarboxylic acid cycle are the main ways to provide energy for the body. 95 percent of the energy needed for cell survival is provided by the mitochondrial respiratory chain. At the same time, hypoxia can lead to cell death and migraine. The pathological opening of the mitochondrial permeability transition pore can promote the interaction between pro-apoptotic protein and mitochondrial, destroy the structure of mPTP, and further lead to cell death. The increase of mPTP permeability can promote the accumulation of reactive oxygen species, which leads to a series of changes in the expression of proteins related to energy metabolism. Both Nitric oxide and Calcitonin gene-related peptide are closely related to the attack of migraine. Recent studies have shown that changes in their contents can also affect the energy metabolism of the body, so this paper reviews the above mechanisms and discusses the mechanism of brain energy metabolism of migraine, to provide new strategies for the prevention and treatment of migraine and promote the development of individualized and accurate treatment of migraine.

Keywords:  CGRP; NO; ROS; energy metabolism; migraine; mitochondrial; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fphys.2023.1133528
Biochim Biophys Acta Mol Basis Dis. 2023 May 01. pii: S0925-4439(23)00094-7. [Epub ahead of print] 166728

Liver acts as a metabolic gate for the traumatic brain injury pathology: Protective action of thyroid hormone.

Mayuri Khandelwal, Gokul Krishna, Zhe Ying, Fernando Gomez-Pinilla.

  Clinical evidence indicates that injury to the brain elicits systemic metabolic disturbances that contributes to the brain pathology. Since dietary fructose is metabolized in the liver, we explored mechanisms by which traumatic brain injury (TBI) and dietary fructose influence liver function and their possible repercussions to brain. Consumption of fructose contributed to the detrimental effects of TBI on liver operation, in terms of glucose and lipid metabolism, de novo lipogenesis, lipid peroxidation. Thyroid hormone (T4) is metabolized in the liver and found that T4 supply improved lipid metabolism by reducing de novo lipogenesis, lipid accumulation, lipogenic enzymes (ACC, AceCS1, FAS), lipid peroxidation in liver in response to fructose and fructose-TBI. T4 supply also helped to normalize glucose metabolism and improve insulin sensitivity. Furthermore, T4 counteracted elevations of the pro-inflammatory cytokines, Tnfα and Mcp-1 after TBI and/or fructose intake in liver and circulation. T4 also exerted an effect on isolated primary hepatocytes by potentiating phosphorylation of AMPKα and AKT substrate, AS160, leading to increased glucose uptake. In addition, T4 restored the metabolism of DHA in the liver disrupted by TBI and fructose, adding important information to optimize the action of DHA in therapeutics. The overall evidence seems to indicate that the liver works as a gate for the regulation of the effects of brain injury and foods on brain pathologies.

Keywords:  Fluid percussion injury; Fructose; Insulin signaling; Lipid metabolism; Liver; Thyroid hormone

DOI:  https://doi.org/10.1016/j.bbadis.2023.166728
Neurobiol Dis. 2023 Apr 28. pii: S0969-9961(23)00155-9. [Epub ahead of print] 106141

Ellagic acid and its metabolites urolithins A/B ameliorate most common disease phenotypes in cellular and mouse models for lysosomal storage disorders by enhancing extracellular vesicle secretion.

Beatriz Soto-Huelin, Bohdan Babiy, Oscar Pastor, Mario Díaz-García, Ana Toledano-Zaragoza, María Dolores Frutos, Juan Carlos Espín, Francisco A Tomás-Barberán, Rebeca Busto, María Dolores Ledesma.

  Niemann Pick diseases types A (NPDA) and C (NPDC) are lysosomal storage disorders (LSDs) leading to cognitive impairment, neurodegeneration, and early death. NPDA and NPDC have different genetic origins, being caused by mutations in the acid sphingomyelinase (ASM) or the cholesterol transport protein NPC1, respectively. However, they share a common pathological hallmark in the accumulation of lipids in the endolysosomal compartment. Here, we tested the hypothesis that polyphenols reduce lipid overload in NPD cells by enhancing the secretion of extracellular vesicles (ECVs). We show that among the polyphenols tested, the ellagic acid metabolites, urolithin A and B, were the safest and most efficient in increasing ECV secretion. They reduced levels of accumulating lipids and lysosomal size and permeabilization in cultured bone marrow-derived macrophages and neurons from ASMko and NPC1 mutant mice, which mimic NPDA and NPDC, respectively. Moreover, oral treatment with ellagic acid reduced lipid levels, ameliorated lysosomal alterations, and diminished microglia activation in the brain of NPD mice. These results support the therapeutic value of ECV secretion and polyphenols for NPDs, which may also help treat other LSDs characterized by intracellular lipid overload.

Keywords:  Brain; Extracellular vesicles; Lysosomal storage disorders; Niemann pick; Polyphenols

DOI:  https://doi.org/10.1016/j.nbd.2023.106141
Hum Mol Genet. 2023 May 02. pii: ddad068. [Epub ahead of print]

Correction to: Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway-implications for Parkinson's disease.

DOI: https://doi.org/10.1093/hmg/ddad068
Front Mol Biosci. 2023 ;10 1113570

Porcine blood cell and brain tissue energy metabolism: Effects of "early life stress".

Franziska Münz, Eva-Maria Wolfschmitt, Fabian Zink, Nadja Abele, Melanie Hogg, Andrea Hoffmann, Michael Gröger, Enrico Calzia, Christiane Waller, Peter Radermacher, Tamara Merz.

  Background: Early Life Stress (ELS) may exert long-lasting biological effects, e.g., on PBMC energy metabolism and mitochondrial respiration. Data on its effect on brain tissue mitochondrial respiration is scarce, and it is unclear whether blood cell mitochondrial activity mirrors that of brain tissue. This study investigated blood immune cell and brain tissue mitochondrial respiratory activity in a porcine ELS model. Methods: This prospective randomized, controlled, animal investigation comprised 12 German Large White swine of either sex, which were weaned at PND (postnatal day) 28-35 (control) or PND21 (ELS). At 20-24 weeks, animals were anesthetized, mechanically ventilated and surgically instrumented. We determined serum hormone, cytokine, and "brain injury marker" levels, superoxide anion (O2 •¯) formation and mitochondrial respiration in isolated immune cells and immediate post mortem frontal cortex brain tissue. Results: ELS animals presented with higher glucose levels, lower mean arterial pressure. Most determined serum factors did not differ. In male controls, TNFα and IL-10 levels were both higher than in female controls as well as, no matter the gender in ELS animals. MAP-2, GFAP, and NSE were also higher in male controls than in the other three groups. Neither PBMC routine respiration and brain tissue oxidative phosphorylation nor maximal electron transfer capacity in the uncoupled state (ETC) showed any difference between ELS and controls. There was no significant relation between brain tissue and PBMC, ETC, or brain tissue, ETC, and PBMC bioenergetic health index. Whole blood O2 •¯ concentrations and PBMC O2 •¯ production were comparable between groups. However, granulocyte O2 •¯ production after stimulation with E. coli was lower in the ELS group, and this effect was sex-specific: increased O2 •¯ production increased upon stimulation in all control animals, which was abolished in the female ELS swine. Conclusion: This study provides evidence that ELS i) may, gender-specifically, affect the immune response to general anesthesia as well as O2 •¯ radical production at sexual maturity, ii) has limited effects on brain and peripheral blood immune cell mitochondrial respiratory activity, and iii) mitochondrial respiratory activity of peripheral blood immune cells and brain tissue do not correlate.

Keywords:  PBMC; electron spin resonance; granulocyte; high resolution respirometry; mitochondrial respiration; superoxide anion

DOI:  https://doi.org/10.3389/fmolb.2023.1113570
Front Neurosci. 2023 ;17 1134080

Serum short chain fatty acids mediate hippocampal BDNF and correlate with decreasing neuroinflammation following high pectin fiber diet in mice.

Jamie S Church, Jane A M Bannish, Leighelle A Adrian, Kimberly Rojas Martinez, Asari Henshaw, Jared J Schwartzer.

   Introduction: Dietary components, such as prebiotic fiber, are known to impact brain chemistry via the gut-brain axis. In particular, short chain fatty acids (SCFAs) generated from excessive soluble fiber consumption are thought to impact neuroimmune signaling and brain function through increased production of neurotropic factors. Given reports that high dietary fiber intake is associated with increased mental health and improved quality of life scores, we set out to identify whether changes in SCFA levels as a result of a high soluble fiber diet mediate hippocampal neuroinflammation and brain derived neurotrophic factor (BDNF) in mice.
Methods: Adult male and female C57BL/6 mice were fed a 1-month high pectin fiber or cellulose-based control diet. Following 1 month of excessive pectin consumption, serum SCFAs were measured using gas chromatography-mass spectrometry (GC-MS) and hippocampal cytokines and BDNF were assessed via multiplex magnetic bead immunoassay.
Results: Pectin-based fiber diet increased circulating acetic acid in both sexes, with no effect on propionic or butyric acid. In the hippocampus, a high fiber diet decreased TNFa, IL-1ß, IL-6, and IFNγ and increased BDNF levels. Furthermore, increased SCFA levels were inversely correlated with neuroinflammation in the hippocampus, with acetic acid revealed as a strong mediator of increased BDNF production.
Conclusion: Collectively, these findings highlight the beneficial effects of fiber-induced molecular changes in a brain region known to influence mood- and cognition-related behaviors. Dietary composition should be considered when developing mental health management plans for men and women with an emphasis on increasing soluble fiber intake.

Keywords:  BDNF; SCFAs; cytokines; diet; hippocampus; pectin fiber

DOI:  https://doi.org/10.3389/fnins.2023.1134080
Exp Mol Med. 2023 May 01.

Sex differences in the progression of glucose metabolism dysfunction in Alzheimer's disease.

Jong-Chan Park, Hanbyeol Lim, Min Soo Byun, Dahyun Yi, Gihwan Byeon, Gijung Jung, Yu Kyeong Kim, Dong Young Lee, Sun-Ho Han, Inhee Mook-Jung.

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD.

DOI: https://doi.org/10.1038/s12276-023-00993-3
Elife. 2023 May 04. pii: e86336. [Epub ahead of print]12

Modulation of sleep by trafficking of lipids through the Drosophila blood brain barrier.

Fu Li, Gregory Artiushin, Amita Sehgal.

  Endocytosis through Drosophila glia is a significant determinant of sleep amount and occurs preferentially during sleep in glia of the blood brain barrier (BBB). To identify metabolites whose trafficking is mediated by sleep-dependent endocytosis, we conducted metabolomic analysis of flies that have increased sleep due to a block in glial endocytosis. We report that acylcarnitines, fatty acids conjugated to carnitine to promote their transport, accumulate in heads of these animals. In parallel, to identify transporters and receptors whose loss contributes to the sleep phenotype caused by blocked endocytosis, we screened genes enriched in barrier glia for effects on sleep. We find that knockdown of lipid transporters LRP1&2 or of carnitine transporters ORCT1&2 increases sleep. In support of the idea that the block in endocytosis affects trafficking through specific transporters, knockdown of LRP or ORCT transporters also increases acylcarnitines in heads. We propose that lipid species, such as acylcarnitines, are trafficked through the BBB via sleep-dependent endocytosis, and their accumulation reflects an increased need for sleep.

Keywords:  D. melanogaster; neuroscience

DOI:  https://doi.org/10.7554/eLife.86336
Mult Scler Relat Disord. 2023 Mar 31. pii: S2211-0348(23)00179-7. [Epub ahead of print]74 104675

Vascular disease risk factors in multiple sclerosis: Effect on metabolism and brain volumes.

Manoj K Sammi, Allison Fryman, Eric Baker, Brendan Moloney, Katherine Powers, Randy West, Frank Bittner, Michael Lane, Kayla Martin, Yuliya Pepelyayeva, Valerie C Anderson, William D Rooney, Vijayshree Yadav.

   BACKGROUND: Vascular disease risk factors (VDRF) such as hypertension, hyperlipidemia, obesity, diabetes and heart disease likely play a role in disease progression in people with multiple sclerosis (PwMS) (Marrie, Rudick et al. 2010). Studies exploring the mechanistic connection between vascular disease and MS disease progression are scant. We hypothesized that phosphate energy metabolism impairment in PwMS with VDRFs (VDRF+) will be greater compared to PwMS without VDRFs (VDRF-) and is related to increased brain atrophy in VDRF+. To test this hypothesis, we planned to study the differences in the high energy phosphate (HEP) metabolites in cerebral gray matter as assessed by 31P magnetic resonance spectroscopic imaging (MRSI) and MRI brain volumetric in the VDRF+ and VDRF- PwMS at four different timepoints over a 3 yearlong period using a 7T MR system. We present here the results from the cross-sectional evaluation of HEP metabolites and brain volumes. We also evaluated the differences in clinical impairment, blood metabolic biomarkers and quality of life in VDRF+ and VDRF- PwMS in this cohort.
METHODS: Group differences in high energy phosphate metabolites were assessed from a volume of interest in the occipital region using linear mixed models. Brain parenchymal and white matter lesion volumes were determined from MR anatomic images. We present here the cross-sectional analysis of the baseline data collected as part of a longitudinal 3 yearlong study where we obtained baseline and subsequent 6-monthly clinical and laboratory data and annual 7T MRI volumetric and 31P MR spectroscopic imaging (MRSI) data on 52 PwMS with and without VDRF. Key clinical and laboratory outcomes included: body mass index (BMI), waist and thigh circumferences and disability [Expanded Disability Status Scale (EDSS)], safety (complete blood count with differential, complete metabolic), lipid panel including total cholesterol and HbA1C. We analyzed clinical and laboratory data for the group differences using student's t or χ2 test. We investigated relationship between phosphate metabolites and VDRF using mixed effect linear regression.
RESULTS: Complete MRI data were available for 29 VDRF+, age 56.3 (6.8) years [mean (SD)] (83% female), and 23 VDRF-, age 52.5 (7.5) years (57% female) individuals with MS. The mean value of normalized adenosine triphosphate (ATP) (calculated as the ratio of ATP to total phosphate signal in a voxel) was decreased by 4.5% (p < .05) in VDRF+ compared to VDRF- MS group. White matter lesion (WML) volume fraction in VDRF+ individuals {0.007 (0.007)} was more than doubled compared to VDRF- participants {0.003 (0.006), p= .02}.
CONCLUSIONS: We found significantly lower brain ATP and higher inorganic phosphate (Pi) in those PwMS with VDRFs compared to those without. ATP depletion may reflect mitochondrial dysfunction. Ongoing longitudinal data analysis from this study, not presented here, will evaluate the relationship of phosphate metabolites, brain atrophy and disease progression in PwMS with and without vascular disease.

Keywords:  Comorbidities; Magnetic resonance imaging; Mitochondrial function; Multiple sclerosis; Vascular risk

DOI:  https://doi.org/10.1016/j.msard.2023.104675
Exp Cell Res. 2023 Apr 29. pii: S0014-4827(23)00161-1. [Epub ahead of print] 113614

AMP-activated protein kinase: An energy sensor and survival mechanism in the reinstatement of metabolic homeostasis.

Ankita Sharma, Sumit Kr Anand, Neha Singh, Upendra Nath Dwivedi, Poonam Kakkar.

  Cells are programmed to favorably respond towards the nutrient availability by adapting their metabolism to meet energy demands. AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine energy-sensing kinase. It gets activated upon a decrease in the cellular energy status as reflected by an increased AMP/ATP ratio, ADP, and also during the conditions of glucose starvation without change in the adenine nucelotide ratio. AMPK functions as a centralized regulator of metabolism, acting at cellular and physiological levels to circumvent the metabolic stress by restoring energy balance. This review intricately highlights the integrated signaling pathways by which AMPK gets activated allosterically or by multiple non-canonical upstream kinases. AMPK activates the ATP generating processes (e.g., fatty acid oxidation) and inhibits the ATP consuming processes that are non-critical for survival (e.g., cell proliferation, protein and triglyceride synthesis). An integrated signaling network with AMPK as the central effector regulates all the aspects of enhanced stress resistance, qualified cellular housekeeping, and energy metabolic homeostasis. Importantly, the AMPK mediated amelioration of cellular stress and inflammatory responses are mediated by stimulation of transcription factors such as Nrf2, SIRT1, FoxO and inhibition of NF-κB serving as main downstream effectors. Moreover, many lines of evidence have demonstrated that AMPK controls autophagy through mTOR and ULK1 signaling to fine-tune the metabolic pathways in response to different cellular signals. This review also highlights the critical involvement of AMPK in promoting mitochondrial health, and homeostasis, including mitophagy. Loss of AMPK or ULK1 activity leads to aberrant accumulation of autophagy-related proteins and defective mitophagy thus, connecting cellular energy sensing to autophagy and mitophagy.

Keywords:  AMPK; Autophagy; Cellular stress; Metabolic stress; Mitophagy

DOI:  https://doi.org/10.1016/j.yexcr.2023.113614
J Transl Med. 2023 May 03. 21(1): 297

Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia.

Ting Guo, Manli Chen, Ji Liu, Zengyu Wei, Jinjin Yuan, Wenwen Wu, Zhiyun Wu, Yongxing Lai, Zijun Zhao, Hongbin Chen, Nan Liu.

   OBJECTIVES: Available literature documents that ischemic stroke can disrupt the morphology and function of mitochondria and that the latter in other disease models can be preserved by neuropilin-1 (NRP-1) via oxidative stress suppression. However, whether NRP-1 can repair mitochondrial structure and promote functional recovery after cerebral ischemia is still unknown. This study tackled this very issue and explored the underlying mechanism.
METHODS: Adeno-associated viral (AAV)-NRP-1 was stereotaxically inoculated into the cortex and ipsilateral striatum posterior of adult male Sprague-Dawley (SD) rats before a 90-min transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion. Lentivirus (LV)-NRP-1 was transfected into rat primary cortical neuronal cultures before a 2-h oxygen-glucose deprivation and reoxygenation (OGD/R) injury to neurons. The expression and function of NRP-1 and its specific protective mechanism were investigated by Western Blot, immunofluorescence staining, flow cytometry, magnetic resonance imaging, transmission electron microscopy, etc. The binding was detected by molecular docking and molecular dynamics simulation.
RESULTS: Both in vitro and in vivo models of cerebral ischemia/reperfusion (I/R) injury presented a sharp increase in NRP-1 expression. The expression of AAV-NRP-1 markedly ameliorated the cerebral I/R-induced damage to the motor function and restored the mitochondrial morphology. The expression of LV-NRP-1 alleviated mitochondrial oxidative stress and bioenergetic deficits. AAV-NRP-1 and LV-NRP-1 treatments increased the wingless integration (Wnt)-associated signals and β-catenin nuclear localization. The protective effects of NRP-1 were reversed by the administration of XAV-939.
CONCLUSIONS: NRP-1 can produce neuroprotective effects against I/R injury to the brain by activating the Wnt/β-catenin signaling pathway and promoting mitochondrial structural repair and functional recovery, which may serve as a promising candidate target in treating ischemic stroke.

Keywords:  Ischemia/reperfusion; Mitochondrial structure and function; NRP-1; Neuronal apoptosis; Oxidative stress

DOI:  https://doi.org/10.1186/s12967-023-04125-3
Biosci Rep. 2023 May 03. pii: BSR20222496. [Epub ahead of print]

Kinetic data for modeling the dynamics of the enzymes involved in animal fatty acid synthesis.

Chilperic Armel Foko Kuate, Oliver Ebenhöh, Barbara Marleen Bakker, Adélaïde Raguin.

  The synthesis and modification of fatty acids from carbohydrates are paramount for the production of lipids. Simultaneously, lipids are pivotal energy storage in human health. They are associated with various metabolic diseases and their production pathways are for instance candidate therapeutic targets for cancer treatments. The fatty acid de novo synthesis (FADNS) occurs in the cytoplasm, while the microsomal modification of fatty acids (MMFA) happens at the surface of the endoplasmic reticulum. The kinetics and regulation of these complex processes involve several enzymes. In mammals, those are the acetyl-CoA carboxylase (ACC), the fatty acid synthase (FAS), the very-long-chain fatty acid elongases (ELOVL 1-7), and the desaturases (delta family). Their mechanisms and expression in different organs have been studied for more than 50 years. However, modeling them in the context of complex metabolic pathways is still a challenge. Distinct modeling approaches can be implemented. Here we focus on dynamic modeling using ordinary differential equations based on kinetic rate laws. This requires a combination of knowledge on the enzymatic mechanisms and their kinetics, as well as the interactions between the metabolites, and between enzymes and metabolites. In this review, after recalling the modeling framework, we support the development of such a mathematical approach by reviewing the available kinetic information of the enzymes involved.

Keywords:  Enzyme kinetics; Fatty acid synthesis; Mathematical modeling; Metabolism

DOI:  https://doi.org/10.1042/BSR20222496
Neurotherapeutics. 2023 May 03.

Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species.

Fei Tang, Liu-Yao Zhou, Ping Li, Ling-Ling Jiao, Kang Chen, Yu-Jie Guo, Xu-Long Ding, Si-Yu He, Biao Dong, Ru-Xiang Xu, Huan Xiong, Peng Lei.

  Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP+) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.

Keywords:  ACSL4; Ferroptosis; Lipid peroxidation; Neuroprotection; Parkinson’s disease

DOI:  https://doi.org/10.1007/s13311-023-01382-4
J Investig Med. 2023 May 04. 10815589231169452

Metabolomics in acromegaly: a systematic review.

Oana Pînzariu, Carmen Emanuela Georgescu.

  The therapeutic response heterogeneity in acromegaly persists, despite the medical-surgical advances of recent years. Thus, personalized medicine implementation, which focuses on each patient, is justified. Metabolomics would decipher the molecular mechanisms underlying the therapeutic response heterogeneity. Identification of altered metabolic pathways would open new horizons in the therapeutic management of acromegaly. This research aimed to evaluate the metabolomic profile in acromegaly and metabolomics' contributions to understanding disease pathogenesis. A systematic review was carried out by querying four electronic databases and evaluating patients with acromegaly through metabolomic techniques. In all, 21 studies containing 362 patients were eligible. Choline, the ubiquitous metabolite identified in growth hormone (GH)-secreting pituitary adenomas (Pas) by in vivo magnetic resonance spectroscopy (MRS), negatively correlated with somatostatin receptors type 2 expression and positively correlated with magnetic resonance imaging T2 signal and Ki-67 index. Moreover, elevated choline and choline/creatine ratio differentiated between sparsely and densely granulated GH-secreting PAs. MRS detected low hepatic lipid content in active acromegaly, which increased after disease control. The panel of metabolites of acromegaly deciphered by mass spectrometry (MS)-based techniques mainly included amino acids (especially branched-chain amino acids and taurine), glyceric acid, and lipids. The most altered pathways in acromegaly were the metabolism of glucose (particularly the downregulation of the pentose phosphate pathway), linoleic acid, sphingolipids, glycerophospholipids, arginine/proline, and taurine/hypotaurine. Matrix-assisted laser desorption/ionization coupled with MS imaging confirmed the functional nature of GH-secreting PAs and accurately discriminated PAs from healthy pituitary tissue.

Keywords:  Amino acids; lipid metabolism; lipids; magnetic resonance spectroscopy; mass spectrometry

DOI:  https://doi.org/10.1177/10815589231169452
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 29. pii: S0925-4439(23)00091-1. [Epub ahead of print] 166725

Intermittent fasting alleviates type 1 diabetes-induced cognitive dysfunction by improving the frontal cortical metabolic disorder.

Fen Xiong, Kaiyuan Jiang, Yali Wu, Cong Lou, Chengjie Ding, Wenli Zhang, Xi Zhang, Chen Li, Hong Zheng, Hongchang Gao.

  Intermittent fasting (IF) is an ecological strategy to control various metabolic disorder symptoms, but its protective effect on type 1 diabetes (T1D)-induced cognitive dysfunction and the underlying mechanisms remain poorly defined. Herein, we examined the efficacy of IF in altering the behaviors and brain metabolome in T1D mice and investigated the potential molecular mechanisms. We demonstrated that IF remarkably improved frontal cortical-dependent memory in T1D mice and reduced the loss of neuronal cells. Metabolomics and targeted mass spectrometry assay showed that IF reprogrammed the frontal cortical metabolome composition, including activated the aspartate and glutamate pathway and reversed glycerophospholipid and sphingolipid depositions in T1D mice. Mechanistically, IF attenuated the levels of oxidative stress proteins, such as NOX2, NOX4, 8-OHdG, 4-HNE, and inhibited the levels of pro-apoptotic factors Bax and cleaved Caspase-3, finally improved the memory ability of T1D mice. In vitro studies confirmed the protective effect of the supplemented N-acetylaspartate, a pivotal metabolite involved in IF-regulated T1D-induced cognitive dysfunction, in high glucose-stimulated SH-SY5Y cells by eliminating toxic lipids accumulation, oxidative stress and apoptosis. To conclude, the frontal cortical metabolites mediated the protective effects of IF against T1D-induced cognitive dysfunction by attenuating oxidative stress and apoptotic signaling. Thus, IF can be a potential therapeutic strategy for T1D-induced cognitive dysfunction.

Keywords:  Apoptosis; Cognitive dysfunction; Intermittent fasting; Metabolomics; Oxidative stress; Type 1 diabetes

DOI:  https://doi.org/10.1016/j.bbadis.2023.166725
Sci Adv. 2023 May 03. 9(18): eadf0138

Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress.

Ramya S Kuna, Avi Kumar, Karl A Wessendorf-Rodriguez, Hector Galvez, Courtney R Green, Grace H McGregor, Thekla Cordes, Reuben J Shaw, Robert U Svensson, Christian M Metallo.

Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied 13C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.

DOI: https://doi.org/10.1126/sciadv.adf0138
Animal Model Exp Med. 2023 Apr;6(2): 155-167

A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes.

Hanxuan Sheng, Dan Lu, Xiaolong Qi, Yahao Ling, Jing Li, Xu Zhang, Wei Dong, Wei Chen, Shan Gao, Xiang Gao, Li Zhang, Lianfeng Zhang.

   BACKGROUND: Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.
METHODS: We generated neuron-specific Isca1 knockout rat (Isca1flox/flox -NeuN-Cre) using CRISPR-Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.
RESULTS: This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis.
CONCLUSIONS: This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

Keywords:  ISCA1; MMDS5; mitochondrial iron-sulfur cluster; neuron oncosis

DOI:  https://doi.org/10.1002/ame2.12318
Cell Metab. 2023 Apr 28. pii: S1550-4131(23)00139-0. [Epub ahead of print]

The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.

Chih-Ling Wang, Rika Ohkubo, Wei-Chieh Mu, Wei Chen, Jiang Lan Fan, Zehan Song, Ayane Maruichi, Peter H Sudmant, Angela O Pisco, Dena B Dubal, Na Ji, Danica Chen.

  Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.

Keywords:  SIRT1; SIRT2; SIRT3; SIRT6; SIRT7; cognitive aging; mitochondrial unfolded protein response; neural stem cell aging; sirtuin; stem cell aging

DOI:  https://doi.org/10.1016/j.cmet.2023.04.012