bims-medebr 2024-08-04 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–08–04
25 papers selected by
Regina F. Fernández, Johns Hopkins University

Tafazzin deficiency causes substantial remodeling in the lipidome of a mouse model of Barth Syndrome cardiomyopathy.
Organelle-Targeted Laurdans Measure Heterogeneity in Subcellular Membranes and Their Responses to Saturated Lipid Stress.
Lactate is a potentially harmful substitute for brain glucose fuel: consequences for metabolic restoration of neurotransmission.
Cholesterol imbalance and neurotransmission defects in neurodegeneration.
Clinical and genetic analysis of children with glucose transporter type 1 deficiency syndrome.
Lactate-carried Mitochondrial Energy Overflow.
Ketogenic effect of coconut oil in ALS patients.
New insights into metabolism dysregulation after TBI.
Preliminary Observations of the Loke Microdialysis in an Experimental Pig Model: Are We Ready for Continuous Monitoring of Brain Energy Metabolism?
β-hydroxybutyrate and ischemic stroke: roles and mechanisms.
Understanding the effects of omega-3 fatty acid supplementation on the physical properties of brain lipid membranes.
Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.
Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.
Mapping small metabolite changes after traumatic brain injury using AP-MALDI MSI.
Neurometabolic topography and associations with cognition in Alzheimer's disease: A whole-brain high-resolution 3D MRSI study.
IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.
BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.
Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.
Microglia Signaling in Health and Disease - Implications in Sex-Specific Brain Development and Plasticity.
Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus.
The subtherapeutic dose of valproic acid induces the activity of cardiolipin-dependent proteins.
The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation.
Mitochondria-containing extracellular vesicles from mouse vs. human brain endothelial cells for ischemic stroke therapy.
Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency.
Astrocyte-derived apolipoprotein D is required for neuronal survival in Parkinson's disease.

Front Mol Med. 2024 ;4 1389456

Tafazzin deficiency causes substantial remodeling in the lipidome of a mouse model of Barth Syndrome cardiomyopathy.

Malte Hachmann, Güntas Gülcan, Ranjithkumar Rajendran, Marcus Höring, Gerhard Liebisch, Akash Bachhuka, Michael Kohlhaas, Christoph Maack, Süleyman Ergün, Jan Dudek, Srikanth Karnati.

  Barth Syndrome (BTHS) is a rare X-linked disease, characterized clinically by cardiomyopathy, skeletal myopathy, neutropenia, and growth retardation. BTHS is caused by mutations in the phospholipid acyltransferase tafazzin (Gene: TAFAZZIN, TAZ). Tafazzin catalyzes the final step in the remodeling of cardiolipin (CL), a glycerophospholipid located in the inner mitochondrial membrane. As the phospholipid composition strongly determines membrane properties, correct biosynthesis of CL and other membrane lipids is essential for mitochondrial function. Mitochondria provide 95% of the energy demand in the heart, particularly due to their role in fatty acid oxidation. Alterations in lipid homeostasis in BTHS have an impact on mitochondrial membrane proteins and thereby contribute to cardiomyopathy. We analyzed a transgenic TAFAZZIN-knockdown (TAZ-KD) BTHS mouse model and determined the distribution of 193 individual lipid species in TAZ-KD and WT hearts at 10 and 50 weeks of age, using electrospray ionization tandem mass spectrometry (ESI-MS/MS). Our results revealed significant lipid composition differences between the TAZ-KD and WT groups, indicating genotype-dependent alterations in most analyzed lipid species. Significant changes in the myocardial lipidome were identified in both young animals without cardiomyopathy and older animals with heart failure. Notable alterations were found in phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC) and plasmalogen species. PC species with 2-4 double bonds were significantly increased, while polyunsaturated PC species showed a significant decrease in TAZ-KD mice. Furthermore, Linoleic acid (LA, 18:2) containing PC and PE species, as well as arachidonic acid (AA, 20:4) containing PE 38:4 species are increased in TAZ-KD. We found higher levels of AA containing LPE and PE-based plasmalogens (PE P-). Furthermore, we are the first to show significant changes in sphingomyelin (SM) and ceramide (Cer) lipid species Very long-chained SM species are accumulating in TAZ-KD hearts, whereas long-chained Cer and several hexosyl ceramides (HexCer) species accumulate only in 50-week-old TAZ-KD hearts These findings offer potential avenues for the diagnosis and treatment of BTHS, presenting new possibilities for therapeutic approaches.

Keywords:  Barth Syndrome; electrospray ionization-tandem mass spectrometry (ESI-MS/MS); heart failure; lipidome; lipids; tafazzin

DOI:  https://doi.org/10.3389/fmmed.2024.1389456
ACS Chem Biol. 2024 Jul 28.

Organelle-Targeted Laurdans Measure Heterogeneity in Subcellular Membranes and Their Responses to Saturated Lipid Stress.

Adrian M Wong, Itay Budin.

Organelles feature characteristic lipid compositions that lead to differences in membrane properties. In cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to lipid packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells; therefore, it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out the membrane packing of individual cellular organelles. The set of organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes, and Golgi compartments with high specificity while retaining the spectral resolution needed to detect biological changes in membrane ordering. We show that ratiometric imaging with OTLs can resolve membrane heterogeneity within organelles as well as changes in lipid packing resulting from inhibition of trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While the ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application in interrogating lipid dysregulation.

DOI: https://doi.org/10.1021/acschembio.4c00249
Neural Regen Res. 2025 May 01. 20(5): 1403-1404

Lactate is a potentially harmful substitute for brain glucose fuel: consequences for metabolic restoration of neurotransmission.

Oliver Kann, Lennart Söder, Babak Khodaie.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00262
Exp Mol Med. 2024 Aug 01.

Cholesterol imbalance and neurotransmission defects in neurodegeneration.

Kyung Chul Shin, Houda Yasmine Ali Moussa, Yongsoo Park.

The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation.

DOI: https://doi.org/10.1038/s12276-024-01273-4
Med Int (Lond). 2024 Nov-Dec;4(6):4(6): 57

Clinical and genetic analysis of children with glucose transporter type 1 deficiency syndrome.

Hao Qian, Guohuan Ying, Haifeng Xu, Shangyu Wang, Bing Wu, Xin Wang, Hongdan Qi, Mingying He, M Jalal Ud Din, Tingting Huang, Yimei Wu, Gang Zhang.

  Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare metabolic encephalopathy with a wide variety of clinical phenotypes. In the present study, 15 patients diagnosed with GLUT1-DS were selected, all of whom had obvious clinical manifestations and complete genetic testing. Their clinical data and genetic reports were collated. All patients were provided with a ketogenic diet (KD) and an improvement in their symptoms was observed during a follow-up period of up to 1 year. The results revealed that the 15 cases had clinical symptoms, such as convulsions or dyskinesia. Although none had a cerebrospinal fluid/glucose ratio <0.4, the genetic report revealed that all had the solute carrier family 2 member 1 gene variant, and their clinical symptoms basically improved following the use of the KD. GLUT1-DS is a genetic metabolic disease that causes a series of neurological symptoms due to glucose metabolism disorders in the brain. Low glucose levels in cerebrospinal fluid and genetic testing are key diagnostic criteria, and the KD is a highly effective treatment option. By summarizing and analyzing patients with GLUT1-DS, summarizing clinical characteristics and expanding their gene profile, the findings of the present study may be of clinical significance for the early recognition and diagnosis of the disease, so as to conduct early treatment and shorten the duration of brain energy deficiency. This is of utmost importance for improving the prognosis and quality of life of affected children.

Keywords:  children; epilepsy; glucose transporter type 1 deficiency syndrome; ketogenic diet; solute carrier family 2 member 1

DOI:  https://doi.org/10.3892/mi.2024.181
bioRxiv. 2024 Jul 20. pii: 2024.07.19.604361. [Epub ahead of print]

Lactate-carried Mitochondrial Energy Overflow.

Daniela Rauseo, Yasna Contreras-Baeza, Hugo Faurand, Nataly Cárcamo, Raibel Suárez, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.

We addressed the question of mitochondrial lactate metabolism using genetically-encoded sensors. The organelle was found to contain a dynamic lactate pool that leads to dose- and time-dependent protein lactylation. In neurons, mitochondrial lactate reported blood lactate levels with high fidelity. The exchange of lactate across the inner mitochondrial membrane was found to be mediated by a high affinity H+-coupled transport system involving the mitochondrial pyruvate carrier MPC. Assessment of electron transport chain activity and determination of lactate flux showed that mitochondria are tonic lactate producers, a phenomenon driven by energization and stimulated by hypoxia. We conclude that an overflow mechanism caps the redox level of mitochondria, while saving energy in the form of lactate.

DOI: https://doi.org/10.1101/2024.07.19.604361
Front Nutr. 2024 ;11 1429498

Ketogenic effect of coconut oil in ALS patients.

Sandra Carrera-Juliá, Elena Obrador, Rafael López-Blanch, María Oriol-Caballo, Paz Moreno-Murciano, José M Estrela.

  A recent pilot study in amyotrophic lateral sclerosis (ALS) patients analyzed the effect of a Mediterranean diet (MeDi) supplemented with nicotinamide riboside (NR, a NAD+ promoter), pterostilbene (PTER, a natural antioxidant) and/or coconut oil on anthropometric variables in ALS patients. The results suggested that the MeDi supplemented with NR, PTER and coconut oil is the nutritional intervention showing the greatest benefits at anthropometric levels. Over the last 30 years, glucose intolerance has been reported in ALS patients. Thus, suggesting that an alternative source of energy may be preferential for motor neurons to survive. Ketone bodies (KBs), provided through a MeDi with a lower carbohydrate content but enriched with medium chain triglycerides, could be a therapeutic alternative to improve the neuromotor alterations associated with the disease. Nevertheless, the use of a coconut oil-supplemented diet, as potentially ketogenic, is a matter of controversy. In the present report we show that a MeDi supplemented with coconut oil increases the levels of circulating KBs in ALS patients.

Keywords:  amyotrophic lateral sclerosis; coconut oil; ketogenic diet; nicotinamide riboside; pterostilbene

DOI:  https://doi.org/10.3389/fnut.2024.1429498
J Neuroinflammation. 2024 Jul 29. 21(1): 184

New insights into metabolism dysregulation after TBI.

Helena C Oft, Dennis W Simon, Dandan Sun.

  Traumatic brain injury (TBI) remains a leading cause of death and disability that places a great physical, social, and financial burden on individuals and the health system. In this review, we summarize new research into the metabolic changes described in clinical TBI trials, some of which have already shown promise for informing injury classification and staging. We focus our discussion on derangements in glucose metabolism, cell respiration/mitochondrial function and changes to ketone and lipid metabolism/oxidation to emphasize potentially novel biomarkers for clinical outcome prediction and intervention and offer new insights into possible underlying mechanisms from preclinical research of TBI pathology. Finally, we discuss nutrition supplementation studies that aim to harness the gut/microbiome-brain connection and manipulate systemic/cellular metabolism to improve post-TBI recovery. Taken together, this narrative review summarizes published TBI-associated changes in glucose and lipid metabolism, highlighting potential metabolite biomarkers for clinical use, the cellular processes linking these markers to TBI pathology as well as the limitations and future considerations for TBI "omics" work.

Keywords:  Glucose metabolism; Gut-brain axis; Ketometabolism; Lipid oxidation; Microbiome; Mitochondrial metabolism

DOI:  https://doi.org/10.1186/s12974-024-03177-6
Neurocrit Care. 2024 Jul 31.

Preliminary Observations of the Loke Microdialysis in an Experimental Pig Model: Are We Ready for Continuous Monitoring of Brain Energy Metabolism?

Teodor Svedung Wettervik, Anders Hånell, Kerstin M Ahlgren, Lars Hillered, Anders Lewén.

   BACKGROUND: Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1-4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method.
METHODS: Four pigs aged 2-3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2-3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels.
RESULTS: In a linear mixed-effect model of standard CMD glucose (mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 (p < 0.001) for Loke MD glucose (mM), with an intercept at - 0.19 ± 0.15 (p = 0.20). The model showed a conditional R2 at 0.81 and a marginal R2 at 0.72. In a linear mixed-effect model of standard CMD lactate (mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 (p = 0.01) for Loke MD lactate (mM), with an intercept at 0.33 ± 0.21 (p = 0.25). The model showed a conditional R2 at 0.47 and marginal R2 at 0.17.
CONCLUSIONS: The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

Keywords:  Brain injury; Energy metabolism; Loke; Microdialysis; Neurointensive care

DOI:  https://doi.org/10.1007/s12028-024-02080-5
Mol Brain. 2024 Jul 29. 17(1): 48

β-hydroxybutyrate and ischemic stroke: roles and mechanisms.

Ge Feng, Zongkai Wu, Leyi Yang, Kaimeng Wang, Hebo Wang.

  Stroke is a significant global burden, causing extensive morbidity and mortality. In metabolic states where glucose is limited, ketone bodies, predominantly β-hydroxybutyrate (BHB), act as alternative fuel sources. Elevated levels of BHB have been found in the ischemic hemispheres of animal models of stroke, supporting its role in the pathophysiology of cerebral ischemia. Clinically, higher serum and urinary BHB concentrations have been associated with adverse outcomes in ischemic stroke, highlighting its potential utility as a prognostic biomarker. In both animal and cellular models, exogenous BHB administration has exhibited neuroprotective effects, reduction of infarct size, and improvement of neurological outcomes. In this review, we focus on the role of BHB before and after ischemic stroke, with an emphasis on the therapeutic potential and mechanisms of ketone administration after ischemic stroke.

Keywords:  Ischemic stroke; Neuroprotective effect; Prognostic biomarker; β-hydroxybutyrate

DOI:  https://doi.org/10.1186/s13041-024-01119-0
iScience. 2024 Jul 19. 27(7): 110362

Understanding the effects of omega-3 fatty acid supplementation on the physical properties of brain lipid membranes.

María L Longarzo, Romina F Vázquez, María J Bellini, Ricardo A Zamora, Lorena Redondo-Morata, Marina I Giannotti, Osvaldo N Oliveira, María L Fanani, Sabina M Maté.

  A deficiency in omega-3 fatty acids (ω3 FAs) in the brain has been correlated with cognitive impairment, learning deficiencies, and behavioral changes. In this study, we provided ω3 FAs as a supplement to spontaneously hypertensive rats (SHR+ ω3). Our focus was on examining the impact of dietary supplementation on the physicochemical properties of the brain-cell membranes. Significant increases in ω3 levels in the cerebral cortex of SHR+ ω3 were observed, leading to alterations in brain lipid membranes molecular packing, elasticity, and lipid miscibility, resulting in an augmented phase disparity. Results from synthetic lipid mixtures confirmed the disordering effect introduced by ω3 lipids, showing its consequences on the hydration levels of the monolayers and the organization of the membrane domains. These findings suggest that dietary ω3 FAs influence the organization of brain membranes, providing insight into a potential mechanism for the broad effects of dietary fat on brain health and disease.

Keywords:  Cell biology; Membrane architecture; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2024.110362
J Lipid Res. 2024 Jul 31. pii: S0022-2275(24)00116-0. [Epub ahead of print] 100611

Etomoxir-carnitine, a novel pharmaco-metabolite of etomoxir, inhibits phospholipases A2 and mitochondrial respiration.

Sung Ho Moon, Xinping Liu, Christopher M Jenkins, Beverly Gibson Dilthey, Gary J Patti, Richard W Gross.

  Mitochondrial fatty acid oxidation serves as an essential process for cellular survival, differentiation, proliferation, and energy metabolism. Numerous studies have utilized etomoxir (ETO) for the irreversible inhibition of carnitine palmitoylcarnitine transferase 1 (CPT1) which catalyzes the rate-limiting step for mitochondrial long-chain fatty acid β-oxidation to examine the bioenergetic roles of mitochondrial fatty acid metabolism in many tissues in multiple diverse disease states. Herein, we demonstrate that intact mitochondria robustly metabolize etomoxir to etomoxir-carnitine (ETO-carnitine) prior to nearly complete etomoxir-mediated inhibition of CPT1. The novel pharmaco-metabolite, ETO-carnitine, was conclusively identified by accurate mass, fragmentation patterns, and isotopic fine structure. On the basis of these data, ETO-carnitine was successfully differentiated from isobaric structures (e.g., 3-hydroxy-C18:0 carnitine and 3-hydroxy-C18:1 carnitine). Mechanistically, generation of ETO-carnitine from mitochondria required exogenous Mg2+, ATP or ADP, CoASH, and L-carnitine indicating that thioesterification by long-chain acyl-CoA synthetase to form ETO-CoA precedes its conversion to ETO-carnitine by CPT1. CPT1-dependent generation of ETO-carnitine was substantiated by an orthogonal approach using ST1326 (a CPT1 inhibitor) which effectively inhibits mitochondrial ETO-carnitine production. Surprisingly, purified ETO-carnitine potently inhibited calcium-independent PLA2γ and PLA2β as well as mitochondrial respiration independent of CPT1. Robust production and release of ETO-carnitine from HepG2 cells incubated in the presence of ETO was also demonstrated. Collectively, this study identifies the chemical mechanism for the biosynthesis of a novel pharmaco-metabolite of etomoxir, ETO-carnitine, that is generated by CPT1 in mitochondria and likely impacts multiple downstream (non-CPT1 related) enzymes and processes in multiple subcellular compartments.

Keywords:  Lipidomics; Lipids/Chemistry; Lipolysis and fatty acid metabolism; carnitine palmitoyltransferase (CPT); etomoxir; etomoxir-carnitine; mitochondria; off-target effects; pharmaco-metabolite; phospholipases A(2)

DOI:  https://doi.org/10.1016/j.jlr.2024.100611
JCI Insight. 2024 Aug 01. pii: e176887. [Epub ahead of print]

Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.

Eduardo Vieira Neto, Meicheng Wang, Austin J Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van't Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H El-Gharbawy, Tamil S Anthonymuthu, Yulia Y Tyurina, Vladimir A Tyurin, Valerian Kagan, Hülya Bayir, Jerry Vockley.

  Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in either HADHA and HADHB, which encode the TFPα and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting cardiolipin metabolism might be dependent on patient genotype.

Keywords:  Fatty acid oxidation; Genetics; Intermediary metabolism; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.176887
Anal Bioanal Chem. 2024 Aug 01.

Mapping small metabolite changes after traumatic brain injury using AP-MALDI MSI.

Angela Marika Siciliano, Federico Moro, Giulia De Simone, Francesca Pischiutta, Aurelia Morabito, Roberta Pastorelli, Laura Brunelli, Elisa R Zanier, Enrico Davoli.

  Traumatic brain injury (TBI) is an alteration of brain function caused by a sudden transmission of an external force to the head. The biomechanical impact induces acute and chronic metabolic changes that highly contribute to injury evolution and outcome. TBI heterogeneity calls for approaches allowing the mapping of regional molecular and metabolic changes underpinning disease progression, with mass spectrometry imaging (MSI) as an efficient tool to study the spatial distribution of small metabolites. In this study, we applied an innovative targeted atmospheric pressure-MALDI mass spectrometry imaging (AP-MALDI MSI) approach, starting from an extensive list of metabolites, representative of different metabolic pathways, individually validated on the tissue under analysis with original standards using 2,5-dihydroxybenzoic acid (DHB), to characterize the impact of TBI on regional changes to small metabolites in the brain. Brains from sham and TBI mice obtained 21 days post-injury were analyzed to examine the spatial metabolic profile of small metabolites belonging to different metabolic pathways. By a whole brain analysis, we identified four metabolites (alanine, lysine, histidine, and inosine) with higher abundance in TBI than sham mice. Within the TBI group, lysine, histidine, and inosine were higher in the hemisphere ipsilateral to the biomechanical impact vs. the contralateral one. Images showed a major involvement of the ipsilateral thalamus characterized by the increase of arginine, lysine, histidine, and inosine and a significant reduction of glutamic acid, and N-acetylaspartic acid compared to the contralateral thalamus. These findings indicate high-resolution imaging mass spectrometry as a powerful tool to identify region-specific changes after a TBI to understand the metabolic changes underlying brain injury evolution.

Keywords:  AP-MALDI; Mass spectrometry imaging; Small metabolites; Traumatic brain injury

DOI:  https://doi.org/10.1007/s00216-024-05422-6
Alzheimers Dement. 2024 Jul 29.

Neurometabolic topography and associations with cognition in Alzheimer's disease: A whole-brain high-resolution 3D MRSI study.

Jialin Hu, Miao Zhang, Yaoyu Zhang, Huixiang Zhuang, Yibo Zhao, Yudu Li, Wen Jin, Xiao-Hang Qian, Lijun Wang, Guanyu Ye, Huidong Tang, Jun Liu, Biao Li, Parashkev Nachev, Zhi-Pei Liang, Yao Li.

   INTRODUCTION: Altered neurometabolism, detectable via proton magnetic resonance spectroscopic imaging (1H-MRSI), is spatially heterogeneous and underpins cognitive impairments in Alzheimer's disease (AD). However, the spatial relationships between neurometabolic topography and cognitive impairment in AD remain unexplored due to technical limitations.
METHODS: We used a novel whole-brain high-resolution 1H-MRSI technique, with simultaneously acquired 18F-florbetapir positron emission tomography (PET) imaging, to investigate the relationship between neurometabolic topography and cognitive functions in 117 participants, including 22 prodromal AD, 51 AD dementia, and 44 controls.
RESULTS: Prodromal AD and AD dementia patients exhibited spatially distinct reductions in N-acetylaspartate, and increases in myo-inositol. Reduced N-acetylaspartate and increased myo-inositol were associated with worse global cognitive performance, and N-acetylaspartate correlated with five specific cognitive scores. Neurometabolic topography provides biological insights into diverse cognitive dysfunctions.
DISCUSSION: Whole-brain high-resolution 1H-MRSI revealed spatially distinct neurometabolic topographies associated with cognitive decline in AD, suggesting potential for noninvasive brain metabolic imaging to track AD progression.
HIGHLIGHTS: Whole-brain high-resolution 1H-MRSI unveils neurometabolic topography in AD. Spatially distinct reductions in NAA, and increases in mI, are demonstrated. NAA and mI topography correlates with global cognitive performance. NAA topography correlates with specific cognitive performance.

Keywords:  Alzheimer's disease; N‐acetylaspartate; cognition; magnetic resonance spectroscopic imaging; myo‐inositol

DOI:  https://doi.org/10.1002/alz.14137
EMBO Rep. 2024 Jul 29.

IMPDH2 filaments protect from neurodegeneration in AMPD2 deficiency.

Marco Flores-Mendez, Laura Ohl, Thomas Roule, Yijing Zhou, Jesus A Tintos-Hernández, Kelsey Walsh, Xilma R Ortiz-González, Naiara Akizu.

  Metabolic dysregulation is one of the most common causes of pediatric neurodegenerative disorders. However, how the disruption of ubiquitous and essential metabolic pathways predominantly affect neural tissue remains unclear. Here we use mouse models of a childhood neurodegenerative disorder caused by AMPD2 deficiency to study cellular and molecular mechanisms that lead to selective neuronal vulnerability to purine metabolism imbalance. We show that mouse models of AMPD2 deficiency exhibit predominant degeneration of the hippocampal dentate gyrus, despite a general reduction of brain GTP levels. Neurodegeneration-resistant regions accumulate micron-sized filaments of IMPDH2, the rate limiting enzyme in GTP synthesis, while these filaments are barely detectable in the hippocampal dentate gyrus. Furthermore, we show that IMPDH2 filament disassembly reduces GTP levels and impairs growth of neural progenitor cells derived from individuals with human AMPD2 deficiency. Together, our findings suggest that IMPDH2 polymerization prevents detrimental GTP deprivation, opening the possibility of exploring the induction of IMPDH2 assembly as a therapy for neurodegeneration.

Keywords:  Ampd2; Impdh2 Filaments; Metabolons; Pontocerebellar Hypoplasia; Purine Nucleotides

DOI:  https://doi.org/10.1038/s44319-024-00218-2
bioRxiv. 2024 Jul 22. pii: 2024.01.23.576931. [Epub ahead of print]

BETA-HYDROXYBUTYRATE COUNTERACTS THE DELETERIOUS EFFECTS OF A SATURATED HIGH-FAT DIET ON SYNAPTIC AMPA RECEPTORS AND COGNITIVE PERFORMANCE.

Rocío Rojas, Christian Griñán-Ferré, Aida Castellanos, Ernesto Griego, Marc Martínez, Juan de Dios Navarro-López, Lydia Jiménez-Díaz, José Rodríguez-Álvarez, David Soto Del Cerro, Pablo E Castillo, Mercè Pallàs, Rut Fadó, Núria Casals.

The ketogenic diet, characterized by high fat and low carbohydrates, has gained popularity not only as a strategy for managing body weight but also for its efficacy in delaying cognitive decline associated with neurodegenerative diseases and the aging process. Since this dietary approach stimulates the liver's production of ketone bodies, primarily β-hydroxybutyrate (BHB), which serves as an alternative energy source for neurons, we investigated whether BHB could mitigate impaired AMPA receptor trafficking, synaptic dysfunction, and cognitive decline induced by metabolic challenges such as saturated fatty acids. Here, we observe that, in cultured primary cortical neurons, exposure to palmitic acid (200μM) decreased surface levels of glutamate GluA1-containing AMPA receptors, whereas unsaturated fatty acids, such as oleic acid and ω-3 docosahexaenoic acid (200μM), and BHB (5mM) increased them. Furthermore, BHB countered the adverse effects of palmitic acid on synaptic GluA1 levels in hippocampal neurons, as well as excitability and plasticity in hippocampal slices. Additionally, daily intragastric administration of BHB (100 mg/kg/day) for two months reversed cognitive impairment induced by a saturated high-fat diet (49% of calories from fat) in a mouse experimental model of obesity. In summary, our findings underscore the significant impact of fatty acids and ketone bodies on AMPA receptors abundance, synaptic function and neuroplasticity, shedding light on the potential use of BHB to delay cognitive impairments associated with metabolic diseases.

DOI: https://doi.org/10.1101/2024.01.23.576931
bioRxiv. 2024 Jul 17. pii: 2024.07.15.603186. [Epub ahead of print]

Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice.

Ali Yousefian-Jazi, Suhyun Kim, Seung-Hye Choi, Jiyeon Chu, Phuong Thi-Thanh Nguyen, Uiyeol Park, Kayeong Lim, Hongik Hwang, Kyungeun Lee, Yeyun Kim, Seung Jae Hyeon, Hyewhon Rhim, Hannah L Ryu, Grewo Lim, Thor D Stein, Hoon Ryu, Junghee Lee.

Genetic changes and epigenetic modifications are associated with neuronal dysfunction in the pathogenesis of neurodegenerative disorders. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications remains unclear. Here, we identified an ALS-associated SNP located in the intronic region of MEF2C (rs304152), residing in a putative enhancer element, using convolutional neural network. The enhancer mutation of MEF2C reduces own gene expression and consequently impairs mitochondrial function in motor neurons. MEF2C localizes and binds to the mitochondria DNA, and directly modulates mitochondria-encoded gene expression. CRISPR/Cas-9-induced mutation of the MEF2C enhancer decreases expression of mitochondria-encoded genes. Moreover, MEF2C mutant cells show reduction of mitochondrial membrane potential, ATP level but elevation of oxidative stress. MEF2C deficiency in the upper and lower motor neurons of mice impairs mitochondria-encoded genes, and leads to mitochondrial metabolic disruption and progressive motor behavioral deficits. Together, MEF2C dysregulation by the enhancer mutation leads to mitochondrial dysfunction and oxidative stress, which are prevalent features in motor neuronal damage and ALS pathogenesis. This genetic and epigenetic crosstalk mechanism provides insights for advancing our understanding of motor neuron disease and developing effective treatments.

DOI: https://doi.org/10.1101/2024.07.15.603186
Neurosci Biobehav Rev. 2024 Jul 29. pii: S0149-7634(24)00303-8. [Epub ahead of print] 105834

Microglia Signaling in Health and Disease - Implications in Sex-Specific Brain Development and Plasticity.

Subrata Pramanik, M Harini Devi, Saswata Chakrabarty, Berkay Paylar, Ajay Pradhan, Manisha Thaker, Shamini Ayyadhury, Arulmani Manavalan, Per-Erik Olsson, Gopal Pramanik, Klaus Heese.

  Microglia, the intrinsic neuroimmune cells residing in the central nervous system (CNS), exert a pivotal influence on brain development, homeostasis, and functionality, encompassing critical roles during both aging and pathological states. Recent advancements in comprehending brain plasticity and functions have spotlighted conspicuous variances between male and female brains, notably in neurogenesis, neuronal myelination, axon fasciculation, and synaptogenesis. Nevertheless, the precise impact of microglia on sex-specific brain cell plasticity, sculpting diverse neural network architectures and circuits, remains largely unexplored. This article seeks to unravel the present understanding of microglial involvement in brain development, plasticity, and function, with a specific emphasis on microglial signaling in brain sex polymorphism. Commencing with an overview of microglia in the CNS and their associated signaling cascades, we subsequently probe recent revelations regarding molecular signaling by microglia in sex-dependent brain developmental plasticity, functions, and diseases. Notably, C-X3-C motif chemokine receptor 1 (CX3CR1), triggering receptors expressed on myeloid cells 2 (TREM2), calcium (Ca2+), and apolipoprotein E (APOE) emerge as molecular candidates significantly contributing to sex-dependent brain development and plasticity. In conclusion, we address burgeoning inquiries surrounding microglia's pivotal role in the functional diversity of developing and aging brains, contemplating their potential implications for gender-tailored therapeutic strategies in neurodegenerative diseases.

Keywords:  Aging; Brain Development; Microglia; Neurodegenerative Disease; Neuropsychiatric Disease; Sexual Differentiation; Synaptic Plasticity

DOI:  https://doi.org/10.1016/j.neubiorev.2024.105834
CNS Neurosci Ther. 2024 Jul;30(7): e14887

Insulin attenuates LPS-induced cognitive impairment and ferroptosis through regulation of glucose metabolism in hippocampus.

Miao Sun, Min Liu, Qingxiao Li, Siyuan Liu, Huikai Yang, Yuxiang Song, Mengyao Qu, Xiaoying Zhang, Yulong Ma, Weidong Mi.

   AIMS: Neuroinflammation is a recognized contributor to cognitive disorders like Alzheimer's disease, with ferroptosis emerging as a novel mechanism underlying cognitive dysfunction associated with neuroinflammation. Insulin, pivotal in the central nervous system, holds promise for cognitive function enhancement. This study aimed to establish a cognitive impairment model through intracerebroventricular injection of lipopolysaccharide (LPS) and explore the impact of intracerebroventricular insulin injection on cognitive function in mice.
METHODS: We employed diverse experimental techniques, including animal behavior testing, molecular assays, targeted metabolomics, nuclear medicine, and electron microscopy, to assess neurodegenerative changes, brain insulin resistance (IR), glucose uptake and metabolism, and ferroptosis. The model of cognitive impairment was induced via intracerebroventricular injection of LPS, followed by intracerebroventricular administration of insulin to evaluate its effects.
RESULTS: Insulin treatment effectively mitigated LPS-induced cognitive decline and safeguarded against neuronal degeneration. Furthermore, insulin alleviated LPS-induced insulin resistance, enhanced glucose uptake in the hippocampus, and promoted the Pentose Phosphate Pathway (PPP) and nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, insulin activated the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway, reducing lipid peroxidation, and mitochondrial damage characteristic of LPS-induced ferroptosis in the hippocampus.
CONCLUSION: Our findings underscore the therapeutic potential of insulin in alleviating LPS-induced cognitive impairment and ferroptosis by modulating glucose metabolism. This study offers a promising avenue for future interventions targeting cognitive decline.

Keywords:  cognitive impairment; ferroptosis; insulin resistance

DOI:  https://doi.org/10.1111/cns.14887
Biochim Biophys Acta Bioenerg. 2024 Jul 29. pii: S0005-2728(24)00471-7. [Epub ahead of print]1865(4): 149501

The subtherapeutic dose of valproic acid induces the activity of cardiolipin-dependent proteins.

Paulina Horonyova, Ivana Durisova, Petra Cermakova, Lenka Babelova, Barbora Buckova, Lucia Sofrankova, Martin Valachovic, Yuan-Hao Howard Hsu, Maria Balazova.

  A mood-stabilizing anticonvulsant valproic acid (VPA) is a drug with a pleiotropic effect on cells. Here, we describe the impact of VPA on the metabolic function of human HAP1 cells. We show that VPA altered the biosynthetic pathway of cardiolipin (CL) and affected the activities of mitochondrial enzymes such as pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and NADH dehydrogenase. We demonstrate that a therapeutic dose of VPA (0.6 mM) has a harmful effect on cell growth and increases the production of reactive oxygen species and superoxides. On the contrary, less concentrated VPA (0.06 mM) increased the activities of CL-dependent enzymes leading to an increased level of oxidative phosphorylation and ATP production. The effect of VPA was also tested on the Barth syndrome model, which is characterized by a reduced amount of CL and an increased level of monolyso-CL. In this model, VPA treatment slightly attenuated the mitochondrial defects by altering the activities of CL-dependent enzymes. However, the presence of CL was essential for the increase in ATP production by VPA. Our findings highlight the potential therapeutic role of VPA in normalizing mitochondrial function in BTHS and shed light on the intricate interplay between lipid metabolism and mitochondrial physiology in health and disease. SUMMARY: This study investigates the dose-dependent effect of valproate, a mood-stabilizing drug, on mitochondrial function. The therapeutic concentration reduced overall cellular metabolic activity, while a subtherapeutic concentration notably improved the function of cardiolipin-dependent proteins within mitochondria. These findings shed light on novel aspects of valproate's effect and suggest potential practical applications for its use. By elucidating the differential effects of valproate doses on mitochondrial activity, this research underscores the drug's multifaceted role in cellular metabolism and highlights avenues for further exploration in therapeutic interventions.

Keywords:  Barth syndrome; Cardiolipin; Krebs cycle; Mitochondria; Respiration; Valproic acid

DOI:  https://doi.org/10.1016/j.bbabio.2024.149501
Mol Genet Metab. 2024 Jul 16. pii: S1096-7192(24)00424-4. [Epub ahead of print]143(1-2): 108540

The pyruvate dehydrogenase complex at the epigenetic crossroads of acetylation and lactylation.

Peter W Stacpoole, Carolyn O Dirain.

  The pyruvate dehydrogenase complex (PDC) is remarkable for its size and structure as well as for its physiological and pathological importance. Its canonical location is in the mitochondrial matrix, where it primes the tricarboxylic acid (TCA) cycle by decarboxylating glycolytically-derived pyruvate to acetyl-CoA. Less well appreciated is its role in helping to shape the epigenetic landscape, from early development throughout mammalian life by its ability to "moonlight" in the nucleus, with major repercussions for human healthspan and lifespan. The PDC's influence on two crucial modifiers of the epigenome, acetylation and lactylation, is the focus of this brief review.

Keywords:  Acetylation; Epigenetics; Glycolysis; Histones; Inborn metabolic disorders; Lactylation; Nuclear translocation; Pyruvate dehydrogenase complex; Tricarboxylic acid cycle

DOI:  https://doi.org/10.1016/j.ymgme.2024.108540
J Control Release. 2024 Jul 29. pii: S0168-3659(24)00523-6. [Epub ahead of print]

Mitochondria-containing extracellular vesicles from mouse vs. human brain endothelial cells for ischemic stroke therapy.

Kandarp M Dave, Venugopal R Venna, Krithika S Rao, Donna B Stolz, Bodhi Brady, Victoria A Quaicoe, Michael E Maniskas, Ella E Hildebrand, Dawson Green, Mingxi Chen, Jadranka Milosevic, Si-Yang Zheng, Sruti S Shiva, Louise D McCullough, Devika S Manickam.

  Ischemic stroke-induced mitochondrial dysfunction in the blood-brain barrier-forming brain endothelial cells (BECs) results in long-term neurological dysfunction post-stroke. We previously data from a pilot study where intravenous administration of human BEC (hBEC)-derived mitochondria-containing extracellular vesicles (EVs) showed a potential efficacy signal in a mouse middle cerebral artery occlusion (MCAo) model of stroke. We hypothesized that EVs harvested from donor species homologous to the recipient species (e.g., mouse) may improve therapeutic efficacy, and therefore, use of mouse BEC (mBEC)-derived EVs may improve post-stroke outcomes in MCAo mice. We investigated potential differences in the mitochondria transfer of EVs derived from the same species as the recipient cell (mBEC-EVs and recipient mBECs or hBECs-EVs and recipient hBECs) vs. cross-species EVs and recipient cells (mBEC-EVs and recipient hBECs or vice versa). Our results showed that while both hBEC- and mBEC-EVs transferred EV mitochondria, mBEC-EVs outperformed hBEC-EVs in increasing ATP levels and improved recipient mBEC mitochondrial function via increasing oxygen consumption rates. mBEC-EVs significantly reduced brain infarct volume and neurological deficit scores compared to vehicle-injected MCAo mice. The superior therapeutic efficacy of mBEC-EVs in a mouse MCAo stroke support the continued use of mBEC-EVs to optimize the therapeutic potential of mitochondria-containing EVs in preclinical mouse models.

Keywords:  BBB protection; Brain endothelial cells (BECs); Exosomes (120 K EVs); Extracellular vesicles (EVs); Ischemic stroke; Microvesicles (20 K EVs); Mitochondria

DOI:  https://doi.org/10.1016/j.jconrel.2024.07.065
Brain Dev. 2024 Jul 27. pii: S0387-7604(24)00096-2. [Epub ahead of print]

Clinical, biochemical and genetic characteristics and long-term follow-up of five patients with malonyl-CoA decarboxylase deficiency.

J M Zhang, L L Hao, W J Qiu, H W Zhang, T Chen, W J Ji, Y Zhang, F Liu, X F Gu, S H Yang, L S Han.

   BACKGROUND: Malonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease.
METHODS: Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents.
RESULTS: Five patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes.
CONCLUSION: A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder.

Keywords:  Intellectual disability; L-carnitine; MLYCD gene; Malonyl-CoA decarboxylase deficiency; Phenotype

DOI:  https://doi.org/10.1016/j.braindev.2024.07.001
NPJ Parkinsons Dis. 2024 Aug 02. 10(1): 143

Astrocyte-derived apolipoprotein D is required for neuronal survival in Parkinson's disease.

Yingying Dai, Mingxia Bi, Qian Jiao, Xixun Du, Chunling Yan, Hong Jiang.

Apolipoprotein D (ApoD), a lipocalin transporter of small hydrophobic molecules, plays an essential role in several neurodegenerative diseases. It was reported that increased immunostaining for ApoD of glial cells surrounding dopaminergic (DAergic) neurons was observed in the brains of Parkinson's disease (PD) patients. Although preliminary findings supported the role of ApoD in neuroprotection, its derivation and effects on the degeneration of nigral DAergic neurons are largely unknown. In the present study, we observed that ApoD levels released from astrocytes were increased in PD models both in vivo and in vitro. When co-cultured with astrocytes, due to the increased release of astrocytic ApoD, the survival rate of primary cultured ventral midbrain (VM) neurons was significantly increased with 1-methyl-4-phenylpyridillium ion (MPP+) treatment. Increased levels of TAp73 and its phosphorylation at Tyr99 in astrocytes were required for the increased ApoD levels and its release. Conditional knockdown of TAp73 in the nigral astrocytes in vivo could aggravate the neurodegeneration in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice. Our findings reported that astrocyte-derived ApoD was essential for DAergic neuronal survival in PD models, might provide new therapeutic targets for PD.

DOI: https://doi.org/10.1038/s41531-024-00753-8